bluuebunny/crossref_metadata_2025_split huggingface dataset:
Human POMC processing in vitro and in vivo revealed by quantitative peptidomics
Authors: Kirwan Peter , Kay Richard , Brouwers Bas , Herranz-Perez Vicente , Jura Magdalena , Larraufie Pierre , Pembroke Jason , Bartels Theresa , White Anne , Gribble Fiona , Reimann Frank , Farooqi I. Sadaf , O’Rahilly Stephen , Merkle Florian T. 
Published: February 2018

ABSTRACTHuman obesity can result from the aberrant production or processing of proopiomelanocortin (POMC) in hypothalamic neurons, but it is unclear which human POMC-derived peptides are most relevant to body weight regulation. To address this question, we analysed both hypothalamic neurons derived from human pluripotent stem cells (hPSCs) and primary human hypothalamic tissue using quantitative liquid chromatography tandem mass spectroscopy (LC-MS/MS). In both in vitro- and in vivo-derived samples, we found that POMC was processed into β-melanocyte stimulating hormone (β-MSH), whose existence in the human brain has been controversial. β-MSH and desacetyl α-MSH (d-α-MSH) were produced at roughly equimolar concentrations and in vast excess to acetylated α-MSH (5-to 200-fold), suggesting that the importance of both d-α-MSH and β-MSH to human obesity has been underestimated. Since body weight is sensitive to changes in MSH concentration, we asked whether hPSC-derived hypothalamic neurons could provide mechanistic insights into the processing and secretion of MSH peptides. We found that cultured human hypothalamic neurons appropriately trafficked POMC and its derivatives, and robustly (P<0.0001) secreted them when depolarised. Furthermore, the adipocyte-derived hormone leptin significantly (P<0.01) promoted their production of both d-α-MSH and β-MSH. These results establish hPSC-derived hypothalamic neurons as a model system for studying human-specific aspects of POMC processing that might be therapeutically harnessed to treat obesity.
Fragile X mental retardation protein is a size-dependent translational activator
Authors: Greenblatt Ethan J. , Spradling Allan C. 
Published: February 2018

SummaryFMR1 enhances translation of large neural/oocyte proteinsMutations in the highly conservedFragile X mental retardation gene (Fmr1)cause the most common inherited human intellectual disability/autism spectrum disorder.Fmr1is also needed for ovarian follicle development, and lesions are the largest genetic cause of premature ovarian failure (POF). FMR1 associates with ribosomes and is thought to repress translation, but identifying functional targets has been difficult. We analyzed FMR1’s role in quiescentDrosophilaoocytes stored prior to ovulation, cells that depend entirely on translation of stored mRNA. Ribosome profiling revealed that in quiescent oocytes FMR1 stimulates the translation of large proteins, including at least twelve proteins whose human homologs are associated with dominant intellectual disability disorders, and 25 others associated with neural dysfunction. Knockdown of Fmr1 in unstored oocytes did not affect embryo development, but more than 50% of embryos derived from stored oocytes lacking FMR1 developed severe neural defects. Fmr1’s previously unappreciated role promoting the translation of large proteins from stored mRNAs in oocytes and neurons may underlie POF as well as multiple aspects of neural dysfunction.
Rbfox splicing factors maintain skeletal muscle mass by regulating calpain3 and proteostasis
Authors: Singh Ravi K. , Kolonin Arseniy M. , Fiorotto Marta L. , Cooper Thomas A. 
Published: February 2018

ABSTRACTAlternative splicing promotes proteomic diversity important for cellular differentiation and cell fate determination. Here, we show that deletion of the highly conserved Rbfox1 and Rbfox2 alternative splicing regulators in adult mouse skeletal muscle causes rapid, severe loss of muscle mass. Homeostasis of skeletal muscle tissue requires a dynamic balance between protein synthesis and degradation (proteostasis) but the mechanisms that regulate this balance are not well understood. Rbfox deletion did not cause reduced global protein synthesis, but resulted in reduced autophagy flux and altered splicing of hundreds of transcripts including Capn3, which produced an active form of calpain3 protease. The results indicate Rbfox proteins regulate proteostasis in skeletal muscle tissue by control of calpain and autophagy-lysosome pathways.HighlightsProteostasis in adult skeletal muscle is post-transcriptionally regulated, in part by alternative splicing via Rbfox1/2Rbfox1/2 regulate hundreds of targets in skeletal muscle, including Calpn3, to maintain muscle mass in adult miceAutophagy flux is markedly decreased in muscle lacking Rbfox1/2As for neurons, altered proteostasis is detrimental to adult muscle
DNA Topoisomerase I differentially modulates R-loops across the human genome
Authors: Manzo Stefano Giustino , Hartono Stella Regina , Sanz Lionel A. , De Biasi Sara , Cossarizza Andrea , Capranico Giovanni , Chedin Frederic 
Published: February 2018

ABSTRACTBackgroundCo-transcriptional R-loops are abundant non-B DNA structures in mammalian genomes. DNA Topoisomerase I (Top1) is often thought to regulate R-loop formation owing to its ability to resolve both positive and negative supercoils. How Top1 regulates R-loop structures at a global level is unknown.ResultsHere, we performed high-resolution strand-specific R-loop mapping in human cells depleted for Top 1 and found that Top1 depletion resulted in both R-loop gains and losses at thousands of transcribed loci, delineating two distinct gene classes. R-loop gains were characteristic for long, highly transcribed, genes located in gene-poor regions anchored to Lamin B1 domains and in proximity to H3K9me3-marked heterochromatic patches. R-loop losses, by contrast, occurred in gene-rich regions overlapping H3K27me3-marked active replication initiation regions. Interestingly, Top1 depletion coincided with a block of the cell cycle in G0/G1 phase and a trend towards replication delay.ConclusionsOur findings reveal new properties of Top1 in regulating R-loop homeostasis and suggest a potential role for Top1 in controlling replication initiation via R-loop formation.
Structural and histone binding studies of the chromo barrel domain of TIP60
Authors: Zhang Yuzhe , Lei Ming , Liang Xiao , Loppnau Peter , Li Yanjun , Min Jinrong , Liu Yanli 
Published: February 2018

AbstractTIP60 consists of an N-terminal chromo barrel domain (TIP60-CB) and a C-terminal acetyltransferase domain and acetylates histone and non-histone proteins within diverse cellular processes. Whereas the TIP60-CB is thought to recognize histone tails, molecular details of this interaction remain unclear. Here we attempted a quantitative analysis of the interaction between the TIP60-CB and histone peptides, but did not observe any binding through either fluorescence polarization or isothermal titration calorimetry. We solved a crystal structure of the TIP60-CB alone. Analysis of the crystal structure demonstrates a putative peptide binding site that may be occluded by the basic side chain of a residue in a unique β hairpin between the two N-terminal strands of the β barrel.
CALISTA: Clustering and Lineage Inference in Single-Cell Transcriptional Analysis
Authors: Gao Nan Papili , Hartmann Thomas , Fang Tao , Gunawan Rudiyanto 
Published: February 2018

SummaryWe present CALISTA (Clustering and Lineage Inference in Single-Cell Transcriptional Analysis), a numerically efficient and highly scalable toolbox for an end-to-end analysis of single-cell transcriptomic profiles. CALISTA includes four essential single-cell analyses for cell differentiation studies, including single-cell clustering, reconstruction of cell lineage specification, transition gene identification, and pseudotemporal cell ordering. In these analyses, we employ a likelihood-based approach where single-cell mRNA counts are described by a probabilistic distribution function associated with stochastic gene transcriptional bursts and random technical dropout events. We evaluated the performance of CALISTA by analyzing single-cell gene expression datasets from in silico simulations and various single-cell transcriptional profiling technologies, comprising a few hundreds to tens of thousands of cells. A comparison with existing single-cell expression analyses, including MONOCLE 2 and SCANPY, demonstrated the superiority of CALISTA in reconstructing cell lineage progression and ordering cells along cell differentiation paths. CALISTA is freely available on https://www.cabselab.com/calista.
cisTEM: User-friendly software for single-particle image processing
Authors: Grant Tim , Rohou Alexis , Grigorieff Nikolaus 
Published: February 2018

AbstractWe have developed new open-source software called cisTEM (computational imaging system for transmission electron microscopy) for the processing of data for high-resolution electron cryo-microscopy and single-particle averaging. cisTEM features a graphical user interface that is used to submit jobs, monitor their progress, and display results. It implements a full processing pipeline including movie processing, image defocus determination, automatic particle picking, 2D classification, ab-initio 3D map generation from random parameters, 3D classification, and high-resolution refinement and reconstruction. Some of these steps implement newly-developed algorithms; others were adapted from previously published algorithms. The software is optimized to enable processing of typical datasets (2000 micrographs, 200k - 300k particles) on a high-end, CPU-based workstation in half a day or less, comparable to GPU-accelerated processing. Jobs can also be scheduled on large computer clusters using flexible run profiles that can be adapted for most computing environments. cisTEM is available for download from cistem.org.
An Investigation of Detection Biases in the Unattended Periphery During Simulated Driving
Authors: Kingsley Li Musen , Lau Hakwan , Odegaard Brian 
Published: February 2018

AbstractWhile people often think they veridically perceive much of the visual surround, recent findings indicate that when asked to detect targets such as gratings embedded in visual noise, observers make more false alarms in the unattended periphery. Do these results from psychophysics studies generalize to naturalistic settings? We used a modern game engine to create a simulated driving environment where participants (as drivers) had to make judgments about the colors of pedestrians’ clothing in the periphery. Confirming our hypothesis based on previous psychophysics studies, we found that subjects showed liberal biases for unattended locations when detecting specific colors of pedestrians’ clothing. A second experiment showed that this finding was not simply due to a confirmation bias in decision-making when subjects were uncertain. Together, these results support the idea that in everyday visual experience, there is subjective inflation of experienced detail in the periphery, which may happen at the decisional level.
Partially Overlapping Brain Networks for Singing and Cello Playing
Authors: Segado Melanie , Hollinger Avrum , Thibodeau Joseph , Penhune Virginia , Zatorre Robert J. 
Published: February 2018

1AbstractThis research uses an MR-Compatible cello to compare functional brain activation during singing and cello playing within the same individuals to determine the extent to which arbitrary auditory-motor associations, like those required to play the cello, co-opt functional brain networks that evolved for singing. Musical instrument playing and singing both require highly specific associations between sounds and movements. However, vocal motor control is an evolutionarily old human trait and the auditory-motor associations used for singing are also used for speech and nonspeech vocalizations. This sets it apart from the arbitrary auditory-motor associations required to play musical instruments. The pitch range of the cello is similar to that of the human voice, but cello playing is completely independent of the vocal apparatus and can therefore be used to dissociate the auditory-vocal network from that of the auditory-motor network. While in the MR-Scanner, 11 expert cellists listened to and subsequently produced individual tones either by singing or cello playing. All participants were able to sing and play the target tones in tune (within 50Cents). We found that brain activity during cello playing directly overlaps with brain activity during singing in many areas within the auditory-vocal network. These include primary motor, dorsal pre-motor, and supplementary motor cortices, the primary and periprimary auditory cortices within the superior temporal gyrus including Heschl’s gyrus, anterior insula, anterior cingulate cortex, and intraparietal sulcus, and cerebellum but, notably, exclude the periaqueductal grey and basal ganglia. Second, we found that activity within the overlapping areas is positively correlated with, and therefore likely contributing to, both singing and playing in tune determined with performance measures. Third, we found that activity in auditory areas is functionally connected with activity in dorsal motor and pre-motor areas, and that the connectivity between them is positively correlated with good performance on this task. This functional connectivity suggests that the brain areas are working together to contribute to task performance and not just coincidently active. Last, our findings showed that cello playing may directly co-opt vocal areas (including larynx area of motor cortex), especially if musical training begins before age 7.
Unleashing apprenticeship: from onboarding to professional development
Authors: Moon Hanna 
Published: February 2018

PurposeThe purpose of this paper is to explore the process and activities of apprenticeship from onboarding to professional development.Design/methodology/approachLiterature was reviewed to highlight the important characteristics of cognitive and collaborative apprenticeship, onboarding and professional development.FindingsThe conceptual model was developed to identify the specific activities of apprenticeship at the onboarding, developmental and proficient phases.Originality/valueThis study enlightens the aspects of the way in which apprentices can make adjustments to their organizations and become proficient workforces.
An unobserved component analysis of Malaysia’s house prices
Authors: Mohd Daud Siti Nurazira , Marzuki Ainulashikin 
Published: February 2018

PurposeThis paper aims to investigate Malaysia’s house prices behaviour by decomposing trend, cycle and stochastic component.Design/methodology/approachThe authors perform an unobserved component model of a structural time series and Markov switching model that covers the period 1999Q1 to 2015Q4.FindingsThe results reveal that the variation in house price in Malaysia is best explained by its trend level, with a small role played by the cycle component; this implies the potential for gaining returns on investments in property by investors and households. The results also show that Malaysia’s HPI cycle is between 8 and 17 years which, in relative terms, is twice the length of the growth cycle and the business cycle in the economy. Meanwhile, the overall movement of HPI is forecast to have a marginal price increase up to 2028Q2.Originality/valueAs house prices remained elevated during the year, the house price dynamic is pivotal for understanding the source of changes in house price. With major findings centred on the relationship between house prices and macroeconomic as well as policy variables, little attention has been paid to composing the trend, cycle and seasonal pattern from the house price index, thus understanding the behaviour of house prices’ unobserved components.
Corporate performance: does board independence matter? – Indian evidence
Authors: Haldar Arunima , Shah Reeta , Nageswara Rao S.V.D. , Stokes Peter , Demirbas Dilek , Dardour Ali 
Published: February 2018

PurposeThe purpose of this paper is to examine the effect of the presence of independent board directors on financial performance in India.Design/methodology/approachThis study used panel regression models on large listed Indian firms to investigate the impact on financial performance owing to the presence of independent directors.FindingsThe findings suggest that independent board directors in Indian contexts do not significantly affect financial performance.Practical implicationsThis study has implications for the formulation of regulation related to appointment of independent directors and the extent of their representation on the board for them to be effective.Social implicationsThe proportion of independent directors on the board of the firm is influenced by the trade-off between the cost of having independent directors on the board versus the benefits to the firm and society.Originality/valueThe impact of the presence of an independent director on financial performance in highly concentrated ownership remains ambiguous.
Explaining inconsistencies in implicit and explicit attitudes towards domestic and foreign products
Authors: Tseng Ting-Hsiang , Balabanis George , Liu Matthew Tingchi 
Published: February 2018

PurposeThe purpose of this paper is to examine the inconsistency of explicit and implicit domestic country bias (DCB) across different types of products and in the context of two countries.Design/methodology/approachTwo studies in two countries are conducted to examine the inconsistencies in implicit and explicit DCB. The first study collected data through mall intercept survey method in Taiwan and identified 189 valid respondents. The second study applied a mixed (within and between subjects) factorial experiment in China using 200 subjects.FindingsResults show that explicit and implicit attitudes are moderately related to each other. The results also confirm that ethnic product typicality can explain inconsistencies in both explicit and implicit DCB. For ethnically typical products, DCB is more pronounced in consumers’ explicit attitudes than in consumers’ implicit attitudes. On the contrary, for ethnically atypical goods, DCB makes itself present in both explicit and implicit attitudes.Originality/valueThe results shed new light on DCB and confirm that the bias could divaricate between explicit and implicit attitudes in the case of ethnically typical products.
Revisiting the Uppsala internationalization model
Authors: Yamin Mo , Kurt Yusuf 
Published: February 2018

Purpose
The purpose of this paper is to utilize key insights from social network theory (SNT) to enhance understanding of overcoming the liability of outsidership as a prerequisite for firm internationalization. Specifically, it examines the influence of structural attributes of networks on the motivational stance of both network insiders and outsiders in relation to overcoming the liability of outsidership. A related aim is to explore the role of network positions of insider actors in terms of its impact on the speed of market entry.

Design/methodology/approach
The paper draws on the extant literatures on firm internationalization, particularly the liability of outsidership, and SNT to identify to what extent SNT can be utilized to deeply understand the process of overcoming the liability of outsidership. The authors put forward eight propositions linking structural and positioning attributes of networks with overcoming the liability of outsidership.

Findings
SNT provides strong potential for a more comprehensive understanding of the internationalization phenomena through shedding light on the relationship between the liability of foreignness and the liability of outsidership. The paper demonstrates that while the cost of overcoming the liability of outsidership is higher in closed target network as compared to open networks, the expected benefits of an insidership position in closed or open networks are affected by the outsider firm’s perception of the liability of foreignness in the market it wishes to enter. Considering the differential enabling characteristics of closed and open networks in terms of facilitating tacit knowledge sharing as opposed to explicit information flows, the authors reveal that liability of foreignness operates as a negative moderator for the relationship between network structure and the willingness of the outsider to invest in gaining insidership. The analysis of the paper also shows that the positional attributes of the network insider are relevant in outsiders’ motivation in terms of the speed of market entry that they seek to achieve.

Originality/value
This study theoretically contributes to the internationalization research through integrating SNT with the liability of outsidership understanding of firm internationalization. This is a timely attempt as no systematic application of the conceptual apparatus of SNT in the internationalization research context has been studied. It adds a more coherent inside-out perspective into the overcoming the liability of outsidership discussion which has been extensively dominated by an outside-in perspective.
Working with intellectually disabled autistic individuals – a qualitative study using repertory grids
Authors: Worthington Rachel , Patterson Chris , Halder Neel 
Published: February 2018

Purpose
The purpose of this paper is to elucidate how care professionals/providers construe, understand and make sense of the characteristics that are important when providing care to adults with intellectual disability and autism spectrum disorder, based on their experiences of working within their roles within a residential care setting.

Design/methodology/approach
Care professionals and providers working at a community autism and intellectual disability service were interviewed to ascertain their experiences of working with this client group. The research design adopted a qualitative methodology using repertory grids.

Findings
Ten members of staff who agreed to participate formed the study’s sample. This consisted of team leaders, support workers, one member of the executive management team and one clinical member of staff. Ten themes were identified for working effectively with people with autism and intellectual disabilities. These were: making autism-specific adaptations, approachable, reflective/self-aware, strong understanding of their residents/empathetic, benevolent, empowering, follows plans consistently, confident in ability to support residents with autism, resilient, respectful.

Practical implications
The paper discusses each of these ten themes above and how employers can aid in selecting individuals who may be more suited to working with this patient group.

Originality/value
A literature search demonstrated a lack of empirical research, especially qualitative research, on this topic.