bluuebunny/crossref_metadata_2025 huggingface dataset:
Length regulation of multiple flagella that self-assemble from a shared pool of components
Authors: Fai Thomas G. , Mohapatra Lishibanya , Kondev Jane , Amir Ariel
Published: October 2018

Control of organelle size is a problem that has intrigued cell biologists for at least a century. The single-celled green algaeChlamydomonas reinhardtiiwith its two 2agella has proved to be a very useful model organism for studies of size control. Numerous experiments have identi1ed motor-driven transport of tubulin to the growing ends of microtubules at the tip of the 2agella as the key component of the machinery responsible for controlling their length. Here we consider a model of 2agellar length control whose key assumption is that proteins responsible for the intra2agellar transport (IFT) of tubulin are present in limiting amounts. We show that this limiting-pool assumption and simple reasoning based on the law of mass action leads to an inverse relationship between the rate at which a 2agellum grows and its length, which has been observed experimentally, and has been shown theoretically to provide a mechanism for length control. Experiments in which one of the two 2agella are severed have revealed the coupled nature of the growth dynamics of the two 2agella, and we extend our length-control model to two 2agella by considering different mechanisms of their coupling. We describe which coupling mechanisms are capable of reproducing the observed dynamics in severing experiments, and why some that have been proposed previously are not. Within our theoretical framework we conclude that if tubulin and IFT proteins are freely exchanged between 2agella simultaneous length control is not possible if the disassembly rate is constant. However, if disassembly depends on the concentration of IFT proteins at the tip of the 2agellum, simultaneous length control can be achieved. Finally, we make quantitative predictions for experiments that could test this model.
Growth-driven displacement of protein aggregates along the cell length ensures partitioning to both daughter cells inCaulobacter crescentus
Authors: Schramm Frederic D. , Schroeder Kristen , Alvelid Jonatan , Testa Ilaria , Jonas Kristina
Published: October 2018

All living cells must deal with protein aggregation, which can occur as a result of experiencing stress. In the bacteriaEscherichia coliandMycobacterium smegmatis, aggregates collect at the cell poles and are retained over consecutive cell divisions only in the daughter cell that inherits the old pole, resulting in aggregation-free progeny within a few generations. Here we have studied thein vivokinetics of aggregate formation and clearance following heat and antibiotic stress inCaulobacter crescentus, which divides by a pre-programmed asymmetric cell cycle. Unexpectedly, we find that aggregates do not preferentially collect at the cell poles, but form as multiple distributed foci throughout the cell volume. Time-lapse microscopy revealed that under moderate stress, the majority of protein aggregates are short-lived and rapidly dissolved by the major chaperone DnaK and the disaggregase ClpB. Severe stress or genetic perturbation of the protein quality machinery results in long-lived protein aggregates, which individual cells can only clear by passing on to their progeny. Importantly, these persistent aggregates are neither collected at the old pole over multiple generations nor inherited exclusively by the old pole-inheriting stalked cell, but instead are partitioned between both daughter cells during successive division events in the same ratio. Our data indicate that this symmetric mode of aggregate inheritance is driven by the elongation and division of the growing mother cell. In conclusion, our study revealed a new pattern of aggregate inheritance in bacteria.
FoxM1 drives proximal tubule proliferation during repair from acute kidney injury
Authors: Chang-Panesso Monica , Kadyrov Farid F. , Lalli Matthew , Wu Haojia , Ikeda Shiyo , Kobayashi Akio , Humphreys Benjamin D.
Published: October 2018

The proximal tubule has a remarkable capacity for repair after acute injury but the cellular lineage and molecular mechanisms underlying this repair response have been poorly characterized. Here, we developed a Kim-1-GFPCreERt2knockin mouse line (Kim-1-GCE), performed genetic lineage analysis after injury and measured the cellular transcriptome of proximal tubule during repair. Acutely injured genetically labeled clones co-expressed Kim-1, Vimentin, Sox9 and Ki67, indicating a dedifferentiated and proliferative state. Clonal analysis revealed clonal expansion of Kim-1+ cells, indicating that acutely injured, dedifferentiated proximal tubule cells account for repair rather than a fixed tubular progenitor. Translational profiling during injury and repair revealed signatures of both successful and unsuccessful maladaptive repair. The transcription factor FoxM1 was induced early in injury, was required for epithelial proliferation, and was dependent on epidermal growth factor receptor (EGFR) stimulation. In conclusion, dedifferentiated proximal tubule cells effect proximal tubule repair and we reveal a novel EGFR-FoxM1-dependent signaling pathway that drives proliferative repair after injury.
SNAPS: A toolkit for studying cell surface shedding of diverse transmembrane receptors
Authors: Hayward Amanda N. , Aird Eric J. , Gordon Wendy R.
Published: October 2018

Proteolysis of transmembrane receptors is a critical cellular communication mechanism dysregulated in many diseases, yet decoding proteolytic regulation mechanisms of the estimated 400 receptors shed from the cell surface has been hindered by difficulties in controlling stimuli and unknown fates of cleavage products. Notch proteolytic regulation is a notable exception, where decades of study have revealed that intercellular forces drive exposure of a cryptic protease site within a juxtamembrane “proteolytic switch” domain to activate transcriptional programs inside the cell. Thus, we created a Synthetic Notch Assay for Proteolytic Switches (SNAPS) that exploits the modularity and unequivocal input/response of Notch proteolysis to screen surface receptors for other putative proteolytic switches. Here, we identify several new proteolytic switches among receptors with structural homology to Notch. We demonstrate that SNAPS can detect shedding in chimeras of diverse cell surface receptors, leading to new, testable hypotheses. Finally, we establish that the assay can be used to measure modulation of proteolysis by potential therapeutics.
RegTools: Integrated analysis of genomic and transcriptomic data for the discovery of splice-associated variants in cancer
Authors: Cotto Kelsy C. , Feng Yang-Yang , Ramu Avinash , Richters Megan , Freshour Sharon L. , Skidmore Zachary L. , Xia Huiming , McMichael Joshua F. , Kunisaki Jason , Campbell Katie M. , Chen Timothy Hung-Po , Rozycki Emily B. , Adkins Douglas , Devarakonda Siddhartha , Sankararaman Sumithra , Lin Yiing , Chapman William C. , Maher Christopher A. , Arora Vivek , Dunn Gavin P. , Uppaluri Ravindra , Govindan Ramaswamy , Griffith Obi L. , Griffith Malachi
Published: October 2018

Somatic mutations within non-coding regions and even exons may have unidentified regulatory consequences that are often overlooked in analysis workflows. Here we present RegTools (www.regtools.org), a computationally efficient, free, and open-source software package designed to integrate somatic variants from genomic data with splice junctions from bulk or single cell transcriptomic data to identify variants that may cause aberrant splicing. RegTools was applied to over 9,000 tumor samples with both tumor DNA and RNA sequence data. We discovered 235,778 events where a splice-associated variant significantly increased the splicing of a particular junction, across 158,200 unique variants and 131,212 unique junctions. To characterize these somatic variants and their associated splice isoforms, we annotated them with the Variant Effect Predictor (VEP), SpliceAI, and Genotype-Tissue Expression (GTEx) junction counts and compared our results to other tools that integrate genomic and transcriptomic data. While many events were corroborated by the aforementioned tools, the flexibility of RegTools also allowed us to identify novel splice-associated variants and previously unreported patterns of splicing disruption in known cancer drivers, such asTP53, CDKN2A, andB2M, as well as in genes not previously considered cancer-relevant.
Exploratory Gene Ontology Analysis with Interactive Visualization
Authors: Zhu Junjie , Zhao Qian , Katsevich Eugene , Sabatti Chiara
Published: October 2018

The Gene Ontology (GO) is a central resource for functional-genomics research. Scientists rely on the functional annotations in the GO for hypothesis generation and couple it with high-throughput biological data to enhance interpretation of results. At the same time, the sheer number of concepts (>30,000) and relationships (>70,000) presents a challenge: it can be difficult to draw a comprehensive picture of how certain concepts of interest might relate with the rest of the ontology structure. Here we present new visualization strategies to facilitate the exploration and use of the information in the GO. We rely on novel graphical display and software architecture that allow significant interaction. To illustrate the potential of our strategies, we provide examples from high-throughput genomic analyses, including chromatin immunoprecipitation experiments and genome-wide association studies. The scientist can also use our visualizations to identify gene sets that likely experience coordinated changes in their expression and use them to simulate biologically-grounded single cell RNA sequencing data, or conduct power studies for differential gene expression studies using our built-in pipeline. Our software and documentation are available athttp://aegis.stanford.edu.
Trait evolution and historical biogeography shape assemblages of annual killifish
Authors: Helmstetter Andrew J. , Van Dooren Tom J. M. , Papadopulos Alexander S. T. , Igea Javier , Leroi Armand M. , Savolainen Vincent
Published: October 2018

Reconstructions of evolutionary and historical biogeographic processes can improve our understanding of how species ssemblages developed and permit inference of ecological drivers affecting coexistence. We explore this approach inAustrolebias, a genus of annual fishes possessing a wide range of body sizes. Regional assemblages composed of different species with similar size distributions are found in four areas of eastern South America. Using phylogenetic trees, species distribution models and size data we show how trait evolution and historical biogeography have affected the composition of species assemblages. We extend age-range correlations to improve estimates of local historical biogeography. We find that size variation principally arose in a single area and infer that ecological interactions drove size divergence. This large-size lineage spread to two other areas. One of these assemblages was likely shaped by adaptation to a new environment, but this was not associated with additional size divergence. We found only weak evidence that environmental filtering has been important in the construction of the remaining assemblage with the smallest range of sizes. The repeated assemblage structures were the result of different evolutionary and historical processes. Our approach sheds light on how species assemblages were built when typical clustering approaches may fall short.
Establishing a causal role for medial prefrontal cortex in reality monitoring
Authors: Subramaniam Karuna , Kothare Hardik , B. Hinkley Leighton , Tarapore Phiroz , S. Nagarajan Srikantan
Published: October 2018

Reality monitoring is defined as the ability to distinguish internally self-generated information from externally-derived information. Functional imaging studies have consistently found that the medial prefrontal cortex (mPFC) is a key brain region subserving reality monitoring. The aim of this study was to determine a causal role for mPFC in reality monitoring using navigated repetitive transcranial magnetic stimulation (nrTMS). In a subject-blinded sham-controlled crossover design, healthy individuals received either active or sham nrTMS targeting mPFC. Active modulation of mPFC using nrTMS at a frequency of 10 Hz, significantly improved identification of both self-generated and externally-derived information during reality monitoring, when compared to sham or baseline. Targeted excitatory modulation of mPFC also improved positive mood ratings, reduced negative mood ratings and increased overall alertness/arousal. These results establish optimal nrTMS dosing parameters that maximized tolerability/comfort and induced significant neuromodulatory effects in the mPFC target. Importantly, this is a proof-of-concept study that establishes the mPFC as a novel brain target that can be stimulated with nrTMS to causally impact both mood and higher-order reality monitoring.
Integrated analysis of genomics, longitudinal metabolomics, and Alzheimer’s risk factors among 1,111 cohort participants
Authors: Darst Burcu F. , Lu Qiongshi , Johnson Sterling C. , Engelman Corinne D.
Published: October 2018

Although Alzheimer’s disease (AD) is highly heritable, genetic variants known to be associated with AD only explain a small proportion of its heritability. Genetic factors may only convey disease risk in individuals with certain environmental exposures, suggesting that a multi-omics approach could reveal underlying mechanisms contributing to complex traits, such as AD. We developed an integrated network to investigate relationships between metabolomics, genomics, and AD risk factors using Wisconsin Registry for Alzheimer’s Prevention participants. Analyses included 1,111 non-Hispanic Caucasian participants with whole blood expression for 11,376 genes (imputed from dense genome-wide genotyping), 1,097 fasting plasma metabolites, and 17 AD risk factors. A subset of 155 individuals also had 364 fasting cerebral spinal fluid (CSF) metabolites. After adjusting each of these 12,854 variables for potential confounders, we developed an undirected graphical network, representing all significant pairwise correlations upon adjusting for multiple testing. There were many instances of genes being indirectly linked to AD risk factors through metabolites, suggesting that genes may influence AD risk through particular metabolites. Follow-up analyses suggested that glycine mediates the relationship between CPS1 and measures of cardiovascular and diabetes risk, including body mass index, waist-hip ratio, inflammation, and insulin resistance. Further, 38 CSF metabolites explained more than 60% of the variance of CSF levels of tau, a detrimental protein that accumulates in the brain of AD patients and is necessary for its diagnosis. These results further our understanding of underlying mechanisms contributing to AD risk while demonstrating the utility of generating and integrating multiple omics data types.
Object boundary detection in natural images may depend on ‘incitatory’ cell-cell interactions
Authors: Mel Gabriel C. , Ramachandra Chaithanya A. , Mel Bartlett W.
Published: October 2018

Detecting object boundaries is crucial for recognition, but how the process unfolds in visual cortex remains unknown. To study the problem faced by a hypothetical boundary cell, and to predict how cortical circuitry could produce a boundary cell from a population of conventional “simple cells”, we labeled 30,000 natural image patches and used Bayes’ rule to help determine how a simple cell should influence a nearby boundary cell depending on its relative offset in receptive field position and orientation. We identified three basic types of cell-cell interactions: rising and falling interactions with a range of slopes and saturation rates, as well as non-monotonic (bump-shaped) interactions with varying modes and amplitudes. Using simple models we show that a ubiquitous cortical circuit motif consisting of direct excitation and indirect inhibition – a compound effect we call “incitation” – can produce the entire spectrum of simple cell-boundary cell interactions found in our dataset. Moreover, we show that the synaptic weights that parameterize an incitation circuit can be learned by a single-layer “delta” rule. We conclude that incitatory interconnections are a generally useful computing mechanism that the cortex may exploit to help solve difficult natural classification problems.

Significance statement:

Simple cells in primary visual cortex (V1) respond to oriented edges, and have long been supposed to detect object boundaries, yet the prevailing model of a simple cell – a divisively normalized linear filter – is a surprisingly poor natural boundary detector. To understand why, we analyzed image statistics on and off object boundaries, allowing us to characterize the neural-style computations needed to perform well at this difficult natural classification task. We show that a simple circuit motif known to exist in V1 is capable of extracting high-quality boundary probability signals from local populations of simple cells. Our findings suggest a new, more general way of conceptualizing cell-cell interconnections in the cortex.
Pre-stimulus feedback connectivity biases the content of visual experiences
Authors: Rassi Elie , Wutz Andreas , Müller-Voggel Nadia , Weisz Nathan
Published: October 2018

Ongoing fluctuations in neural excitability and in network-wide activity patterns before stimulus onset have been proposed to underlie variability in near-threshold stimulus detection paradigms, i.e. whether an object is perceived or not. Here, we investigated the impact of pre-stimulus neural fluctuations on the content of perception, i.e. whether one or another object is perceived. We recorded neural activity with magnetoencephalography before and while participants briefly viewed an ambiguous image, the Rubin face/vase illusion, and required them to report their perceived interpretation on each trial. Using multivariate pattern analysis, we showed robust decoding of the perceptual report during the post-stimulus period. Applying source localization to the classifier weights suggested early recruitment of V1 and ~160 ms recruitment of category-sensitive FFA. These post-stimulus effects were accompanied by stronger oscillatory power in the gamma frequency band for face vs vase reports. In pre-stimulus intervals, we found no differences in oscillatory power between face vs. vase reports neither in V1 nor in FFA, indicating similar levels of neural excitability. Despite this, we found stronger connectivity between V1 and FFA prior to face reports for low-frequency oscillations. Specifically, the strength of pre-stimulus feedback connectivity (i.e. Granger causality) from FFA to V1 predicted not only the category of the upcoming percept, but also the strength of post-stimulus neural activity associated with the percept. Our work shows that pre-stimulus network states can help shape future processing in category-sensitive brain regions and in this way bias the content of visual experiences.
BIN1 genetic risk factor for Alzheimer is sufficient to induce early structural tract alterations in entorhinal-hippocampal area and memory-related hippocampal multi-scale impairments
Authors: Daudin R , Marechal D , Golgolab R , Wang Q , Abe Y , Tsurugizawa T. , Bourg N , Sartori M , Loe-Mie Y , Lipecka J , Guerrera C , McKenzie A , Potier B , Dutar P , Viard J , Lepagnol-Bestel A.M , Winkeler A , Uszynski I. , Hindié V , Birling MC , Lindner L , Chevalier C , Pavlovic G , Reiss M , Kranz H , Dupuis G , Lévêque-Fort S , Diaz J , Davenas E , Dembele D , Atas-Ozcan H. , Laporte J , Thibault-Carpentier C , Malissen B , Rain J.C , Poupon C. , Le Bihan D , Zhang B , Herault Y , Ciobanu L. , Simonneau M
Published: October 2018

Genetic factors are known to contribute to Late Onset Alzheimer’s disease (LOAD) but their contribution to pathophysiology, specially to prodomic phases accessible to therapeutic approaches are far to be understood.

To translate genetic risk of Alzheimer’s disease (AD) into mechanistic insight, we generated transgenic mouse lines that express a ∼195 kbp human BAC that includes only BIN1, a gene associated to LOAD. This model gives a modest BIN1 overexpression, dependent of the number of BAC copies. At 6 months of age, we detected impaired entorhinal cortex (EC)-hippocampal pathways with specific impairments in EC-dentate gyrus synaptic long-term potentiation, dendritic spines of granular cells and recognition episodic memory. Structural changes were quantified using MRI. Their whole-brain functional impact were analyzed using resting state fMRI with a hypoconnectivity centered on entorhinal cortex.

These early phenotype defects independent of any changes in A-beta can be instrumental in the search for new AD drug targets.
Cytoskeletal tension actively sustains the migratory T cell synaptic contact
Authors: Kumari Sudha , Mak Michael , Poh Yehchuin , Tohme Mira , Watson Nicki , Melo Mariane , Janssen Erin , Dustin Michael , Geha Raif , Irvine Darrell J.
Published: October 2018

When migratory T cells encounter antigen presenting cells (APCs), they arrest and form radially symmetric, stable intercellular junctions termed immunological synapses which facilitate exchange of crucial biochemical information and are critical for T cell immunity. While the cellular processes underlying synapse formation have been well-characterized, those that maintain the symmetry, and thereby the stability of the synapse remain unknown. Here we identify an antigen-triggered mechanism that actively promotes T cell synapse symmetry by generating cytoskeletal tension in the plane of the synapse through focal nucleation of actin via Wiskott -Aldrich syndrome Protein (WASP), and contraction of the resultant actin filaments by myosin II. Following T cell activation, WASP is degraded, leading to cytoskeletal rearrangement and tension decay, which result in synapse breaking. Thus, our study identifies and characterizes a mechanical program within otherwise highly motile T cells that sustains the symmetry and stability of the T cell-APC synaptic contact.
Beta-band activity in medial prefrontal cortex predicts source memory encoding and retrieval accuracy
Authors: Subramaniam Karuna , Hinkley Leighton B.N. , Mizuiri Danielle , Kothare Hardik , Garrett Coleman , Findlay Anne , Houde John F. , Nagarajan Srikantan S.
Published: October 2018

Reality monitoring is defined as the ability to distinguish internally self-generated information from externally-derived information. The medial prefrontal cortex (mPFC) is a key brain region subserving reality monitoring and has been shown to be activated specifically during the retrieval of self-generated information. However, it is unclear if mPFC is activated during the encoding of self-generated information into memory. If so, it is important to understand whether successful retrieval of self-generated information critically depends on enhanced neural activity within mPFC during initial encoding of this self-generated information.

We used magnetoencephalographic imaging (MEGI) to determine the timing and location of cortical activity during a reality-monitoring task involving self generated contextual source memory encoding and retrieval. We found both during encoding and retrieval of self-generated information, when compared to externally-derived information, mPFC showed significant task induced oscillatory power modulation in the beta-band. During initial encoding of self-generated information, greater mPFC beta-band power reductions occurred within a time window of −700ms to −500ms prior to vocalization, activity in mPFC that was not observed during encoding of externally-derived information. This mPFC activity during encoding of self-generated information predicted subsequent retrieval accuracy of self-generated information. Beta-band activity in mPFC was also observed during the initial retrieval of self-generated information within a time window of 300 to 500ms following stimulus onset and correlated with accurate retrieval performance of self-generated information. Together, these results further highlight the importance of mPFC in mediating the initial generation and awareness of participants’ internal thoughts.
Inferring the heritability of large-scale functional networks with a multivariate ACE modeling approach
Authors: Ribeiro Fernanda L. , Santos Felipe R. C. dos , Sato João R. , Pinaya Walter H. L. , Biazoli Claudinei E.
Published: October 2018

Recent evidence suggests that the human functional connectome is stable at different time scales and unique. These characteristics posit the functional connectome not only as an individual marker but also as a powerful discriminatory measure characterized by high intersubject variability. Among distinct sources of intersubject variability, the long-term sources include functional patterns that emerge from genetic factors. Here, we sought to investigate the contribution of additive genetic factors to the variability of functional networks by determining the heritability of the connectivity strength in a multivariate fashion. First, we reproduced and extended the connectome fingerprinting analysis to the identification of twin pairs. Then, we estimated the heritability of functional networks by a multivariate ACE modeling approach with bootstrapping. Twin pairs were identified above chance level using connectome fingerprinting, with monozygotic twin identification accuracy equal to 57.2% on average for whole-brain connectome. Additionally, we found that a visual (0.37), the medial frontal (0.31) and the motor (0.30) functional networks were the most influenced by additive genetic factors. Our findings suggest that genetic factors not only partially determine intersubject variability of the functional connectome, such that twins can be identified using connectome fingerprinting, but also differentially influence connectivity strength in large-scale functional networks.
Horizontal acquisition of a patchwork Calvin cycle by symbiotic and free-living Campylobacterota (formerly Epsilonproteobacteria)
Authors: Assié Adrien , Leisch Nikolaus , Meier Dimitri V. , Gruber-Vodicka Harald , Tegetmeyer Halina E. , Meyerdirks Anke , Kleiner Manuel , Hinzke Tjorven , Joye Samantha , Saxton Matthew , Dubilier Nicole , Petersen Jillian M.
Published: October 2018

Although the majority of known autotrophs use the Calvin-Benson-Bassham (CBB) cycle for carbon fixation, all currently described autotrophs from the Campylobacterota (previously Epsilonproteobacteria) use the reductive tricarboxylic acid cycle (rTCA) instead. We discovered campylobacterotal epibionts (“CandidatusThiobarba”) of deep-sea mussels that have acquired a complete CBB cycle and lost key genes of the rTCA cycle. Intriguingly, the phylogenies of campylobacterotal CBB genes suggest they were acquired in multiple transfers from Gammaproteobacteria closely related to sulfur-oxidizing endosymbionts associated with the mussels, as well as from Betaproteobacteria. We hypothesize that “Ca.Thiobarba” switched from the rTCA to a fully functional CBB cycle during its evolution, by acquiring genes from multiple sources, including co-occurring symbionts. We also found key CBB cycle genes in free-living Campylobacterota, suggesting that the CBB cycle may be more widespread in this phylum than previously known. Metatranscriptomics and metaproteomics confirmed high expression of CBB cycle genes in mussel-associated “Ca.Thiobarba”. Direct stable isotope fingerprinting showed that “Ca.Thiobarba” has typical CBB signatures, additional evidence that it uses this cycle for carbon fixation. Our discovery calls into question current assumptions about the distribution of carbon fixation pathways across the tree of life, and the interpretation of stable isotope measurements in the environment.
Exploring the Correlation between the Cognitive Benefits of Drug Combinations in a Clinical Alzheimer Disease Database and the Efficacies of the Same Drug Combinations Predicted from a Computational Model
Authors: Anastasio Thomas J.
Published: October 2018

INTRODUCTION

Identification of drug combinations that could be effective in Alzheimer’s treatment is made difficult by the number of possible combinations. This analysis identifies as potentially therapeutic those drug combinations that rank highest when their efficacy is determined jointly from two independent data sources.

METHODS

Estimates of the efficacy of the same drug combinations were derived from a clinical dataset and from pre-clinical data, in the form of a computational model of neuroinflammation. Standard linear regression was used to show that the two sets of estimates were correlated, and to rule out possible confounds.

RESULTS

The ten highest ranking, jointly determined drug combinations most frequently consisted of COX2 inhibitors and aspirin, along with various antihypertensive medications.

DISCUSSION

Ten combinations of from five to nine drugs, and the three-drug combination of a COX2 inhibitor, aspirin, and a calcium-channel blocker, are discussed as candidates for consideration in future clinical and pre-clinical studies.
Differential effects of corticosteroids and anti-TNF on tumor-specific immune responses - implications for the management of irAEs
Authors: Draghi Arianna , Borch Troels Holz , Radic Haja Dominike , Chamberlain Christopher Aled , Gokuldass Aishwarya , Svane Inge Marie , Donia Marco
Published: October 2018

Up to 60% of patients treated with cancer immunotherapy develop severe or life threatening immune-related adverse events (irAEs). Immunosuppression with high doses of corticosteroids or, in refractory cases, with tumor necrosis factor (TNF) antagonists, are the mainstay of treatment for irAEs. It is currently unknown what is the impact of corticosteroids and anti-TNF on the activity of antitumor T cells. In this study, the influences of clinically relevant doses of dexamethasone (corresponding to an oral dose of 10 to 125 mg prednisolone) and infliximab (anti-TNF) on the activation and killing ability of tumor-infiltrating lymphocytes (TILs) was tested in vitro. Overall, dexamethasone at low or intermediate/high dose impaired the activation (respectively −46% and −62%) and tumor-killing ability (respectively −48% and −53%) of tumor-specific TILs. In contrast, a standard clinical dose of infliximab only had a minor effect on T cell activation (−20%) and tumor killing (−10%). A brief resting following exposure to dexamethasone was sufficient to rescue the in vitro activity of TILs. In conclusion, clinically-relevant doses of infliximab only influenced to a lesser extent the activity of tumor-specific TILs in vitro, whereas even low doses of corticosteroids markedly impaired the antitumor activity of TILs. These data support steroid-sparing strategies and early initiation of anti-TNF for the treatment of irAEs in immuno-oncology.
Examining Academic Leader’s work in implementing Competency-based Medical Education using Organizational Learning Theory
Authors: Fernandez Nicolas , Leduc Nicole , Caire Fon Nathalie , Ste-Marie Louis-Georges , Nguyen-Dinh Dat , Boucher Andrée
Published: October 2018

Context

Competency-based medical education (CBME) implementation is being carried out in many medical schools worldwide. Academic Leadership is a strategy where selected Faculty act to influence peers to adopt change. The Université de Montréal medical school, has adopted this strategy to implement CBME.

Purpose

This paper aims to describe the work of Academic Leaders in the process of CBME implementation and to explore relevance of the Nonaka and Toyama organizational learning theory to map implementation progress.

Method

Because knowledge creation model focuses on the relationships between leaders and social structures, embedded case study was selected. Diverse sampling method was used to select three departments: internal medicine, surgery and psychiatry, based on the number of CBME training activities. Data collection was at two intervals, two years apart. Semi-structured interviews (individual and group) were conducted with Department Heads and Academic Leaders. Thematic analysis was conducted on the 15 interview transcriptions.

Results

As implementation begins, Leaders critically revisit accepted teaching routines and develop a common conception of CBME. This enables leaders to communicate with a wider audience and work within existing committees and working groups where they “break down” CBME into practical concepts. This practical understanding, disseminated through Entrustable Professional Activities, enables observable change.

Conclusion

Leaders’ roles evolved from an “expert” that disseminates knowledge about CBME through lectures, to a responsive and pragmatic supporting role by developing and writing practical tools in collaboration with peers and program directors.
SmbHLH37 functions antagonistically with SmMYC2 in regulating jasmonate-mediated biosynthesis of phenolic acids in Salvia miltiorrhiza
Authors: Du Tang-Zhi , Niu Jun-Feng , Su Jiao , Li Sha-Sha , Guo Xiao-Rong , Li Lin , Cao Xiao-Yan , Kang Jie-Fang
Published: October 2018

Jasmonates (JAs) are integral to various defense responses and induce biosynthesis of many secondary metabolites. MYC2, a basic helix-loop-helix (bHLH) transcription factor (TF), acts as a transcriptional activator of JA signaling. MYC2 is repressed by the JASMONATE ZIM-domain (JAZ) proteins in the absence of JA, but de-repressed by the protein complex SCFCOI1 on perception of JA. We previously reported that overexpression of SmMYC2 promotes the production of salvianolic acid B (Sal B) in Salvia miltiorrhiza. However, the responsible molecular mechanism is unclear. Here, we showed that SmMYC2 binds to and activates the promoters of its target genes SmTAT1, SmPAL1, and SmCYP98A14 to activate Sal B accumulations. SmbHLH37, a novel bHLH gene significantly up-regulated by constitutive expression of SmMYC2, was isolated from S. miltiorrhiza for detailed functional characterization. SmbHLH37 forms a homodimer and interacts with SmJAZ3/8. Overexpression of SmbHLH37 substantially decreased yields of Sal B. SmbHLH37 binds to the promoters of its target genes SmTAT1 and SmPAL1 and blocks their expression to suppress the pathway for Sal B biosynthesis. These results indicate that SmbHLH37 negatively regulates JA signaling and functions antagonistically with SmMYC2 in regulating Sal B biosynthesis in S. miltiorrhiza.
A novel optimal method of robotic weld assembly line balancing problems with changeover times: a case study
Authors: Zhou Binghai , Wu Qiong
Published: October 2018

Purpose

The balancing of robotic weld assembly lines has a significant influence on achievable production efficiency. This paper aims to investigate the most suitable way to assign both assembly tasks and type of robots to every workstation, and present an optimal method of robotic weld assembly line balancing (ALB) problems with the additional concern of changeover times. An industrial case of a robotic weld assembly line problem is investigated with an objective of minimizing cycle time of workstations.

Design/methodology/approach

This research proposes an optimal method for balancing robotic weld assembly lines. To solve the problem, a low bound of cycle time of workstations is built, and on account of the non-deterministic polynomial-time (NP)-hard nature of ALB problem (ALBP), a genetic algorithm (GA) with the mechanism of simulated annealing (SA), as well as self-adaption procedure, was proposed to overcome the inferior capability of GA in aspect of local search.

Findings

Theory analysis and simulation experiments on an industrial case of a car body welding assembly line are conducted in this paper. Satisfactory results show that the performance of GA is enhanced owing to the mechanism of SA, and the proposed method can efficiently solve the real-world size case of robotic weld ALBPs with changeover times.

Research limitations/implications

The additional consideration of tool changing has very realistic significance in manufacturing. Furthermore, this research work could be modified and applied to other ALBPs, such as worker ALBPs considering tool-changeover times.

Originality/value

For the first time in the robotic weld ALBPs, the fixtures’ (tools’) changeover times are considered. Furthermore, a mathematical model with an objective function of minimizing cycle time of workstations was developed. To solve the proposed problem, a GA with the mechanism of SA was put forth to overcome the inferior capability of GA in the aspect of local search.
UAV application for precision agriculture
Authors: Perz Rafal , Wronowski Kacper
Published: October 2018

Purpose

The purpose of this study is to show the potentials of a cost-effective unmanned aerial vehicles (UAV) system for agriculture industry. The current population growth rate is so vast that farming industry must be highly efficient and optimized. As a response for high quality food demands, the new branch of the agriculture industry has been formed – the precision agriculture. It supports farming process with sensors, automation and innovative technologies. The UAV advantages over regular aviation are withering. Not only they can fly at lower altitude and are more precise but also offer same high quality and are much cheaper.

Design/methodology/approach

The main objective of this project was to implement an exemplary cost-effective UAV system with electronic camera stabilizer for gaining useful data for agriculture. The system was based on small, unmanned flying wing able to perform fully autonomous missions, a commercially available camera and an own-design camera stabilizer. The research plan was to integrate the platform and run numerous experimental flights over farms, fields and woods collecting aerial pictures. All the missions have been planned to serve for local farming and forest industries and cooperated with local business authorities.

Findings

In preliminary flight tests, the variety of geodetic, forest and agriculture data have been acquired, placed for post processing and applied for the farming processes. The results of the research were high quality orthophoto maps, 3D maps, digital surface models and images mosaics with normalized difference vegetation index. The end users were astonished with the high-quality results and claimed the high importance for their business.

Originality/value

The case study results proved that this kind of a small UAV system is exceptional to manage and optimize processes at innovative farms. So far only professional, high-cost UAV platforms or traditional airships have been applied for agriculture industry. This paper shows that even simple, commercially available equipment could be used for professional applications.
Topology optimization of a novel fuselage structure in the conceptual design phase
Authors: Liu Dianzi , Zhang Chuanwei , Wan Z. , Du Z.
Published: October 2018

Purpose

In recent years, innovative aircraft designs have been investigated by researchers to address the environmental and economic issues for the purpose of green aviation. To keep air transport competitive and safe, it is necessary to maximize design efficiencies of the aircrafts in terms of weight and cost. The purpose of this paper is to focus on the research which has led to the development of a novel lattice fuselage design of a forward-swept wing aircraft in the conceptual phase by topology optimization technique.

Design/methodology/approach

In this paper, the fuselage structure is modelled with two different types of elements – 1D beam and 2D shell – for the validation purpose. Then, the finite element analysis coupled with topology optimization is performed to determine the structural layouts indicating the efficient distributed reinforcements. Following that, the optimal fuselage designs are obtained by comparison of the results of 1D and 2D models.

Findings

The topological results reveal the need for horizontal stiffeners to be concentrated near the upper and lower extremities of the fuselage cross section and a lattice pattern of criss-cross stiffeners should be well-placed along the sides of the fuselage and near the regions of window locations. The slight influence of windows on the optimal reinforcement layout is observed. To form clear criss-cross stiffeners, modelling the fuselage with 1D beam elements is suggested, whereas the less computational time is required for the optimization of the fuselage modelled using 2D shell elements.

Originality/value

The authors propose a novel lattice fuselage design in use of topology optimization technique as a powerful design tool. Two types of structural elements are examined to obtain the clear reinforcement detailing, which is also in agreement with the design of the DLR (German Aerospace Center) demonstrator. The optimal lattice layout of the stiffeners is distinctive to the conventional semi-monocoque fuselage design and this definitely provides valuable insights into the more efficient utilization of composite materials for novel aircraft designs.
The quicker, the better? The antecedents and consequences of response timing strategy in the aftermath of a corporate crisis
Authors: Yao Nengzhi (Chris) , Wei Jiuchang , Zhu Weiwei , Bondar Alexander
Published: October 2018

Purpose

The conclusions on the importance of corporate response timing to a crisis have remained inconsistent. Some studies suggest that active response may reduce negative impacts, whereas managers argue that issuing official response frustrates stakeholders and thus decreases the firm value. The purpose of this paper is to investigate the role of external media in the response timing strategy and the consequent stock market reaction.

Design/methodology/approach

Based on 130 corporate crises that befell publicly listed firms in China from 2007 to 2014, this paper uses the Baidu News Search Engine and Chinese Lexical Analysis System to construct the variables of the media characteristics. A structural equation model is established to test the hypotheses.

Findings

The results of this paper suggest that media coverage drives response timing after a crisis. Although an official response is a burden for firms, the timing strategy has multidimensional benefits including effectively alleviating negative effects (defined as buffering effects) and repairing the market (defined as restoring effects). Moreover, the buffering effects of response timing are stronger when completeness of response is low.

Originality/value

This study mainly contributes to crisis communication literature by introducing the role of media in prompting managers to make timing decisions. The findings of this study provide empirical support for the importance of timing response strategy.
Ownership structure, board of directors and firm performance: evidence from Taiwan
Authors: Kao Mao-Feng , Hodgkinson Lynn , Jaafar Aziz
Published: October 2018

Purpose

Using a data set of listed firms domiciled in Taiwan, this paper aims to empirically assess the effects of ownership structure and board of directors on firm value.

Design/methodology/approach

Using a sample of Taiwanese listed firms from 1997 to 2015, this study uses a panel estimation to exploit both the cross-section and time–series nature of the data. Furthermore, two stage least squares (2SLS) regression model is used as robustness test to mitigate the endogeneity issue.

Findings

The main results show that the higher the proportion of independent directors, the smaller the board size, together with a two-tier board system and no chief executive officer duality, the stronger the firm’s performance. With respect to ownership structure, block-holders’ ownership, institutional ownership, foreign ownership and family ownership are all positively related to firm value.

Research limitations/implications

Although the Taiwanese corporate governance reform concerning the independent director system which is mandatory only for newly-listed companies is successful, the regulatory authority should require all listed companies to appoint independent directors to further enhance the Taiwanese corporate governance.

Originality/value

First, unlike most of the previous literature on Western developed countries, this study examines the effects of corporate governance mechanisms on firm performance in a newly industrialised country, Taiwan. Second, while a number of studies used a single indicator of firm performance, this study examines both accounting-based and market-based firm performance. Third, this study addresses the endogeneity issue between corporate governance factors and firm performance by using 2SLS estimation, and details the econometric tests for justifying the appropriateness of using 2SLS estimation.
Family influences in the internationalization of the top 1,000 Taiwanese enterprises
Authors: Wei Yu-Chen , Tsao Chiung-Wen
Published: October 2018

Purpose

This paper aims to investigate the moderating effects of employee commitment, customer loyalty and corporate reputation on the relationship between family influence and international expansion.

Design/methodology/approach

A cross-national research design was conducted using both survey and secondary data of 119 firms taken from the top 1,000 Taiwanese enterprises.

Findings

This study found moderating effects in the positive impact of family influence on international expansion. Specifically, the study found the relationship between family influence and international expansion stronger for companies with greater relational support from employees, customers and the public.

Research limitations/implications

Multi-level data collection and a longitudinal research design in future research could help in further understanding the relationships between the variables in this study.

Practical implications

This paper suggests that family business should establish enduring relationship with their employees and customers and have a plan to improve family reputation that will benefit international market expansion.

Originality/value

This study draws on the relational perspective to investigate how family influence results in different international expansion.