bluuebunny/crossref_metadata_2025 huggingface dataset:
Non-canonical autophagy in dendritic cells restricts cross-presentation and anti-tumor immunity
Authors: Sil Payel , Zhao Fei , Muse Ginger W. , Wong Sing-Wai , Kolb Joseph P. , DeGraff Laura Miller , Tucker Charles J. , Scappini Erica , Snyder Annelise G. , Grimm Sara , Oberst Andrew , Martinez Jennifer
Published: October 2019

Major Histocompatibility Complex I (MHC-I) molecules classically present peptides derived from endogenous antigens, but exogenous antigens can also gain access to the MHC-I machinery in dendritic cells (DCs), which can activate antigen-specific CD8+T cells. This process, termed cross-presentation, can be triggered by the uptake of dying autologous cells, including tumor cells, by DCs. The molecular mechanisms that underlie efficient cross-presentation remain largely uncharacterized, and an improved understanding of these mechanisms might reveal novel strategies for anti-tumor therapies. Rubicon (RUBCN) is a molecule required for LC3-associated phagocytosis (LAP), but dispensable for canonical autophagy, and mice lacking this protein develop an autoimmune inflammatory pathology with age. Here, we demonstrate thatRubcn-deficient DCs have increased retention of engulfed cellular cargo in immature phagosomes resulting in increased phagosome-to-cytosol escape and antigen access to proteasome-mediated degradation. As a result, mice selectively lackingRubcnin DCs mount stronger tumor antigen-specific CD8+T cell responses and exhibit decreased tumor burden compared to wild type littermates. These findings identify LAP as a key regulator of cross-presentation and suggest that targeting RUBCN might represent a novel strategy for anti-tumor therapy.
Defining the DmsA Signal Sequence Interaction with DmsD And TatBC
Authors: Ghosh Deepanjan , Ramasamy Sureshkumar
Published: October 2019

Redox – enzyme maturation proteins (REMP) ensure co-factor loading and folding of proteins targeted to the twin-arginine translocation (Tat) pathway. The details of the interaction of a REMP with the corresponding signal sequence of its substrate are not well understood. Here, we demonstrate the features of the signal sequence for the Tat substrate DmsA (ssDmsA) responsible for complex formation with its REMP, DmsD, and with the Tat membrane complex TatB & TatC (TatBC). A heterologously expressed ssDmsA/DmsD complex forms two stochiometric populations corresponding to monomeric and dimeric forms of the complex. The monomeric complex has a higher affinity for the TatBC complex than the dimeric, which imply higher level regulation process to ensure the maturation of protein before translocation. Results from various binding studies yielded the shortest signal peptide required for ssDmsA/DmsA interaction and the region responsible for the TatBC interaction. Further experiments like alanine scanning in this peptide highlight the possible residues that are essential for this complex formation.
Dopamine 2 receptor signaling controls the daily burst in phagocytic activity in the mouse retinal pigment epithelium
Authors: Goyal Varunika , DeVera Christopher , Laurent Virginie , Sellers Jana , Chrenek Micah A. , Hicks David , Baba Kenkichi , Iuvone P. Michael , Tosini Gianluca
Published: October 2019

Purpose

A burst in phagocytosis of spent photoreceptor outer fragments by retinal pigment epithelium (RPE) is a rhythmic process occurring 1-2 hours after the onset of light. This phenomenon is considered crucial for the health of the photoreceptors and RPE. We have recently reported that dopamine, via dopamine 2 receptor (D2R), shifts the circadian rhythm in the RPE.

Methods

Here, we first investigated the impact of the removal of D2R on the daily peak of phagocytosis by RPE and then we analyzed the function and morphology of retina and RPE in the absence of D2R.

Results

D2R KO mice do not show a daily burst of phagocytic activity after the onset of light. Also, in contrast to control, phosphorylation of FAK did not increase significantly in KO mice at ZT1. RNA sequencing revealed a total of 394 differentially expressed genes (DEGs) between ZT23 and ZT1 in the control mice, whereas in D2R KO mice, we detected 1054 DEGs. Pathway analysis of the gene expression data implicated integrin signaling to be one of the upregulated pathways in control but not in D2R KO mice. No difference in retinal thickness, visual function, or morphology of RPE cells was observed between WT and D2R KO mice at the age of 3 and 12 months.

Conclusions

Our data suggest that removal of D2R prevents the burst in phagocytosis and a related increase in the phosphorylation of FAK after light onset. The pathway analysis points towards a putative role of D2R in controlling integrin signaling, which is known to play an important role in the control of the daily burst of phagocytosis by the RPE. Our data also indicate that the absence in the burst of phagocytic activity in the early morning does not produce any apparent deleterious effect on the retina or RPE up to one year of age.
FvLcp1, a type-D fungal LysM protein with Chitin-binding domains, is a secreted protein involved in host recognition and fumonisin production in Fusarium verticillioides - maize kernel interaction
Authors: Zhang Huan , Kim Man S. , Huang Jun , Yan Huijuan , Yang Tao , Song Linlin , Yu Wenying , Shim Won Bo
Published: October 2019

Fusarium verticillioides is one of the key maize ear rot pathogens and produces fumonisins, a group of mycotoxins detrimental to humans and animals. Unfortunately, our understanding on how this fungus interacts with maize kernels to trigger mycotoxin biosynthesis is very limited.

We performed a systematic computational network-based analysis of large-scale F. verticillioides RNA-seq datasets to identify potential gene subnetwork modules that are associated with virulence and fumonisin regulation.

Among the highly discriminative subnetwork modules, we identified a putative hub gene FvLCP1, which encodes a putative a type-D fungal LysM protein with a signal peptide, three LysM domains, and two chitin binding domains. FvLcp1 is a unique protein that harbors these domains amongst five representative Fusarium species.

FvLcp1 is a secreted protein important for fumonisin production with LysM domain playing acritical role. Chitin-binding domain was essential for in vitro chitin binding.

Using rice blast fungus, we learned that FvLcp1 accumulates in appressoria, a key infection structure, suggesting that FvLcp1 could be involved in host recognition and infection. Also, full length FvLcp1 was able to suppress the BAX triggered plant cell death in Nicotiana benthamiana.

This is the first report where a unique type-D LysM secreted protein with chitin-binding domain in mycotoxigenic fungus F. verticillioides was shown to be potentially involved in suppressing host cell death and promoting fumonisins biosynthesis while the pathogen colonizes maize kernels.
Temperature shapes movement and habitat selection by a heat-sensitive ungulate
Authors: Alston Jesse M. , Joyce Michael J. , Merkle Jerod A. , Moen Ron A.
Published: October 2019

Context

Warmer weather caused by climate change poses increasingly serious threats to the persistence of many species, but animals can modify behavior to mitigate at least some of the threats posed by warmer temperatures. Identifying and characterizing how animals modify behavior to avoid the negative consequences of acute heat will be crucial for understanding how animals will respond to warmer temperatures in the future.

Objectives

We studied the extent to which moose (Alces alces), a species known to be sensitive to heat, mitigates heat on hot summer days via multiple different behaviors: (1) reduced movement, (2) increased visitation to shade, (3) increased visitation to water, or (4) a combination of these behaviors.

Methods

We used GPS telemetry and a step-selection function to analyze movement and habitat selection by moose in northeastern Minnesota, USA.

Results

Moose reduced movement, used areas of the landscape with more shade, and traveled nearer to mixed forests and bogs during periods of heat. Moose used shade far more than water to ameliorate heat, and the most pronounced changes in behavior occurred between 15°C and 20°C.

Conclusions

Research characterizing the behaviors animals use to facilitate thermoregulation will aid conservation of heat-sensitive species in a warming world. The modeling framework presented in this study is a promising method for evaluating the influence of temperature on movement and habitat selection.
Metabolome-informed microbiome analysis refines metadata classifications and reveals unexpected medication transfer in captive cheetahs
Authors: Gauglitz Julia M. , Morton James T. , Tripathi Anupriya , Hansen Shalisa , Gaffney Michele , Carpenter Carolina , Weldon Kelly C. , Shah Riya , Parampil Amy , Fidgett Andrea , Swafford Austin D. , Knight Rob , Dorrestein Pieter C.
Published: October 2019

Structured Abstract

Even high-quality collection and reporting of study metadata in microbiome studies can lead to various forms of inadvertently missing or mischaracterized information that can alter the interpretation or outcome of the studies, especially with non-model organisms. Metabolomic profiling of fecal microbiome samples can provide empirical insight into unanticipated confounding factors that are not possible to obtain even from detailed care records. We illustrate this point using data from cheetahs from the San Diego Zoo Safari Park. The metabolomic characterization indicated that one cheetah had to be moved from the non-antibiotic-exposed to the antibiotic-exposed group. The detection of the antibiotic in this second cheetah was likely due to grooming interactions with the cheetah that was administered antibiotics. Similarly, because transit time for stool is variable, early fecal samples within the first few days of antibiotic prescription do not all contain detectable antibiotics. Therefore, the microbiome is not affected by the antibiotics at those time points. These insights significantly altered the way the samples were grouped for analysis (antibiotic vs no antibiotic), and the subsequent understanding of the effect of the antibiotics on the cheetah microbiome. Metabolomics also revealed information about numerous other medications, and provided unexpected dietary insights that in turn improved our understanding of the molecular patterns on the impact on the community microbial structure. These results suggest that untargeted metabolomics data provide empirical evidence to correct records of non-model organisms in captivity, although we also expect these methods will be appropriate for experimental conditions typical in human studies.

Importance

Metabolome-informed analyses can enhance ‘omics studies by enabling the correct partitioning of samples by identifying hidden confounders inadvertently misrepresented or omitted from carefully curated metadata. We demonstrate the utility of metabolomics in a study characterizing the microbiome associated with liver disease in cheetahs. Metabolome-informed reinterpretation of metagenome and metabolome profiles factored in an unexpected transfer of antibiotics preventing misinterpretation of the data. Our work suggests that untargeted metabolomics can be used to verify, augment, and correct sample metadata to support improved grouping of sample data for microbiome analyses, here for non-model organisms in captivity. However, the techniques also suggest a path forward for correcting clinical information in human studies to enable higher-precision analyses.
Shigella flexneridisruption of host cell-cell tension promotes intercellular spread
Authors: Duncan Jeffrey K. , Wiscovitch Alexandra L. , Goldberg Marcia B. , Russo Brian C.
Published: October 2019

During infection, a subset of bacterial pathogens invades into the eukaryotic cytosol and spreads between cells of an epithelial layer. This intercellular spread is essential for disease and requires actin-based motility leading to the formation of plasma membrane protrusions. Protrusions are engulfed by the adjacent cell in an active process requiring both bacterial and eukaryotic proteins. Here, we demonstrate that theShigellaspp. type 3 secretion system protein IpaC promotes bacterial spread by reducing intercellular tension.S. flexneriproducing a point mutant of IpaC that cannot interact with the cell-cell adhesion protein β-catenin were unable to reduce intercellular tension, form protrusions, or spread, demonstrating that interaction of IpaC with β-catenin is required for these processes. Spread was restored by chemical reduction of intercellular tension or genetic depletion of β-catenin. This work defines a molecular mechanism by whichShigellaovercomes host cell-cell tension to mediate spread.
Reduced fronto-striatal volume in ADHD in two cohorts across the lifespan
Authors: Cupertino Renata Basso , Soheili-Nezhad Sourena , Grevet Eugenio Horacio , Bandeira Cibele Edom , Picon Felipe Almeida , Tavares Maria Eduarda , Naaijen Jilly , van Rooij Daan , Akkermans Sophie , Vitola Eduardo Schneider , Zwiers Marcel P , Hoekstra Pieter J. , Breda Vitor , Oosterlaan Jaap , Hartman Catharina A , Beckmann Christian F. , Buitelaar Jan K. , Franke Barbara , Dotto Bau Claiton Henrique , Sprooten Emma
Published: October 2019

Objective

Neuroimaging studies have associated Attention-Deficit/Hyperactivity Disorder (ADHD) with altered brain anatomy. However, small and heterogeneous study samples, and the use of region-of-interest and tissue-specific analyses have limited the consistency and replicability of these effects. The present study uses a fully data-driven multivariate approach to investigate alterations in both gray and white matter simultaneously, and capture neuroanatomical features associated with ADHD in two large, independent, demographically different cohorts.

Methods

The study comprised two ADHD cohorts with structural magnetic resonance imaging data: the Dutch NeuroIMAGE cohort (n=890, average age 17.2 years, discovery sample) and the Brazilian IMpACT cohort (n=180, average age 44.2 years, cross validation sample). Using independent component analysis of whole-brain morphometry images in the NeuroIMAGE cohort, 375 independent components of neuroanatomical variations were extracted and assessed their association with ADHD. Afterwards, ADHD-associated components were cross validated in the Brazilian IMpACT cohort.

Results

In both discovery (corrected-p=0.020) and validation (p=0.033) cohorts, ADHD diagnosis was significantly associated with reduced brain volume in a component mapping to frontal lobes, striatum, and their interconnecting white-matter tracts. The most pronounced case-control differences were localized in white matter adjacent to the orbitofrontal cortex.

Conclusion

Independent component analysis is a sensitive approach to uncover neuroanatomical alterations in ADHD and avoid bias attributable toa prioriregion-of-interest based methods. Current results provide further evidence for the role of the fronto-striatal circuit in ADHD. The fact that the two cohorts are from different continents and comprising different age ranges highlights the robustness of the findings.
3D super-resolution deep-tissue imaging in living mice
Authors: Velasco Mary Grace M. , Zhang Mengyang , Antonello Jacopo , Yuan Peng , Allgeyer Edward S. , May Dennis , M’Saad Ons , Kidd Phylicia , Barentine Andrew E. S. , Greco Valentina , Grutzendler Jaime , Booth Martin J. , Bewersdorf Joerg
Published: October 2019

Stimulated emission depletion (STED) microscopy enables the three-dimensional (3D) visualization of dynamic nanoscale structures in living cells, offering unique insights into their organization. However, 3D-STED imaging deep inside biological tissue is obstructed by optical aberrations and light scattering. We present a STED system that overcomes these challenges. Through the combination of 2-photon excitation, adaptive optics, far-red emitting organic dyes, and a long-working distance water-immersion objective lens, our system achieves aberration-corrected 3D super-resolution imaging, which we demonstrate 164 µm deep in fixed mouse brain tissue and 76 µm deep in the brain of a living mouse.
Systematic Establishment of Robustness and Standards in Patient-Derived Xenograft Experiments and Analysis
Authors: Evrard Yvonne A. , Srivastava Anuj , Randjelovic Jelena , Arunachalam Sasi , Bult Carol J. , Chen Huiqin , Chen Lily , Davies Michael , Davies Sherri , Davis-Dusenbery Brandi , DiGiovanna Jack , Ding Li , Doroshow James H. , Fang Bingliang , Frech Christian , Govindan Ramaswamy , Ha Min Jin , Herlyn Meenhard , Jeon Ryan , Kossenkov Andrew , Lewis Michael T. , Li Shunqiang , Lloyd Michael , Meric-Bernstam Funda , Miletic Nevena , Moscow Jeffrey A. , Neuhauser Steven , Nix David , Patidar Rajesh , Rebecca Vito , Robinson Peter N. , Rosains Jacqueline , Roth Jack , Seth Isheeta , Stankovic Tamara , Stanojevic Adam , Tine Brian A. Van , Welm Alana L. , Welm Bryan E. , Wickramasinghe Jayamanna , Woo XingYi , Xiao Min , Zhao Zi-ming , Dean Dennis A. , Morris Jeffrey S. , Chuang Jeffrey H.
Published: October 2019

Patient-Derived Xenografts (PDXs) are tumor-in-mouse models for cancer. PDX collections, such as those supported by the NCI PDXNet program, are powerful resources for preclinical therapeutic testing. However, variations in experimental design and analysis procedures have limited interpretability. To determine the robustness of PDX studies, the PDXNet tested temozolomide drug response for three pre-validated PDX models (sensitive, resistant, and intermediate) across four blinded PDX Development and Trial Centers (PDTCs) using independently selected SOPs. Each PDTC was able to correctly identify the sensitive, resistant, and intermediate models, and statistical evaluations were concordant across all groups. We also developed and benchmarked optimized PDX informatics pipelines, and these yielded robust assessments across xenograft biological replicates. These studies show that PDX drug responses and sequence results are reproducible across diverse experimental protocols. Here we share the range of experimental procedures that maintained robustness, as well as standardized cloud-based workflows for PDX exome-seq and RNA-Seq analysis and for evaluating growth.
Massive haplotypes underlie ecotypic differentiation in sunflowers
Authors: Todesco Marco , Owens Gregory L. , Bercovich Natalia , Légaré Jean-Sébastien , Soudi Shaghayegh , Burge Dylan O. , Huang Kaichi , Ostevik Katherine L. , Drummond Emily B. M. , Imerovski Ivana , Lande Kathryn , Pascual Mariana A. , Cheung Winnie , Staton S. Evan , Muños Stéphane , Nielsen Rasmus , Donovan Lisa A. , Burke John M. , Yeaman Sam , Rieseberg Loren H.
Published: October 2019

Species often include multiple ecotypes that are adapted to different environments. But how do ecotypes arise, and how are their distinctive combinations of adaptive alleles maintained despite hybridization with non-adapted populations? Re-sequencing of 1506 wild sunflowers from three species identified 37 large (1-100 Mbp), non-recombining haplotype blocks associated with numerous ecologically relevant traits, and soil and climate characteristics. Limited recombination in these regions keeps adaptive alleles together, and we find that they differentiate several sunflower ecotypes; for example, they control a 77 day difference in flowering between ecotypes of silverleaf sunflower (likely through deletion of a FLOWERING LOCUS T homolog), and are associated with seed size, flowering time and soil fertility in dune-adapted sunflowers. These haplotypes are highly divergent, associated with polymorphic structural variants, and often appear to represent introgressions from other, possibly extinct, congeners. This work highlights a pervasive role of structural variation in maintaining complex ecotypic adaptation.
Read coverage as an indicator of misassembly in a short-read based genome assembly
Authors: Wang Peipei , Meng Fanrui , Moore Bethany M. , Shiu Shin-Han
Published: October 2019

Availability of genome sequences has led to significant advance in biology. With few exceptions, the great majority of existing genome assemblies are derived from short read sequencing technologies with highly uneven read coverages indicative of sequencing and assembly issues. In tomato, 0.6% (5.1 Mb) and 9.7% (79.6 Mb) of short-read based assembly had significantly higher and lower coverage compared to background, respectively. We established machine learning models capable of predicting genomic regions with variable coverages and found that high coverage regions tend to have lower simple sequence repeat but higher tandem gene densities compared to background regions. To determine if the high coverage regions were misassembled, we examined a recently available long-read based assembly and found that 27.8% (1.41 Mb) of high coverage regions were potentially mis-assembled of duplicate sequences, compared to 1.4% in background regions. In addition, using a machine learning model that can distinguish correctly and incorrectly assembled high coverage regions, we found that misassembled, high coverage regions tend to be flanked by simple sequence repeats, pseudogenes, and transposon elements. Our study provides insights on the causes of variable coverage regions and a quantitative assessment of factors contributing to misassembly when using short reads.
MAGOS: Discovering Subclones in Tumors Sequenced at Standard Depths
Authors: Ahmadinejad Navid , Troftgruben Shayna , Maley Carlo , Wang Junwen , Liu Li
Published: October 2019

Understanding intratumor heterogeneity is critical to designing personalized treatments and improving clinical outcomes of cancers. Such investigations require accurate delineation of the subclonal composition of a tumor, which to date can only be reliably inferred from deep-sequencing data (>300x depth). To enable accurate subclonal discovery in tumors sequenced at standard depths (30-50x), we develop a novel computational method that incorporates an adaptive error model into statistical decomposition of mixed populations, which corrects the mean-variance dependency of sequencing data at the subclonal level. Tested on extensive computer simulations and real-world data, this new method, named model-based adaptive grouping of subclones (MAGOS), consistently outperforms existing methods on minimum sequencing depth, decomposition accuracy and computation efficiency. MAGOS supports subclone analysis using single nucleotide variants and copy number variants from one or more samples of an individual tumor. Applications of MAGOS to whole-exome sequencing data of 331 liver cancer samples discovered a significant association between subclonal diversity and patient overall survival. MAGOS is freely available as an R package at github (https://github.com/liliulab/magos).
Genetic Algorithms for model refinement and rule discovery in a high-dimensional agent-based model of inflammation
Authors: Cockrell R Chase , An Gary
Published: October 2019

Introduction

Agent-based modeling frequently used modeling method for multi-scale mechanistic modeling. However, the same properties that make agent-based models (ABMs) well suited to representing biological systems also present significant challenges with respect to their construction and calibration, particularly with respect to the selection of potential mechanistic rules and the large number of free parameters often present in these models. We have proposed that various machine learning approaches (such as genetic algorithms (GAs)) can be used to more effectively and efficiently deal with rule selection and parameter space characterization; the current work applies GAs to the challenge of calibrating a complex ABM to a specific data set, while preserving biological heterogeneity.

Methods

This project uses a GA to augment the rule-set for a previously validated ABM of acute systemic inflammation, the Innate Immune Response ABM (IIRABM) to clinical time series data of systemic cytokine levels from a population of burn patients. The genome for the GA is a vector generated from the IIRABM’s Model Rule Matrix (MRM), which is a matrix representation of not only the constants/parameters associated with the IIRABM’s cytokine interaction rules, but also the existence of rules themselves. Capturing heterogeneity is accomplished by a fitness function that incorporates the sample value range (“error bars”) of the clinical data.

Results

The GA-enabled parameter space exploration resulted in a set of putative MRM rules and associated parameterizations which closely match the cytokine time course data used to design the fitness function. The number of non-zero elements in the MRM increases significantly as the model parameterizations evolve towards a fitness function minimum, transitioning from a sparse to a dense matrix. This results in a model structure that more closely resembles (at a superficial level) the structure of data generated by a standard differential gene expression experimental study.

Conclusion

We present an HPC-enabled evolutionary computing approach to calibrate a complex ABM to clinical data while preserving biological heterogeneity. The integration of machine learning, HPC, and multi-scale mechanistic modeling provides a pathway forward to effectively represent the heterogeneity of clinical populations and their data.

Author Summary

In this work, we utilize genetic algorithms (GA) to operate on the internal rule set of a computational of the human immune response to injury, the Innate Immune Response Agent-Based Model (IIRABM), such that it is iteratively refined to generate cytokine time series that closely match what is seen in a clinical cohort of burn patients. At the termination of the GA, there exists an ensemble of candidate model rule-sets/parameterizations which are validated by the experimental data;
Homeostatic mechanisms regulate distinct aspects of cortical circuit dynamics
Authors: Wu Yue , Hengen Keith B. , Turrigiano Gina G. , Gjorgjieva Julijana
Published: October 2019

Homeostasis is indispensable to counteract the destabilizing effects of Hebbian plasticity. Although it is commonly assumed that homeostasis modulates synaptic strength, membrane excitability and firing rates, its role at the neural circuit and network level is unknown. Here, we identify changes in higher-order network properties of freely behaving rodents during prolonged visual deprivation. Strikingly, our data reveal that pairwise functional correlations and their structure are subject to homeostatic regulation. Using a computational model, we demonstrate that the interplay of different plasticity and homeostatic mechanisms can capture the initial drop and delayed recovery of firing rates and correlations observed experimentally. Moreover, our model indicates that synaptic scaling is crucial for the recovery of correlations and network structure, while intrinsic plasticity is essential for the rebound of firing rates, suggesting that synaptic scaling and intrinsic plasticity can serve distinct functions in homeostatically regulating network dynamics.
Combining tRNA sequencing methods to characterize plant tRNA expression and post-transcriptional modification
Authors: Warren Jessica M. , Salinas-Giegé Thalia , Hummel Guillaume , Coots Nicole L. , Svendsen Joshua M. , Brown Kristen C. , Maréchal-Drouard Laurence , Sloan Daniel B.
Published: October 2019

Differences in tRNA expression have been implicated in a remarkable number of biological processes. There is growing evidence that tRNA genes can play dramatically different roles depending on both expression and post-transcriptional modification, yet sequencing tRNAs to measure abundance and detect modifications remains challenging. Their secondary structure and extensive post-transcriptional modifications interfere with RNA-seq library preparation methods and have limited the utility of high-throughput sequencing technologies. Here, we combine two modifications to standard RNA-seq methods by treating with the demethylating enzyme AlkB and ligating with tRNA-specific adapters in order to sequence tRNAs from four species of flowering plants, a group that has been shown to have some of the most extensive rates of post-transcriptional tRNA modifications. This protocol has the advantage of detecting full-length tRNAs and sequence variants that can be used to infer many post-transcriptional modifications. We used the resulting data to produce a modification index of almost all unique reference tRNAs inArabidopsis thaliana, which exhibited many anciently conserved similarities with humans but also positions that appear to be “hot spots” for modifications in angiosperm tRNAs. We also found evidence based on northern blot analysis and droplet digital PCR that, even after demethylation treatment, tRNA-seq can produce highly biased estimates of absolute expression levels most likely due to biased reverse transcription. Nevertheless, the generation of full-length tRNA sequences with modification data is still promising for assessing differences in relative tRNA expression across treatments, tissues or subcellular fractions and help elucidate the functional roles of tRNA modifications.
A novel technology for objective, accurate and non-invasive early diagnosis and monitoring of Alzheimer’s disease in clinics and clinical trials
Authors: Vejdani Kaveh , Liebmann Thomas , Pannetier Nicolas , Khosravi Elham , Yousefnezhad Mohsen , Krishnamurthy Pavan , Farzan Nima , Bahar Cameron , Salehi Ahmad , Esfandyarpour Hesaam , Kamali-Zare Padideh
Published: October 2019

We have developed a novel medical image processing technology for objective, accurate, and non-invasive diagnosis, prognosis, and monitoring of Alzheimer’s disease using standard clinical brain MRI (magnetic resonance imaging) and basic clinical cognitive assessment. The technology is a robust, highly accurate, fully automated, high-throughput, cloud-based platform, which operates in a fully integrated and controlled environment. In diagnosis mode, our technology performs with 91% balanced accuracy on blind testing to diagnose the current neurocognitive status, and in prognosis modeor early detection at mild cognitive impairment (MCI) stage with 88% balanced accuracy on blind testing to predict progression from MCI to Alzheimer’s dementia (AD) within 5 years. Such prognostic capability is currently non-existent, even in specialty clinics and hospitals, a major factor in Alzheimer’s clinical trial failures. The algorithm’s diagnostic certainty precisely mirrors the diagnostic confidence of an expert cognitive neurologist for both MCI (Spearman’s Rho = 1) and AD (Rho = 1). In addition to widespread clinical applications, this novel technology can enable correct patient selection and therapeutic effect monitoring in clinical trials of Alzheimer’s disease, the crucial elements to finding a cure.
Paradoxical Aortic Stiffening and Subsequent Cardiac Dysfunction in Hutchinson-Gilford Progeria Syndrome
Authors: Murtada S-I. , Kawamura Y. , Caulk A.W. , Amadzadeh H. , Mikush N. , Zimmerman K. , Kavanagh D. , Weiss D. , Latorre M. , Zhang Z.W. , Shadel G.S. , Braddock D.T. , Humphrey J.D.
Published: October 2019

Hutchinson-Gilford Progeria Syndrome (HGPS) is an ultra-rare disorder with devastating sequelae resulting in early death, presently believed to stem primarily from heart failure secondary to central arterial stiffening. We analyze novel longitudinal cardiovascular data from a mouse model of HGPS (LmnaG609G/G609G) using allometric scaling and advanced computational modelling and show that a late-stage increase in pulse wave velocity, with associated diastolic dysfunction but preserved systolic function, emerges with a loss of aortic function, independent of sex. Specifically, there is a dramatic late-stage loss of smooth muscle function and cells and an excessive accumulation of proteoglycans along the entire aorta, which result in a loss of biomechanical function (contractility and elastic energy storage) and marked structural stiffening despite a distinctly low intrinsic material stiffness that is consistent with the lack of functional lamin A. Importantly, vascular function appears to be normal within the low stress environment of development, only to succumb progressively to pressure-related effects of the lamin A mutation and become extreme in the peri-morbid period. Because the dramatic life-threatening aortic phenotype manifests during the last quarter of life there may be a therapeutic window in maturity that could alleviate concerns with therapies administered during early periods of arterial development.

Disclosures

D.T.B is an equity holder in, and receives research and consulting support from, Inozyme Pharma, Inc. for therapeutics for ENPP1 deficiency. None of the other authors declare any conflict, financial or otherwise.
Interplay between Desmoglein2 and hypoxia controls metastasis in breast cancer
Authors: Chang Po-Hao , Chen Min-Che , Tsai Ya-Ping , Tan Grace Y.T. , Hsu Pang-Hung , Jeng Yung-Ming , Tsai Yi-Fang , Yang Muh-Hwa , Hwang-Verslues Wendy W.
Published: October 2019

Metastasis is the major cause of cancer death. An increased level of circulating tumor cells (CTCs), metastatic cancer cells that have intravasated into the circulatory system, is particularly associated with colonization of distant organs and poor prognosis. However, the key factors required for tumor cell dissemination and colonization remain elusive. We found that high expression of Desmoglein2 (DSG2), a component of desmosome-mediated intercellular adhesion complexes, promoted tumor growth, increased the prevalence of CTC clusters and facilitated distant organ colonization. The dynamic regulation of DSG2 by hypoxia was key to this process as downregulation of DSG2 in hypoxic regions of primary tumors led to elevated epithelial-mesenchymal transition (EMT) gene expression, allowing cells to detach from the primary tumor and undergo intravasation. Subsequent derepression of DSG2 after intravasation and release of hypoxic stress was associated with an increased ability to colonize distant organs. This dynamic regulation of DSG2 was mediated by Hypoxia-Induced Factor1α (HIF1α). In contrast to its more widely observed function to promote expression of hypoxia-inducible genes, HIF1α repressed DSG2 by recruitment of the Polycomb Repressive Complex 2 components, EZH2 and SUZ12, to the DSG2 promoter in hypoxic cells. Consistent with our experimental data, DSG2 expression level correlated with poor prognosis and recurrence risk in breast cancer patients. Together, these results demonstrated the importance of DSG2 expression in metastasis and revealed a new mechanism by which hypoxia drives metastasis.

Significance Statement

During metastasis, hypoxia is a major force driving primary tumor cells to disseminate into the circulatory system. The key factors that promote circulating tumor cells (CTC) dissemination and allow them to successfully colonize distal sites are still incompletely known. We found that downregulation of DSG2 in hypoxic tumor allowed single tumor cell dissemination while DSG2 expressing tumors generated more CTC clusters. Re-induction of DSG2 expression in single CTCs may contribute to CTC survival and colonization in distant organs. These findings highlight the importance of DSG2 in breast cancer progression and metastasis.
Applying Machine Learning to Investigate Long Term Insect-Plant Interactions Preserved on Digitized Herbarium Specimens
Authors: Meineke E.K. , Tomasi C. , Yuan S. , Pryer K.M.
Published: October 2019

Premise of the study

Despite the economic importance of insect damage to plants, long-term data documenting changes in insect damage (‘herbivory’) and diversity are limited. Millions of pressed plant specimens are now available online for collecting big data on plant-insect interactions during the Anthropocene.

Methods

We initiated development of machine learning methods to automate extraction of herbivory data from herbarium specimens. We trained an insect damage detector and a damage type classifier on two distantly related plant species. We experimented with 1) classifying six types of herbivory and two control categories of undamaged leaf, and 2) detecting two of these damage categories for which several hundred annotations were available.

Results

Classification models identified the correct type of herbivory 81.5% of the time. The damage classifier was accurate for categories with at least one hundred test samples. We show anecdotally that the detector works well when asked to detect two types of damage.

Discussion

The classifier and detector together are a promising first step for the automation of herbivory data collection. We describe ongoing efforts to increase the accuracy of these models to allow other researchers to extract similar data and apply them to address a variety of biological hypotheses.
Identification of risk variants and characterization of the polygenic architecture of disruptive behavior disorders in the context of ADHD
Authors: Demontis Ditte , Walters Raymond , Rajagopal Veera M. , Waldman Irwin D. , Grove Jakob , Als Thomas D. , Dalsgaard Søren , Ribases Marta , Grauholm Jonas , Bækvad-Hansen Marie , Werge Thomas , Nordentoft Merete , Mors Ole , Mortensen Preben Bo ,   ADHD Working Group of the Psychiatric Genomics Consortium (PGC), Cormand Bru , Hougaard David M. , Neale Benjamin M. , Franke Barbara , Faraone Stephen V. , Børglum Anders D.
Published: October 2019

Attention-Deficit/Hyperactivity Disorder (ADHD) is a childhood psychiatric disorder often comorbid with disruptive behavior disorders (DBDs). ADHD comorbid with DBDs (ADHD+DBDs) is a complex phenotype with a risk component that can be attributed to common genetic variants. Here we report a large GWAS meta-analysis of ADHD+DBDs based on seven cohorts in total including 3,802 cases and 31,305 controls. Three genome-wide significant loci were identified on chromosomes 1, 7, and 11. A GWAS meta-analysis including a Chinese cohort supported the locus on chromosome 11 to be a strong risk locus for ADHD+DBDs across European and Chinese ancestries (rs7118422, P=3.15×10-10, OR=1.17). This locus was not associated with ADHD without DBDs in a secondary GWAS of 13,583 ADHD cases and 22,314 controls, suggesting that the locus is a specific risk locus for the comorbid phenotype.

We found a higher SNP heritability for ADHD+DBDs (h2SNP =0.34) when compared to ADHD without DBDs (h2SNP =0.20). Genetic correlations of ADHD+DBDs with aggressive (rg =0.81) and anti-social behaviors (rg=0.82) were high, and polygenic risk score analyses revealed a significant increased burden of variants associated with ADHD and aggression in individuals with ADHD+DBDs compared to ADHD without DBDs. Our results suggests that ADHD+DBDs represent a more severe phenotype with respect to the genetic risk load than ADHD without DBDs, in line with previous studies, and that the risk load to some extent can be explained by variants associated with aggressive behavior.
Effects of Aging on the Encoding of Spatial Direction in the Human Brain
Authors: Koch Christoph , Li Shu-Chen , Polk Thad A. , Schuck Nicolas W.
Published: October 2019

Human aging is characterized by impaired spatial cognition and reductions in the distinctiveness of category-specific fMRI activation patterns. Yet, little is know about age-related decline in neural distinctiveness of spatial information. Here, we asked whether neural tuning functions of walking direction are broadened in older versus younger adults. To test this idea, we developed a novel method that allowed us to investigate changes in fMRI-measured pattern similarity while participants navigated in different directions in a virtual spatial navigation task. We expected that directional tuning functions would be broader in older adults, and thus activation patterns that reflect neighboring directions would be less distinct as compared to non-adjacent directions. Because loss of distinctiveness leads to more confusions when information is read out by downstream areas, we analyzed predictions of a decoder trained on these representations and asked (1) whether decoder confusions between two directions increase proportionally to their angular similarity, (2) and how this effect may differ between age groups. Evidence for tuning-function-like signals was found in the retrosplenial complex and primary visual cortex. Significant age differences in tuning width, however, were only found in the primary visual cortex, suggesting that less precise visual information could lead to worse directional signals in older adults. Yet, age differences in visual tuning were not related to behavior. Instead, directional information encoded in RSC correlated with memory on task. These results shed new light on neural mechanisms underling age-related spatial navigation impairments and introduce a novel approach to measure tuning specificity using fMRI.
Micro-scale fluid behavior during cryo-EM sample blotting
Authors: Armstrong M. , Han B-G. , Gomez S. , Turner J. , Fletcher D. A. , Glaeser R. M.
Published: October 2019

Blotting has been the standard technique for preparing aqueous samples for single-particle electron cryo-microscopy (cryo-EM) for over three decades. This technique removes excess solution from a TEM grid by pressing absorbent filter paper against the specimen prior to vitrification. However, this standard technique produces vitreous ice with inconsistent thickness from specimen to specimen and from region to region within the same specimen, the reasons for which are not understood. Here, high-speed interference-contrast microscopy is used to demonstrate that the irregular pattern of fibers in the filter paper imposes tortuous, highly variable boundaries during removal of excess liquid from a flat, hydrophilic surface. As a result, aqueous films of nonuniform thickness are formed while the filter paper is pressed against the substrate. This pattern of nonuniform liquid thickness changes again after the filter paper is pulled away, but the thickness still does not become completely uniform. We suggest that similar topological features of the liquid film are produced during the standard technique used to blot EM grids and that these manifest in nonuniform ice after vitrification. These observations suggest that alternative thinning techniques, which do not rely on direct contact between the filter paper and the grid, may result in more repeatable and uniform sample thicknesses.

STATEMENT OF SIGNIFICANCE

Multiple imaging techniques are used to observe dynamic, micro-scale events as excess water is removed from a substrate by blotting with filter paper. As a result, new insight is gained about why the thickness values of remaining sample material are so variable across a single EM grid, as well as from one grid to the next. In addition, quantitative estimates are made of the shear forces to which macromolecular complexes can be exposed during blotting. The fact that sample thicknesses and flow rates are seen to be inherently under poor control during blotting suggests that other methods of removing excess water may be better suited for consistently achieving large sample areas that are suitable for use in electron cryo-microscopy.
Social inequity, taxes and welfare in Australasia
Authors: Marriott Lisa , Sim Dalice
Published: October 2019

Purpose

The purpose of this paper is to highlight, challenge and explain the inequitable treatment of tax and welfare fraudsters in the criminal justice systems of Australia and New Zealand. The authors offer prejudice by way of explanation and suggest that it is also prejudice that restricts the implementation of more equitable processes. A second objective of the study is to highlight the importance of critical tax research as an instrument to agitate for social change.

Design/methodology/approach

A survey captures 3,000 respondents’ perceptions of the likelihood that different “types” of people will commit welfare or tax fraud. Using social dominance theory, the authors investigate the extent to which prejudice impacts on attitudes towards those engaged in these fraudulent activities.

Findings

The authors find the presence of traditional stereotypes, such as the perception that businessmen are more likely to commit tax fraud and people receiving welfare assistance are more likely to commit fraud. The authors also find strong preferences towards respondents’ own in-group, whereby businessmen, Maori and people receiving welfare assistance believed that their own group was less likely to commit either crime.

Social implications

Where in-group preference exists among those who construct and enforce the rules relating to investigations, prosecutions and sentencing of tax and welfare fraud, it is perhaps unsurprising that welfare recipients attract less societal support than other groups who have support from their own in-groups that have greater power, resources and influence.

Originality/value

The study highlights the difficulty of social change in the presence of strong in-group preference and prejudice. Cognisance of in-group preference is relevant to the accounting profession where elements of self-regulation remain. In-group preferences may impact on services provided, as well as professional development and education.
The civic mission of schools and students’ participation in school governance
Authors: Yuen Timothy Wai Wa , Cheng Chi Keung Eric , Guo Chunlan , Leung Yan Wing
Published: October 2019

Purpose

The purpose of this paper is to examine the relationships between the civic mission of schools and students on participation in school governance through an empirical study. It articulates the importance of school mission on nurturing citizenship of high school students.

Design/methodology/approach

The research used a mixed method with questionnaire survey in the first phase and qualitative interviews in the second phase. Quantitative data were obtained from a survey completed by 3,209 students and 495 teachers (including principals) from 51 secondary schools in Hong Kong. Qualitative data were collected from 41 individual interviews with principals and teachers and 17 focus group interviews with 56 students in five case study schools.

Findings

Both students and teachers believed that good citizenship qualities should include students’ participation in school governance. Schools in general took up the civic mission to nurture good and participatory citizens. A mission of nurturing students to become good and participatory citizens made a significant and positive contribution toward achieving students’ actual participation in school governance. However, students’ actual impact on major school policies was minimal. A paradox existed whereby students, knowing their influence over managerial issues was much circumscribed, still gave it a higher rating than their teachers.

Originality/value

The paper contributes an empirical model for school leaders to develop school vision for promoting student participation in school governance. Based on a large-scale research supported by public funding, the paper contributes an empirical model for school leaders to develop school vision for promoting student participation in school governance. It further adds to the literature on relationship between citizenship education, civic mission of school and student participation in governance.