bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic encoding of targeted MRI contrast agents for in vivo tumor imaging
Authors: Schuerle Simone , Furubayashi Maiko , Soleimany Ava P. , Gwisai Tinotenda , Huang Wei , Voigt Christopher , Bhatia Sangeeta N. 
Published: October 2019

AbstractTumor-selective contrast agents have the potential to aid in the diagnosis and treatment of cancer using noninvasive imaging modalities such as magnetic resonance imaging (MRI). Such contrast agents can consist of magnetic nanoparticles incorporating functionalities that respond to cues specific to tumor environments. Genetically engineering magnetotactic bacteria to display peptides has been investigated as a means to produce contrast agents that combine the robust image contrast effects of magnetosomes with transgenic targeting peptides displayed on their surface. This work reports the first use of magnetic nanoparticles that display genetically-encoded pH low insertion peptide (pHLIP), a long peptide intended to enhance MRI contrast by targeting the extracellular acidity associated with the tumors. To demonstrate the modularity of this versatile platform to incorporate diverse targeting ligands by genetic engineering, we also incorporated the cyclic αv integrin-binding peptide iRGD into separate magnetosomes. Specifically, we investigate their potential for enhanced binding and tumor imaging both in vitro and in vivo. Our experiments indicate that these tailored magnetosomes retain their magnetic properties, making them well-suited as T2 contrast agents, while exhibiting increased binding compared to wild-type magnetosomes.
Major changes in plastid protein import and the origin of the Chloroplastida
Authors: Knopp Michael , Garg Sriram G. , Handrich Maria , Gould Sven B. 
Published: October 2019

AbstractWhile core components of plastid protein import (Toc and Tic) and the principle of using N-terminal targeting sequences (NTS) are conserved, lineage-specific differences are known. Rhodophytes and glaucophytes carry a conserved NTS motif, which was lost in the green lineage that also added novel proteins to Toc and Tic. Here we compare the components of plastid protein import and generated RNA-Seq, pigment profile and trans-electron microscopy data based on high-light stress from representatives of the three archaeplastidal groups. In light of plastid protein targeting, we compare the response to high-light stress of archaeplastidal representatives based on RNA-Seq, pigment profile and trans-electron microscopy data. Like land plants, the chlorophyte Chlamydomonas reinhardtii displays a broad respond to high-light stress, not observed to the same degree in the glaucophyte Cyanophora paradoxa or the rhodophyte Porphyridium purpureum. We find that only the green lineage encodes a conserved duplicate of the outer plastid membrane protein channel Oep80, namely Toc75 and suggest that the ability to respond to high-light stress entailed evolutionary changes in protein import, including the departure from phenylalanine-based targeting and the introduction of a green-specific Toc75 next to other import components unique to Chloroplastida. One consequence of relaxed NTS specificity was the origin of dual-targeting of plastid derived proteins to mitochondria and vice versa, using a single ambiguous NTS. Changes in the plastid protein import enabled the green lineage to import proteins at a more efficient rate, including those required for high-light stress response, a prerequisite for the colonization of land.High-lightsLoss of Phe-based N-terminal targeting sequences (NTS) triggered the origin of dual-targeting using a single ambiguous NTSThe Chloroplastida evolved a green-specific Toc75 for high throughput import, next to a universal and ancient Omp85 present in all ArchaeplastidaA broad response to high-light stress appears unique to ChloroplastidaRelaxation of functional constraints allowed a broader modification of the green Toc/Tic machineryCritical changes in plastid targeting enabled the origin and success of the Chloroplastida and their later conquer of land
Joint Universal Modular Plasmids (JUMP): A flexible and comprehensive platform for synthetic biology
Authors: Valenzuela-Ortega Marcos , French Christopher 
Published: October 2019

AbstractComplex multi-gene plasmids can be built from basic DNA parts in a reliable and automation friendly way using modular cloning standards, based on Golden Gate cloning. However, each toolkit or standard is limited to one or a few different vectors, which has led to an overabundance of toolkits with varying degrees of compatibility. Here, we present the Joint Universal Modular Plasmids (JUMP), a vector design that overcomes the limitations of current toolkits by expanding the paradigm of modular cloning: all vectors can be modified using modular cloning in an orthogonal way using multiple cloning sites. This allows researchers to introduce any feature into any JUMP vector and simplifies the Design-Build-Test cycle of synthetic biology. JUMP vectors are compatible with PhytoBrick basic parts, BioBricks and the Registry of Standard Biological Parts, and the Standard European Vector Architecture (SEVA). Due to their flexible design, JUMP vectors have the potential to be a universal platform for synthetic biology regardless of host and application. A collection of JUMP backbones and microbial PhytoBrick basic parts are available for distribution.
Gliotransmission orchestrates neuronal type-specific axon regeneration
Authors: Wang Fei , Ruppell Kendra Takle , Zhou Songlin , Qu Yun , Gong Jiaxin , Shang Ye , Li Yi , Xiang Yang 
Published: October 2019

SUMMARYWhy closely related neuronal types differ in their axon regenerative abilities remains elusive. Here, we demonstrate gliotransmission determines such a difference in Drosophila larval sensory neurons. Axotomy activates ensheathing glia, which signal to regenerative neurons through the gliotransmitter adenosine, to mount regenerative programs including neuronal activity and Ras. Surprisingly, ensheathing glia do not signal to non-regenerative neurons. Such neuronal type-specific responses to gliotransmission result from specific expression of adenosine receptors in regenerative neurons. Disrupting gliotransmission impedes regeneration of regenerative neurons. Strikingly, reconstitution of gliotransmission in non-regenerative neurons enables them to regenerate. Furthermore, activation of an adenosine receptor ortholog in adult mice promotes both regeneration and survival of retinal ganglion cells, uncovering a conserved pro-regenerative role of adenosine receptors. Our studies demonstrate gliotransmission as a novel mechanism by which glia instruct axon regeneration, with neuronal type-specificity, and suggest targeting purinergic signaling as a new strategy for mammalian central nervous system repair.HIGHLIGHTSEnsheathing glia differentially interact with Drosophila sensory neuron types through gliotransmissionGliotransmission mounts axon regenerative programs in selective neuronal typesNeuronal firing pattern but not overall excitability dictates axon regeneration outcomeAdenosine receptor activation in adult mice promotes both regeneration and survival of RGCs
An endogenous glucocorticoid-cytokine signaling circuit promotes CD8+T cell dysfunction in the tumor microenvironment
Authors: Acharya Nandini , Madi Asaf , Zhang Huiyuan , Klapholz Max , Christian Elena , Dixon Karen O. , Fell Geoffrey , Tooley Katherine , Mangani Davide , Xia Junrong , Singer Meromit , Neuberg Donna , Rozenblatt-Rosen Orit , Regev Aviv , Kuchroo Vijay K. , Anderson Ana C. 
Published: October 2019

AbstractIdentifying signals in the tumor microenvironment (TME) that promote CD8+T cell dysfunction can inform improved therapeutic approaches for cancer. Here, we identify thatNr3c1, the gene encoding the glucocorticoid receptor (GR), is highly expressed in dysfunctional CD8+tumor-infiltrating lymphocytes (TILs). The GR transactivates expression of multiple checkpoint receptors and loss of GR in CD8+T cells limits dysfunctional phenotype in CD8+TILs resulting in improved tumor growth control. We show that glucocorticoids can be produced in the TME and that they co-operate with the immunosuppressive cytokine IL-27 to promote the dysfunction gene program in CD8+T cells. The presence of the glucocorticoid + IL27 signature in CD8+TILs correlates with failure to respond to checkpoint blockade in melanoma patients, highlighting the relevance of this immunoregulatory glucocorticoid-cytokine circuit in tumor tissue.
Estrogen Receptor α Regulates Ethanol Excitation of Ventral Tegmental Area Neurons and Binge Drinking in Female Mice
Authors: Vandegrift Bertha J. , Hilderbrand Elisa R. , Satta Rosalba , Tai Rex , He Donghong , You Chang , Coles Cassandre , Chen Hu , Brodie Mark S. , Lasek Amy W. 
Published: October 2019

AbstractElevations in estrogen (17β-estradiol, E2) are associated with increased alcohol drinking by women and experimentally in rodents. E2 alters the activity of the dopamine system, including the ventral tegmental area (VTA) and its projection targets, which plays an important role in binge drinking. A previous study demonstrated that during high E2 states, VTA dopamine neurons in female mice are more sensitive to ethanol excitation. However, the mechanisms responsible for the ability of E2 to enhance ethanol sensitivity of VTA dopamine neurons have not been investigated. In this study, we used selective agonists and antagonists to examine the role of estrogen receptor subtypes (ERα and ERβ) in regulating the ethanol sensitivity of VTA dopamine neurons and found that ERα promotes the enhanced ethanol response of VTA dopamine neurons. We also demonstrated that the E2-induced increase in ethanol excitation requires the activity of the metabotropic glutamate receptor, mGluR1, which is known to couple with ERα at the plasma membrane. To investigate the behavioral relevance of these findings, we administered lentivirus expressing short hairpin RNAs targeting either ERα or ERβ into the VTA and found that knockdown of each receptor in the VTA reduced binge-like ethanol drinking in female, but not male, mice. Reducing ERα in the VTA had a more dramatic effect on binge-like drinking than reducing ERβ, consistent with the ability of ERα to alter ethanol sensitivity of dopamine neurons. These results provide important insight into sex-specific mechanisms that drive excessive alcohol drinking.Significance StatementEstrogen has potent effects on the dopamine system and increases the vulnerability of females to develop addiction to substances such as cocaine and alcohol. We investigated the mechanisms by which estrogen increases the response of dopamine neurons in the ventral tegmental area to ethanol. We found that activation of the estrogen receptor, ERα, increased the ethanol-induced excitation of dopamine neurons and that this required the metabotropic glutamate receptor mGluR1. We also demonstrated that estrogen receptors in the ventral tegmental area regulate binge-like alcohol drinking by female, but not male, mice. The influence of estrogen receptors on binge drinking in female mice suggests that treatments for alcohol use disorder in women may need to account for this sex difference.
Inference of Single-Cell Phylogenies from Lineage Tracing Data
Authors: Jones Matthew G. , Khodaverdian Alex , Quinn Jeffrey J. , Chan Michelle M. , Hussmann Jeffrey A. , Wang Robert , Xu Chenling , Weissman Jonathan S. , Yosef Nir 
Published: October 2019

AbstractThe pairing of CRISPR/Cas9-based gene editing with massively parallel single-cell readouts now enables large-scale lineage tracing. However, the rapid growth in complexity of data from these assays has outpaced our ability to accurately infer phylogenetic relationships. To address this, we provide three resources. First, we introduce Cassiopeia - a suite of scalable and theoretically grounded maximum parsimony approaches for tree reconstruction. Second, we provide a simulation framework for evaluating algorithms and exploring lineage tracer design principles. Finally, we generate the most complex experimental lineage tracing dataset to date - consisting of 34,557 human cells continuously traced over 15 generations, 71% of which are uniquely marked - and use it for benchmarking phylogenetic inference approaches. We show that Cassiopeia outperforms traditional methods by several metrics and under a wide variety of parameter regimes, and provide insight into the principles for the design of improved Cas9-enabled recorders. Together these should broadly enable large-scale mammalian lineage tracing efforts. Cassiopeia and its benchmarking resources are publicly available at www.github.com/YosefLab/Cassiopeia.
Large X-linked palindromes undergo arm-to-arm gene conversion across Mus lineages
Authors: Swanepoel Callie M. , Gerlinger Emma R. , Mueller Jacob L. 
Published: October 2019

AbstractLarge (>10kb), nearly-identical (>99% nucleotide identity), palindromic sequences are enriched on mammalian sex chromosomes. Primate Y-palindromes undergo high rates of arm-to-arm gene conversion, a proposed mechanism for maintaining their sequence integrity in the absence of X-Y recombination. It is unclear whether X-palindromes, which can freely recombine in females, undergo arm-to-arm gene conversion and, if so, at what rate. We generated high-quality sequence assemblies of Mus molossinus and Mus spretus X-palindromic regions and compared them to orthologous Mus musculus X-palindromes. Our evolutionary sequence comparisons found evidence of X-palindrome arm-to-arm gene conversion at rates comparable to rates of autosomal allelic gene conversion in mice. Mus X-palindrome genes also exhibit higher than expected sequence diversification, indicating gene conversion may facilitate the rapid evolution of palindrome-associated genes. We conclude that in addition to maintaining genes’ sequence integrity via sequence homogenization, arm-to-arm gene conversion can also rapidly drive genetic evolution via sequence diversification.
Transcriptomic signatures predict regulators of drug synergy and clinical regimen efficacy against Tuberculosis
Authors: Ma Shuyi , Jaipalli Suraj , Larkins-Ford Jonah , Lohmiller Jenny , Aldridge Bree B. , Sherman David R. , Chandrasekaran Sriram 
Published: October 2019

ABSTRACTThe rapid spread of multi-drug resistant strains has created a pressing need for new drug regimens to treat tuberculosis (TB), which kills 1.8 million people each year. Identifying new regimens has been challenging due to the slow growth of the pathogen M. tuberculosis (MTB), coupled with large number of possible drug combinations. Here we present a computational model (INDIGO-MTB) that identified synergistic regimens featuring existing and emerging anti-TB drugs after screening in silico over 1 million potential drug combinations using MTB drug transcriptomic profiles. INDIGO-MTB further predicted the gene Rv1353c as a key transcriptional regulator of multiple drug interactions, and we confirmed experimentally that Rv1353c up-regulation reduces the antagonism of the bedaquiline-streptomycin combination. Retrospective analysis of 57 clinical trials of TB regimens using INDIGO-MTB revealed that synergistic combinations were significantly more efficacious than antagonistic combinations (p-value = 1 × 10−4) based on the percentage of patients with negative sputum cultures after 8 weeks of treatment. Our study establishes a framework for rapid assessment of TB drug combinations and is also applicable to other bacterial pathogens.IMPORTANCEMulti-drug combination therapy is an important strategy for treating tuberculosis, the world’s deadliest bacterial infection. Long treatment durations and growing rates of drug resistance have created an urgent need for new approaches to prioritize effective drug regimens. Hence, we developed a computational model called INDIGO-MTB, which identifies synergistic drug regimens from an immense set of possible drug combinations using pathogen response transcriptome elicited by individual drugs. Although the underlying input data for INDIGO-MTB was generated under in vitro broth culture conditions, the predictions from INDIGO-MTB correlated significantly with in vivo drug regimen efficacy from clinical trials. INDIGO-MTB also identified the transcription factor Rv1353c as a regulator of multiple drug interaction outcomes, which could be targeted for rationally enhancing drug synergy.
Reconsidering school improvement through the community equity literacy leadership assessment (CELLA) for principals
Authors: Green Terrance , Castro Andrene J. , Lowe Tracie , Sikes Chloe , Gururaj Suchitra , Mba Chioma 
Published: October 2019

PurposeThe purpose of this paper is to reconsider school improvement from the perspectives of community leaders who support urban schools in equitable ways.Design/methodology/approachThis study employs the Delphi method to elicit feedback from community leaders.FindingsFindings highlight how the community equity literacy leadership assessment’s (CELLA) constructs can be expanded to include essential knowledge and practices that improve schooling conditions for students.Originality/valueThis study extends the existing research on school improvement in two ways. First, this study reconsiders school improvement from the perspectives of community leaders who support urban schools in equitable ways. Second, and in doing so, this study examines how a panel of 16 “expert community leaders” offered feedback on the CELLA for principals, an emerging survey instrument to help educational leaders improve school and community conditions.
Implementing experiential action learning in the MBA: use of an international consulting experience
Authors: Schaupp Ludwig Christian , Vitullo Elizabeth A. 
Published: October 2019

PurposeExperiential learning projects require students to go further than the typical theoretical and conceptual MBA coursework requiring them to draw on their previously acquired skills to solve actual business problems from a real-world client. The purpose of this paper is to offer a detailed overview of an experiential learning global consulting project and its potential benefits, along with practical classroom recommendations.Design/methodology/approachThis paper describes a global consulting project embedded in an MBA international consulting course involving a German manufacturing company operating a single production facility in the USA.FindingsFindings suggest that in post-class assessments students were quite supportive, touting is as one of the most beneficial to their MBA education and their job placement upon graduation.Research limitations/implicationsThis experiential project has largely been assessed through qualitative feedback from both the students and the client. Future research efforts should assess the project in a more robust fashion. Going forward, the use of survey assessments on the project as a whole would provide more objective feedback. Obtaining feedback from graduates 1 to 5 years post-graduation would provide a valuable perspective on the project’s overall effectiveness.Practical implicationsThe global consulting project described in this manuscript provided students with a vehicle to mimic a consulting engagement with an actual client in a real-world context.Social implicationsThe global consulting project described in this manuscript provided students with an opportunity to develop further their global and cultural competence. In addition, it provides an opportunity for students to fully develop the critical thinking skills, business acumen and the soft skills required of them to be successful in their future careers.Originality/valueThe combination of an international context and high degree of client engagement on this project make it a unique learning opportunity. This project is different as it provides a comprehensive, step-by-step, integrated approach that begins with an extensive interview process to secure a spot on the team with limited openings, then client discussions to identify the problem and determine the scope of engagement, which includes a client contract that outlines the objective and the deliverable of the engagement, followed by personal skill assessment to draw upon meta-competences necessary for the project’s success. Immersing the students in the client engagement, wherever it may take them both intellectually as well as physically (i.e. domestic and international locations) creates a template from which they can draw upon periodically as they progress in their professional.
Understanding acquisition and processing error in microseismic data: An example from Pouce Coupe Field, Canada
Authors: Bray Matthew , White Isabel 
Published: October 2019

ABSTRACTA challenge in microseismic monitoring is quantification of survey acquisition and processing errors, and how these errors jointly affect estimated locations. Quantifying acquisition and processing errors and uncertainty has multiple benefits, such as more accurate and precise estimation of locations, anisotropy, moment tensor inversion and, potentially, allowing for detection of 4D reservoir changes. Here, we quantify uncertainty due to acquisition, receiver orientation error, and hodogram analysis. Additionally, we illustrate the effects of signal to noise ratio variances upon event detection. We apply processing steps to a downhole microseismic dataset from Pouce Coupe, Alberta, Canada. We use a probabilistic location approach to identify the optimal bottom well location based upon known source locations. Probability density functions are utilized to quantify uncertainty and propagate it through processing, including in source location inversion to describe the three‐dimensional event location likelihood. Event locations are calculated and an amplitude stacking approach is used to reduce the error associated with first break picking and the minimization with modelled travel times. Changes in the early processing steps have allowed for understanding of location uncertainty of the mapped microseismic events.
A high‐precision time–frequency analysis for thin hydrocarbon reservoir identification based on synchroextracting generalized S‐transform
Authors: Hu Ying , Chen Hui , Qian Hongyan , Zhou Xinyue , Wang Yuanjun , Lyu Bin 
Published: October 2019

ABSTRACTImproving the seismic time–frequency resolution is a crucial step for identifying thin reservoirs. In this paper, we propose a new high‐precision time–frequency analysis algorithm, synchroextracting generalized S‐transform, which exhibits superior performance at characterizing reservoirs and detecting hydrocarbons. This method first calculates time–frequency spectra using generalized S‐transform; then, it squeezes all but the most smeared time–frequency coefficients into the instantaneous frequency trajectory and finally obtains highly accurate and energy‐concentrated time–frequency spectra. We precisely deduce the mathematical formula of the synchroextracting generalized S‐transform. Synthetic signal examples testify that this method can correctly decompose a signal and provide a better time–frequency representation. The results of a synthetic seismic signal and real seismic data demonstrate that this method can identify some reservoirs with thincknesses smaller than a quarter wavelength and can be successfully applied for hydrocarbon detection. In addition, examples of synthetic signals with different levels of Gaussian white noise show that this method can achieve better results under noisy conditions. Hence, the synchroextracting generalized S‐transform has great application prospects and merits in seismic signal processing and interpretation.