bluuebunny/crossref_metadata_2025_split huggingface dataset:
adductomicsR: A package for detection and quantification of protein adducts from mass spectra of tryptic digests
Authors: Hayes Josie , Edmands William M. B. , Yano Yukiko , Grigoryan Hasmik , Schiffman Courtney , Dudoit Sandrine , Rappaport Stephen M. 
Published: November 2018

ABSTRACTSummaryLiquid chromatography-high resolution mass spectrometry (LC-HRMS) has been used to establish a method, referred to as ‘adductomics’, for characterisation of putative protein adducts at selected loci in human serum albumin (HSA). Applications of this method have been limited by the lack of software for untargeted analysis of modified peptides in protein digests. Here we present adductomicsR, an open-source R package for processing LC-HRMS data from analysis of adducted HSA peptides. The software interrogates mass spectra to correct for retention-time drift, and to discover and quantify putative adducts along with those for a housekeeping peptide and internal standard.Availability and implementationadductomicsR is written in R and publicly available at https://github.com/JosieLHayes/adductomicsR, which includes a vignette with example data.Supplementary informationmzXML files for the vignette and test dataset are available in an associated data package adductData (https://github.com/JosieLHayes/adductData).Contactjosie.hayes@berkeley.eduIssue SectionAPPLICATIONS NOTE
Repression of Dlx1/2 Signaling byNolz-1/Znf503is Essential for Parcellation of the Striatal Complex into Dorsal and Ventral Striatum
Authors: Lu Kuan-Ming , Chen Shih-Yun , Ko Hsin-An , Huang Ting-Hao , Hsin-Jou Hao Janice , Yan Yu-Ting , Li-Yun Chang Sunny , Evans Sylvia , Liu Fu-Chin 
Published: November 2018

ABSTRACTThe division of the striatum into dorsal and ventral districts is of central clinical importance. The dorsal striatum is differentially affected in Huntington’s disease, dopamine in the ventral striatum is differentially spared in Parkinson’s disease, and human brain imaging studies implicate the ventral striatum in addictive disorders. If fits that the dorsal striatum contains the cells of origin of the direct and indirect basal ganglia pathways for motor control. The ventral striatum is a node in neural circuits related to motivation and affect. Despite these striking neurobiologic contrasts, there is almost no information about how the dorsal and ventral divisions of the striatum are set up during development. Here, we demonstrate that interactions between the two key transcription factors Nolz-1 and Dlx1/2 control the migratory paths of developing striatal neurons to the dorsal or ventral striatum. Moreover, these same transcription factors control the cell identity of striatal projection neurons in both the dorsal and ventral striatum including the cell origin of the direct and indirect pathways. We show that Nolz-1 suppresses Dlx1/2 expression. Deletion of Nolz-1 or over-expression of Dlx1/2 can produce a striatal phenotype characterized by withered dorsal striatum and a swollen ventral striatum, and that we can rescue this phenotype by manipulating the interactions between Nolz-1 and Dlx1/2 transcription factors. This evidence suggests that the fundamental basis for divisions of the striatum known to be differentially vulnerable at maturity is already encoded by the time embryonic striatal neurons begin their migrations into the developing striatum.
The transcription factors TFEB and TFE3 link the FLCN-AMPK signaling axis to innate immune response and pathogen resistance
Authors: El-Houjeiri Leeanna , Possik Elite , Vijayaraghavan Tarika , Paquette Mathieu , Martina José A , Kazan Jalal M. , Ma Eric H. , Jones Russell , Blanchette Paola , Puertollano Rosa , Pause Arnim 
Published: November 2018

AbstractTFEB and TFE3 are transcriptional regulators of the innate immune response, but the mechanisms regulating their activation upon pathogen infection are poorly elucidated. UsingC. elegansand mammalian models, we report that the master metabolic modulator 5’-AMP-activated protein kinase (AMPK) and its negative regulator Folliculin (FLCN) act upstream of TFEB/TFE3 in the innate immune response, independently of the mTORC1 signaling pathway. In nematodes, loss of FLCN or overexpression of AMPK conferred pathogen resistanceviaactivation of TFEB/TFE3-dependent antimicrobial genes, while ablation of total AMPK activity abolished this phenotype. Similarly, in mammalian cells, loss of FLCN or pharmacological activation of AMPK induced TFEB/TFE3-dependent pro-inflammatory cytokine expression. Importantly, a rapid reduction in cellular ATP levels in murine macrophages was observed upon lipopolysaccharide (LPS) treatment accompanied by an acute AMPK activation and TFEB nuclear localization. These results uncover an ancient, highly conserved and pharmacologically actionable mechanism coupling energy status with innate immunity.
Single-cell transcriptome analysis of Physcomitrella leaf cells during reprogramming using microcapillary manipulation
Authors: Kubo Minoru , Nishiyama Tomoaki , Tamada Yosuke , Sano Ryosuke , Ishikawa Masaki , Murata Takashi , Imai Akihiro , Lang Daniel , Demura Taku , Reski Ralf , Hasebe Mitsuyasu 
Published: November 2018

AbstractBackgroundNext-generation sequencing technologies have made it possible to carry out transcriptome analysis at the single-cell level. Single-cell RNA-sequencing (scRNA-seq) data provide insights into cellular dynamics, including intercellular heterogeneity as well as inter- and intra-cellular fluctuations in gene expression that cannot be studied using populations of cells. The utilization of scRNA-seq is, however, restricted to specific types of cells that can be isolated from their original tissues, and it can be difficult to obtain precise positional information for these cells in situ.ResultsHere, we established single cell-digital gene expression (1cell-DGE), a method of scRNA-seq that uses micromanipulation to extract the contents of individual living cells in intact tissue while recording their positional information. Furthermore, we employed a unique molecular identifier to reduce amplification bias in the cDNA libraries. With 1cell-DGE, we could detect differentially expressed genes (DEGs) during the reprogramming of leaf cells into stem cells in excised tissues of the moss Physcomitrella patens, identifying 6,382 DEGs between cells at 0 h and 24 h after excision. We found substantial variations in both the transcript levels of previously reported reprogramming factors and the overall expression profiles between cells, which appeared to be related to their different reprogramming abilities or the estimated states of the cells according to the pseudotime based on the transcript profiles.ConclusionsWe developed 1cell-DGE with microcapillary manipulation, a technique that can be used to analyze the gene expression of individual cells without detaching them from their tightly associated tissues, enabling us to retain positional information and investigate cell–cell interactions.
De novo clustering of long-read transcriptome data using a greedy, quality-value based algorithm
Authors: Sahlin Kristoffer , Medvedev Paul 
Published: November 2018

AbstractLong-read sequencing of transcripts with PacBio Iso-Seq and Oxford Nanopore Technologies has proven to be central to the study of complex isoform landscapes in many organisms. However, current de novo transcript reconstruction algorithms from long-read data are limited, leaving the potential of these technologies unfulfilled. A common bottleneck is the dearth of scalable and accurate algorithms for clustering long reads according to their gene family of origin. To address this challenge, we develop isONclust, a clustering algorithm that is greedy (in order to scale) and makes use of quality values (in order to handle variable error rates). We test isONclust on three simulated and five biological datasets, across a breadth of organisms, technologies, and read depths. Our results demonstrate that isONclust is a substantial improvement over previous approaches, both in terms of overall accuracy and/or scalability to large datasets. Our tool is available at https://github.com/ksahlin/isONclust.
Mammalian kinetochores count attached microtubules in a sensitive and switch-like manner to control cell cycle progression
Authors: Kuhn Jonathan , Dumont Sophie 
Published: November 2018

AbstractThe Spindle Assembly Checkpoint (SAC) maintains genomic integrity by preventing anaphase until all kinetochores attach to the spindle. What specific signals are required for SAC satisfaction at mammalian kinetochores, and in what magnitude, are not well understood and central to understanding SAC signal processing and function. Here, we directly and independently tune candidate input signals – spindle forces and Hec1-microtubule binding – and map SAC outputs. By detaching microtubules from the spindle, we first demonstrate that the SAC does not respond to changes in spindle pulling forces. We then tune and fix the fraction of Hec1 molecules capable of microtubule binding, and interpret SAC output changes as coming from changes in binding, and not spindle forces. While the speed of satisfaction reduces with fewer attached microtubules, the kinetochore turns off the SAC even with few – approximately four – such microtubules. Thus, the mammalian kinetochore responds specifically to microtubule binding, and does so as a single, switch-like, sensitive unit. This may allow the kinetochore to rapidly react to attachments and maintain a robust response despite dynamic microtubule numbers.
A uniformin vitroefficacy dataset to guide antimicrobial peptide design
Authors: Nagarajan Deepesh , Nagarajan Tushar , Nanajkar Neha , Chandra Nagasuma 
Published: November 2018

ABSTRACTAntimicrobial peptides are ubiquitous molecules that form the innate immune system of organisms across all kingdoms of life. Despite their prevalence and early origins, they continue to remain potent natural antimicrobial agents. Antimicrobial peptides are therefore promising drug candidates in the face of overwhelming multi-drug resistance to conventional antibiotics. Over the past few decades, thousands of antimicrobial peptides have been characterizedin vitro, and their efficacy data is now available in a multitude of public databases. Computational antimicrobial peptide design attempts typically use such data. However, utilizing heterogenous data aggregated from different sources presents significant drawbacks. In this report, we present a uniform dataset containing 20 antimicrobial peptides assayed against 30 organisms spanning gram positive, gram negative, fungal, and mycobacterial origin. We draw inferences from the results of 600 individual MIC assays, and discuss what characteristics are essential for antimicrobial peptide efficacy. We expect our uniform dataset to be useful for future projects involving computational antimicrobial peptide design.
Lasy-Seq: a high-throughput library preparation method for RNA-Seq and its application in the analysis of plant responses to fluctuating temperatures
Authors: Kamitani Mari , Kashima Makoto , Tezuka Ayumi , Nagano Atsushi J. 
Published: November 2018

AbstractRNA-Seq is a whole-transcriptome analysis method used to research biological mechanisms and functions; its use in large-scale experiments is limited by costs and labour. In this study, we established a high-throughput and cost effective RNA-Seq library preparation method that did not require mRNA enrichment. The method adds unique index sequences to samples during reverse transcription (RT) that is conducted at a higher temperature (≥62°C) to suppress RT of A-rich sequences in rRNA, and then pools all samples into a single tube. Both single-read and paired end sequencing of libraries is enabled. We found that the pooled RT products contained large amounts of RNA, mainly rRNA, and caused over-estimations of the quantity of DNA, resulting in unstable tagmentation results. Degradation of RNA before tagmentation was necessary for the stable preparation of libraries. We named this protocol low-cost and easy RNA-Seq (Lasy-Seq), and used it to investigate temperature responses inArabidopsis thaliana. We analysed how sub-ambient temperatures (10–30°C) affected the plant transcriptomes, using time-courses of RNA-Seq from plants grown in randomly fluctuating temperature conditions. Our results suggest that there are diverse mechanisms behind plant temperature responses at different time scales.
PETISCO is a novel protein complex required for 21U RNA biogenesis and embryonic viability
Authors: Cordeiro Rodrigues Ricardo J. , de Jesus Domingues António Miguel , Hellmann Svenja , Dietz Sabrina , de Albuquerque Bruno F. M. , Renz Christian , Ulrich Helle D. , Butter Falk , Ketting René F. 
Published: November 2018

AbstractPiwi proteins are important for germ cell development in almost all animals studied thus far. These proteins are guided to specific targets, such as transposable elements, by small guide RNAs, often referred to as piRNAs, or 21U RNAs in C. elegans. In this organism, even though genetic screens have uncovered a number of potential 21U RNA biogenesis factors, little is known about how these factors interact or what they do. Based on the previously identified 21U biogenesis factor PID-1, we here define a novel protein complex, PETISCO, that is required for 21U RNA biogenesis. PETISCO contains both potential 5’-cap and 5’-phosphate RNA binding domains, suggesting involvement in 5’ end processing. We define the interaction architecture of PETISCO and reveal a second function for PETISCO in embryonic development. This essential function of PETISCO is not mediated by PID-1, but by TOST-1. Vice versa, TOST-1 is not involved in 21U RNA biogenesis. Both PID-1 and TOST-1 are small, intrinsically disordered proteins that interact directly with the PETISCO protein ERH-2 (enhancer of rudimentary homolog 2) using a conserved sequence motif. Finally, our data suggest an important role for TOST-1:PETISCO in SL1 homeostasis in the early embryo. Our work describes the first molecular platform for 21U RNA production in C. elegans, and strengthens the view that 21U RNA biogenesis is built upon a much more widely used, snRNA-related pathway.
Inferring causal connectivity from pairwise recordings and optogenetics
Authors: Lepperød Mikkel Elle , Stöber Tristan , Hafting Torkel , Fyhn Marianne , Kording Konrad Paul 
Published: November 2018

AbstractTo understand the neural mechanisms underlying brain function, neuroscientists aim to quantify causal interactions between neurons, for instance by perturbing the activity of neuron A and measuring the effect on neuron B. Recently, manipulating neuron activity using light-sensitive opsins, optogenetics, has increased the specificity of neural perturbation. However, using widefield optogenetic interventions, multiple neurons are usually perturbed, producing a confound – any of the stimulated neurons can have affected the postsynaptic neuron making it challenging to discern which neurons produced the causal effect. Here, we show how such confounds produce large biases in interpretations. We explain how confounding can be reduced by combining instrumental variables (IV) and difference in differences (DiD) techniques from econometrics. Combined, these methods can estimate (causal) effective connectivity by exploiting the weak, approximately random signal resulting from the interaction between stimulation and the absolute refractory period of the neuron. In simulated neural networks, we find that estimates using ideas from IV and DiD outperform naïve techniques suggesting that methods from causal inference can be useful to disentangle neural interactions in the brain.
Structure of a bacterial ATP synthase
Authors: Guo Hui , Suzuki Toshiharu , Rubinstein John L. 
Published: November 2018

AbstractATP synthases produce ATP from ADP and inorganic phosphate with energy from a transmembrane proton motive force. Bacterial ATP synthases have been studied extensively because they are the simplest form of the enzyme and because of the relative ease of genetic manipulation of these complexes. We expressed theBacillusPS3 ATP synthase inEschericia coli, purified it, and imaged it by cryo-EM, allowing us to build atomic models of the complex in three rotational states. The position of subunitεshows how it is able to inhibit ATP hydrolysis while allowing ATP synthesis. The architecture of the membrane region shows how the simple bacterial ATP synthase is able to perform the same core functions as the equivalent, but more complicated, mitochondrial complex. The structures reveal the path of transmembrane proton translocation and provide a model for understanding decades of biochemical analysis interrogating the roles of specific residues in the enzyme.
Increased association between Epstein-Barr virus EBNA2 from type 2 strains and the transcriptional repressor BS69 restricts B cell growth
Authors: Ponnusamy Rajesh , Khatri Ritika , Correia Paulo B. , Mancini Erika , Farrell Paul J. , West Michelle J. 
Published: November 2018

AbstractNatural variation separates Epstein-Barr virus (EBV) into type 1 and type 2 strains. Type 2 EBV is less transformingin vitrodue to sequence differences in the EBV transcription factor EBNA2. This correlates with reduced activation of the EBV oncogene LMP1 and some cell genes. Transcriptional activation by type 1 EBNA2 can be suppressed through the binding of two PXLXP motifs in its transactivation domain (TAD) to the dimeric coiled-coil MYND domain (CC-MYND) of the BS69 repressor protein (ZMYND11). We identified a third conserved PXLXP motif in type 2 EBNA2. We found that type 2 EBNA2 peptides containing this motif bound BS69CC-MYNDefficiently and that the type 2 EBNA2TADbound an additional BS69CC-MYNDmolecule. Full-length type 2 EBNA2 also bound BS69 more efficiently in pull-down assays. Molecular weight analysis and low-resolution structures obtained using small-angle X-ray scattering showed that three BS69CC-MYNDdimers bound two molecules of type 2 EBNA2TAD, in line with the dimeric state of full-length EBNA2in vivo. Importantly, mutation of the third BS69 binding motif in type 2 EBNA2 improved B-cell growth maintenance. Our data indicate that increased association with BS69 restricts growth promotion by EBNA2 and may contribute to reduced B-cell transformation by type 2 EBV.Author summaryEpstein-Barr virus (EBV) drives the development of many human cancers worldwide including specific types of lymphoma and carcinoma. EBV infects B lymphocytes and immortalises them, thus contributing to lymphoma development. The virus promotes B lymphocyte growth and survival by altering the level at which hundreds of genes are expressed. The EBV protein EBNA2 is known to activate many growth-promoting genes. Natural variation in the sequence of EBNA2 defines the two main EBV strains: type 1 and type 2. Type 2 strains immortalise B lymphocytes less efficiency and activate some growth genes poorly, although the mechanism of this difference is unclear. We now show that sequence variation in type 2 EBNA2 creates a third site of interaction for the repressor protein (BS69, ZMYND11). We have characterised the complex formed between type 2 EBNA2 and BS69 and show that three dimers of BS69 form a bridged complex with two molecules of type 2 EBNA2. We demonstrate that mutation of the additional BS69 interaction site in type 2 EBNA2 improves its growth-promoting function. Our results therefore provide a molecular explanation for the different B lymphocyte growth promoting activities of type 1 and type 2 EBV. This aids our understanding of immortalisation by EBV.
In the uncertain world of Qontrac International: navigating through family, growth and succession management challenges
Authors: D’Costa Diantha , Bodolica Virginia , Spraggon Martin 
Published: November 2018

Learning outcomes
Upon completion of this case study analysis, the course audience is expected to achieve four learning outcomes. In particular, students should be able to conduct a comprehensive organizational diagnosis to uncover the peculiarities of managing a family business; analyze the specific challenges faced by family-owned enterprises in the context of emerging markets; evaluate the succession management practices in family organizations and design a profile of a successful successor; assess the effectiveness of managerial decision-making and provide recommendations for securing the sustainability of a family firm.

Case overview/synopsis
This case study unveils the tumultuous story of Vishwanath Shetty, an ambitious entrepreneur who transformed his small venture into a profitable family business with operations in Middle East, Asia and Africa. Since the early establishment of Qontrac International in 1989, he relied on the ownership and management participation of several members of his and his wife’s families. Over the years, Vishwanath was successful in pursuing a strategy of continuous growth and geographic diversification by taking advantage of the business opportunities in several regions and opening up branches in Oman, the United Arab Emirates (UAE), Ghana and India. Yet, almost three decades after its launch, the company was confronted with a number of family, growth and succession management challenges that endangered its survival in the long run. The Shetty family experienced a serious rift due to financial reasons, the performance of the two branches managed by siblings declined, and the old firm structure and management style did not fit well with the newly enlarged and geographically dispersed Qontrac International. To deal with these organizational issues, Vishwanath was faced with an additional dilemma of securing the support of a suitable intra-family candidate who could join the family business and become his successor. By describing the strategic events and family dynamics that shaped the evolution of Qontrac International over time, the case provides an opportunity to assess the effectiveness of managerial decision-making in the context of family firms and provide viable recommendations for ensuring firm survival and longevity.

Complexity academic level
Upper-level undergraduate audience Graduate audience (in Master of Global Entrepreneurial Management program).

Supplementary materials
Teaching Notes are available for educators only. Please contact your library to gain login details or email support@emeraldinsight.com to request teaching notes.

Subject code
Strategy.
Housing and health – a shared history, a shared future
Authors: van Doorn Andrew , Dearnaley Patricia 
Published: November 2018

Purpose
The 2017 Naylor Review has been the subject of some controversy, with some of the press, social media and other critics portraying its recommendations as a “fire sale” or privatisation of the NHS. The purpose of this paper is to examine preceding reports into efficiency and best value of the NHS, the evidence behind the review recommendations, and analyse data into housing affordability for the capital’s NHS staff. It concludes by advocating for partnerships with housing associations to deliver social and financial value by utilising redundant NHS land to deliver the affordable housing that London and the rest of the UK so urgently needs.

Design/methodology/approach
The paper was developed using the content analysis of preceding independent reviews of NHS efficiency, published critiques of the Naylor Review and analysis of NHS produced data to consider the potential savings and opportunities for reinvestment in capital projects.

Findings
The paper identifies existing partnership models and examples of good practice and advocates the adoption of joint ventures and other forms of partnership to ensure that both best value is achieved from the sale of NHS assets, and publicly owned assets are reused for social purpose.

Originality/value
The paper uses existing data, analysis and context to map a route for achieving best value in managing the publicly owned asset base and reinvesting the proceeds of the sale of redundant properties into UK public services.