bluuebunny/crossref_metadata_2025 huggingface dataset:
Communication: Molecular-level description of constrained chain topologies in multiblock copolymer gel networks
Authors: Tuhin Mohammad O. , Woloszczuk Sebastian , Mineart Kenneth P. , Pasquinelli Melissa A. , Sadler J. David , Smith Steven D. , Banaszak Michal , Spontak Richard J.
Published: June 2018

Network characteristics in physical gels composed of solvated block copolymers varying in molecular design are examined here by dynamic rheology and computer simulations. In two triblock copolymer series, one with chain length (N) varied at constant copolymer composition (f) and the other with f varied at constant N, we discern the dependence of equilibrium network metrics on both N and f. Increasing the block number in a linear multiblock series at constant N and f escalates conformational complexity, which dominates network connectivity classified according to a midblock conformation index.
Titanium-hydrogen interaction at high pressure
Authors: Mazitov Arslan B. , Oganov Artem R. , Yanilkin Alexey V.
Published: June 2018

The process of transport of metal particles (ejecta) in gases is the subject of recent works in the field of nuclear energetics. We studied the process of dissolution of titanium ejecta in warm dense hydrogen at hundred GPa pressure. Thermodynamic and kinetic properties of the process were investigated using classical and quantum molecular dynamics methods. We estimated the dissolution time of ejecta, the saturation limit of titanium atoms with hydrogen, and the heat of dissolution. It was found that particles with a radius of 1 μm dissolve in hydrogen in a time of 1.5×10−2 μs, while the process of mixing can be described by diffusion law. The presented approach demonstrates the final state of the titanium-hydrogen system as a homogenized fluid with completely dissolved titanium particles. This result can be generalized to all external conditions under which titanium and hydrogen are atomic fluids.
Energy and protein requirements of crossbred Holstein × Gyr calves fed commercial milk replacer and amino acid supplement
Authors: Chagas J. C. C. , Ferreira M. A. , Campos M. M. , Machado F. S. , Silva L. C. , Faciola A. , Marcondes M. I.
Published: June 2018

This experiment aimed to estimate the energy and protein requirements for Holstein × Gyr calves up to 60 days of age fed with milk replacer and amino acid supplement. Fifty male calves were used, of which seven were randomly allocated into the reference group and slaughtered at 8 days of age, seven were randomly allocated into the maintenance group slaughtered at 30 days of age, and the 36 remaining calves were included in the experiment at 8 days of age and randomly supplied with four dietary methionine+cysteine:lysine ratios (RMCL; 44%, 48%, 52%, and 56%) through amino acid supplement added as 1 kg/day of milk replacer reconstituted at 13.8% of dry matter. Different RMCL were tested for the models, and there were no significant effects on energy and protein requirements. The net energy requirement for maintenance was 75.2 kcal/empty bodyweight (EBW)0.75.day, with an energy use efficiency for maintenance of 67.38%. The prediction equation of net energy requirement for gain (Mcal/day) was energy retained = 0.0879 × EBW0.75 × empty bodyweight gain (EBWG)0.7580, with an energy use efficiency for gain of 47.57%. The estimated requirements for metabolisable protein for maintenance were 4.83 g/EBW0.75.day. The estimated equation for net protein requirements for gain (g/day) was NPg = EBWG × 246.73 × EBW–0.1204, with a protein use efficiency for gain of 71.55%. The estimated requirements for energy and proteins were greater than the values reported for calves fed with milk. Milk replacers are less efficiently used by calves up to 60 days of age when compared with whole milk.
Inflamed neutrophils sequestered at entrapped tumor cells via chemotactic confinement promote tumor cell extravasation
Authors: Chen Michelle B. , Hajal Cynthia , Benjamin David C. , Yu Cathy , Azizgolshani Hesham , Hynes Richard O. , Kamm Roger D.
Published: June 2018

Significance

Systemic inflammation that occurs during the course of tumor treatment is often correlated with adverse oncological outcomes independent of the infectious insult. As the first line of defense against infection, it is likely that neutrophils play an important role in modulating the progression of distant metastases in these scenarios. This study uses a multiplexed microfluidic model of human microcirculation combined with LPS-stimulated neutrophils as a model of systemic infection to probe the dynamic interactions between intravascular tumor cells and neutrophils at high spatiotemporal resolutions. We uncover chemokine-dependent neutrophil migration patterns which result in enhanced tumor cell extravasation rates. These findings may provide a basis for inhibiting the proextravasation and possibly prometastatic effect of inflamed neutrophils.
Genomic organization underlying deletional robustness in bacterial metabolic systems
Authors: Hosseini Sayed-Rzgar , Wagner Andreas
Published: June 2018

Significance

From the organismal and the anatomical levels down to the molecular level, all complex biological systems manifest astonishing organization and order that are counterintuitive and challenging to explain by evolutionary mechanisms. In this study, we focus specifically on one aspect of this biological organization: the arrangement of metabolic genes in bacterial genomes. We show that this organization ensures a substantially higher robustness to large-scale gene deletions than expected from random genomic ordering. We systematically investigate the possible evolutionary mechanisms behind the emergence of such robust organizations. Our analysis provides several lines of evidence indicating that bacteria may have gained a robust genome organization through pervasive gene loss events.
Serine metabolism in the brain regulates starvation-induced sleep suppression in
Drosophila melanogaster
Authors: Sonn Jun Young , Lee Jongbin , Sung Min Kyung , Ri Hwajung , Choi Jung Kyoon , Lim Chunghun , Choe Joonho
Published: June 2018

Significance

Foraging and sleep are two conflicting behaviors in starved animals; however, it remains elusive how metabolic status governs sleep drive. In this study, we show that a biosynthetic pathway for the amino acid serine is transcriptionally up-regulated by starvation in adult fly brains. The behavioral response to genetic manipulation of key enzymes involved in serine metabolism supports the sleep-suppressing effect of serine in response to starvation. In a society where daily diet is becoming increasingly important to the sleep quality of individuals, our study defines an amino acid metabolic pathway that underlies adaptive sleep behaviors upon dietary stress.
Nonlocal supercurrent of quartets in a three-terminal Josephson junction
Authors: Cohen Yonatan , Ronen Yuval , Kang Jung-Hyun , Heiblum Moty , Feinberg Denis , Mélin Régis , Shtrikman Hadas
Published: June 2018

Significance

In this work we present detailed studies of a nondissipative current, called “quartet supercurrent,” where two distinct Cooper pairs, originating in different terminals, recombine into a four-electron quasiparticle: a quartet. Employing conductance measurements and highly sensitive cross-correlation of current fluctuation, we identified the existence of such a coherent nonlocal state.
Decimation by sea star wasting disease and rapid genetic change in a keystone species,
Pisaster ochraceus
Authors: Schiebelhut Lauren M. , Puritz Jonathan B. , Dawson Michael N
Published: June 2018

Significance

Opportunities to study microevolution in wild populations are rare and challenging. Annual monitoring allowed us to capture both the prelude to and aftermath of one of the largest marine mass mortality events on record in a keystone marine species. Median mortality of 81% across populations was recorded along with significant allele frequency shifts at multiple loci in the adult population. Shifts were consistent across locations and also occurred in new recruits, with few exceptions. These results indicate a long-term species-wide change in allele frequencies will persist through future generations. Population genomic monitoring, at a time when marine diseases and mass mortalities are on the rise, will be essential for documenting rapid genetic shifts in response to chronic and extreme events.
Crystal structures of a [NiFe] hydrogenase large subunit HyhL in an immature state in complex with a Ni chaperone HypA
Authors: Kwon Sunghark , Watanabe Satoshi , Nishitani Yuichi , Kawashima Takumi , Kanai Tamotsu , Atomi Haruyuki , Miki Kunio
Published: June 2018

Significance

The large subunit of [NiFe] hydrogenase undergoes Ni insertion into the active site by the Ni chaperone HypA during its posttranslational process (maturation process). However, the detailed mechanism of the Ni insertion has been elusive. Here, we report the structures of an immature large subunit HyhL in complex with HypA, which enable us to infer a series of conformational changes involved in the Ni delivery. The structures show that the N-terminal tail of HyhL interacts with the Ni-binding domain of HypA. Structural comparison of the immature large subunit HyhL with a mature one reveals that the Ni insertion may induce spatial rearrangement of the N- and C-terminal tails of HyhL.
Dye-sensitized photoelectrochemical water oxidation through a buried junction
Authors: Xu Pengtao , Huang Tian , Huang Jianbin , Yan Yun , Mallouk Thomas E.
Published: June 2018

Significance

Artificial photosynthetic systems use molecular light absorbers to convert sunlight into useful chemical fuels such as hydrogen, methanol, or ammonia. A key bottleneck in these systems is the oxidation of water to produce O
2
. This anodic reaction occurs under strongly oxidizing conditions that result in damage to organic dyes, electron relays, and catalyst molecules. Here we show that encapsulation of the molecular components of a solid-state dye-sensitized solar cell by a 2-nm-thick coating of TiO
2
dramatically improves cell stability under water-splitting conditions. The physical separation of the dye from the solution in which the water-splitting reaction takes place enables the use of dyes that efficiently absorb in the visible and allows optimization of the pH of catalytic water oxidation.
Multiple feedback loops of the Arabidopsis circadian clock provide rhythmic robustness across environmental conditions
Authors: Shalit-Kaneh Akiva , Kumimoto Roderick W. , Filkov Vladimir , Harmer Stacey L.
Published: June 2018

Significance

While all eukaryotic circadian clocks depend on transcriptional feedback loops, the plant circadian network is uniquely complex. An apparent redundancy in the plant clock is two types of transcription factors that antagonistically regulate common target genes. Here, we show that, although loss of either repressor- or activator-type factors perturbs clock pace and plant development, simultaneous loss of both types of factors restores near–wild-type development and largely rescues circadian period and phase phenotypes at ambient temperatures. However, in the higher-order mutant, rhythmic amplitude is reduced under optimal temperature, and rhythmicity is lost at low or high temperatures within the physiologically relevant range. Our data suggest that the multiple feedback loops of the plant clock help ensure rhythmicity under adverse environmental conditions.
The complexities of written Chinese and the cognitive-linguistic precursors to reading, with consequent implications for reading interventions
Authors: Kalindi Sylvia Chanda , Chung Kevin Kien Hoa , Liu Duo Phil , Wang Li-Chih Angus
Published: June 2018

This chapter will review universal and unique cognitive-linguistic precursors to reading acquisition and impairment, such as reading disabilities and dyslexia, in the Chinese language. The chapter will examine research evidence linking phonological awareness, morphological awareness, orthographic awareness, rapid automatized naming (RAN), and visual skills to reading acquisition among children in mainland China, Hong Kong, and Taiwan. Understanding these cognitive-linguistic constructs and their mechanisms underlying reading acquisition is essential in order to explain reading impairment. Compared to dyslexic children of alphabetic languages, Chinese children with dyslexia present different and often multiple profiles of cognitive-linguistic deficits, the most dominant being RAN, orthographic awareness, and morphological awareness and the less dominant being phonological awareness. In particular, the review will examine the causes, characteristics, uniqueness or idiosyncrasies found in speakers of Chinese, and consequences of dyslexia in children in the three Chinese societies. Such a review will offer insight into and lay foundations for developing effective evidence-based interventions for children with reading impairment both inside and outside of school. Implications for current evidence-based practices in interventions are also discussed.
Brain mechanisms of Chinese word reading
Authors: Cao Fan
Published: June 2018

Research on Chinese reading provides important insights into the understanding of language-universal and script-specific mechanisms of reading, because Chinese is contrastively different from alphabetic languages. In this chapter, I will first summarize neuroimaging findings of Chinese word reading in adults in comparison to English word reading. Then, I will discuss how the brain adapts to one’s language with learning and development. Then, I will focus on the topic of second language learning, including how one brain processes Chinese and English in bilinguals, how first language influences second language learning, and whether there are different optimal learning methods for different second languages. This chapter will address these important questions based on neuroimaging studies.
Compliments and Positive Assessments
Authors: Strubel-Burgdorf Susanne
Published: June 2018

Compliments are among the most widely studied speech acts in pragmatics. The present study takes a new sequential approach by investigating compliments in context, considering compliment form, as part of a Positive Remark continuum, with the respective Response Strategy uttered in response. Analyzed quantitatively and qualitatively in multi-party conversations of the Santa Barbara Corpus of American English, the sequences suggest a connection between the address and reference terms in the Positive Remarks and the strategies chosen as a response.
Loan verbs in Egyptian Arabic
Authors: Hassan Ashraf F.
Published: June 2018

This paper will explain the strategies of loan verbs integration in Egyptian Arabic (EA). As a recipient language, EA adopts
two strategies: (a) insertion with ‘Light Verb Strategy’; and (b) Direct Insertion either with or without ‘Reduction to
Root.’

While direct insertion strategy without ‘reduction to root’ is used almost exclusively for imperative loan verbs, the same
strategy with ‘reduction to root’ is open to any ‘input form’. To each loan verb EA assigns a root and the loan verb assumes
one of the EA verbal forms.

An investigation of new loan verbs passed to EA through Social Media, while they are being integrated, gives us further
insight, and therefore a better understanding, into the integration process of loan verbs in general.
Gender difference in higher education in Ethiopia: a case of Addis Ababa University (AAU)
Authors: Kassie Kitaw
Published: June 2018

This study intends to indicate the extent of gender disparity; compare gender gap in science and engineering with that of social science and health fields; and explore the reasons for gender gap in Addis Ababa University (AAU). It employed a mixed design, using document analysis for collecting quantitative data regarding the extent of disparity and using interview for collecting qualitative data regarding the reasons for disparity. Quantitative data were analyzed using percentages while qualitative data were analyzed using thematic analysis. Accordingly, the study showed that the gender gap in enrolments, in graduates, and in honours lists in the last five years remains wide in favour of males. Females’ underrepresentation was worse in science and engineering fields. Moreover, females’ educational attainment was lower as compared to males; and their attainment in science and engineering fields was lower than that in social science fields. It appears that females’ underrepresentation in the university in general and in science and engineering fields in particular is attributable to different factors rooted in social and cultural norms and practices.
The disappearance of bromuconazole fungicide in domestic waste anaerobic fermentation
Authors: Hariyadi H R
Published: June 2018

A previous study recommended observing degradation of bromuconazole in waste anaerobic fermentation. This research, therefore, was carried out to study the disappearance of bromuconazole in waste anaerobic fermentation. Bromuconazole is a fungicide which is effective against Ascomycetes, Basidiomycetes and fungi imperfecti in cereals, grapes, top fruits and vegetables. It is also effective against Alternaria and Fusarium sp. In this study, one-month old refuse added with bromuconazole was anaerobically incubated in the 500 ml bottles at 30°C with no shaking in the dark room. Bromuconazole with total concentration of 200 mg/L was added in day 0 and 31. As a control, a bottle with refuse and bromuconazole at concentration of 200 mg/L was autoclaved and incubated at the same condition. High-performance Liquid Chromatography with UV detector and a 100 RP18 5µm Lichrosphere column was used to determine bromuconazole concentration. Methane content was determined by Gas Chromatography method equipped with a flame ionization detector and a metal column packed with 5% neopentyl glycol sebacate and 1% H3PO4 on Chromosorb W-AW (mesh 80-100). The disappearance of bromuconazole in anaerobic enrichments can be observed from mass balance determination after incubation for 225 days. The result showed that there was no change in bromuconazole mass balance. Bromuconazole was mostly adsorbed by the refuse. Bromuconazole inhibited the production of methane (99.58 mM), less than that of the control bottle with no added bromuconazole (121.78 mM). This phenomenon indicated the persistence of bromuconazole and its toxicity against methanogen bacterial activity. The presence of bromuconazole in the anaerobic process caused the refuse to be imperfectly fermented and so the production of methane was inhibited and volatile fatty acids were accumulated. Accumulation of the volatile fatty acids may cause further pollution in aquatic environment around the landfills site.
The future of Heritage Science and Technologies from a legal point of view
Authors: Segnalini S.
Published: June 2018

The development and the prospect of future cultural heritage should certainly be confronted with the development of new technologies applied to the arts which, from a legal point of view, implies mainly three important aspects.

1.
Copyrights for software
: this seems to be the least interesting for the jurists as many aspects have already been addressed and solved, and therefore on will just quickly list some of them. In fact the copyright explicitely protects the software as work of wit and consequently it is clear that the author is the dominus of his creation in the sense that he is the only person who can decide how to allow other people use his software. So f.e. the relationship between the copyright legislation and open source is actually less difficult than it maybe thought. In addition open source use is fully regulated by Law no. 633/1941 (so called “legge sul diritto d’autore”) which guarantees its proper use.

2.
Legal issues related to the so-called BIM technology
: Building Information Modelling (BIM) is a software for plannig and implementing building projects based on 3D modeling of buildings or structures models. The BIM has already been adopted internationally for the realization of major project and one of the most exciting challenges for a lawyer is to develop a specific BIM contract for the particular field of art and cultural heritage.

3.
Legal issues related to artificial intelligence
: this certainly represents a field yet to be discovered by jurists and here I will present a series of legal concerns that will engage jurists in the coming years. Such as responsibility and ethics of artificial intelligence. For the above-mentioned considerations, the European Parliament’s Legal Affairs Committee approved a report calling on the European Commission to introduce a set of regulations on robotics.
RiboSketch: versatile visualization of multi-stranded RNA and DNA secondary structure
Authors: Lu Jacob S , Bindewald Eckart , Kasprzak Wojciech K , Shapiro Bruce A
Published: June 2018

Creating clear, visually pleasing 2D depictions of RNA and DNA strands and their interactions is important to facilitate and communicate insights related to nucleic acid structure. Here we present RiboSketch, a secondary structure image production application that enables the visualization of multistranded structures via layout algorithms, comprehensive editing capabilities, and a multitude of simulation modes. These interactive features allow RiboSketch to create publication quality diagrams for structures with a wide range of composition, size and complexity. The program may be run in any web browser without the need for installation, or as a standalone Java application.

Availability and implementation

https://rnastructure.cancer.gov/ribosketch
BioStructMap: a Python tool for integration of protein structure and sequence-based features
Authors: Guy Andrew J , Irani Vashti , Richards Jack S , Ramsland Paul A
Published: June 2018

A sliding window analysis over a protein or genomic sequence is commonly performed, and we present a Python tool, BioStructMap, that extends this concept to three-dimensional (3D) space, allowing the application of a 3D sliding window analysis over a protein structure. BioStructMap is easily extensible, allowing the user to apply custom functions to spatially aggregated data. BioStructMap also allows mapping of underlying genomic sequences to protein structures, allowing the user to perform genetic-based analysis over spatially linked codons—this has applications when selection pressures arise at the level of protein structure.

Availability and implementation

The Python BioStructMap package is available at https://github.com/andrewguy/biostructmap and released under the MIT License. An online server implementing standard functionality is available at https://biostructmap.burnet.edu.au.

Supplementary information

Supplementary data are available at Bioinformatics online.
panISa: ab initio detection of insertion sequences in bacterial genomes from short read sequence data
Authors: Treepong Panisa , Guyeux Christophe , Meunier Alexandre , Couchoud Charlotte , Hocquet Didier , Valot Benoit
Published: June 2018

Motivation

The advent of next-generation sequencing has boosted the analysis of bacterial genome evolution. Insertion sequence (IS) elements play a key role in prokaryotic genome organization and evolution, but their repetitions in genomes complicate their detection from short-read data.

Results

PanISa is a software pipeline that identifies IS insertions ab initio in bacterial genomes from short-read data. It is a highly sensitive and precise tool based on the detection of read-mapping patterns at the insertion site. PanISa performs better than existing IS detection systems as it is based on a database-free approach. We applied it to a high-risk clone lineage of the pathogenic species Pseudomonas aeruginosa, and report 43 insertions of five different ISs (among which three are new) and a burst of ISPa1635 in a hypermutator isolate.

Availability and implementation

PanISa is implemented in Python and released as an open source software (GPL3) at https://github.com/bvalot/panISa.

Supplementary information

Supplementary data are available at Bioinformatics online.
The ancestral KH peptide at the root of a domain family with three different folds
Authors: Pereira Joana , Lupas Andrei N
Published: June 2018

Motivation

The direct ancestor of the DNA-protein world of today is considered to have been an RNA-peptide world, in which peptides were co-factors of RNA-mediated catalysis and replication. Evidence for these ancestral peptides, from which folded proteins evolved, can be derived even today from regions of local sequence similarity within globally dissimilar folds. One of these is the 45-residue motif common to both folds of the hnRNP K homology (KH) domain.

Results

In a survey of KH domains, we found a third fold that contains the KH motif at its core. This corresponds to the Small Domain of bacterial Ribonucleases G/E and, like type I and type II KH domains, it cannot be related to the others by a single genetic event, providing further support for the KH motif as an ancestral peptide predating folded proteins.

Supplementary information

Supplementary data are available at Bioinformatics online.
Accurate prediction of protein contact maps by coupling residual two-dimensional bidirectional long short-term memory with convolutional neural networks
Authors: Hanson Jack , Paliwal Kuldip , Litfin Thomas , Yang Yuedong , Zhou Yaoqi
Published: June 2018

Motivation

Accurate prediction of a protein contact map depends greatly on capturing as much contextual information as possible from surrounding residues for a target residue pair. Recently, ultra-deep residual convolutional networks were found to be state-of-the-art in the latest Critical Assessment of Structure Prediction techniques (CASP12) for protein contact map prediction by attempting to provide a protein-wide context at each residue pair. Recurrent neural networks have seen great success in recent protein residue classification problems due to their ability to propagate information through long protein sequences, especially Long Short-Term Memory (LSTM) cells. Here, we propose a novel protein contact map prediction method by stacking residual convolutional networks with two-dimensional residual bidirectional recurrent LSTM networks, and using both one-dimensional sequence-based and two-dimensional evolutionary coupling-based information.

Results

We show that the proposed method achieves a robust performance over validation and independent test sets with the Area Under the receiver operating characteristic Curve (AUC) > 0.95 in all tests. When compared to several state-of-the-art methods for independent testing of 228 proteins, the method yields an AUC value of 0.958, whereas the next-best method obtains an AUC of 0.909. More importantly, the improvement is over contacts at all sequence-position separations. Specifically, a 8.95%, 5.65% and 2.84% increase in precision were observed for the top L∕10 predictions over the next best for short, medium and long-range contacts, respectively. This confirms the usefulness of ResNets to congregate the short-range relations and 2D-BRLSTM to propagate the long-range dependencies throughout the entire protein contact map ‘image’.

Availability and implementation

SPOT-Contact server url: http://sparks-lab.org/jack/server/SPOT-Contact/.

Supplementary information

Supplementary data are available at Bioinformatics online.
Participatory planning in a low-income neighbourhood in Ontario, Canada: building capacity and collaborative interactions for influence
Authors: Nasca Tessa F , Changfoot Nadine , Hill Stephen D
Published: June 2018

This research evaluated a community-led participatory planning process that sought to involve citizens who are often marginalized within planning processes. Participatory planning – which is theoretically informed by communicative planning theory – may shift the legacy of power and marginalization within planning processes and improve planning outcomes, foster social cohesion, and enhance the quality of urban life. The two-year Stewart Street Active Neighbourhoods Canada (ANC) project aimed to build capacity among residents of a low-income neighbourhood in Peterborough, Ontario and to influence City planning processes impacting the neighbourhood. The project, led by a community-based organization, GreenUP, fostered collaborative interactions between residents and planning experts and supported residents to build and leverage collective power within planning processes. The participatory planning approach applied in the Stewart Street ANC transformed – and at times unintentionally reproduced – inequitable power relations within the planning process. Importantly, we found that GreenUP was a vital power broker between marginalized residents and more formal power holders, and successfully supported residents to voice their collective visions within professionalized planning contexts.
Dialogues on the Threshold: Dialogical Learning for Humanism and Justice
Authors: Kumagai Arno K. , Richardson Lisa , Khan Sarah , Kuper Ayelet
Published: June 2018

Given the constant pressures of overflowing clinics, hospital wards, and emergency departments; shortened duty hours; and increased accreditation requirements, overburdened clinician teachers ask, “How does one teach for humanism and justice?” How does one step away—even momentarily—and focus teaching on the individual in front of us, the person who requires our attention and care? This approach must not only involve content (the patient’s perspective of illness, social context, and life story) but also must be tightly linked with the ways in which these lessons in living are learned and taught. In this article, the authors propose recognition and use of a style of communication that is already implicitly present in clinical conversations and that is uniquely capable of stimulating reflection on the human dimensions of medicine: that of dialogue.

Dialogue involves committing one’s whole self to communicative exchange and emphasizes interpersonal relationships and trust. Its result is often not a specific answer; rather, it is enhanced understanding through the generation of new questions and possibilities and action in implementing solutions. It requires a reorientation of the teacher–learner relationship from top-down to one of open exchange and shared authority and responsibility. In the context of professional identity development, these conversations become dialogues on the threshold of transformative change. Through an exploration of dialogical teaching, the authors envision clinical education as constantly stepping in and out of goal-oriented discussions and reflective dialogues, all with the overall goal to educate physicians who practice with excellence, compassion, and justice.
Mitochondrial replacement therapy
Authors: Dougherty Michael P. , Dolitsky Shelley , Chattopadhyay Rhea , Sauer Mark V.
Published: June 2018

Purpose of review

The present study briefly reviews the history of mitochondrial replacement therapy (MRT); however, the focus is on recent advancements and future directions of the field. Specifically addressing societal and legal concerns and advances in MRT.

Recent findings

There continue to be new ethical debates surrounding MRT. In addition, there have been advancements in MRT techniques which could improve potential outcomes. Furthermore, advances in genetics continue to provide alternative approaches to treatment of many diseases, including alternatives to MRT.

MRT may be beneficial to eradicate a severely debilitating and often fatal disease. Despite significant supporting safety and efficacy, there are still many social and legal barriers to instituting MRT to clinical practice.
Language is more abstract than you think, or, why aren't languages more iconic?
Authors: Lupyan Gary , Winter Bodo
Published: June 2018

How abstract is language? We show that abstractness pervades every corner of language, going far beyond the usual examples of
freedom
and
justice
. In the light of the ubiquity of abstract words, the need to understand where abstract meanings come from becomes ever more acute. We argue that the best source of knowledge about abstract meanings may be language itself. We then consider a seemingly unrelated question: Why isn't language more iconic? Iconicity—a resemblance between the form of words and their meanings—can be immensely useful in language learning and communication. Languages could be much more iconic than they currently are. So why aren't they? We suggest that one reason is that iconicity is inimical to abstraction because iconic forms are too connected to specific contexts and sensory depictions. Form–meaning arbitrariness may allow language to better convey abstract meanings.

This article is part of the theme issue ‘Varieties of abstract concepts: development, use and representation in the brain’.
Approach motivation in human cerebral cortex
Authors: Brookshire Geoffrey , Casasanto Daniel
Published: June 2018

Different regions of the human cerebral cortex are specialized for different emotions, but the principles underlying this specialization have remained unknown. According to thesword and shield hypothesis, hemispheric specialization for affective motivation, a basic dimension of human emotion, varies across individuals according to the way they use their hands to perform approach- and avoidance-related actions. In a test of this hypothesis, here we measured approach motivation before and after five sessions of transcranial direct current stimulation to increase excitation in the left or right dorsolateral prefrontal cortex, in healthy adults whose handedness ranged from strongly left-handed to strongly right-handed. The strength and direction of participants' handedness predicted whether electrical stimulation to frontal cortex caused an increase or decrease in their experience of approach-related emotions. The organization of approach motivation in the human cerebral cortex varies across individuals as predicted by the organization of the individuals’ motor systems. These results show that the large-scale cortical organization of abstract concepts corresponds with the way people use their hands to interact with the world. Affective motivation may re-use neural circuits that evolved for performing approach- and avoidance-related motor actions.

This article is part of the theme issue ‘Varieties of abstract concepts: development, use and representation in the brain’.
Whole genome sequencing of Neisseria meningitidis W isolates from the Czech Republic recovered in 1984 – 2017
Authors: Honskus Michal , Okonji Zuzana , Musilek Martin , Kozakova Jana , Krizova Pavla
Published: June 2018

Introduction

The study presents the analysis of whole genome sequence (WGS) data for Neisseria meningitidis serogroup W isolates recovered in the Czech Republic in 1984 – 2017 and their comparison with WGS data from other countries.

Material and Methods

Thirty-one Czech N. meningitidis W isolates, 22 from invasive meningococcal disease (IMD) and nine from healthy carriers were analysed. The 33-year study period was divided into three periods: 1984-1999, 2000-2009, and 2010-2017.

Results

Most study isolates from IMD and healthy carriers were assigned to clonal complex cc22 (n = 10) in all study periods. The second leading clonal complex was cc865 (n = 8) presented by IMD (n = 7) and carriage (n = 1) isolates that emerged in the last study period, 2010 – 2017. The third clonal complex was cc11 (n = 4) including IMD isolates from the first (1984 – 1999) and third (2010 – 2017) study periods. The following clonal complex was cc174 (n = 3) presented by IMD isolates from the first two study periods, i.e. 1984 – 1999 and 2000 – 2009. One isolate of each cc41/44 and cc1136 originated from healthy carriers from the second study period, 2000 - 2009. The comparison of WGS data for N. meningitidis W isolates recovered in the Czech Republic in the study period 1984 – 2017 and for isolates from other countries recovered in the same period showed that clonal complex cc865, ST-3342 is unique to the Czech Republic since 2010. Moreover, the comparison shows that cc11 in the Czech Republic does not comprise novel hypervirulent lineages reported from both European and non-European countries. WGS data for Czech serogroup W meningococci point to the presence of MenB vaccine antigen genes and confirm the hypothesis about the MenB vaccine potential against N. meningitidis serogroup W. All 31 study isolates were assigned to Bexsero® Antigen Sequence Types (BAST), and seven of them were of newly described BASTs.

Conclusions

WGS analysis contributed considerably to a more detailed molecular characterization of N. meningitidis W isolates recovered in the Czech Republic over a 33-year period and allowed for a spatial and temporal comparison of these characteristics between isolates from the Czech Republic and other countries. In addition, the WGS data precised the base for the update of the recommendation for vaccination in the Czech Republic.
Computational evidence of a new allosteric communication pathway between active sites and putative regulatory sites in the alanine racemase ofMycobacterium tuberculosis
Authors: Jyothikumar Jayanthy , Chandani Sushil , Ramakrishna Tangirala
Published: June 2018

Alanine racemase, a popular drug target fromMycobacterium tuberculosis, catalyzes the biosynthesis of D-alanine, an essential component in bacterial cell walls. With the help of elastic network models of alanine racemase fromMycobacterium tuberculosis, we show that the mycobacterial enzyme fluctuates between two undiscovered states—a closed and an open state. A previous experimental screen identified several drug-like lead compounds against the mycobacterial alanine racemase, whose inhibitory mechanisms are not known. Docking simulations of the inhibitor leads onto the mycobacterial enzyme conformations obtained from the dynamics of the enzyme provide first clues to a putative regulatory role for two new pockets targeted by the leads. Further, our results implicate the movements of a short helix, behind the communication between the new pockets and the active site, indicating allosteric mechanisms for the inhibition. Based on our findings, we theorize that catalysis is feasible only in the open state. The putative regulatory pockets and the enzyme fluctuations are conserved across several alanine racemase homologs from diverse bacterial species, mostly pathogenic, pointing to a common regulatory mechanism important in drug discovery.

Author summary

In spite of the discovery of many inhibitors against the TB-causing pathogenMycobacterium tuberculosis, only a very few have reached the market as effective TB drugs. Most of the marketed TB drugs induce toxic side effects in patients, as they non-specifically target human cells in addition to pathogens. One such TB drug, D-cycloserine, targets pyridoxal phosphate moiety non-specifically regardless of whether it is present in the pathogen or the human host enzymes. D-cycloserine was developed to inactivate alanine racemase in TB causing pathogen. Alanine racemase is a bacterial enzyme essential in cell wall synthesis. Serious side effects caused by TB drugs like D-cycloserine, lead to patients’ non-compliance with treatment regimen, often causing fatal outcomes. Current drug discovery efforts focus on finding specific, non-toxic TB drugs. Through computational studies, we have identified new pockets on the mycobacterial alanine racemase and show that they can bind drug-like compounds. The location of these pockets away from the pyridoxal phosphate-containing active site, make them attractive target sites for novel, specific TB drugs. We demonstrate the presence of these pockets in alanine racemases from several pathogens and expect our findings to accelerate the discovery of non-toxic drugs against TB and other bacterial infections.
DrosophilaIMP regulates Kuzbanian to control the timing of Notch signalling in the follicle cells
Authors: Fic Weronika , Faria Celia , Johnston Daniel St
Published: June 2018

The timing ofDrosophilaegg chamber development is controlled by a germline Delta signal that activates Notch in the follicle cells to induce them to cease proliferation and differentiate. Here we report that follicle cells lacking the RNA-binding protein IMP go through one extra division due to a delay in the Delta-dependent S2 cleavage of Notch. The timing of Notch activation has previously been shown to be controlled by cis-inhibition by Delta in the follicle cells, which is relieved when the miRNA pathway represses Delta expression.impmutants are epistatic toDeltamutants and give an additive phenotype withbelleanddicermutants, indicating that IMP functions independently of both cis-inhibition and the miRNA pathway. We find that theimpphenotype is rescued by over-expression of Kuzbanian, the metalloprotease that mediates the Notch S2 cleavage. Furthermore, Kuzbanian is not enriched at the apical membrane inimpmutants, accumulating instead in late endosomes. Thus, IMP regulates Notch signalling by controlling the localisation of Kuzbanian to the apical domain, where Notch cleavage occurs, revealing a novel regulatory step in the Notch pathway.

IMP regulates Notch signalling in follicle cells by controlling Kuzbanian localisation to the apical domain, where Notch cleavage occurs, revealing a novel regulatory step in the Notch pathway.
BAP1 deubiquitinase is a potent repressor of fetal hemoglobin biosynthesis
Authors: Yu Lei , Jearawiriyapaisarn Natee , Lee Mary P. , Hosoya Tomonori , Wu Qingqing , Myers Greggory , Lim Kim-Chew , Kurita Ryo , Nakamura Yukio , Vojtek Anne B. , Rual Jean-François , Engel James Douglas
Published: June 2018

Human globin gene production transcriptionally “switches” from fetal to adult synthesis shortly after birth, and is controlled by macromolecular complexes that enhance or suppress transcription by cis-elements scattered throughout the locus. The DRED repressor is recruited to the ε- and γ-globin promoters by the orphan nuclear receptors TR2 (NR2C1) and TR4 (NR2C2) to engender their silencing in adult erythroid cells. Here we found that nuclear receptor corepressor-1 (NCoR1) is a critical component of DRED that acts as a scaffold to unite the DNA binding and epigenetic enzyme components (e.g. DNMT1 and LSD1) that elicit DRED function. We also describe a potent new regulator of γ-globin repression: the deubiquitinase BAP1 is a component of the repressor complex whose activity maintains NCoR1 at sites in the β-globin locus, and BAP1 inhibition in erythroid cells massively induces γ-globin synthesis. These data provide new mechanistic insights through the discovery of novel epigenetic enzymes that mediate γ-globin gene repression.
Machine learning approach to identify resting-state functional connectivity pattern serving as an endophenotype of autism spectrum disorder
Authors: Yamagata Bun , Itahashi Takashi , Fujino Junya , Ohta Haruhisa , Nakamura Motoaki , Kato Nobumasa , Mimura Masaru , Hashimoto Ryu-ichiro , Aoki Yuta
Published: June 2018

Endophenotype refers to a measurable and heritable component between genetics and diagnosis and exists in both individuals with a diagnosis and their unaffected siblings. We aimed to identify a pattern of endophenotype consisted of multiple connections. We enrolled adult male individuals with autism spectrum disorder (ASD) endophenotype (i.e., individuals with ASD and their unaffected siblings) and individuals without ASD endophenotype (i.e., pairs of typical development (TD) siblings) and utilized a machine learning approach to classify people with and without endophenotypes, based on resting-state functional connections (FCs). A sparse logistic regression successfully classified people as to the endophenotype (area under the curve=0.78, classification accuracy=75%), suggesting the existence of endophenotype pattern. A binomial test identified that nine FCs were consistently selected as inputs for the classifier. The least absolute shrinkage and selection operator with these nine FCs predicted severity of communication impairment among individuals with ASD (r=0.68,p=0.021). In addition, two of the nine FCs were statistically significantly correlated with the severity of communication impairment (r=0.81,p=0.0026 andr=-0.60,p=0.049). The current findings suggest that an ASD endophenotype pattern exists in FCs with a multivariate manner and is associated with clinical ASD phenotype.
Characterization ofDrosophila Nidogen/entactinreveals roles in basement membrane stability, barrier function and nervous system plasticity
Authors: Wolfstetter Georg , Dahlitz Ina , Pfeifer Kathrin , Alt Joscha Arne , Töpfer Uwe , Pfeifer Daniel Christoph , Lakes-Harlan Reinhard , Baumgartner Stefan , Palmer Ruth H. , Holz Anne
Published: June 2018

Basement membranes (BMs) are specialized layers of extracellular matrix (ECM) mainly composed of Laminin, type IV Collagen, Perlecan and Nidogen/entactin (NDG). While the essential and evolutionary conserved functions of Laminin, Collagen and Perlecan are well documented inDrosophilaand other species, the proposed role of NDG as the major ECM linker molecule has been challenged by severalin vivostudies revealing that NDG is dispensable for viability and BM formation. Here, we report the characterization of the singleNdggene inDrosophila.EmbryonicNdgexpression differed from that of other BM components and was primarily observed in mesodermal tissues and the chordotonal organs, whereas NDG protein localized to all BMs. While loss of Laminin strongly affected BM-localization of NDG,Ndgnull mutants exhibited no overt changes in the distribution of BM core components. However, loss of NDG led to ultrastructural BM defects compromising barrier function and stabilityin vivo.AlthoughNdgmutants were viable, loss of NDG led to decreased fecundity in flies as well as impaired crawling behavior and reduced response to vibrational stimuli in larvae. Further morphological analysis revealed accompanying defects in the larval peripheral nervous system especially in the chordotonal organs and the neuromuscular junction (NMJ), whereNdggenetically interacted with theLeukocyte-antigen-related-like (Lar) receptorgene to regulate NMJ extension and synaptic differentiation. Taken together, our analysis suggests that NDG is not essential for BM assembly but mediates BM stability and ECM-dependent neural plasticity duringDrosophiladevelopment.

Summary Statement

In this study we characterizeDrosophila Nidogen/Entactin (Ndg)mutants revealing that loss of Ndg impairs basement membrane (BM) stability and permeability as well as proper function of the nervous system.
Predicting peptide presentation by major histocompatibility complex class I using one million peptides
Authors: Boehm Kevin Michael , Bhinder Bhavneet , Raja Vijay Joseph , Dephoure Noah , Elemento Olivier
Published: June 2018

Improved computational tools are needed to prioritize putative neoantigens within immunotherapy pipelines for cancer treatment. Herein, we assemble a database of over one million human peptides presented by major histocompatibility complex class I (MHC-I), the largest known database of its type. We use these data to train a random forest classifier (ForestMHC) to predict likelihood of MHC-I presentation. The information content of features mirrors the canonical importance of positions two and nine in determining likelihood of binding. Our random forest-based method outperforms NetMHC and NetMHCpan on test sets, and it outperforms both these methods and MixMHCpred on new mass spectrometry data from an ovarian carcinoma sample. Furthermore, the random forest scores correlate monotonically with peptide binding affinities, when known. Finally, we examine the effect size of gene expression on peptide presentation and find a moderately strong relationship. The ForestMHC method is a promising modality to prioritize neoantigens for experimental testing in immunotherapy.