bluuebunny/crossref_metadata_2025 huggingface dataset:
‘Posidonia meadows calling’: a ubiquitous fish sound with monitoring potential
Authors: Di Iorio Lucia , Raick Xavier , Parmentier Eric , Boissery Pierre , Valentini‐Poirier Cathy‐Anna , Gervaise Cédric
Published: January 2018

In the Mediterranean Sea, the seagrass Posidonia oceanica plays a key ecological role, and is protected by a range of legislation. Standard Posidonia monitoring programmes generally focus on the plant at different spatial and short temporal scales, without considering the organisms dependent on the ecosystem. Passive acoustic monitoring (PAM) has a high potential to non‐intrusively monitor biological activities and biodiversity at high temporal resolution, and to assess ecosystem health. This is particularly relevant considering that Posidonia meadows host numerous sound‐producing fish species. In this study, bottom‐moored hydrophones were deployed in nine Western Mediterranean meadows covering a distance of more than 200 km to identify acoustic features potentially relevant to monitor this critical habitat. Among eight identified fish sound categories, we found a single type of sound (that we will refer to as /kwa/) dominating the soundscape of Posidonia meadows over a time span of 7 months. Compared to other low‐frequency sounds, the /kwa/ presented unique characteristics that suggest it is produced by a fish via fast contracting muscles. The /kwa/ was the only sound detectable under anthropogenic noise conditions, and little affected by it. Cluster analyses performed on 13 acoustic features revealed a high degree of call diversity. /kwa/ diversity, combined with its large‐scale (all meadows), long‐term (7 months) occurrence and low noise interference, make the /Kwa/ a promising candidate for PAM of Posidonia meadows. Furthermore, variability in acoustic features suggests a central role of the /kwa/ in communication. Overall, this work sets the basis for establishing the relevance of the /kwa/ in monitoring P. oceanica meadows and developing PAM techniques for this critical habitat.
In Situ Tissue Regeneration of Renal Tissue Induced by Collagen Hydrogel Injection
Authors: Lee Sang Jin , Wang Hung-Jen , Kim Tae-Hyoung , Choi Jin San , Kulkarni Gauri , Jackson John D. , Atala Anthony , Yoo James J.
Published: January 2018

Host stem/progenitor cells can be mobilized and recruited to a target location using biomaterials, and these cells may be used for in situ tissue regeneration. The objective of this study was to investigate whether host biologic resources could be used to regenerate renal tissue in situ. Collagen hydrogel was injected into the kidneys of normal mice, and rat kidneys that had sustained ischemia/reperfusion injury. After injection, the kidneys of both animal models were examined up to 4 weeks for host tissue response. The infiltrating host cells present within the injection regions expressed renal stem/progenitor cell markers, PAX-2, CD24, and CD133, as well as mesenchymal stem cell marker, CD44. The regenerated renal structures were identified by immunohistochemistry for renal cell specific markers, including synaptopodin and CD31 for glomeruli and cytokeratin and neprilysin for tubules. Quantitatively, the number of glomeruli found in the injected regions was significantly higher when compared to normal regions of renal cortex. This phenomenon occurred in normal and ischemic injured kidneys. Furthermore, the renal function after ischemia/reperfusion injury was recovered after collagen hydrogel injection. These results demonstrate that introduction of biomaterials into the kidney is able to facilitate the regeneration of glomerular and tubular structures in normal and injured kidneys. Such an approach has the potential to become a simple and effective treatment for patients with renal failure.
Effect of Jeffamine®‐Modified Phosphotungstic Acid on Porphyrin Synthesis in Water
Authors: Suppan Thangamani , Kunjunni Meenu K. , Barik Atanu , Bhattacharjee Rama R.
Published: January 2018

Synthesis of porphyrin derivatives in water can be challenging due to the inimical conditions associated with the initial condensation equilibrium. Here in, we report the synthesis of meso‐tetraphenyl porphyrin (H2TPP) in water in presence of phosphotungstic acid (PTA) and its liquid‐derivative with a polyether amine (Jeffamine®). The PTA‐Jeffamine® derivative was found to simultaneously catalyze both the condensation as well as oxidation stages of H2TPP formation. Few other derivatives of H2TPP were synthesized. All the products were characterized by UV‐vis, FTIR and NMR spectroscopy. Singlet oxygen efficiency of the catalytically synthesized H2TPP matched well with that of H2TPP obtained from conventional process. The PTA‐Jeffamine® derivative showed better yield compared to the reaction with pure PTA.
Fast Synthesis of Spherical Silica Aerogel Powders by Emulsion Polymerization from Water Glass
Authors: Lee Kyoung‐Jin , Kim Young H. , Lee Je K. , Hwang Hae‐Jin
Published: January 2018

In this study, a fast synthesis technique for silica aerogel powder was proposed that reduces the length of the tedious surface modification and solvent exchange processes. Spherical silica aerogel powder could be fabricated by an emulsion polymerization method from water glass and n‐hexane. A stable water glass‐in‐hexane emulsion with a water glass to hexane ratio of 5:5 was fabricated using the surfactant, sorbitan monooleate (Span80). It was found that acetic acid and isopropanol catalysts for the hydrolysis and condensation of water glass droplets dispersed in the emulsion were crucial for the synthesis of the spherical silica aerogel powder with a narrow particle size distribution and for reducing production time. In addition, the particle size of the spherical silica aerogel could be controlled by changing the water glass droplet size.
The Viridin Biosynthesis Gene Cluster of Trichoderma virens and Its Conservancy in the Bat White‐Nose Fungus Pseudogymnoascus destructans
Authors: Bansal Ravindra , Sherkhane Pramod D. , Oulkar Dasharath , Khan Zareen , Banerjee Kaushik , Mukherjee Prasun K.
Published: January 2018

Viridin group of furano‐steroidal antibiotics are known to function as anti‐fungal and anti‐cancer agents, in addition to their roles as radio‐ and chemo‐sensitizers. Discovered in 1945 as a metabolite of Trichoderma virens, viridins continue to receive significant attention of several synthetic chemists and clinicians as a very strong PI3 kinase inhibitor. However, till date, researchers have not been able to discover a single gene that is involved in viridin biosynthesis. In this study, we present the complete gene cluster for the biosynthesis of viridin in T. virens, and provide genetic evidence of its involvement in viridin formation. Also, we show that the same cluster is present in a distantly related fungus Pseudogymnoascus destructans that causes bat white‐nose disease, which is leading to the devastation of the bat population in North America. Our findings, thus, pave not only the way for further research on the elucidation of the complete biosynthesis pathway and possible tuning of viridin production in the plant beneficial fungus Trichoderma virens, but also are expected to trigger investigations on the role of this gene cluster in pathogenicity of the devastating bat pathogen.
Refined Bainite Microstructure and Mechanical Properties of a High‐Strength Low‐Carbon Bainitic Steel Treated by Austempering Below and Above MS
Authors: Tian Junyu , Xu Guang , Zhou Mingxing , Hu Haijiang
Published: January 2018

Four isothermal heat treatment schedules are designed to study the effects of transformation temperature below and above martensite starting temperature (MS) on bainitic transformation kinetics, microstructure, and mechanical properties of a low‐carbon bainitic steel. The results indicate that the product of tensile strength and elongation (PSE) of tested steel do not show any improvement when the samples are austempered at a temperature below MS. Finer bainite microstructure can be observed when the samples are austempered at a temperature below MS, but the highest PSE is obtained in the sample austempered at a temperature above MS (400 °C). Lower PSE of the samples transformed below MS is mainly attributed to less bainite and retained austenite (RA) amount and more amount of athermal martensite, as well as the existence of carbide. In addition, with the decrease of the isothermal transformation temperature, the PSE first increases and then decreases. Different from austempering above MS, when the sample is austempered below MS, PSE decreases with the decrease of transformation temperature. Moreover, whether the treatment below MS can improve mechanical property of bainitic steels depends on the composition of steels and transformation temperature.
Risk modeling of communications, navigation, and surveillance complex systems of systems for future aviation
Authors: Lewis Bryan R. , Haimes Yacov Y.
Published: January 2018

The planned integration of Communications (C), Navigation (N), and Surveillance (S) by the U.S. Federal Aviation Administration (FAA) would convert their currently safely coordinated operations into a single vulnerable interdependent and interconnected CNS complex systems of systems (Complex SoS). We model the ensuing vulnerability of planned Complex SoS by tracing specific new interdependencies and interconnections manifested by their shared/common (i) States (variables), (ii) Decisions, (iii) Decision makers, and (iv) Resources (cyber‐physical) among the three C, N, and S systems?. Other contributions stem from our exploiting the use of fault trees (without the reliance on reliability data). Exploiting fault trees enabled us to quantify the accrued knowledge of interdependencies and interconnectedness tabulated in Tables 1–4 in terms of AND Gates (systems connected in Parallel), and OR Gates (systems connected in Series); and to discover dangerous shared C, N, and S systems on the critical path. Namely, if all systems (subsystems) in the minimal cut set fail, then the entire CNS Complex SoS would fail. Significantly, this modeling approach alerted the FAA on “what not to do” by identifying subsystems early in the planned integration of C, N, and S that would result in a single catastrophic failure of the planned CNS Complex SoS.
Network‐constrained hydrothermal unit commitment using benders and optimality condition decompositions
Authors: Wang Chaoqun , Wei Hua , Wu Siyuan
Published: January 2018

This paper presents a new network‐constrained hydrothermal unit commitment (NCHTUC) model that considers nonlinear hydro generation functions and AC power flow constraints. In addition, the proposed NCHTUC includes dynamic water balance equations of cascaded hydro plants. To cope with the large‐scale and mixed‐integer nonlinear nature of the model, a new hybrid computational strategy consisting of generalized Benders decomposition and optimality condition decomposition is proposed. By using this method, the NCHTUC problem is decomposed into a master problem, a hydro plant subproblem, and a thermal plant subproblem with independent OPF (optimal power flow) solutions for each time period. In order to verify the effectiveness of the proposed model and decomposition strategy, numerical tests are performed on three test systems of up to 703 buses over a 24‐h horizon. Test results indicate that the developed methodology has excellent convergence and is capable of solving large‐scale NCHTUC problems without loss of accuracy. © 2018 Institute of Electrical Engineers of Japan. Published by John Wiley & Sons, Inc.
GE‐RM: Efficient global estimation and refined model for salient object detection via elaborate receptive fields
Authors: Wang Ziqin , Jiang Peilin , Wang Fei
Published: January 2018

Recently, a deep learning technique has been introduced to saliency detection and has achieved promising results, but most of them are based on superpixel algorithms. Consequently, their performances and efficiencies depend largely on the results of a segmentation algorithm. Instead of classifying superpixels, we treat salient object detection as a dense prediction task. Fully convolutional networks show strong potential in dense prediction tasks, but the resolution and the quality of output maps need improving due to the loss of location information. In order to achieve high‐quality saliency maps, we propose a very efficient method using two Fully Convolutional Networks (FCNs) to extract global and local information respectively via different receptive fields. The global model produces accurate but coarse saliency maps, while the refined model produces full‐sized, fine results. We evaluate our method on eight public datasets and find that our method outperforms the other state‐of‐the‐art methods. Besides, our method runs much faster than the existing deep learning methods.
Evaluation of the UVB‐screening capacity and restorative effects exerted by farnesol gel on UVB‐caused sunburn
Authors: Wu Guan Xuan , Huang Han Hsiang , Chang Huoy Rou , Kuo Shyh Ming
Published: January 2018

Farnesol, a natural 15‐carbon organic compound, has various microbiological and cellular activities. It has been found to exert apoptosis‐inducing effects against carcinoma cells as well as antiallergic and anti‐inflammatory effects in vivo. In the current study, a series of formulations composed of various concentrations of hydroxypropyl methylcellulose (HPMC) with the addition of hyaluronan (HA) and xanthan gum (XG) was designed to evaluate the UVB‐screening and H2O2‐eliminating effects of farnesol in normal fibroblasts. Farnesol at 0.005, 0.0075, and 0.01% exhibited significant capacity for H2O2 scavenging; at 0.0025%, it showed insignificant effects. Under 120‐min UVB exposure, screening with plural gel composed of 0.0025% farnesol, 0.5% HA, and 0.5% XG containing 1.5% or 2% HPMC retained normal fibroblast viability. After 60‐min exposure to UVB, screening with plural gel composed of farnesol, HA, XG, and 0.5%, 1.0%, 1.5%, or 2% HPMC decreased the ratio of the G1 phase and increased ratio of the S phase in comparison with the accumulated cell cycle of the normal fibroblasts without screening. The gel with 2% HPMC displayed the strongest cell cycle‐reversal ability. In vivo histopathological results showed that the prepared plural gels with 0.5% or 2% HPMC and farnesol, HA, and XG had greater antiphotoaging and reparative effects against UVB‐induced changes and damage in the skin. In conclusion, the current in vitro and in vivo results demonstrated that the prepared plural composed of 0.0025% farnesol, 0.5% HA, 0.5% XG, and 2% HPMC possessed the greatest UVB‐screening capacity and the strongest restorative effects on UVB‐induced sunburned skin.
Mike to Michaela: male‐to‐female genital reconstruction
Authors: Rashid Tina
Published: January 2018

With referrals to gender identity clinics doubling over the last five years and an increasing number of people coming forward for treatment, both primary and secondary care doctors are likely to encounter transgender people in their clinical practice. In this article, Tina Rashid discusses gender dysphoria and male‐to‐female genital reconstruction.
Brachytherapy in prostate cancer: techniques and clinical outcomes
Authors: Prentice Mark , Nei Wenlong , Lewis Amy , Davda Reena , Payne Heather
Published: January 2018

Brachytherapy for prostate cancer involves placing radioactive seeds directly into the prostate, with the aim of protecting healthy surrounding tissue. This article reviews the current indications for brachytherapy treatment and the different options available. The practicalities and potential complications of treatment are also considered.
Children's at Home: Pilot Study Assessing Dedicated Social Media for Parents of Adolescents with Neurofibromatosis Type 1
Authors: Akre Christina , Polvinen Julie , Ullrich Nicole J. , Rich Michael
Published: January 2018

The aim of this pilot study was to evaluate Children's at Home (C@H), a dedicated social media website for parents of adolescents with neurofibromatosis type 1 (NF1). The interventional study included two phases: (1) creating video intervention/prevention assessment (VIA) visual narratives about having an adolescent with NF1 and (2) interacting on C@H, a secure, medically moderated social media website. C@H was evaluated qualitatively at three time points. At enrollment (T0, N = 17), participants reported needing C@H to break their isolation, connect with other families, and receive accurate information, advice, and support from others facing similar challenges. At T1, after creating VIA during 6 months (N = 13, 145 videos), participants mostly valued the opportunity to speak about the challenges they face with NF1 and their journey since diagnosis. At T2, after interacting on C@H for 7 weeks (N = 10, two sign‐ins/week/parent), participants reported connecting with other parents of children with NF1 for the first time, valuing the “real faces” and emotions of other parents with shared experiences providing a sense of normalcy. Qualitative analysis suggested that C@H decreased feelings of isolation, provided relief to talk about NF1 without having to explain it, provided new knowledge about NF1 and the opportunity to address non‐medical issues of NF1 never discussed in clinic, and helped participants with putting their lives into perspective. C@H allowed parents of adolescents with NF1 to overcome previous isolation and connect for the first time. Innovative applications of social media dedicated to those who care for children with chronic conditions can provide peer‐to‐peer support, shared experience, and reliable medical information.
School-Based Programme for Young Children with Disruptive Behaviours: Two-Year Follow-Up
Authors: Plath Debbie
Published: January 2018

Got It!is an early intervention programme for children with emerging conduct problems offered to families in schools. This article builds on prior research and reports on outcomes and experiences for a cohort of participants two years after programme completion. Strengths and Difficulties Questionnaire (SDQ) child conduct scores were obtained pre-intervention, and at three post-intervention time-points, and were used to map children's behaviour trajectories. Whilst statistically significant two-year post-intervention improvement was not found for the whole sample, qualitative parent interviews produced insights into experiences of children in different behaviour trajectory groups, including sustained improvement, no improvement and fluctuating child behaviour. The findings provide a better understanding of the role thatGot It!can play in assisting families with young children with conduct concerns. The targeted group intervention appears to have a lasting impact for children who maintain a shift from the abnormal to normal behaviour bands. For the group of children who began and remained in the abnormal or borderline bands, however,Got It!also had a role to play in linking families with specialist follow-up services. The integration ofGot It!within schools and the value of professional development and consultation for teachers is also indicated.
Barnacles, their molluscan hosts, and comparative ecology in the St. Mary’s Formation (late Miocene) of Maryland, USA
Authors: Vermeij Geerat J. , Ruch Sara K.
Published: January 2018

Fossils can inform the study of modern ecosystems by showing how species interactions in ancient communities compare with those today and how extinction is selective not only with respect to species but also with respect to entire modes of life. We studied the life habits and pattern of occurrence of the barnacleChesaconcavus chesapeakensisZullo, 1992 on the shells of the gastropodConradconfusus parilis(Conrad) and the bivalveChesapecten santamaria(Tucker) from Chancellor’s Point in the Windmill Point Member of the St. Mary’s Formation (late Miocene, Tortonian) of Maryland. Using several criteria, we show that the barnacle occupied living hosts only. The 59% incidence of the barnacle onConradconfusus parilisis high compared to known living associations between barnacles and gastropods. AlthoughConradconfusus pariliswith and without barnacles do not differ in size, suggesting that the barnacle had little effect on this gastropod, there is some indication thatChesapecten santamariawith barnacles are somewhat smaller than those without and may therefore have been adversely affected by the presence of barnacles. On the basis of morphology and the low (15%) incidence of repaired scars,Conradconfusus pariliswas a predator that did not use its shell lip to subdue prey. No ecological equivalents ofConradconfususandChesaconcavushave existed in the temperate northwestern Atlantic between Cape Cod and Cape Hatteras for the past three million years.
Undisciplined, selfish big babies? The cultural framing of the Italian financial crisis
Authors: Storti Luca , Dagnes Joselle , González Díez Javier
Published: January 2018

In the public debate played out in the media, the financial crisis in Italy is often depicted through a culturalist frame; the country’s difficulties are traced deterministically to an ethos, supposedly widespread among Italians, of amoral familism and a limited sense of civic engagement. This paper illustrates three issues that exemplify the country’s financial problems, and which are often seen through this type of culturalist lens: i) a lack of discipline in managing public finances; ii) a lack of interest in co-operation caused by the excessive importance given to family ties; iii) a lack of agency from the people involved, symbolised by a reluctance to leave home and to adopt an intense pace of work. Considering the relevant literature and various statistics, we show that a culturalist approach helps to spread a stereotyped and misleading view of these three issues. Instead, we suggest that a more accurate reading of the situation, and more stimulating when it comes to public debate, can be obtained by observing the way individuals adapt to the limitations and opportunities of the context in which they operate.
-CONTRACTIBILITY AND -CONNES AMENABILITY COINCIDE WITH SOME OLDER NOTIONS
Authors: MAHMOODI AMIN
Published: January 2018

It is shown that various definitions of $\unicode[STIX]{x1D711}$-Connes amenability and $\unicode[STIX]{x1D711}$-contractibility are equivalent to older and simpler concepts.
INFLUENCE OF THE NATIVE LANGUAGE ON SENSITIVITY TO LEXICAL STRESS
Authors: Segal Osnat , Kishon-Rabin Liat
Published: January 2018

Arabic stress is predictable, varies across words, and does not have a contrastive role, whereas, Hebrew stress although nonpredictable, carries contrastive value. Stress processing was assessed in speakers of the two languages at three processing levels: discrimination, short-term memory, and metalinguistic awareness. In Experiment 1, Arabic speakers with Hebrew as L2 (n = 15) and native Hebrew speakers (n = 15) were tested on discrimination and memory of stress placements. Arabic speakers had fewer correct responses and longer reaction times compared to Hebrew speakers. In Experiment 2, the influence of nonnative language acquisition on metalinguistic awareness of stress was assessed. Arabic speakers (n = 10) were less able to identify stress in their native and nonnative languages compared to Arabic speakers with advanced knowledge of English and Hebrew (n = 10) and Hebrew speakers (n = 10). Our findings support the assumption that variations in stress at the surface level of L1 are insufficient to facilitate awareness and memory for stress placement.
INCIDENTAL VOCABULARY ACQUISITION THROUGH VIEWING L2 TELEVISION AND FACTORS THAT AFFECT LEARNING
Authors: Peters Elke , Webb Stuart
Published: January 2018

Research has begun to demonstrate that L2 words can be learned incidentally through watching audio-visual materials. Although there are a large number of studies that have investigated incidental vocabulary learning through reading a single text, there are no studies that have explored incidental vocabulary learning through viewing a single full-length TV program. The present study fills this gap. Additionally, three word-related variables (frequency of occurrence, cognateness, word relevance) and one learner-related variable (prior vocabulary knowledge) that might contribute to incidental vocabulary learning were examined. Two experiments were conducted with Dutch-speaking EFL learners to measure the effects of viewing TV on form recognition and meaning recall (Experiment 1) and meaning recognition (Experiment 2). The findings showed that viewing TV resulted in incidental vocabulary learning at the level of meaning recall and meaning recognition. The research also revealed that learning was affected by frequency of occurrence, prior vocabulary knowledge, and cognateness.
Writing Groups as Models for Peer Mentorship among Female Faculty in Political Science
Authors: Cassese Erin C. , Holman Mirya R.
Published: January 2018

Women are underrepresented among political science faculty and leave academic careers at far greater rates than their male colleagues. Women’s lower research productivity is one reason for the declining number of women in advanced academic ranks. Mentoring can provide necessary advice and feedback to encourage scholarly production, but research shows that female scholars face challenges in traditional mentoring arrangements. We propose that peer mentoring can provide a missing link by supporting research productivity. Using a case study of an existing peer-mentoring group, we document how writing groups can provide flexible mechanisms for peer mentoring that circumvent the obstacles women face with mentoring and complement existing mentoring relationships. We discuss the structure of this group—as well as a survey-based assessment of it—to demonstrate how this approach can be readily adopted by other women in the profession who seek to expand their network of mentors to include peers in their subfield.
Lessons on Running a Laboratory Experiment (in Graduate School)
Authors: Mallinson Daniel J.
Published: January 2018

Experimentation has taken on a new life in political science. As the use of experimental methods proliferates, it is important for researchers to share their experiences and best practices, particularly with early-career researchers. This article provides reflections from practical experience in the laboratory, particularly geared toward graduate students and early-career researchers who are conducting their first laboratory experiment. These lessons do not apply only to first-time experimenters. Experiences are presented regarding time management, using confederates and deception, incentivizing participation, and keeping a laboratory notebook. Finally, early-career researchers are encouraged to “go for it” if the methods are appropriate to their research question.
WICKSELL ON WALRAS’S EARLY TREATMENT OF CAPITAL AND INTEREST
Authors: Imperia Andrea , Maffeo Vincenzo , Ravagnani Fabio
Published: January 2018

In this paper we examine the criticism that Knut Wicksell advanced against Léon Walras’s treatment of capital and interest at the end of the nineteenth century, as well as the views of two distinguished followers of Walras concerning the points raised by the Swedish economist. As regards the first aspect, it should be noted that the criticism put forward by Wicksell at that time refers to the earlier editions of the Éléments, in which circulating capital is excluded from the analysis. We thus endeavor to clarify Wicksell’s remarks on the consequences of that exclusion for both the representation of the social production process and the determination of the interest rate. As to the second aspect, our discussion indicates that the appropriate way of treating the capitalistic element of production was an unsettled issue within the small circle of Walras’s followers at the end of the nineteenth century.
COUPLE MICROSCALE PERIODIC PATCHES TO SIMULATE MACROSCALE EMERGENT DYNAMICS
Authors: ALOTAIBI HAMMAD , COX BARRY , ROBERTS A. J.
Published: January 2018

Macroscale “continuum” level predictions are made by a new way to construct computationally efficient “wrappers” around fine-scale, microscopic, detailed descriptions of dynamical systems, such as molecular dynamics. It is often significantly easier to code a microscale simulator with periodicity: so the challenge addressed here is to develop a scheme that uses only a given periodic microscale simulator; specifically, one for atomistic dynamics. Numerical simulations show that applying a suitable proportional controller within “action regions” of a patch of atomistic simulation effectively predicts the macroscale transport of heat. Theoretical analysis establishes that such an approach will generally be effective and efficient, and also determines good values for the strength of the proportional controller. This work has the potential to empower systematic analysis and understanding at a macroscopic system level when only a given microscale simulator is available.
White House Announces Choice to Head U.S. Geological Survey
Authors: Showstack Randy
Published: January 2018

Observers said the nominee appears to have strong credentials but voiced uncertainty about his management qualifications and noted the challenge of maintaining the agency’s strengths.
Genetic estimators of DNA methylation provide insights into the molecular basis of polygenic traits
Authors: Freytag Virginie , Vukojevic Vanja , Wagner-Thelen Holger , Milnik Annette , Vogler Christian , Leber Markus , Weinhold Leonie , Böhmer Anne C. , Riedel-Heller Steffi , Maier Wolfgang , de Quervain Dominique J.-F. , Ramirez Alfredo , Papassotiropoulos Andreas
Published: January 2018

The large biological distance between genetic risk loci and their mechanistic consequences in the tissue of interest limits the ability to establish functionality of susceptibility variants for genetically complex traits. Such a biological gap may be reduced through the systematic study of molecular mediators of genomic action, such as epigenetic modification. Here, we report the identification of robust genetic estimators of whole-blood CpG methylation, which can serve as intermediate molecular traits amenable to association testing with other genetically complex traits. We describe the relationship between these estimators and gene expression, demonstrate their genome-wide applicability to association testing even in the absence of individual genotypic data, and show that these estimators powerfully identify methylation-related genomic loci associated with polygenic traits and common diseases, such as schizophrenia. The use of genetic estimators for blood DNA methylation, which are made publically available, can serve as a valuable tool for the identification of epigenetic underpinnings of complex traits.
Dopamine, psychosis and schizophrenia: the widening gap between basic and clinical neuroscience
Authors: Kesby JP , Eyles DW , McGrath JJ , Scott JG
Published: January 2018

The stagnation in drug development for schizophrenia highlights the need for better translation between basic and clinical research. Understanding the neurobiology of schizophrenia presents substantial challenges but a key feature continues to be the involvement of subcortical dopaminergic dysfunction in those with psychotic symptoms. Our contemporary knowledge regarding dopamine dysfunction has clarified where and when dopaminergic alterations may present in schizophrenia. For example, clinical studies have shown patients with schizophrenia show increased presynaptic dopamine function in the associative striatum, rather than the limbic striatum as previously presumed. Furthermore, subjects deemed at high risk of developing schizophrenia show similar presynaptic dopamine abnormalities in the associative striatum. Thus, our view of subcortical dopamine function in schizophrenia continues to evolve as we accommodate this newly acquired information. However, basic research in animal models has been slow to incorporate these clinical findings. For example, psychostimulant-induced locomotion, the commonly utilised phenotype for positive symptoms in rodents, is heavily associated with dopaminergic activation in the limbic striatum. This anatomical misalignment has brought into question how we assess positive symptoms in animal models and represents an opportunity for improved translation between basic and clinical research. The current review focuses on the role of subcortical dopamine dysfunction in psychosis and schizophrenia. We present and discuss alternative phenotypes that may provide a more translational approach to assess the neurobiology of positive symptoms in schizophrenia. Incorporation of recent clinical findings is essential if we are to develop meaningful translational animal models.
Extended amygdala connectivity changes during sustained shock anticipation
Authors: Torrisi Salvatore , Gorka Adam X. , Gonzalez-Castillo Javier , O’Connell Katherine , Balderston Nicholas , Grillon Christian , Ernst Monique
Published: January 2018

The bed nucleus of the stria terminalis (BNST) and central amygdala (CeA) of the extended amygdala are small, anatomically interconnected brain regions. They are thought to mediate responses to sustained, unpredictable threat stimuli and phasic, predictable threat stimuli, respectively. They perform these operations largely through their interconnected networks. In two previous studies, we mapped and contrasted the resting functional connectivity networks of the BNST and CeA at 7 Tesla with high resolution. This follow-up study investigates the changes in functional connectivity of these structures during sustained anticipation of electric shock. Results show that the BNST and CeA become less strongly coupled with the ventromedial prefrontal cortex (vmPFC), cingulate, and nucleus accumbens in shock threat relative to a safety condition. In addition, the CeA becomes more strongly coupled with the thalamus under threat. An exploratory, whole-brain connectivity analysis reveals that, although the BNST/CeA exhibits generally decreased connectivity, many other cortical regions demonstrate greater coupling under threat than safety. Understanding the differential network structures of these two regions and how they contribute to processing under threat will help elucidate the building blocks of the anxious state.
Gs- versus Golf-dependent functional selectivity mediated by the dopamine D1 receptor
Authors: Yano Hideaki , Cai Ning-Sheng , Xu Min , Verma Ravi Kumar , Rea William , Hoffman Alexander F. , Shi Lei , Javitch Jonathan A. , Bonci Antonello , Ferré Sergi
Published: January 2018

The two highly homologous subtypes of stimulatory G proteins Gαs (Gs) and Gαolf (Golf) display contrasting expression patterns in the brain. Golf is predominant in the striatum, while Gs is predominant in the cortex. Yet, little is known about their functional distinctions. The dopamine D1 receptor (D1R) couples to Gs/olf and is highly expressed in cortical and striatal areas, making it an important therapeutic target for neuropsychiatric disorders. Using novel drug screening methods that allow analysis of specific G-protein subtype coupling, we found that, relative to dopamine, dihydrexidine and N-propyl-apomorphine behave as full D1R agonists when coupled to Gs, but as partial D1R agonists when coupled to Golf. The Gs/Golf-dependent biased agonism by dihydrexidine was consistently observed at the levels of cellular signaling, neuronal function, and behavior. Our findings of Gs/Golf-dependent functional selectivity in D1R ligands open a new avenue for the treatment of cortex-specific or striatum-specific neuropsychiatric dysfunction.
Ventromedial medulla inhibitory neuron inactivation induces REM sleep without atonia and REM sleep behavior disorder
Authors: Valencia Garcia Sara , Brischoux Frédéric , Clément Olivier , Libourel Paul-Antoine , Arthaud Sébastien , Lazarus Michael , Luppi Pierre-Hervé , Fort Patrice
Published: January 2018

Despite decades of research, there is a persistent debate regarding the localization of GABA/glycine neurons responsible for hyperpolarizing somatic motoneurons during paradoxical (or REM) sleep (PS), resulting in the loss of muscle tone during this sleep state. Combining complementary neuroanatomical approaches in rats, we first show that these inhibitory neurons are localized within the ventromedial medulla (vmM) rather than within the spinal cord. We then demonstrate their functional role in PS expression through local injections of adeno-associated virus carrying specific short-hairpin RNA in order to chronically impair inhibitory neurotransmission from vmM. After such selective genetic inactivation, rats display PS without atonia associated with abnormal and violent motor activity, concomitant with a small reduction of daily PS quantity. These symptoms closely mimic human REM sleep behavior disorder (RBD), a prodromal parasomnia of synucleinopathies. Our findings demonstrate the crucial role of GABA/glycine inhibitory vmM neurons in muscle atonia during PS and highlight a candidate brain region that can be susceptible to α-synuclein-dependent degeneration in RBD patients.
The effects of death and post-mortem cold ischemia on human tissue transcriptomes
Authors: Ferreira Pedro G. , Muñoz-Aguirre Manuel , Reverter Ferran , Sá Godinho Caio P. , Sousa Abel , Amadoz Alicia , Sodaei Reza , Hidalgo Marta R. , Pervouchine Dmitri , Carbonell-Caballero Jose , Nurtdinov Ramil , Breschi Alessandra , Amador Raziel , Oliveira Patrícia , Çubuk Cankut , Curado João , Aguet François , Oliveira Carla , Dopazo Joaquin , Sammeth Michael , Ardlie Kristin G. , Guigó Roderic
Published: January 2018

Post-mortem tissues samples are a key resource for investigating patterns of gene expression. However, the processes triggered by death and the post-mortem interval (PMI) can significantly alter physiologically normal RNA levels. We investigate the impact of PMI on gene expression using data from multiple tissues of post-mortem donors obtained from the GTEx project. We find that many genes change expression over relatively short PMIs in a tissue-specific manner, but this potentially confounding effect in a biological analysis can be minimized by taking into account appropriate covariates. By comparing ante- and post-mortem blood samples, we identify the cascade of transcriptional events triggered by death of the organism. These events do not appear to simply reflect stochastic variation resulting from mRNA degradation, but active and ongoing regulation of transcription. Finally, we develop a model to predict the time since death from the analysis of the transcriptome of a few readily accessible tissues.
Higher-generation type III-B rotaxane dendrimers with controlling particle size in three-dimensional molecular switching
Authors: Kwan Chak-Shing , Zhao Rundong , Van Hove Michel A. , Cai Zongwei , Leung Ken Cham-Fai
Published: January 2018

Type III-B rotaxane dendrimers (T3B-RDs) are hyperbranched macromolecules with mechanical bonds on every branching unit. Here we demonstrate the design, synthesis, and characterization of first to third (G1–G3), and up to the fourth (G4) generation (MW > 22,000 Da) of pure organic T3B-RDs and dendrons through the copper-catalyzed alkyne–azide cycloaddition (CuAAC) reaction. By utilizing multiple molecular shuttling of the mechanical bonds within the sphere-like macromolecule, a collective three-dimensional contract-extend molecular motion is demonstrated by diffusion ordered spectroscopy (DOSY) and atomic force microscopy (AFM). The discrete T3B-RDs are further observed and characterized by AFM, dynamic light scattering (DLS), and mass spectrometry (MS). The binding of chlorambucil and pH-triggered switching of the T3B-RDs are also characterized by 1H-NMR spectroscopy.
No evidence that carotenoid pigments boost either immune or antioxidant defenses in a songbird
Authors: Koch Rebecca E. , Kavazis Andreas N. , Hasselquist Dennis , Hood Wendy R. , Zhang Yufeng , Toomey Matthew B. , Hill Geoffrey E.
Published: January 2018

Dietary carotenoids have been proposed to boost immune system and antioxidant functions in vertebrate animals, but studies aimed at testing these physiological functions of carotenoids have often failed to find support. Here we subject yellow canaries (Serinus canaria), which possess high levels of carotenoids in their tissue, and white recessive canaries, which possess a knockdown mutation that results in very low levels of tissue carotenoids, to oxidative and pathogen challenges. Across diverse measures of physiological performance, we detect no differences between carotenoid-rich yellow and carotenoid-deficient white canaries. These results add further challenge to the assumption that carotenoids are directly involved in supporting physiological function in vertebrate animals. While some dietary carotenoids provide indirect benefits as retinoid precursors, our observations suggest that carotenoids themselves may play little to no direct role in key physiological processes in birds.
Publisher Correction: Non-invasive assessment of hepatic mitochondrial metabolism by positional isotopomer NMR tracer analysis (PINTA)
Authors: Perry Rachel J. , Peng Liang , Cline Gary W. , Butrico Gina M. , Wang Yongliang , Zhang Xian-Man , Rothman Douglas L. , Petersen Kitt Falk , Shulman Gerald I.
Published: January 2018

The originally published version of this Article contained an error in Equation 30, which was inadvertently introduced during the production process. This has now been corrected in the PDF and HTML versions of the Article.
Breast cancer risk factors and mammographic density among high-risk women in urban China
Authors: Sung Hyuna , Ren Jiansong , Li Jing , Pfeiffer Ruth M. , Wang Yong , Guida Jennifer L. , Fang Yi , Shi Jufang , Zhang Kai , Li Ni , Wang Shen , Wei Luopei , Hu Nan , Gierach Gretchen L. , Dai Min , Yang Xiaohong R. , He Jie
Published: January 2018

Elevated mammographic density (MD) is an established breast cancer risk factor. Studies examining relationships between MD and breast cancer risk factors are limited in China, where established breast cancer risk factors are less prevalent but dense breasts are more prevalent than Western countries. This study included 11,478 women (45-69 years; 36% premenopausal) participating in an ongoing national cancer screening program in 11 urban provinces in China and predicted as having high-risk for breast cancer. Polytomous logistic regression was performed to assess associations between MD and risk factors by comparing each higher Breast Imaging Reporting and Data System (BI-RADS) category (2, 3, or 4) to the lowest category (BI-RADS, 1). We found associations of increasing age, body mass index, weight, postmenopausal status, and parity with lower MD. Higher levels of education, increasing height, and later first birth were associated with higher MD. These associations did not vary by menopausal status. Additionally, the association between longer period of breastfeeding and lower MD was seen among postmenopausal women only (Pinteraction = 0.003). Having first-degree relatives with breast cancer diagnosed before 50 years was associated with lower MD only among premenopausal women (Pinteraction = 0.061). We found effects of established breast cancer risk factors on MD showed similar directions in Chinese and Western women, supporting the hypothesis that MD represents cumulative exposure to breast cancer risk factors over the life course. Our findings help to understand the biological basis of the association of MD with breast cancer risk and have implications for breast cancer prevention research in China.
Spatial and Temporal Characteristics of 2014 Dengue Outbreak in Guangdong, China
Authors: Sanna Mattia , Wu Jianyong , Zhu Yanshan , Yang Zhicong , Lu Jiahai , Hsieh Ying-Hen
Published: January 2018

The record-breaking number of dengue cases reported in Guangdong, China in 2014 has been topic for many studies. However, the spatial and temporal characteristics of this unexpectedly explosive outbreak are still poorly understood. We adopt an integrated approach to ascertain the spatial-temporal progression of the outbreak in each city in Guangdong as well as in each district in Guangzhou, where the majority of cases occurred. We utilize the Richards model, which determines the waves of reported cases at each location and identifies the turning point for each wave, in combination with a spatial association analysis conducted by computing the standardized G* statistic that measures the degree of spatial autocorrelation of a set of geo-referenced data from a local perspective. We found that Yuexiu district in Guangzhou was the initial hot spot for the outbreak, subsequently spreading to its neighboring districts in Guangzhou and other cities in Guangdong province. Hospital isolation of cases during early stage of outbreak in neighboring Zhongshan (in effort to prevent disease transmission to the vectors) might have played an important role in the timely mitigation of the disease. Integration of modeling approach and spatial association analysis allows us to pinpoint waves that spread the disease to communities beyond the borders of the initially affected regions.
Loss-of-function uORF mutations in human malignancies
Authors: Schulz Julia , Mah Nancy , Neuenschwander Martin , Kischka Tabea , Ratei Richard , Schlag Peter M. , Castaños-Vélez Esmeralda , Fichtner Iduna , Tunn Per-Ulf , Denkert Carsten , Klaas Oliver , Berdel Wolfgang E. , von Kries Jens P. , Makalowski Wojciech , Andrade-Navarro Miguel A. , Leutz Achim , Wethmar Klaus
Published: January 2018

Ribosome profiling revealed widespread translational activity at upstream open reading frames (uORFs) and validated uORF-mediated translational control as a commonly repressive mechanism of gene expression. Translational activation of proto-oncogenes through loss-of-uORF mutations has been demonstrated, yet a systematic search for cancer-associated genetic alterations in uORFs is lacking. Here, we applied a PCR-based, multiplex identifier-tagged deep sequencing approach to screen 404 uORF translation initiation sites of 83 human tyrosine kinases and 49 other proto-oncogenes in 308 human malignancies. We identified loss-of-function uORF mutations in EPHB1 in two samples derived from breast and colon cancer, and in MAP2K6 in a sample of colon adenocarcinoma. Both mutations were associated with enhanced translation, suggesting that loss-of-uORF-mediated translational induction of the downstream main protein coding sequence may have contributed to carcinogenesis. Computational analysis of whole exome sequencing datasets of 464 colon adenocarcinomas subsequently revealed another 53 non-recurrent somatic mutations functionally deleting 22 uORF initiation and 31 uORF termination codons, respectively. These data provide evidence for somatic mutations affecting uORF initiation and termination codons in human cancer. The insufficient coverage of uORF regions in current whole exome sequencing datasets demands for future genome-wide analyses to ultimately define the contribution of uORF-mediated translational deregulation in oncogenesis.