bluuebunny/crossref_metadata_2025 huggingface dataset:
A Fluorescence‐Based Assay for Quantitative Analysis of Phospholipid:Diacylglycerol Acyltransferase Activity
Authors: Falarz Lucas , Xu Yang , Singer Stacy D. , Chen Guanqun
Published: September 2019

Phospholipid:diacylglycerol acyltransferase (PDAT) catalyzes the acyl‐CoA‐independent triacylglycerol (TAG) biosynthesis in plants and oleaginous microorganisms and thus is a key target in lipid research. The conventional in vitro PDAT activity assay involves the use of radiolabeled substrates, which, however, are expensive and demand strict regulation. In this study, a reliable fluorescence‐based method using nitrobenzoxadiazole‐labeled diacylglycerol (NBD‐DAG) as an alternative substrate was established and subsequently used to characterize the enzyme activity and kinetics of a recombinant Arabidopsis thaliana PDAT1 (AtPDAT1). We also demonstrate that the highly toxic benzene used in typical PDAT assays can be substituted with diethyl ether without affecting the formation rate of NBD‐TAG. Overall, this method works well with a broad range of PDAT protein content and shows linear correlation with the conventional method with radiolabeled substrates, and thus may be applicable to PDAT from various plant and microorganism species.
Inverted duplication, triplication and quintuplication through sequential breakage‐fusion‐bridge events induced by a terminal deletion at 5p in a case of spontaneous abortion
Authors: Chai Hongyan , Grommisch Brittany , DiAdamo Autumn , Wen Jiadi , Hui Pei , Li Peining
Published: September 2019

Background

Integrated chromosome, fluorescence in situ hybridization (FISH) and array comparative genomic hybridization (aCGH) analyses have been effective in defining unbalanced chromosomal rearrangements. Discordant chromosome and aCGH results are rarely reported.

Methods

Routine cytogenomic analyses and literature review were performed in the study of a case from products of conception (POC).

Results

Chromosome and FISH analysis revealed a mosaic pattern consisting of a primary aberration of an inverted duplication of 5p and derived secondary and tertiary aberrations from sequential triplication and quintuplication of 5p, respectively. The aCGH analysis detected only a 1.521 Mb terminal deletion at 5p15.33 with no other pathogenic copy number variants in the genome. This mosaic karyotypic pattern likely resulted from chromosome instability induced by sequential breakage‐fusion‐bridge events during in vitro cell culture. A review of literature found heterogeneous distal deletion and inverted duplication of 5p in prenatal and pediatric cases.

Conclusion

This is the first case reported in POC with a unique mosaic pattern and discordant chromosome and aCGH results. Caution should be applied in reporting and interpreting these discordant results and further analysis for underlying mechanism should be considered.
Alkylboranes in Conventional and Controlled Radical Polymerization
Authors: Lv Chunna , Du Yuxuan , Pan Xiangcheng
Published: September 2019

Utilizations of alkylboranes reagents in radical polymerization are summarized in this minireview. Alkylboranes act as conventional radical initiators or radical chain‐transfer agents in free‐radical polymerization and controlled radical polymerization. This review discusses various polymerizations operating through different alkylborane reagents with their accompanying mechanisms. The aim of this minireview is to present the state of art of alkylboranes in radical polymerization and to provide the future aspects of this direction. © 2019 Wiley Periodicals, Inc. J. Polym. Sci. 2020, 58, 14–19
A perceptual computing–based method to prioritize intervention actions in the probabilistic risk assessment techniques
Authors: Yazdi Mohammad
Published: September 2019

Probabilistic risk assessment techniques as the systematic tools have been widely used on the different type of industrial sectors to reduce the estimated risk to an acceptable level. The fact is to design inherently safety; hazards have to be eliminated and reduced in risk as much as possible with the consideration of several interventions. In this regard, multicriteria decision making (MCDM) science is commonly integrated with the probabilistic risk assessment techniques to improve the safety performance of a system. Thus, it has been widely used to assist decision makers in controlling the identified process hazards in a different type of engineering applications. However, by increasing the complexity of industrial sectors as well as human being judgments, typical MCDM methods cannot highly guarantee their output results. According to this point, proposing MCDM methods based on mathematical programming have been interested in scholars due to high reliability and feasibility of the results. In this paper, we extended integration of MULTIMOORA approach with the Choquet integral under subjectivity circumstances to prioritize corrective actions in a typical probabilistic risk assessment technique. To illustrate the efficiency and feasibility of the proposed method, it has been applied in a real case study.
From ecology to remote sensing: using animals to map land cover
Authors: Remelgado Ruben , Safi Kamran , Wegmann Martin
Published: September 2019

Land cover is a key variable in monitoring applications and new processing technologies made deriving this information easier. Yet, classification algorithms remain dependent on samples collected on the field and field campaigns are limited by financial, infrastructural and political boundaries. Here, animal tracking data could be an asset. Looking at the land cover dependencies of animal behaviour, we can obtain land cover samples over places that are difficult to access. Following this premise, we evaluated the potential of animal movement data to map land cover. Specifically, we used 13 White Storks (Cicona cicona) individuals of the same population to map agriculture within three test regions distributed along their migratory track. The White Stork has adapted to foraging over agricultural lands, making it an ideal source of samples to map this land use. We applied a presence–absence modelling approach over a Normalized Difference Vegetation Index (NDVI) time series and validated our classifications, with high‐resolution land cover information. Our results suggest White Stork movement is useful to map agriculture, however, we identified some limitations. We achieved high accuracies (F1‐scores > 0.8) for two test regions, but observed poor results over one region. This can be explained by differences in land management practices. The animals preferred agriculture in every test region, but our data showed a biased distribution of training samples between irrigated and non‐irrigated land. When both options occurred, the animals disregarded non‐irrigated land leading to its misclassification as non‐agriculture. Additionally, we found difference between the GPS observation dates and the harvest times for non‐irrigated crops. Given the White Stork takes advantage of managed land to search for prey, the inactivity of these fields was the likely culprit of their underrepresentation. Including more species attracted to agriculture – with other land‐use dependencies and observation times – can contribute to better results in similar applications.
The First Bis(μ‐acetato)(μ‐oxido)diruthenium(III) Complexes Containing Sulfur Donor Ligands
Authors: Ido Yohei , Fujihara Takashi , Sugaya Tomoaki , Nagasawa Akira
Published: September 2019

Novel diruthenium(III) complexes of general formula [RuIII2(μ‐O)‐(μ‐CH3CO2)2(bpy)2L2](PF6)2 (L: tetrahydrothiophene, (3); 4,5‐dihydro‐3(2H)‐thiophenone, (4); thiazole, (5); 4‐methylthiazole, (6); bpy: 2,2’‐bipyridine), which contain sulfur or nitrogen donor ligands at the trans‐to‐oxido sites, have been synthesized. The Ru–S bond distance in 4 is determined by X‐ray crystallography to be 2.447 Å, and the Ru–N(trans‐to‐oxido) length in 5 (2.157 Å) is similar to that of the complex having pyridine as the L ligand, 1. The spectroscopic properties and redox behavior of the complexes bearing sulfur donor ligands have been investigated and compared with those containing nitrogen donor ligands. The potentials of the redox couples of Ru2II,III/Ru2III,III and Ru2III,III/Ru2III,IV for 3 and 4 shift to positive regions compared with those of complexes with nitrogen donor ligands, 1, 5 and 6. The density functional theory (DFT) calculations reveal that the contribution of the trans ligand to the visible absorption is larger in 3 and 4 than in 1, 2 (L: CH3CN), 5 and 6.
Antimicrobial Effects of ZnPc Delivered into Liposomes on Multidrug Resistant (MDR)‐Mycobacterium tuberculosis
Authors: Miretti Mariana , Juri Leticia , Cosiansi María C. , Tempesti Tomas C. , Baumgartner María T.
Published: September 2019

Tuberculosis is one of the most important global health problems. Multidrug resistant (MDR)‐tuberculosis is caused by Mycobacterium tuberculosis (M. tuberculosis) resistant to the first line drugs (rifampin‐isoniazid). Photodynamic antimicrobial chemotherapy (PACT) has reemerged as an alternative against resistant bacteria. In this work, we synthetized liposomes of Dipalmitoylphosphatidylcholine and Cholesterol as carrier of ZnPc. The ZnPc‐liposomes photodynamic activity was tested in two strains of M. tuberculosis, a sensible (ATCC 27294) and MDR‐M. tuberculosis. As result, both strains were inactivated by ZnPc‐liposomes. The photodynamic activity was dependent of incubation time and light dose supplied. The photokilling activity was considerably higher for sensible strain than for MDR one.
Spinel/Lithium‐Rich Manganese Oxide Hybrid Nanofibers as Cathode Materials for Rechargeable Lithium‐Ion Batteries
Authors: Liu Junxiang , Wang Jiaqi , Ni Youxuan , Zhang Yudong , Luo Jun , Cheng Fangyi , Chen Jun
Published: September 2019

Lithium‐rich layered oxides are among the most promising cathode candidates to build high‐energy‐density rechargeable Li‐ion batteries but suffer from capacity/voltage fade, low reversibility, and poor rate capability. Herein, the synthesis and electrochemical application of heterostructured spinel/layered oxide (Li1.15Ni0.20Mn0.87O2) nanofibers as superior cathode materials are reported. The synergistic effect of 1D nanostructure and spinel/layer heterostructure enhances charge transfer, lithium diffusivity, and structural stability, resulting in improved initial Coulombic efficiency (≈100%), rate performance (150 mAh g−1 at 5C), and cyclability (258 mAh g−1 after 70 cycles). In situ X‐ray diffraction and Raman combined with first‐principle calculations reveal that the spinel stabilizes the layered Li‐rich Mn‐based oxide structure via maintaining oxygen vacancy and suppressing the structural variation and oxygen overoxidation.
3D CNTs Networks Enable MnO2 Cathodes with High Capacity and Superior Rate Capability for Flexible Rechargeable Zn–MnO2 Batteries
Authors: Zhang Xiyue , Wu Shuwei , Deng Shengjue , Wu Weixing , Zeng Yinxiang , Xia Xinhui , Pan Guoxiang , Tong Yexiang , Lu Xihong
Published: September 2019

The advancement of flexible rechargeable Zn–MnO2 batteries largely relies on directional design and fabrication of flexible cathode materials. However, the sluggish electron transfer and inferior mass diffusion rate of MnO2 cathodes hinder their application in high‐power systems. Herein, the design of flexible 3D carbon nanotube (CNT) conductive networks as excellent electron and charge transfer substrates is reported to achieve a high‐rate MnO2 cathode. With further structural protection of conductive poly(3,4‐ethylenedioxythiophene) (PEDOT), Zn2+ storage kinetics in the composite CNT/MnO2/PEDOT (denoted as CMOP) the cathode is optimized to deliver high capacity of 306.1 mAh g−1 at 1.1 A g−1 and superior rate capability of 176.8 mAh g−1 when the current density increases by tenfold (10.8 A g−1), representing a state‐of‐the‐art of current MnO2 based cathodes. Moreover, the as‐assembled quasi‐solid‐state Zn–CMOP batteries with good mechanical properties can afford a high energy density of 379.4 Wh kg−1 (17.5 mWh cm−3) and a peak power density of 17.1 kW kg−1 (0.8 W cm−3). This innovative achievement will be a critical step forward toward next‐generation quick charging electronics.
On the impact of Majorana masses in gravity-matter systems
Authors: de Brito Gustavo P. , Hamada Yuta , Pereira Antonio D. , Yamada Masatoshi
Published: September 2019

Abstract

We investigate the Higgs-Yukawa system with Majorana masses of a fermion within asymptotically safe quantum gravity. Using the functional renormalization group method we derive the beta functions of the Majorana masses and the Yukawa coupling constant and discuss the possibility of a non-trivial fixed point for the Yukawa coupling constant. In the gravitational sector we take into account higher derivative terms such as R
2 and R

μν

R

μν
in addition to the Einstein-Hilbert term for our truncation. For a certain value of the gravitational coupling constants and the Majorana masses, the Yukawa coupling constant has a non-trivial fixed point value and becomes an irrelevant parameter being thus a prediction of the theory. We also discuss consequences due to the Majorana mass terms to the running of the quartic coupling constant in the scalar sector.
Pileup and underlying event mitigation with iterative constituent subtraction
Authors: Berta P. , Masetti L. , Miller D.W. , Spousta M.
Published: September 2019

Abstract

The hard-scatter processes in hadronic collisions are often largely contaminated with soft background coming from pileup in proton-proton collisions, or underlying event in heavy-ion collisions. This paper presents a new background subtraction method for jets and event observables (such as missing transverse energy) which is based on the previously published Constituent Subtraction algorithm. The new subtraction method, called Iterative Constituent Subtraction, applies event-wide implementation of Constituent Subtraction iteratively in order to fully equilibrate the background subtraction across the entire event. Besides documenting the new method, we provide guidelines for setting the free parameters of the subtraction algorithm. Using particle-level simulation, we provide a comparison of Iterative Constituent Subtraction with several existing methods from which we conclude that the new method has a significant potential to improve the background mitigation in both proton-proton and heavy-ion collisions.
Competition and microcredit interest rates: international evidence
Authors: Al-Azzam Moh’d , Parmeter Christopher
Published: September 2019

The limited number of existing papers that link competition among microfinance institutions (MFIs) and microcredit interest rates, provide inconclusive and counterintuitive results. This paper uses data from 1997 MFIs operating in 109 countries between the years 2003 and 2016 to construct three measures of competition and evaluate their impacts on interest rates. These measures reflect three different aspects of competition: geographical expansion, market concentration, and the marginal pricing. While the results for market concentration are inconclusive, the results for both geographical expansion and marginal pricing show an economically strong impact of competition on interest rates. Specifically, regardless of whether an MFI is a for-profit or nonprofit, we find meaningful evidence that competition reduces interest rates. Our findings evince that lower interest rates are needed if the microfinance movement is to continue to be relied on as an effective means to alleviate poverty.
Relevance of Level IIb Neck Dissection in Patients with Head and Neck Squamous Cell Carcinomas
Authors: Hosokawa Seiji , Mochizuki Daiki , Takahashi Goro , Okamura Jun , Imai Atsushi , Ishikawa Ryuji , Takizawa Yoshinori , Yamatodani Takashi , Misawa Kiyoshi , Mineta Hiroyuki
Published: September 2019

Background

Cervical nodal metastasis is the most important prognostic factor in patients with head and neck cancers. Unfortunately, nodal dissection at level IIb carries a risk of damage to the spinal accessory nerve. We aimed to determine the prevalence of level IIb metastasis and the relevance of nodal dissection at level IIb in patients with head and neck squamous cell carcinomas.

Methods

During neck dissection, level IIb lymph nodes obtained from 181 patients with head and neck squamous cell carcinomas were removed, processed, and histopathologically examined. All specimens were divided into two groups according to the side (affected and unaffected sides). The number of dissected lymph nodes and prevalence of level IIb metastasis in each group were then determined and compared according to the preoperative clinical N stage (cN0 and cN+).

Results

The study included 158 men and 23 women with a median age of 65 years (range, 17–89 years). The prevalence of pathologically confirmed level IIb metastasis was 0% for clinically node‐negative (cN0) necks on the unaffected side and 10.34% for clinically node‐positive necks (cN+), with an overall prevalence of 2.4%. There was a significant association between clinically determined and pathologically confirmed node negativity at level IIb.

Conclusion

Our findings suggest that level IIb neck dissection in patients with head and neck squamous cell carcinomas may be required only if preoperative examination reveals multilevel or level IIa metastasis or suspicious level IIb metastasis.
Optimal loss-carry-forward taxation for Lévy risk processes stopped at general draw-down time
Authors: Wang Wenyuan , Zhang Zhimin
Published: September 2019

Motivated by Avram, Vu and Zhou (2017), Kyprianou and Zhou (2009), Li, Vu and Zhou (2017), Wang and Hu (2012), and Wang and Zhou (2018), we consider in this paper the problem of maximizing the expected accumulated discounted tax payments of an insurance company, whose reserve process (before taxes are deducted) evolves as a spectrally negative Lévy process with the usual exclusion of negative subordinator or deterministic drift. Tax payments are collected according to the very general loss-carry-forward tax system introduced in Kyprianou and Zhou (2009). To achieve a balance between taxation optimization and solvency, we consider an interesting modified objective function by considering the expected accumulated discounted tax payments of the company until the general draw-down time, instead of until the classical ruin time. The optimal tax return function and the optimal tax strategy are derived, and some numerical examples are also provided.
Zahedan School Fire: Endless Fire Incidents in Iranian Schools
Authors: Heidari Mohammad , Jafari Hamid , Heidari Samaneh
Published: September 2019

Emergencies frequently happen and sometimes their victims are school students. School age children and adolescents may be more vulnerable to life events and require more attention than adults, depending on the stage of their growth. The private elementary school of Osveh Hasaneh in Zahedan, Iran, caught fire on December 18, 2018, at 9:00 AM, where 4 students were killed. This school fire is the highest rate of mortality in Iran in terms of the number of student deaths. Considering the repeated nature of such incidents in Iranian schools, it is necessary to increase the awareness of risk of fire in schools to promote a culture of fire prevention in society.
Partially hyperbolic surface endomorphisms
Authors: HALL LAYNE , HAMMERLINDL ANDY
Published: September 2019

We prove that a class of weakly partially hyperbolic endomorphisms on $\mathbb{T}^{2}$ are dynamically coherent and leaf conjugate to linear toral endomorphisms. Moreover, we give an example of a partially hyperbolic endomorphism on $\mathbb{T}^{2}$ which does not admit a centre foliation.
The deglaciation of Barton Peninsula (King George Island, South Shetland Islands, Antarctica) based on geomorphological evidence and lacustrine records
Authors: Oliva Marc , Antoniades Dermot , Serrano Enrique , Giralt Santiago , Liu Emma J. , Granados Ignacio , Pla-Rabes Sergi , Toro Manuel , Hong Soon Gyu , Vieira Gonçalo
Published: September 2019

Barton Peninsula is an ice-free area located in the southwest corner of King George Island (South Shetland Islands, Antarctica). Following the Last Glacial Maximum, several geomorphological features developed in newly exposed ice-free terrain and their distribution provide insights about past environmental evolution of the area. Three moraine systems are indicative of three main glacial phases within the long-term glacial retreat, which also favoured the development of numerous lakes. Five of these lakes were cored to understand in greater detail the pattern of deglaciation through the study of lacustrine records. Radiocarbon dates from basal lacustrine sediments enabled the reconstruction of the chronology of Holocene glacial retreat. Tephra layers present in lake sediments provided additional independent age constraints on environmental changes based on geochemical and geochronological correlation with Deception Island-derived tephra. Shrinking of the Collins Glacier exposed the southern coastal fringe of Barton Peninsula at 8 cal ky BP. After a period of relative stability during the mid-Holocene, the ice cap started retreating northwards after 3.7 cal ky BP, confining some glaciers within valleys as shown by moraine systems. Lake sediments confirm a period of relative glacial stability during the last 2.4 cal ky BP.
AUTONOMY AND INDOCTRINATION: WHY WE NEED AN EMOTIONAL CONDITION FOR AUTONOMOUS REASONING AND REFLECTIVE ENDORSEMENT
Authors: Pérez de Calleja Mirja
Published: September 2019

I argue that none of the main accounts of autonomy in the literature can explain the fact that people who undergo a certain subtle but powerful kind of indoctrination are not autonomous or self-governing in reflectively acquiring and endorsing the views, values, goals, and practical commitments that they are successfully indoctrinated to adopt. I suggest that, assuming there are historical conditions on autonomous reasoning and reflective endorsement, there is a condition that specifically concerns emotions: the person’s emotional state and dispositions, and her web of emotional dependencies. I explain what we know so far about the kind of indoctrination on which I focus, and I motivate the claim that people who are successfully indoctrinated in this way are not self-governed in reflectively acquiring and endorsing even the first views and values that they adopt as a result of indoctrination. I argue that this heteronomy is not explained by any of the accounts that postulate historical conditions on autonomy: neither by classical accounts such as Rousseau’s and Piaget’s, nor by so-called historical accounts in the contemporary literature, nor by relational accounts. I argue that an accurate account of autonomy must include an emotional condition on autonomous reasoning and reflective endorsement that goes beyond the emotional conditions postulated or implied by historical accounts, and I offer a tentative sketch of this condition.
Randomized controlled trial of Family Connects: Effects on child emergency medical care from birth to 24 months
Authors: Goodman W. Benjamin , Dodge Kenneth A. , Bai Yu , O'Donnell Karen J. , Murphy Robert A.
Published: September 2019

One of Tom Dishion's most significant contributions to prevention science was the development of affordable, ecologically valid interventions, such as the Family Check-Up, that screen for child and family risk factors broadly, but concentrate family-specific interventions on those with greatest potential for population impact. In the spirit of this approach, investigators examined effects of a brief, universal postnatal home visiting program on child emergency medical care and billing costs from birth to age 24 months. Family Connects is a community-wide public health intervention that combines identification and alignment of community services and resources with brief, postpartum nurse home visits designed to assess risk, provide supportive guidance, and connect families with identified risk to community resources. Over 18 months, families of all 4,777 resident Durham County, North Carolina, births were randomly assigned based on even or odd birth date to receive a postnatal nurse home visiting intervention or services as usual (control). Independently, 549 of these families were randomly selected and participated in an impact evaluation study. Families, blind to study goals, provided written consent to access hospital administrative records. Results indicate that children randomly assigned to Family Connects had significantly less total emergency medical care (by 37%) through age 24 months, with results observed across almost all subgroups. Examination of billing records indicate a $3.17 decrease in total billing costs for each $1 in program costs. Overall, results suggest that community-wide postpartum support program can significantly reduce population rates of child emergency medical care through age 24 months while being cost-beneficial to communities.
Clinical characterisation of a novel SCN5A variant associated with progressive malignant arrhythmia and dilated cardiomyopathy
Authors: Kean Adam C. , Helm Benjamin M. , Vatta Matteo , Ayers Mark D. , Parent John J. , Darragh Robert K.
Published: September 2019

Introduction:

The SCN5A gene is implicated in many arrhythmogenic and cardiomyopathic processes. We identified a novel SCN5A variant in a family with significant segregation in individuals affected with progressive sinus and atrioventricular nodal disease, atrial arrhythmia, dilated cardiomyopathy, and early sudden cardiac arrest.

Methods:

A patient pedigree was created following the clinical evaluation of three affected individuals, two monozygotic twins and a paternal half-brother, which lead to the evaluation of a paternal half-sister (four siblings with the same father and three mothers) all of whom experienced varying degrees of atrial arrhythmias, conduction disease, and dilated cardiomyopathy in addition to a paternal history of unexplained death in his 50s with similar autopsy findings. The index male underwent sequencing of 58 genes associated with cardiomyopathies. Sanger sequencing was used to provide data for bases with insufficient coverage and for bases in some known regions of genomic segmental duplications. All clinically significant and novel variants were confirmed by independent Sanger sequencing.

Results:

All relatives tested were shown to have the same SCN5A variant of unknown significance (p. Asp197His) and the monozygotic twins shared a co-occurring NEXN (p. Glu575*). Segregation analysis demonstrates likely pathogenic trait for the SCN5A variant with an additional possible role for the NEXN variant in combination.

Conclusions:

There is compelling clinical evidence suggesting that the SCN5A variant p. Asp197His may be re-classified as likely pathogenic based on the segregation analysis of our family of interest. Molecular mechanism studies are pending.
Multifunctional metaoptics based on bilayer metasurfaces
Authors: Zhou You , Kravchenko Ivan I. , Wang Hao , Zheng Hanyu , Gu Gong , Valentine Jason
Published: September 2019

Optical metasurfaces have become versatile platforms for manipulating the phase, amplitude, and polarization of light. A platform for achieving independent control over each of these properties, however, remains elusive due to the limited engineering space available when using a single-layer metasurface. For instance, multiwavelength metasurfaces suffer from performance limitations due to space filling constraints, while control over phase and amplitude can be achieved, but only for a single polarization. Here, we explore bilayer dielectric metasurfaces to expand the design space for metaoptics. The ability to independently control the geometry and function of each layer enables the development of multifunctional metaoptics in which two or more optical properties are independently designed. As a proof of concept, we demonstrate multiwavelength holograms, multiwavelength waveplates, and polarization-insensitive 3D holograms based on phase and amplitude masks. The proposed architecture opens a new avenue for designing complex flat optics with a wide variety of functionalities.
The selective orexin-2 antagonist seltorexant (JNJ-42847922/MIN-202) shows antidepressant and sleep-promoting effects in patients with major depressive disorder
Authors: Recourt Kasper , de Boer Peter , Zuiker Rob , Luthringer Remy , Kent Justine , van der Ark Peter , Van Hove Ilse , van Gerven Joop , Jacobs Gabriel , van Nueten Luc , Drevets Wayne
Published: September 2019

Excessive arousal has a role in the pathophysiology of major depressive disorder (MDD). Seltorexant (JNJ-42847922/MIN-202) is a selective antagonist of the human orexin-2 receptor (OX2R) that may normalize excessive arousal and thereby attenuate depressive symptoms. In this study, the effects of night-time arousal suppression on depressive symptoms were investigated. 47 MDD patients with a total Inventory of Depressive Symptomatology (IDS) score of ≥30 at screening were included in a randomized, double-blind, diphenhydramine-, and placebo-controlled multicentre study. Symptoms of depression were rated using the 17-item Hamilton Depression Rating Scale (HDRS17). Effects on sleep were evaluated by polysomnography and by the Leeds Sleep Evaluation Questionnaire (LSEQ). To investigate the safety and tolerability of seltorexant, vital signs, suicidal ideation and adverse events were monitored. At baseline the severity of depressive symptoms correlated with sleep efficiency (SE), wake after sleep onset (WASO), duration of stage 2 sleep, and ruminations. Ten days of treatment with seltorexant (and not diphenhydramine) resulted in a significant improvement of core depressive symptoms compared to placebo; the antidepressant efficacy of seltorexant was maintained with continued treatment up to 28 days. Compared to placebo, the antidepressant efficacy of seltorexant coincided with an overall increase in (left posterior) EEG power and a relative increase in delta- and decrease in theta-, alpha- and beta power during stage 2 sleep. Treatment with seltorexant was associated with mild, self-limiting adverse drug reactions. Seltorexant affected core symptoms of depression in the absence of overt changes in the hypnogram; in contrast, diphenhydramine was not efficacious.
Irrelevance of linear controllability to nonlinear dynamical networks
Authors: Jiang Junjie , Lai Ying-Cheng
Published: September 2019

There has been tremendous development in linear controllability of complex networks. Real-world systems are fundamentally nonlinear. Is linear controllability relevant to nonlinear dynamical networks? We identify a common trait underlying both types of control: the nodal “importance”. For nonlinear and linear control, the importance is determined, respectively, by physical/biological considerations and the probability for a node to be in the minimum driver set. We study empirical mutualistic networks and a gene regulatory network, for which the nonlinear nodal importance can be quantified by the ability of individual nodes to restore the system from the aftermath of a tipping-point transition. We find that the nodal importance ranking for nonlinear and linear control exhibits opposite trends: for the former large-degree nodes are more important but for the latter, the importance scale is tilted towards the small-degree nodes, suggesting strongly the irrelevance of linear controllability to these systems. The recent claim of successful application of linear controllability to Caenorhabditis elegans connectome is examined and discussed.
Non-classical tissue monocytes and two functionally distinct populations of interstitial macrophages populate the mouse lung
Authors: Schyns Joey , Bai Qiang , Ruscitti Cecilia , Radermecker Coraline , De Schepper Sebastiaan , Chakarov Svetoslav , Farnir Frédéric , Pirottin Dimitri , Ginhoux Florent , Boeckxstaens Guy , Bureau Fabrice , Marichal Thomas
Published: September 2019

Resident tissue macrophages (RTM) can fulfill various tasks during development, homeostasis, inflammation and repair. In the lung, non-alveolar RTM, called interstitial macrophages (IM), importantly contribute to tissue homeostasis but remain little characterized. Here we show, using single-cell RNA-sequencing (scRNA-seq), two phenotypically distinct subpopulations of long-lived monocyte-derived IM, i.e. CD206+ and CD206−IM, as well as a discrete population of extravasating CD64+CD16.2+ monocytes. CD206+ IM are peribronchial self-maintaining RTM that constitutively produce high levels of chemokines and immunosuppressive cytokines. Conversely, CD206−IM preferentially populate the alveolar interstitium and exhibit features of antigen-presenting cells. In addition, our data support that CD64+CD16.2+ monocytes arise from intravascular Ly-6Clo patrolling monocytes that enter the tissue at steady-state to become putative precursors of CD206−IM. This study expands our knowledge about the complexity of lung IM and reveals an ontogenic pathway for one IM subset, an important step for elaborating future macrophage-targeted therapies.
Transparent proton transport through a two-dimensional nanomesh material
Authors: Xu Jiyu , Jiang Hongyu , Shen Yutian , Li Xin-Zheng , Wang E. G. , Meng Sheng
Published: September 2019

Molecular sieving is of great importance to proton exchange in fuel cells, water desalination, and gas separation. Two-dimensional crystals emerge as superior materials showing desirable molecular permeability and selectivity. Here we demonstrate that a graphdiyne membrane, an experimentally fabricated member in the graphyne family, shows superior proton conductivity and perfect selectivity thanks to its intrinsic nanomesh structure. The trans-membrane hydrogen bonds across graphdiyne serve as ideal channels for proton transport in Grotthuss mechanism. The free energy barrier for proton transfer across graphdiyne is ~2.4 kJ mol−1, nearly identical to that in bulk water (2.1 kJ mol−1), enabling “transparent” proton transport at room temperature. This results in a proton conductivity of 0.6 S cm−1 for graphdiyne, four orders of magnitude greater than graphene. Considering its ultimate pore size of 0.55 nm, graphdiyne membrane blocks soluble fuel molecules and exhibits superior proton selectivity. These advantages endow graphdiyne a great potential as proton exchange material.
Author Correction: Genome-wide association study of alcohol consumption and use disorder in 274,424 individuals from multiple populations
Authors: Kranzler Henry R. , Zhou Hang , Kember Rachel L. , Smith Rachel Vickers , Justice Amy C. , Damrauer Scott , Tsao Philip S. , Klarin Derek , Baras Aris , Reid Jeffrey , Overton John , Rader Daniel J. , Cheng Zhongshan , Tate Janet P. , Becker William C. , Concato John , Xu Ke , Polimanti Renato , Zhao Hongyu , Gelernter Joel
Published: September 2019

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Defects in t6A tRNA modification due to GON7 and YRDC mutations lead to Galloway-Mowat syndrome
Authors: Arrondel Christelle , Missoury Sophia , Snoek Rozemarijn , Patat Julie , Menara Giulia , Collinet Bruno , Liger Dominique , Durand Dominique , Gribouval Olivier , Boyer Olivia , Buscara Laurine , Martin Gaëlle , Machuca Eduardo , Nevo Fabien , Lescop Ewen , Braun Daniela A. , Boschat Anne-Claire , Sanquer Sylvia , Guerrera Ida Chiara , Revy Patrick , Parisot Mélanie , Masson Cécile , Boddaert Nathalie , Charbit Marina , Decramer Stéphane , Novo Robert , Macher Marie-Alice , Ranchin Bruno , Bacchetta Justine , Laurent Audrey , Collardeau-Frachon Sophie , van Eerde Albertien M. , Hildebrandt Friedhelm , Magen Daniella , Antignac Corinne , van Tilbeurgh Herman , Mollet Géraldine
Published: September 2019

N6-threonyl-carbamoylation of adenosine 37 of ANN-type tRNAs (t6A) is a universal modification essential for translational accuracy and efficiency. The t6A pathway uses two sequentially acting enzymes, YRDC and OSGEP, the latter being a subunit of the multiprotein KEOPS complex. We recently identified mutations in genes encoding four out of the five KEOPS subunits in children with Galloway-Mowat syndrome (GAMOS), a clinically heterogeneous autosomal recessive disease characterized by early-onset steroid-resistant nephrotic syndrome and microcephaly. Here we show that mutations in YRDC cause an extremely severe form of GAMOS whereas mutations in GON7, encoding the fifth KEOPS subunit, lead to a milder form of the disease. The crystal structure of the GON7/LAGE3/OSGEP subcomplex shows that the intrinsically disordered GON7 protein becomes partially structured upon binding to LAGE3. The structure and cellular characterization of GON7 suggest its involvement in the cellular stability and quaternary arrangement of the KEOPS complex.
Prediction of ferroelectricity-driven Berry curvature enabling charge- and spin-controllable photocurrent in tin telluride monolayers
Authors: Kim Jeongwoo , Kim Kyoung-Whan , Shin Dongbin , Lee Sang-Hoon , Sinova Jairo , Park Noejung , Jin Hosub
Published: September 2019

In symmetry-broken crystalline solids, pole structures of Berry curvature (BC) can emerge, and they have been utilized as a versatile tool for controlling transport properties. For example, the monopole component of the BC is induced by the time-reversal symmetry breaking, and the BC dipole arises from a lack of inversion symmetry, leading to the anomalous Hall and nonlinear Hall effects, respectively. Based on first-principles calculations, we show that the ferroelectricity in a tin telluride monolayer produces a unique BC distribution, which offers charge- and spin-controllable photocurrents. Even with the sizable band gap, the ferroelectrically driven BC dipole is comparable to those of small-gap topological materials. By manipulating the photon handedness and the ferroelectric polarization, charge and spin circular photogalvanic currents are generated in a controllable manner. The ferroelectricity in group-IV monochalcogenide monolayers can be a useful tool to control the BC dipole and the nonlinear optoelectronic responses.
Exploration of stem endophytic communities revealed developmental stage as one of the drivers of fungal endophytic community assemblages in two Amazonian hardwood genera
Authors: Skaltsas Demetra N. , Badotti Fernanda , Vaz Aline Bruna Martins , Silva Felipe Ferreira da , Gazis Romina , Wurdack Kenneth , Castlebury Lisa , Góes-Neto Aristóteles , Chaverri Priscila
Published: September 2019

Many aspects of the dynamics of tropical fungal endophyte communities are poorly known, including the influence of host taxonomy, host life stage, host defence, and host geographical distance on community assembly and composition. Recent fungal endophyte research has focused on Hevea brasiliensis due to its global importance as the main source of natural rubber. However, almost no data exist on the fungal community harboured within other Hevea species or its sister genus Micrandra. In this study, we expanded sampling to include four additional Hevea spp. and two Micrandra spp., as well as two host developmental stages. Through culture-dependent and -independent (metagenomic) approaches, a total of 381 seedlings and 144 adults distributed across three remote areas within the Peruvian Amazon were sampled. Results from both sampling methodologies indicate that host developmental stage had a greater influence in community assemblage than host taxonomy or locality. Based on FunGuild ecological guild assignments, saprotrophic and mycotrophic endophytes were more frequent in adults, while plant pathogens were dominant in seedlings. Trichoderma was the most abundant genus recovered from adult trees while Diaporthe prevailed in seedlings. Potential explanations for that disparity of abundance are discussed in relation to plant physiological traits and community ecology hypotheses.
Milk-derived miRNA profiles elucidate molecular pathways that underlie breast dysfunction in women with common genetic variants in SLC30A2
Authors: Kelleher Shannon L. , Gagnon Annie , Rivera Olivia C. , Hicks Steven D. , Carney Molly C. , Alam Samina
Published: September 2019

Studies in humans and pre-clinical animal models show milk-derived miRNAs reflect mammary gland function during lactation. The zinc transporter SLC30A2/ZnT2 plays a critical role in mammary gland function; ZnT2-null mice have profound defects in mammary epithelial cell (MEC) polarity and secretion, resulting in sub-optimal lactation. Non-synonymous genetic variation in SLC30A2 is common in humans, and several common ZnT2 variants are associated with changes in milk components that suggest breast dysfunction in women. To identify novel mechanisms through which dysfunction might occur, milk-derived miRNA profiles were characterized in women harboring three common genetic variants in SLC30A2 (D103E, T288S, and Exon 7). Expression of ten miRNAs differed between genotypes, and contributed to distinct spatial separation. Studies in breast milk and cultured MECs confirmed expression of ZnT2 variants alters abundance of protein levels of several predicted mRNA targets critical for breast function (PRLR, VAMP7, and SOX4). Moreover, bioinformatic analysis identified two novel gene networks that may underlie normal MEC function. Thus, we propose that genetic variation in genes critical for normal breast function such as SLC30A2 has important implications for lactation performance in women, and that milk-derived miRNAs can be used to identify novel mechanisms and for diagnostic potential.
Mathematical modeling of drug-induced receptor internalization in the HER2-positive SKBR3 breast cancer cell-line
Authors: Fehling-Kaschek Mirjam , Peckys Diana B. , Kaschek Daniel , Timmer Jens , Jonge Niels de
Published: September 2019

About 20% of breast cancer tumors over-express the HER2 receptor. Trastuzumab, an approved drug to treat this type of breast cancer, is a monoclonal antibody directly binding at the HER2 receptor and ultimately inhibiting cancer cell growth. The goal of our study was to understand the early impact of trastuzumab on HER2 internalization and recycling in the HER2-overexpressing breast cancer cell line SKBR3. To this end, fluorescence microscopy, monitoring the amount of HER2 expression in the plasma membrane, was combined with mathematical modeling to derive the flux of HER2 receptors from and to the membrane. We constructed a dynamic multi-compartment model based on ordinary differential equations. To account for cancer cell heterogeneity, a first, dynamic model was expanded to a second model including two distinct cell phenotypes, with implications for different conformational states of HER2, i.e. monomeric or homodimeric. Our mathematical model shows that the hypothesis of fast constitutive HER2 recycling back to the plasma membrane does not match the experimental data. It conclusively describes the experimental observation that trastuzumab induces sustained receptor internalization in cells with membrane ruffles. It is also concluded that for rare, non-ruffled (flat) cells, HER2 internalization occurs three orders of magnitude slower than for the bulk, ruffled cell population.
High-throughput-compatible assays using a genetically-encoded calcium indicator
Authors: Wu Nyantsz , Nishioka Walter K. , Derecki Noël C. , Maher Michael P.
Published: September 2019

Measurement of intracellular calcium in live cells is a key component of a wide range of basic life science research, and crucial for many high-throughput assays used in modern drug discovery. Synthetic calcium indicators have become the industry standard, due their ease of use, high reliability, wide dynamic range, and availability of a large variety of spectral and chemical properties. Genetically-encoded calcium indicators (GECIs) have been optimized to the point where their performance rivals that of synthetic calcium indicators in many applications. Stable expression of a GECI has distinct advantages over synthetic calcium indicators in terms of reagent cost and simplification of the assay process. We generated a clonal cell line constitutively expressing GCaMP6s; high expression of the GECI was driven by coupling to a blasticidin resistance gene with a self-cleaving cis-acting hydrolase element (CHYSEL) 2A peptide. Here, we compared the performance of the GECI GCaMP6s to the synthetic calcium indicator fluo-4 in a variety of assay formats. We demonstrate that the pharmacology of ion channel and GPCR ligands as determined using the two indicators is highly similar, and that GCaMP6s is viable as a direct replacement for a synthetic calcium indicator.
Expression of immune regulatory genes correlate with the abundance of specific Clostridiales and Verrucomicrobia species in the equine ileum and cecum
Authors: Lindenberg F. , Krych L. , Fielden J. , Kot W. , Frøkiær H. , van Galen G. , Nielsen D. S. , Hansen A. K.
Published: September 2019

Billions of bacteria inhabit the gastrointestinal tract. Immune-microbial cross talk is responsible for immunological homeostasis, and symbiotic microbial species induce regulatory immunity, which helps to control the inflammation levels. In this study we aimed to identify species within the equine intestinal microbiota with the potential to induce regulatory immunity. These could be future targets for preventing or treating low-grade chronic inflammation occurring as a result of intestinal microbial changes and disruption of the homeostasis. 16S rRNA gene amplicon sequencing was performed on samples of intestinal microbial content from ileum, cecum, and colon of 24 healthy horses obtained from an abattoir. Expression of genes coding for IL-6, IL-10, IL-12, IL-17, 18 s, TNFα, TGFβ, and Foxp3 in the ileum and mesenteric lymph nodes was measured by qPCR. Intestinal microbiota composition was significantly different in the cecum and colon compared to the ileum, which contains large abundances of Proteobacteria. Especially members of the Clostridiales order correlated positively with the regulatory T-cell transcription factor Foxp3 and so did the phylum Verrucomicrobia. We conclude that Clostridiales and Verrucomicrobia have the potential to induce regulatory immunity and are possible targets for intestinal microbial interventions aiming at regulatory immunity improvement.
Muscle transcriptome analysis reveals genes and metabolic pathways related to mineral concentration in Bos indicus
Authors: Afonso Juliana , Coutinho Luiz Lehmann , Tizioto Polyana Cristine , da Silva Diniz Wellison Jarles , de Lima Andressa Oliveira , Rocha Marina Ibelli Pereira , Buss Carlos Eduardo , Andrade Bruno Gabriel Nascimento , Piaya Otávio , da Silva Juliana Virginio , Lins Laura Albuquerque , Gromboni Caio Fernando , Nogueira Ana Rita Araújo , Fortes Marina Rufino Salinas , Mourao Gerson Barreto , de Almeida Regitano Luciana Correia
Published: September 2019

Mineral content affects the biological processes underlying beef quality. Muscle mineral concentration depends not only on intake-outtake balance and muscle type, but also on age, environment, breed, and genetic factors. To unveil the genetic factors involved in muscle mineral concentration, we applied a pairwise differential gene expression analysis in groups of Nelore steers genetically divergent for nine different mineral concentrations. Here, based on significant expression differences between contrasting groups, we presented candidate genes for the genetic regulation of mineral concentration in muscle. Functional enrichment and protein-protein interaction network analyses were carried out to search for gene regulatory processes concerning each mineral. The core genetic regulation for all minerals studied, except Zn, seems to rest on interactions between components of the extracellular matrix. Regulation of adipogenesis-related pathways was also significant in our results. Antagonistic patterns of gene expression for fatty acid metabolism-related genes may explain the Cu and Zn antagonistic effect on fatty acid accumulation. Our results shed light on the role of these minerals on cell function.