bluuebunny/crossref_metadata_2025 huggingface dataset:
Cellular pathways of calcium transport and concentration towards mineral formation in sea urchin larvae
Authors: Kahil Keren , Varsano Neta , Sorrentino Andrea , Pereiro Eva , Rez Peter , Weiner Steve , Addadi Lia
Published: August 2020

Sea urchin larvae have an endoskeleton consisting of two calcitic spicules. The primary mesenchyme cells (PMCs) are the cells that are responsible for spicule formation. PMCs endocytose sea water from the larval internal body cavity into a network of vacuoles and vesicles, where calcium ions are concentrated until they precipitate in the form of amorphous calcium carbonate (ACC). The mineral is subsequently transferred to the syncytium, where the spicule forms. Using cryo-soft X-ray microscopy (cryo-SXM) we imaged intra-cellular calcium-containing particles in the PMCs and acquired Ca-L2,3X-ray absorption near edge spectra (XANES) of these Ca-particles. Using the pre-peak/main peak (L2’/ L2) intensity ratio, which reflects the atomic order in the first Ca coordination shell, we determined the state of the calcium ions in each particle. The concentration of Ca in each of the particles was also determined by the integrated area in the main Ca absorption peak. We observed about 700 Ca-particles with order parameters, L2’/ L2, ranging from solution to hydrated and anhydrous ACC, and with concentrations ranging between 1-15 M. We conclude that in each cell the calcium ions exist in a continuum of states. This implies that most, but not all water, is expelled from the particles. This cellular process of calcium concentration may represent a widespread pathway in mineralizing organisms.

Significance

Organisms form mineralized skeletons, many of which are composed of calcium salts. Marine organisms extract calcium ions from sea water. One of the main unresolved issues is how organisms concentrate calcium by more than 3 orders of magnitude, to achieve mineral deposition in their skeleton. Here we determine the calcium state in each of the calcium-containing vesicles inside the spicule-building cells of sea urchin larvae. We show that within one cell there is a wide range of concentrations and states from solution to solid. We hypothesize that calcium concentration increases gradually in each vesicle, starting from sea water levels and until mineral is deposited. This model might well be relevant to other phyla, thus advancing the understanding of biomineralization processes.
Cooperative Binding of Transcription Factors is a Hallmark of Active Enhancers
Authors: Rao Satyanarayan , Ahmad Kami , Ramachandran Srinivas
Published: August 2020

Enhancers harbor binding motifs that recruit transcription factors (TFs) for gene activation. While cooperative binding of TFs at enhancers is known to be critical for transcriptional activation of a handful of developmental enhancers, the extent TF cooperativity genome-wide is unknown. Here, we couple high-resolution nuclease footprinting with single-molecule methylation profiling to characterize TF cooperativity at active enhancers in theDrosophilagenome. Enrichment of short MNase-protected DNA segments indicates that the majority of enhancers harbor two or more TF binding sites, and we uncover protected fragments that correspond to co-bound sites in thousands of enhancers. We integrate MNase-seq, methylation accessibility profiling, and CUT&RUN chromatin profiling as a comprehensive strategy to characterize co-binding of the Trithorax-like (TRL) DNA binding protein and multiple other TFs and identify states where an enhancer is bound by no TF, by either single factor, by multiple factors, or where binding sites are occluded by nucleosomes. From the analysis of co-binding, we find that cooperativity dominates TF bindingin vivoat a majority of active enhancers. TF cooperativity can occur without apparent protein-protein interactions and provides a mechanism to effectively clear nucleosomes and promote enhancer function.
The anti-sigma factor MucA is required for viability inPseudomonas aeruginosa
Authors: Schofield Melissa C. , Rodriguez Daniela , Kidman Amanda A. , Cassin Erin K. , Michaels Lia A. , Campbell Elizabeth A. , Jorth Peter A. , Tseng Boo Shan
Published: August 2020

During decades-long infections in the cystic fibrosis (CF) airway,Pseudomonas aeruginosaundergoes selection. One bacterial genetic adaptation often observed in CF isolates ismucAmutations. MucA inhibits the sigma factor AlgU. Mutations inmucAlead to AlgU misregulation, resulting in a mucoid phenotype that is associated with poor CF disease outcomes. Due to its ability to be mutated,mucAis assumed to be dispensable for bacterial viability. Here we show that, paradoxically, a portion ofmucAis essential inP. aeruginosa. We demonstrate thatmucAis no longer required in a strain lackingalgU, thatmucAalleles encoding for proteins that do not bind to AlgU are insufficient for viability, and thatmucAis no longer essential in mutant strains containing AlgU variants with reduced sigma factor activity. Furthermore, we found that overexpression ofalgUprevents cell growth in the absence of MucA, and that this phenotype can be rescued by overproduction of RpoD, the housekeeping sigma factor. Together, these results suggest that in the absence of MucA, the inability to regulate AlgU activity results in the loss of bacterial viability. Finally, we speculate that essentiality of anti-sigma factors that regulate envelope function may be a widespread phenomenon in bacteria.
FLIMJ: an open-source ImageJ toolkit for fluorescence lifetime image data analysis
Authors: Gao Dasong , Barber Paul R , Chacko Jenu V , Sagar Md Abdul Kader , Rueden Curtis T , Grislis Aivar R , Hiner Mark C , Eliceiri Kevin W
Published: August 2020

In the field of fluorescence microscopy, there is continued demand for dynamic technologies that can exploit the complete information from every pixel of an image. One imaging technique with proven ability for yielding additional information from fluorescence imaging is Fluorescence Lifetime Imaging Microscopy (FLIM). FLIM allows for the measurement of how long a fluorophore stays in an excited energy state and is affected by changes in its chemical microenvironment, such as proximity to other fluorophores, pH, and hydrophobic regions. This ability to provide information about the microenvironment has made FLIM a powerful tool for cellular imaging studies ranging from metabolic measurement to measuring distances between proteins. The increased use of FLIM has necessitated the development of computational tools for integrating FLIM analysis with image and data processing. To address this need, we have created FLIMJ, an ImageJ plugin, and toolkit that allows for easy use and development of extensible image analysis workflows with FLIM data. Built on the FLIMLib decay curve fitting library and the ImageJ Ops framework, FLIMJ offers FLIM fitting routines with seamless integration with other ImageJ components, and the ability to be extended to create complex FLIM analysis workflows. Building on ImageJ Ops also enables FLIMJ’s routines to be used with Jupyter notebooks and integrate naturally with science-friendly programming in, e.g., Python and Groovy. We show the extensibility of FLIMJ in two analysis scenarios: lifetime-based image segmentation and image colocalization. We also validate the fitting routines by comparing against industry FLIM analysis standards.
BARcode DEmixing through Non-negative Spatial Regression (BarDensr)
Authors: Chen Shuonan , Loper Jackson , Chen Xiaoyin , Vaughan Alex , Zador Anthony M. , Paninski Liam
Published: August 2020

Modern spatial transcriptomics methods can target thousands of different types of RNA transcripts in a single slice of tissue. Many biological applications demand a high spatial density of transcripts relative to the imaging resolution, leading to partial mixing of transcript rolonies in many voxels; unfortunately, current analysis methods do not perform robustly in this highly-mixed setting. Here we develop a new analysis approach,BARcode DEmixing through Non-negative Spatial Regression(BarDensr): we start with a generative model of the physical process that leads to the observed image data and then apply sparse convex optimization methods to estimate the underlying (demixed) rolony densities. We apply Bar-Densr to simulated and real data and find that it achieves state of the art signal recovery, particularly in densely-labeled regions or data with low spatial resolution. Finally, BarDensr is fast and parallelizable. We provide open-source code as well as an implementation for the ‘NeuroCAAS’ cloud platform.

Author Summary

Spatial transcriptomics technologies allow us to simultaneously detect multiple molecular targets in the context of intact tissues. These experiments yield images that answer two questions: which kinds of molecules are present, and where are they located in the tissue? In many experiments (e.g., mapping RNA expression in fine neuronal processes), it is desirable to increase the signal density relative to the imaging resolution. This may lead to mixing of signals from multiple RNA molecules into single imaging voxels; thus we need todemixthe signals from these images. Here we introduce BarDensr, a new computational method to perform this demixing. The method is based on a forward model of the imaging process, followed by a convex optimization approach to approximately ‘invert’ mixing induced during imaging. This new approach leads to significantly improved performance in demixing imaging data with dense expression and/or low spatial resolution.
Genetic diversity of maize landraces from the South-West of France
Authors: Diaw Yacine , Tollon-Cordet Christine , Charcosset Alain , Nicolas Stéphane , Madur Delphine , Ronfort Joëlle , David Jacques , Gouesnard Brigitte
Published: August 2020

From the 17th century until the arrival of hybrids in 1960s, maize landraces were cultivated in the South-West of France, a traditional region for maize cultivation. A set of landraces were collected in this region between the 1950s and 1980s and were then conservedex situin a germplam collection. Previous studies using molecular markers on approx. twenty landraces fo this region showed that they belonged to a Pyrenees-Galicia Flint genetic group and originated from hybridization between Caribbean and Northern Flint germplasms introduced in Europe. In this study, we assessed the structure and genetic diversity of 194 SWF maize landraces to elucidate their origin, using a 50K SNP array and a bulk DNA approach. We identified two weakly differentiated genetic groups, one in the Western part and the other in the Eastern part. We highlighted the existence of a longitudinal gradient along the SWF area that was probably maintained through the interplay between genetic drifts and restricted gene flows, rather than through differential climatic adaptation. The contact zone between the two groups observed near the Garonne valley may be the result of these evolutionnary forces. We found only few significant cases of hybridization between Caribbean and Northern Flint germplasms in the region. We also found gene flows from various maize genetic groups to SWF landraces. Thus, we assumed that SWF landraces had a multiple origin with a slightly higher influence of Tropical germplasm in the West and preponderance of Northern Flint germplasm in the East.
Oligomeric hypercomplex of the complete oxidative phosphorylation system in heart mitochondria
Authors: Nesterov S.V. , Chesnokov Yu.M. , Kamyshinsky R.A. , Panteleeva A.A , Lyamzaev K.G. , Vasilov R.G. , Yaguzhinsky L.S.
Published: August 2020

The existence of a complete oxidative phosphorylation system supercomplex including both electron transport system and ATP synthases has long been assumed based on functional evidence. However, no conclusive structural confirmation has been obtained. In this study cryo-electron tomography was used to reveal the supramolecular architecture of the rat heart mitochondria cristae. We show that rows of respiratory chain supercomplexes are connected with rows of ATP synthases forming the oligomeric hypercomplex. The discovered hypercomplexes may increase the effectiveness of oxidative phosphorylation ensuring a direct proton transfer from pumps to ATP synthase along the membrane without energy dissipation.
Genetic drift from the out-of-Africa bottleneck leads to biased estimation of genetic architecture and selection
Authors: Ashraf Bilal , Lawson Daniel John
Published: August 2020

Most complex traits evolved in the ancestors of all modern humans and have been under negative or balancing selection to maintain the distribution of phenotypes observed today. Yet all large studies mapping genomes to complex traits occur in populations that have experienced the Out-of-Africa bottleneck. Does this bottleneck affect the way we characterise complex traits? We demonstrate using the 1000 Genomes dataset and hypothetical complex traits that genetic drift can strongly affect the joint distribution of effect size and SNP frequency, and that the bias can be positive or negative depending on subtle details. Characterisations that rely on this distribution therefore conflate genetic drift and selection. We provide a model to identify the underlying selection parameter in the presence of drift, and demonstrate that a simple sensitivity analysis may be enough to validate existing characterisations. We conclude that biobanks characterising more worldwide diversity would benefit studies of complex traits.
Enhancers regulate 3′ end processing activity to control expression of alternative 3′UTR isoforms
Authors: Kwon Buki , Fansler Mervin M. , Patel Neil D. , Lee Jihye , Ma Weirui , Mayr Christine
Published: August 2020

Multi-UTR genes are widely transcribed but show cell type-specific 3′UTR isoform expression. As transcriptional enhancers regulate mRNA expression, we investigated if they also regulate mRNA isoform expression. Deletion of an endogenous enhancer of a multi-UTR gene did not impair transcript production but prevented a switch in 3′UTR isoform expression. Also, the same enhancers are able to increase transcript production in the context of single-UTR gene promoters, but they increase 3′ end processing activity when paired with multi-UTR gene promoters. We show that transcription factors regulate processing activity of weak polyadenylation sites to control cell type-specific alternative 3′UTR isoform expression of widely expressed genes.
Single-Strand DNA Breaks Cause Replisome Disassembly
Authors: Vrtis Kyle B. , Dewar James M. , Chistol Gheorghe , Wu R. Alex , Graham Thomas G. W. , Walter Johannes C.
Published: August 2020

DNA damage impedes replication fork progression and threatens genome stability. Upon encounter with most DNA adducts, the replicative CMG helicase (CDC45-MCM2-7-GINS) stalls or uncouples from the point of synthesis, yet CMG eventually resumes replication. However, little is known about the effect on replication of single-strand breaks or “nicks”, which are abundant in mammalian cells. UsingXenopusegg extracts, we reveal that CMG collision with a nick in the leading strand template generates a blunt-ended double-strand break (DSB). Moreover, CMG, which encircles the leading strand template, “runs off” the end of the DSB. In contrast, CMG collision with a lagging strand nick generates a broken end with a single-stranded overhang. In this setting, CMG translocates beyond the nick on double-stranded DNA and is then actively removed from chromatin by the p97 ATPase. Our results show that nicks are uniquely dangerous DNA lesions that invariably cause replisome disassembly, and they argue that CMG cannot be deposited on dsDNA while cells resolve replication stress.

Highlights

The structures of leading and lagging strand collapsed forks are different

CMG passively “runs off” the broken DNA end during leading strand fork collapse

CMG is unloaded from duplex DNA after lag collapse in a p97-dependent manner

Nicks are uniquely toxic lesions that cause fork collapse and replisome disassembly
Extracellular matrix and cyclic stretch alter fetal cardiomyocyte proliferation and maturation in a rodent model of heart hypoplasia
Authors: Watson Matthew C. , Williams Corin , Wang Raymond M. , Perreault Luke R. , Sullivan Kelly E. , Stoppel Whitney L. , Black Lauren D.
Published: August 2020

Birth defects, particularly those that affect development of the heart, are a leading cause of morbidity and mortality in infants and young children. Babies born with heart hypoplasia (HH) disorders often have a poor prognosis. It remains unclear whether cardiomyocytes from hypoplastic hearts retain the potential to recover growth, although this knowledge would be beneficial for developing therapies for HH disorders. The objective of this study was to determine the proliferation and maturation potential of cardiomyocytes from hypoplastic hearts and whether these behaviors are influenced by biophysical signaling from the extracellular matrix (ECM) and cyclic mechanical stretch. Congenital diaphragmatic hernia (CDH)-associated HH was induced in rat fetuses by maternal exposure to nitrofen. Hearts were isolated from embryonic day 21 nitrofen-treated fetuses positive for CDH (CDH+) and from fetuses without nitrofen administration during gestation. CDH+ hearts were smaller and had decreased myocardial proliferation, along with evidence of decreased maturity compared to healthy hearts. In culture, CDH+ cardiomyocytes remained immature and demonstrated increased proliferative capacity compared to their healthy counterparts. Culture on ECM derived from CDH+ hearts led to a significant reduction in proliferation for both CDH+ and healthy cardiomyocytes. Healthy cardiomyocytes were dosed with exogenous nitrofen to examine whether nitrofen may have an abhorrent effect on the proliferative ability of cardiomyocyte, yet no significant change in proliferation was observed. When subjected to stretch, CDH+ cardiomyocytes underwent lengthening of sarcomeres while healthy cardiomyocyte sarcomeres were unaffected. Taken together, our results suggest that alterations to environmental cues such as ECM and stretch may be important factors in the pathological progression of HH.
UhAVR1, an HR-triggering avirulence effector ofUstilago hordei, is secreted via the ER-Golgi pathway to the cytosol of barley coleoptile cells and contributes to virulence early in infection
Authors: Alonso Ana Priscilla Montenegro , Ali Shawkat , Song Xiao , Linning Rob , Bakkeren Guus
Published: August 2020

The basidiomyceteUstilago hordei(Uh) causes covered smut disease of barley and oats. Virulence effectors that aid the infection process and support the pathogen’s lifestyle have been described for this fungus. Genetically, six avirulence genes are known and one codes for UhAVR1, the only proven avirulence effector identified in smut pathogens to date that triggers complete immunity in barley cultivars carrying the resistance geneRuh1. A prerequisite for resistance breeding is understanding the host targets and molecular function of UhAVR1. Analysis of this effector upon natural infection of barley coleoptiles using teliospores showed that UhAVR1 is expressed during the early stages of fungal infection where it leads to HR triggering in resistant cultivars or performs its virulence function in susceptible cultivars. Fungal secretion of UhAVR1 is directed by its signal peptide and occurs via the BrefeldinA-sensitive ER-Golgi pathway, both in cell culture away from its host, and during barley interaction. Transient expression of this effector in barley and a heterologous host,Nicotiana benthamiana(Nb), supports a cytosolic localization. Delivery of UhAVR1 via foxtail mosaic virus,Pseudomonasspecies orAgrobacterium-mediatedsuppression of cell inducers in barley andNbsupport a role in the suppression of a common component(s) of ETI and PTI which is conserved in both plant systems.
Super-resolution light-sheet fluorescence microscopy by SOFI
Authors: Mizrachi Judith , Narasimhan Arun , Qi Xiaoli , Drewes Rhonda , Palaniswamy Ramesh , Wu Zhuhao , Osten Pavel
Published: August 2020

Here we describe a new method, named LS-SOFI, that combineslight-sheet fluorescence microscopy andsuper-resolutionopticalfluctuationimaging to achieve fast nanoscale-resolution imaging over large fields of view in native 3D tissues. We demonstrate the use of LS-SOFI in super-resolution analysis of neuronal structures and synaptic proteins, including cortical axons, dendritic spines, pre- and postsynaptic cytoskeletal proteins and postsynaptic AMPA receptors, in thick mouse brain sections. We also introduce an algorithm to determine the number of active fluorophore emitters detected, allowing the localization of individual molecules in LS-SOFI images. We conclude that LS-SOFI is a versatile method for fast super-resolution imaging from any tissue of the body using both commercial and custom LSFM instruments.
Evaluation of the Safety of Percutaneous Electrical Stimulation of the Phrenic and Femoral Nerves in a Chronic Porcine Model: A GLP Study
Authors: O’Mahony John , Dingfelder Carlus , Polyakov Igor , Jocewicz Trace , Mischke Jennifer
Published: August 2020

Purpose

Diaphragm pacing has been proposed as a method to prevent ventilator-induced diaphragm dysfunction (VIDD) during mechanical ventilation (MV). The present study assessed the safety of lead deployment and control of diaphragm inspiratory work in synchrony with MV utilizing percutaneous electrical phrenic nerve stimulation (PEPNS) in a sedated and ventilated porcine model.

Methods

The ability to safely place PEPNS four-electrode leads near the femoral nerve using ultrasound visualization and electrical stimulation to guide lead placement using a through the needle (TTN) approach was assessed for 4 animals. The feasibility of using the PEPNS system to activate the diaphragm in synchrony with inspiration within a desired target Work of Breathing (WOB) between 0.3 and 0.7 joules/L over eight hours was tested using three of the four animals with the fourth used as a control. The ability to control WOB during inspiration was assessed for flow and pressure-controlled breaths using a flow and pressure sensor attached to the wye, the connector joining the inspiratory and expiratory limbs to the endotracheal tube. Overall health (moribundity) was assessed at baseline and throughout the study until Day 30 for the surviving animals. Gross pathology and histopathological studies were performed on the femoral nerves and diaphragm muscle tissue following termination of the animals at Day 30.

Results

The lower bound estimate of the proportion of successful stimulation within the desired level of WOB was 95.1%, achieving the study endpoint. Triggering synchrony was statistically significant at <88ms (p<0.0001) with WOB able to be maintained between 0.3 and 0.7 joules/L. There was no evidence of tissue or nerve damage nor impact on overall animal health associated with lead placement or electrical stimulation.

Conclusion

The PEPNS leads were found to be safe for their intended use and the PEPNS system met preestablished study endpoints for synchrony and stimulation efficacy.
UFold: Fast and Accurate RNA Secondary Structure Prediction with Deep Learning
Authors: Fu Laiyi , Cao Yingxin , Wu Jie , Peng Qinke , Nie Qing , Xie Xiaohui
Published: August 2020

Motivation

For many RNA molecules, the secondary structure is essential for the correct function of the RNA. Predicting RNA secondary structure from nucleotide sequences is a long-standing problem in genomics, but the prediction performance has reached a plateau over time. Traditional RNA secondary structure prediction algorithms are primarily based on thermodynamic models through free energy minimization, which imposes strong prior assumptions and is slow to run.

Results

Here we propose a deep learning-based method, called UFold, for RNA secondary structure prediction, trained directly on annotated data without any thermodynamic assumptions. UFold improves substantially upon previous models, with approximately 10~30% improvement over traditional thermodynamic models and 14% improvement over other learning-based methods. It achieves an F1 score of 0.91 on base pair prediction accuracy on an RNA structure prediction benchmark dataset. UFold is also fast with an inference time about 160ms per sequence up to 1600bp length. We provide an online web server that implements UFold for RNA structure prediction and is made freely available.

Availability

An online web server running UFold is available athttps://ufold.ics.uci.edu. Code is available athttps://github.com/uci-cbcl/UFold.

Contact

xhx@uci.edu
Systems vaccinology analysis of a recombinant vaccinia-based vector reveals diverse innate immune signatures at the injection site
Authors: Hazlewood Jessamine E. , Dumenil Troy , Le Thuy T. , Slonchak Andrii , Kazakoff Stephen H. , Patch Ann-Marie , Gray Lesley-Ann , Howley Paul M. , Liu Liang , Hayball John D. , Yan Kexin , Rawle Daniel J. , Prow Natalie A. , Suhrbier Andreas
Published: August 2020

Poxvirus systems have been extensively used as vaccine vectors. Herein a systems vaccinology analysis of intramuscular injection sites provides detailed insights into host innate immune responses, as well as expression of vector and recombinant immunogen genes, after vaccination with a new multiplication defective, vaccinia-based vector, Sementis Copenhagen Vector. Chikungunya and Zika virus immunogen mRNA and protein expression was associated with necrosing skeletal muscle cells surrounded by mixed cellular infiltrates. Adjuvant signatures at 12 hours post-vaccination were dominated by TLR3, 4 and 9, STING, MAVS, PKR and the inflammasome. Th1 cytokine signatures were dominated by IFNγ, TNF and IL1β, and chemokine signatures by CCL5 and CXCL12. Multiple signatures associated with dendritic cell stimulation were evident. By day seven, vaccine transcripts were absent, and cell death, neutrophil, macrophage and inflammation annotations had abated. No compelling arthritis signatures were identified. Such innate systems vaccinology approaches should inform refinements in poxvirus-based vector design.
Controlling for effects of confounding variables on machine learning predictions
Authors: Dinga Richard , Schmaal Lianne , Penninx Brenda W.J.H. , Veltman Dick J. , Marquand Andre F.
Published: August 2020

Machine learning predictive models are being used in neuroimaging to predict information about the task or stimuli or to identify potentially clinically useful biomarkers. However, the predictions can be driven by confounding variables unrelated to the signal of interest, such as scanner effect or head motion, limiting the clinical usefulness and interpretation of machine learning models. The most common method to control for confounding effects is regressing out the confounding variables separately from each input variable before machine learning modeling. However, we show that this method is insufficient because machine learning models can learn information from the data that cannot be regressed out. Instead of regressing out confounding effects from each input variable, we propose controlling for confounds post-hoc on the level of machine learning predictions. This allows partitioning of the predictive performance into the performance that can be explained by confounds and performance independent of confounds. This approach is flexible and allows for parametric and non-parametric confound adjustment. We show in real and simulated data that this method correctly controls for confounding effects even when traditional input variable adjustment produces false-positive findings.
Chronic stress induces co-ordinated cortical microcircuit cell type transcriptomic changes consistent with altered information processing
Authors: Newton Dwight F. , Oh Hyunjung , Shukla Rammohan , Misquitta Keith , Fee Corey , Banasr Mounira , Sibille Etienne
Published: August 2020

Major depressive disorder (MDD) is associated with altered GABAergic and glutamatergic signalling, suggesting altered excitation-inhibition balance (EIB) in cortical mood- and cognition-regulating brain regions. Information processing in cortical microcircuits involves regulation of pyramidal (PYR) cells by Somatostatin-(SST), Parvalbumin-(PV), and Vasoactive intestinal peptide-(VIP) expressing interneurons. Human and rodent studies suggest that impaired PYR-cell dendritic morphology and decreased SST-cell function may mediate altered EIB in MDD. However, knowledge of co-ordinated changes across microcircuit cell types is virtually absent. We thus investigated the co-ordinated transcriptomic effects of UCMS on microcircuit cell types in the medial prefrontal cortex. C57Bl/6 mice, exposed to unpredictable chronic mild stress (UCMS) or control housing for five weeks were assessed for anxiety- and depressive-like behaviours. Microcircuit cell types were laser-microdissected and processed for RNA-sequencing. UCMS-exposed mice displayed predicted elevated behavioural emotionality. Each microcircuit cell type showed a unique transcriptional signature after UCMS. Pre-synaptic functions, oxidative stress response, metabolism, and translational regulation were differentially dysregulated across cell types, whereas nearly all cell types showed down-regulated post-synaptic gene signatures. At the microcircuit level, we observed a shift from distributed transcriptomic co-ordination across cell types in controls towards UCMS-induced increased co-ordination between PYR-, SST- and PV-cells, and a hub-like role for PYR-cells. Lastly, we identified a microcircuit-wide co-expression network enriched in synaptic, bioenergetic, and oxidative stress response genes that correlated with UCMS-induced behaviours. Together, these findings suggest cell-specific deficits, microcircuit-wide synaptic reorganization, and a shift in cortical EIB mediated by increased co-ordinated regulation of PYR-cells by SST- and PV-cells.
Assessing Overall Reproducibility for Large-scale High-throughput MRI-based Association Studies
Authors: Jiao Zeyu , Lai Yinglei , Kang Jujiao , Gong Weikang , Ma Liang , Jia Tianye , Xie Chao , Cheng Wei , Heinz Andreas , Desrivières Sylvane , Schumann Gunter ,   IMAGEN Consortium, Sun Fengzhu , Feng Jianfeng
Published: August 2020

Magnetic Resonance Imaging (MRI) technology has been increasingly used in large-scale association studies. Reproducibility of statistically significant findings generated by MRI-based association studies, especially structural MRI (sMRI) and functional MRI (fMRI), has been recently heavily debated. However, there is still a lack of overall reproducibility assessment for MRI-based association studies. It is also crucial to elucidate the relationship between overall reproducibility and sample size in an experimental design. In this study, we proposed an overall reproducibility index for large-scale high-throughput MRI-based association studies. We performed the overall reproducibility assessments for several recent large sMRI/fMRI databases and observed satisfactory overall reproducibility. Furthermore, we performed the sample size evaluation for the purpose of achieving a desirable overall reproducibility. Additionally, we evaluated the overall reproducibility of GMV changes for UKB vs. PPMI and UKB vs. HCP. We demonstrated that both sample size and some experimental factors play important roles in the overall reproducibility for different experiments. In summary, a systematic assessment of overall reproducibility is fundamental and crucial in the current large-scale high-throughput MRI-based research.
Distinct synaptic and related transcriptional abnormalities in neonatal, childhood and mature autism model of primate: implications for early-age therapeutic intervention
Authors: Watanabe Satoshi , Kurotani Tohru , Oga Tomofumi , Noguchi Jun , Isoda Risa , Nakagami Akiko , Sakai Kazuhisa , Nakagaki Keiko , Sumida Kayo , Hoshino Kohei , Saito Koichi , Miyawaki Izuru , Sekiguchi Masayuki , Wada Keiji , Minamimoto Takafumi , Ichinohe Noritaka
Published: August 2020

Autism spectrum disorder (ASD) is a synapse-related disorder that is diagnosed at around 3 years of age. Earlier intervention is desirable for better ASD prognosis; however, there is limited biological literature regarding early-age ASD. This study aimed to assess altered cortical synapses and gene expression in the ASD model marmoset. There were distinct phenotypes in the model animals across the neonate, childhood, and mature stages in the dorsomedial prefrontal cortex (Brodmann area 8b/9). At the neonate stage, synapses were underdeveloped and modulated genes were enriched with synaptogenesis- and ASD-related genes. At the childhood stage, synaptic features and gene expressions associated with experience-dependent circuit remodeling were altered in model animals. At the mature stage, there were synapse overdevelopment and altered gene expression similar to those in human ASD. These early synaptic phenotypes and altered gene expressions could be novel targets of efficient therapy from a young age.
Control and regulation of acetate overflow inEscherichia coli
Authors: Millard Pierre , Enjalbert Brice , Uttenweiler-Joseph Sandrine , Portais Jean-Charles , Létisse Fabien
Published: August 2020

Overflow metabolism refers to the production of seemingly wasteful by-products by cells during growth on glucose even when oxygen is abundant. Two theories have been proposed to explain acetate overflow inEscherichia coli– global control of the central metabolism and local control of the acetate pathway – but neither accounts for all observations. Here, we develop a kinetic model ofE. colimetabolism that quantitatively accounts for observed behaviors and successfully predicts the response ofE. colito new perturbations. We reconcile these theories and clarify the origin, control and regulation of the acetate flux. We also find that, in turns, acetate regulates glucose metabolism by coordinating the expression of glycolytic and TCA genes. Acetate should not be considered a wasteful end-product since it is also a co-substrate and a global regulator of glucose metabolism inE. coli. This has broad implications for our understanding of overflow metabolism.
A pedigree-based prediction model identifies carriers of deleterious de novo mutations in families with Li-Fraumeni syndrome
Authors: Gao Fan , Pan Xuedong , Dodd-Eaton Elissa B. , Recio Carlos Vera , Montierth Matthew D. , Bojadzieva Jasmina , Mai Phuong L. , Zelley Kristin , Johnson Valen E. , Braun Danielle , Nichols Kim E. , Garber Judy E. , Savage Sharon A. , Strong Louise C. , Wang Wenyi
Published: August 2020

De novo mutations (DNMs) are increasingly recognized as rare disease causal factors. Identifying DNM carriers will allow researchers to study the likely distinct molecular mechanisms of DNMs. We developed Famdenovo to predict DNM status (DNM or familial mutation [FM]) of deleterious autosomal dominant germline mutations for any syndrome. We introduce Famdenovo.TP53 for Li-Fraumeni syndrome (LFS) and analyze 324 LFS family pedigrees from four US cohorts: a validation set of 186 pedigrees and a discovery set of 138 pedigrees. The concordance index for Famdenovo.TP53 prediction was 0.95 (95% CI: [0.92, 0.98]). Forty individuals (95% CI: [30, 50]) were predicted as DNM carriers, increasing the total number from 42 to 82. We compared clinical and biological features of FM versus DNM carriers: (1) cancer and mutation spectra along with parental ages were similarly distributed; (2) ascertainment criteria like early-onset breast cancer (age 20–35 yr) provides a condition for an unbiased estimate of the DNM rate: 48% (23 DNMs vs. 25 FMs); and (3) hotspot mutation R248W was not observed in DNMs, although it was as prevalent as hotspot mutation R248Q in FMs. Furthermore, we introduce Famdenovo.BRCA for hereditary breast and ovarian cancer syndrome and apply it to a small set of family data from the Cancer Genetics Network. In summary, we introduce a novel statistical approach to systematically evaluate deleterious DNMs in inherited cancer syndromes. Our approach may serve as a foundation for future studies evaluating how new deleterious mutations can be established in the germline, such as those in TP53.
TransBorrow: genome-guided transcriptome assembly by borrowing assemblies from different assemblers
Authors: Yu Ting , Mu Zengchao , Fang Zhaoyuan , Liu Xiaoping , Gao Xin , Liu Juntao
Published: August 2020

RNA-seq technology is widely used in various transcriptomic studies and provides great opportunities to reveal the complex structures of transcriptomes. To effectively analyze RNA-seq data, we introduce a novel transcriptome assembler, TransBorrow, which borrows the assemblies from different assemblers to search for reliable subsequences by building a colored graph from those borrowed assemblies. Then, by seeding reliable subsequences, a newly designed path extension strategy accurately searches for a transcript-representing path cover over each splicing graph. TransBorrow was tested on both simulated and real data sets and showed great superiority over all the compared leading assemblers.
Multiscale pink-beam microCT imaging at the ESRF-ID17 biomedical beamline
Authors: Mittone Alberto , Fardin Luca , Di Lillo Francesca , Fratini Michela , Requardt Herwig , Mauro Anthony , Homs-Regojo Roberto Arturo , Douissard Paul-Antoine , Barbone Giacomo E. , Stroebel Johannes , Romano Mariele , Massimi Lorenzo , Begani-Provinciali Ginevra , Palermo Francesca , Bayat Sam , Cedola Alessia , Coan Paola , Bravin Alberto
Published: August 2020

Recent trends in hard X-ray micro-computed tomography (microCT) aim at increasing both spatial and temporal resolutions. These challenges require intense photon beams. Filtered synchrotron radiation beams, also referred to as `pink beams', which are emitted by wigglers or bending magnets, meet this need, owing to their broad energy range. In this work, the new microCT station installed at the biomedical beamline ID17 of the European Synchrotron is described and an overview of the preliminary results obtained for different biomedical-imaging applications is given. This new instrument expands the capabilities of the beamline towards sub-micrometre voxel size scale and simultaneous multi-resolution imaging. The current setup allows the acquisition of tomographic datasets more than one order of magnitude faster than with a monochromatic beam configuration.
Crystal structure of bis(N,N′-dimethylthiourea-κS)bis(thiocyanato-κN)cobalt(II)
Authors: Jochim Aleksej , Radulovic Rastko , Jess Inke , Näther Christian
Published: August 2020

During systematic investigations on the synthesis of coordination polymers with Co(NCS)2 involving different thiourea derivatives as coligands, crystals of the title compound Co(NCS)2(N,N′-dimethylthiourea)2, or [Co(C3H8N2S)2(NCS)2], were obtained. These crystals were non-merohedric twins and therefore, a twin refinement using data in HKLF-5 format was performed. In the crystal structure of this compound, the CoII cations are coordinated by two N-terminally bonded thiocyanate anions as well as two S-bonding N,N′-dimethylthiourea molecules, forming two crystallographically independent discrete complexes each with a strongly distorted tetrahedral geometry. An intricate network of intermolecular N—H...S and C—H...S hydrogen bonds can be found between the complexes. The thermogravimetric curve of the title compound shows two discrete steps in which all coligand molecules have been emitted, which is also accompanied by partial decomposition of the cobalt thiocyanate. If the measurement is stopped after the first mass loss, only broad reflections of CoS can be found in the XRPD pattern of the residue, which proves that this compound decomposes completely upon heating. However, at lower temperatures an endothermic signal can be found in the DTA and DSC curve, which corresponds to melting, as proven by thermomicroscopy.
4,15-Dimethyl-7,12-diazoniatricyclo[10.4.0.02,7]hexadeca-1(12),2,4,6,13,15-hexaene dibromide monohydrate
Authors: Behrman Edward J. , Hansen Alexandar L. , Yuan Chunhua , Parkin Sean
Published: August 2020

The title compound, C16H20N22+·2Br−·H2O (1) is a member of the class of compounds called viologens. Viologens are quaternary salts of dipyridyls and are especially useful as redox indicators as a result of their large negative one-electron reduction potentials. Compound1consists of a dication composed of a pair of 4-methylpyridine rings mutually joined at the 2-position, with a dihedral angle between the pyridine rings of 62.35 (4)°. In addition, the rings are tetheredviathe pyridine nitrogen atoms by a tetramethylene bridge. Charge balance is provided by a pair of bromide anions, which are hydrogen bonded to a single water molecule [DO...Br= 3.3670 (15) and 3.3856 (15) Å]. The crystal structure of1, details of an improved synthesis, and a full analysis of its NMR spectra are presented.
Phytosociological assessment and carbon stock estimation and valuation in the tropical dry deciduous forest of Bihar
Authors: Biswas Saroni , Biswas Anirban , Das Arabinda , Banerjee Saon
Published: August 2020

Purpose

This study aims to assess the biodiversity of the study area and estimate the carbon stock of two dry deciduous forest ranges of Banka Forest Division, Bihar, India.

Design/methodology/approach

The phytosociological analysis was performed and C stock estimation based on volume determination through nondestructive methods was done.

Findings

Phytosociological analysis found total 18,888 [14,893 < 10 cm (diameter at breast height) dbh] and 2,855 (1,783 < 10 cm dbh) individuals at Banka and Bounsi range with basal area of 181,035.00 cm2 and 32,743.76 cm2, respectively. Importance value index was highest for Shorea robusta in both the ranges. Species diversity index and dominance index, 1.89 and 1.017 at Banka and 1.99 and 5.600 at Bounsi indicated the prevalence of biotic pressure. Decreased dbh and tree height resulted in a lowered growing stock volume as 59,140.40 cm3 ha−1 (Banka) and 71,306.37 cm3 ha−1 (Bounsi). Total C stock at Banka and Bounsi range was 51.8 t ha-1 and 12.56 t ha−1, respectively where the highest C stock is recorded for Shorea robusta in both the ranges (9.8 t ha−1 and 2.54 t ha-1, respectively). A positive correlation between volume, total biomass and basal area of tree species with C stock was observed. R2 value for Banka range was 0.9269 (volume-C stock), 1 (total biomass-C stock) and 0.647 (basal area-C stock). Strong positive correlation was also established at Bounsi range with R2 value of 1. Considering the total forest area enumerated, C sequestration potential was about 194.25 t CO2 (Banka) and 45.9 t CO2 (Bounsi). The valuation of C stock was therefore US$2,525.25 (Banka) and US$596.70 (Bounsi).

Practical implications

The research found the potentiality of the study area to sequester carbon. However, for future, the degraded areas would require intervention of management strategies for restoration of degraded lands and protection of planted trees to increase the carbon sequestration potential of the area.

Originality/value

Present study is the first attempt to assess the phytosociology and estimate the regulatory services of forest with respect to biomass and carbon stock estimation for the Banka forest division of Bihar.
Success beyond STEM: an analysis of educational background of the Fortune 50 CEOs
Authors: Welch James
Published: August 2020

Purpose

The purpose of this article is examine some of the most successful contemporary global business leaders in relation to undergraduate institution and undergraduate major in order to examine the value and return of higher education programs for global business leadership. This is an important topic in the modern global context, as there continues to be an increasing global push toward deemphasizing and defunding liberal arts education in favor of science, technology, engineering and math (STEM) fields for college and university students around the globe.

Design/methodology/approach

The educational backgrounds of the 2019 Fortune 50 CEOs were researched in relation to undergraduate institutions attended and undergraduate majors. The study also included an examination of graduate education, if applicable. Using available biographical information regarding the CEOs educational backgrounds, these business leaders were compared relative to the educational data.

Findings

An examination of the undergraduate educational backgrounds of the 2019 Fortune 50 CEOs revealed an exact split between 18 STEM majors, 18 liberal arts majors and 18 business majors, with 1 CEO who began university studies but did not graduate. Upon examination, it is also apparent that some majors were more directly related to a CEO's industry, while other majors ended up having little relation to the CEO's chosen career path.

Practical implications

The results of this study contribute to the very important discussion concerning the long-term value of a college education. At both micro and macro levels, stakeholders are constantly questioning the ultimate return on investment of a college education, and examination of the 2019 Fortune 50 CEOs indicates that the choice of college major is only one ingredient in the overall recipe for professional success. For these business leaders, there were a wide variety of educational paths, in terms of college academic preparations, that eventually led to the very pinnacle of professional and leadership attainment.

Originality/value

This study demonstrates that a particular undergraduate field of study is not going to make or break a career, and the examination of these Fortune 50 CEOs indicates that one's ultimate career achievement is not simply relegated to the specific field of undergraduate major.
The impact of communication technology vs human-related factors on classroom performance: a cross-cultural study
Authors: Šerić Maja
Published: August 2020

Purpose

This paper examines the impact of communication technology and human-related factors on teacher, student and course performance, in particular on teacher's clarity, perceived value of the course and student learning.

Design/methodology/approach

Communication technology factors are analyzed in terms of social media use, while human-related factors are considered through teacher expertise and communication skills, more specifically non-verbal communication (NVC). The research model is tested on a sample of 303 students from two European universities, one in Southwestern and another in Southeastern Europe.

Findings

Findings reveal dominance of human factors over technology ones. Culture moderates some of the relationships examined.

Research limitations/implications

Notwithstanding the relatively limited sample of students according to their national culture, this work offers valuable insights into the impact of technology use in classroom and teacher communication skills.

Practical implications

Teacher NVC and expertise override their use of technology-mediated communication in classroom. Findings have raised important questions whether social media applications should actually have place in nowadays education systems. What seems clear from this research is that technology advancements cannot replace teachers, although further research is necessary to re-examine their impact on different student outcomes and in different cultural contexts.

Originality/value

The originality of this paper lies in comparing the impact of technology vs human-related factors on classroom performance. An additional contribution is provided by considering the moderating role of national culture within the proposed research model.