bluuebunny/crossref_metadata_2025 huggingface dataset:
Interactive effects of microplastic pollution and heat stress on reef-building corals
Authors: Reichert Jessica , Tirpitz Vanessa , Anand Rajshree , Bach Katharina , Knopp Jonas , Schubert Patrick , Wilke Thomas , Ziegler Maren
Published: August 2021

Plastic pollution is an emerging stressor that increases pressure on ecosystems such as coral reefs that are already challenged by climate change. However, the effect of plastic pollution in combination with global warming is largely unknown. Thus, the goal of this study was to determine the cumulative effect of microplastic pollution with that of global warming on reef-building coral species and to compare the severity of both stressors. For this, we conducted a series of three controlled laboratory experiments and exposed a broad range of coral species (Acropora muricata, Montipora digitata, Porites lutea, Pocillopora verrucosa, and Stylophora pistillata) to microplastic particles in a range of concentrations (2.5–2,500 particles L-1) and mixtures (from different industrial sectors) at ambient temperatures and in combination with heat stress. We show that microplastic can occasionally have a negative effect on the corals’ thermal tolerance. In comparison to heat stress, however, microplastic constitutes a minor stressor. While heat stress led to decreased photosynthetic efficiency of algal symbionts, and increased bleaching, tissue necrosis, and mortality, treatment with microplastic particles had only minor effects on the physiology and health of the tested coral species at ambient temperatures. These findings underline that while efforts to reduce plastic pollution should continue, they should not replace more urgent efforts to halt global warming, which are immediately needed to preserve remaining coral reef ecosystems.

Graphical Abstract
Dashboard-style interactive plots for RNA-seq analysis are R Markdown ready with Glimma 2.0
Authors: Kariyawasam Hasaru , Su Shian , Voogd Oliver , Ritchie Matthew E. , Law Charity W.
Published: August 2021

Glimma 1.0 introduced intuitive, point-and-click interactive graphics for differential gene expression analysis. Here, we present a major update to Glimma which brings improved inter-activity and reproducibility using high-level visualisation frame-works for R and JavaScript. Glimma 2.0 plots are now readily embeddable in R Markdown, thus allowing users to create reproducible reports containing interactive graphics. The revamped multidimensional scaling plot features dashboard-style controls allowing the user to dynamically change the colour, shape and size of sample points according to different experimental conditions. Interactivity was enhanced in the MA-style plot for comparing differences to average expression, which now supports selecting multiple genes, export options to PNG, SVG or CSV formats and includes a new volcano plot function. Feature-rich and user-friendly, Glimma makes exploring data for gene expression analysis more accessible and intuitive and is available on Bioconductor and GitHub.
A phenomenological model of neuroimmune interactions in epileptogenesis
Authors: Batulin Danylo , Lagzi Fereshteh , Vezzani Annamaria , Jedlicka Peter , Triesch Jochen
Published: August 2021

Epilepsy can have many different causes and its development (epileptogenesis) involves a bewildering complexity of interacting processes. Here, we present a first-of-its-kind computational model to better understand the role of neuroimmune interactions in the development of acquired epilepsy. Our model describes the interactions between neuroinflammation, blood-brain barrier disruption, neuronal loss, circuit remodeling, and seizures. Formulated as a system of nonlinear differential equations, the model is validated using data from animal models that mimic human epileptogenesis caused by infection, status epilepticus, and blood-brain barrier disruption. The mathematical model successfully explains characteristic features of epileptogenesis such as its paradoxically long timescales (up to decades) despite short and transient injuries, or its dependence on the intensity of an injury. Furthermore, stochasticity in the model captures the variability of epileptogenesis outcomes in individuals exposed to identical injury. Notably, in line with the concept of degeneracy, our simulations reveal multiple routes towards epileptogenesis with neuronal loss as a sufficient but non-necessary component. We show that our framework allows for in silico predictions of therapeutic strategies, providing information on injury-specific therapeutic targets and optimal time windows for intervention.
Privacy-preserving harmonization via distributed ComBat
Authors: Chen Andrew A. , Luo Chongliang , Chen Yong , Shinohara Russell T. , Shou Haochang ,   the Alzheimer’s Disease Neuroimaging Initiative
Published: August 2021

Challenges in clinical data sharing and the need to protect data privacy have led to the development and popularization of methods that do not require directly transferring patient data. In neuroimaging, integration of data across multiple institutions also introduces unwanted biases driven by scanner differences. These scanner effects have been shown by several research groups to severely affect downstream analyses. To facilitate the need of removing scanner effects in a distributed data setting, we introduce distributed ComBat, an adaptation of a popular harmonization method for multivariate data that borrows information across features. We present our fast and simple distributed algorithm and show that it yields equivalent results using data from the Alzheimer’s Disease Neuroimaging Initiative. Our method enables harmonization while ensuring maximal privacy protection, thus facilitating a broad range of downstream analyses in functional and structural imaging studies.
Severe COVID-19 shares a common neutrophil activation signature with other acute inflammatory states
Authors: Schimke Lena F. , Marques Alexandre H.C. , Baiocchi Gabriela Crispim , de Souza Prado Caroline Aliane , Fonseca Dennyson Leandro M. , Freire Paula Paccielli , Plaça Desirée Rodrigues , Filgueiras Igor Salerno , Salgado Ranieri Coelho , Jansen-Marques Gabriel , Oliveira Antonio Edson Rocha , Peron Jean Pierre Schatzmann , Cabral-Miranda Gustavo , Barbuto José Alexandre Marzagão , Camara Niels Olsen Saraiva , Calich Vera Lúcia Garcia , Ochs Hans D. , Condino-Neto Antonio , Overmyer Katherine A. , Coon Joshua J. , Balnis Joseph , Jaitovich Ariel , Schulte-Schrepping Jonas , Ulas Thomas , Schultze Joachim L. , Nakaya Helder I. , Jurisica Igor , Cabral-Marques Otávio
Published: August 2021

Severe COVID-19 patients present a clinical and laboratory overlap with other hyperinflammatory conditions such as hemophagocytic lymphohistiocytosis (HLH). However, the underlying mechanisms of these conditions remain to be explored. Here, we investigated the transcriptome of 1596 individuals, including patients with COVID-19 in comparison to healthy controls, other acute inflammatory states (HLH, multisystem inflammatory syndrome in children [MIS-C], Kawasaky disease [KD]), and different respiratory infections (seasonal coronavirus, influenza, bacterial pneumonia). We observed that COVID-19 and HLH share immunological pathways (cytokine/chemokine signaling and neutrophil-mediated immune responses), including gene signatures that stratify COVID-19 patients admitted to the intensive care unit (ICU) and COVID-19_nonICU patients. Of note, among the common differentially expressed genes (DEG), there is a cluster of neutrophil-associated genes that reflects a generalized hyperinflamatory state since it is also dysregulated in patients with KD and bacterial pneumonia. These genes are dysregulated at protein level across several COVID-19 studies and form an interconnected network with differentially expressed plasma proteins that point to neutrophil hyperactivation in COVID-19 patients admitted to the intensive care unit. scRNAseq analysis indicated that these genes are specifically upregulated across different leukocyte populations, including lymphocyte subsets and immature neutrophils. Artificial intelligence modeling confirmed the strong association of these genes with COVID-19 severity. Thus, our work indicates putative therapeutic pathways for intervention.
Spatiotemporal Dynamics of Stemphylium Leaf Blight and Potential Inoculum Sources in New York Onion Fields
Authors: Hay Frank , Heck Daniel W. , Klein Audrey , Sharma Sandeep , Hoepting Christy , Pethybridge Sarah J.
Published: August 2021

Stemphylium leaf blight (SLB) caused byStemphylium vesicariumis the dominant foliar disease affecting large-scale onion production in New York. The disease is managed by fungicides, but control failures are prevalent and recently attributed to fungicide resistance. Little is known of the relative role of inoculum sources in initiation and spread of SLB epidemics. The spatial and spatiotemporal dynamics of SLB epidemics in six onion fields were evaluated along linear transects in 2017 and 2018. Average SLB incidence increased from 0 to 100% throughout the cropping seasons with an average final lesion length of 28.3 cm. Disease progress was typical of a polycyclic epidemic and the logistic model provided the best fit to 83.3% of the datasets. Spatial patterns were better described by the beta-binomial than binomial distribution in half of the datasets and random patterns were more frequently observed by the index of dispersion. Geostatistical analyses of spatial pattern also found a low frequency of datasets with aggregation. Spatiotemporal analysis of epidemics detected that the aggregation was influenced by disease incidence. However, diseased units were not associated with the previous time period according to the spatiotemporal association function ofSADIE. Variable spatial patterns suggested mixed inoculum sources dependent upon location, and likely an external inoculum source at the sampling scale used in this study. Plate testing of 28 commercially available organic onion seedlots from 2017 and 2018 did not detectS. vesicarium. This finding suggests that althoughS. vesicariumhas been reported as seed transmitted, this is unlikely to be a significant inoculum source in commercially available organic seed lots and even less so in fungicide-treated seed used to establish conventional fields. A small-plot replicated trial was also conducted in each of two years to quantify the effect ofS. vesicarium-infested onion residue on SLB epidemics in a field isolated from other onion fields. SLB incidence was significantly reduced in plots without residue compared to those in which residue remained on the soil surface. Burial of infested residue also significantly reduced epidemic progress in one year. The effect of infested onion residue on SLB epidemics in the subsequent onion crop suggests rotation or residue management may have a substantial effect on epidemics. However, the presence of an inoculum source external to fields in onion production regions as indicated by a lack of spatial aggregation may reduce the efficacy of in-field management techniques.
Deliberation gated by opportunity cost adapts to context with urgency
Authors: Touzel Maximilian Puelma , Cisek Paul , Lajoie Guillaume
Published: August 2021

Finding the right amount of deliberation, between insufficient and excessive, is a hard decision making problem that depends on the value we place on our time. Average-reward, putatively encoded by tonic dopamine, serves in existing reinforcement learning theory as the stationary opportunity cost of time, and of deliberation in particular. However, this cost often varies with environmental context that can change over time. Here, we introduce an opportunity cost of deliberation estimated adaptively on multiple timescales to account for non-stationary contextual factors. We use it in a simple decision-making heuristic based on average-reward reinforcement learning (AR-RL) that we callPerformance-Gated Deliberation(PGD). We propose PGD as a strategy used by animals wherein deliberation cost is implemented directly as urgency, a previously characterized neural signal effectively controlling the speed of the decision-making process. We show PGD outperforms AR-RL solutions in explaining behaviour and urgency of non-human primates in a context-varying random walk prediction task and is consistent with relative performance and urgency in a context-varying random dot motion task. We make readily testable predictions for both neural activity and behaviour and call for an integrated research program in cognitive and systems neuroscience around the value of time.
LEVELNET to Visualise, Explore and Compare Protein-Protein Interaction Networks
Authors: Mohseni Behbahani Yasser , Saighi Paul , Corsi Flavia , Laine Elodie , Carbone Alessandra
Published: August 2021

Abstract

Physical interactions between proteins are central to all biological processes. Yet, the current knowledge of who interacts with whom in the cell and in what manner relies on partial, noisy, and highly heterogeneous data. Thus, there is a need for methods comprehensively describing and organising such data. LEVELNET is a versatile and interactive tool for visualising, exploring and comparing protein-protein interaction (PPI) networks inferred from different types of evidence. LEVELNET helps to break down the complexity of PPI networks by representing them as multilayered graphs and by facilitating the direct comparison of their subnetworks toward biological interpretation. It focuses primarily on the protein chains whose 3D structures are available in the Protein Data Bank. We showcase some potential applications, such as investigating the structural evidence supporting PPIs associated to specific biological processes, assessing the co-localisation of interaction partners, comparing the PPI networks obtained through computational experiments versus homology transfer, and creating PPI benchmarks with desired properties.

Availability: LEVELNET is freely available to the community athttp://www.lcqb.upmc.fr/levelnet/.
Near-infrared spectroscopy calibration strategies to predict multiple nutritional parameters of pasture species from different functional groups
Authors: Catunda Karen L. M. , Churchill Amber C. , Power Sally A. , Moore Ben D.
Published: August 2021

Near-infrared reflectance spectroscopy (NIRS) has been used by the agricultural industry as a high-precision technique to quantify nutritional chemistry in plants both rapidly and inexpensively. The aim of this study was to evaluate the performance of NIRS calibrations in predicting the nutritional composition of ten pasture species that underpin livestock industries in many countries. These species comprised a range of functional diversity (C3 legumes; C3/C4 grasses; annuals/perennials) and origins (tropical/temperate; introduced/native) that grew under varied environmental conditions (control and experimentally induced warming and drought) over a period of more than 2 years (n = 2,622). A maximal calibration set including 391 samples was used to develop and evaluate calibrations for all ten pasture species (global calibrations), as well as for subsets comprised of the plant functional groups. We found that the global calibrations were appropriate to predict the six key nutritional quality parameters studied for our pasture species, with the highest accuracy found for ash (ASH), crude protein (CP), neutral detergent fibre and acid detergent fibre (ADF), and the lowest for ether extract (EE) and acid detergent lignin parameters. The plant functional group calibrations for C3 grasses performed better than the global calibrations for ASH, CP, ADF and EE parameters, whereas for C3 legumes and C4 grasses the functional group calibrations performed less well than the global calibrations for all nutritional parameters of these groups. Additionally, our calibrations were able to capture the range of variation in forage quality caused by future climate scenarios of warming and severe drought.
Gene regulatory networks controlling temporal patterning, neurogenesis, and cell fate specification in the mammalian retina
Authors: Lyu Pin , Hoang Thanh , Santiago Clayton P. , Thomas Eric D. , Timms Andrew E. , Appel Haley , Gimmen Megan , Le Nguyet , Jiang Lizhi , Kim Dong Won , Chen Siqi , Espinoza David , Telger Ariel E. , Weir Kurt , Clark Brian S. , Cherry Timothy J. , Qian Jiang , Blackshaw Seth
Published: August 2021

Gene regulatory networks (GRNs), consisting of transcription factors and their target cis- regulatory sequences, control neurogenesis and cell fate specification in the developing central nervous system, but their organization is poorly characterized. In this study, we performed integrated single-cell RNA- and scATAC-seq analysis in both mouse and human retina to profile dynamic changes in gene expression, chromatin accessibility and transcription factor footprinting during retinal neurogenesis. We identified multiple interconnected, evolutionarily-conserved GRNs consisting of cell type-specific transcription factors that both activate expression of genes within their own network and often inhibit expression of genes in other networks. These GRNs control state transitions within primary retinal progenitors that underlie temporal patterning, regulate the transition from primary to neurogenic progenitors, and drive specification of each major retinal cell type. We confirmed the prediction of this analysis that the NFI transcription factors Nfia, Nfib, and Nfix selectively activate expression of genes that promote late-stage temporal identity in primary retinal progenitors. We also used GRNs to identify additional transcription factors that promote (Insm1/2) and inhibit (Tbx3, Tcf7l1/2) rod photoreceptor specification in postnatal retina. This study provides an inventory of cis- and trans-acting factors that control retinal development, identifies transcription factors that control the temporal identity of retinal progenitors and cell fate specification, and will potentially guide cell-based therapies aimed at replacing retinal neurons lost due to disease.
Multi-omic Analysis of Developing Human Retina and Organoids Reveals Cell-Specific Cis-Regulatory Elements and Mechanisms of Non-Coding Genetic Disease Risk
Authors: Thomas Eric D. , Timms Andrew E. , Giles Sarah , Harkins-Perry Sarah , Lyu Pin , Hoang Thanh , Qian Jiang , Jackson Victoria , Bahlo Melanie , Blackshaw Seth , Friedlander Martin , Eade Kevin , Cherry Timothy J.
Published: August 2021

Cis-regulatory elements (CREs) play a critical role in the development, maintenance, and disease-states of all human cell types. In the human retina, CREs have been implicated in a variety of inherited retinal disorders. To characterize cell-class-specific CREs in the human retina and elucidate their potential functions in development and disease, we performed single-nucleus (sn)ATAC-seq and snRNA-seq on the developing and adult human retina and on human retinal organoids. These analyses allowed us to identify cell-class-specific CREs, enriched transcription factor binding motifs, putative target genes, and to examine how these features change over development. By comparing DNA accessibility between the human retina and retinal organoids we found that CREs in organoids are highly correlated at the single-cell level, validating the use of organoids as a model for studying disease-associated CREs. As a proof of concept, we studied the function of a disease-associated CRE at 5q14.3 in organoids, identifying its principal target gene as the miR-9-2 primary transcript and demonstrating a dual role for this CRE in regulating neurogenesis and gene regulatory programs in mature glia. This study provides a rich resource for characterizing cell-class-specific CREs in the human retina and showcases retinal organoids as a model in which to study the function of retinal CREs that influence retinal development and disease.

HIGHLIGHTS

Single-cell map of cis-regulatory elements in developing and adult human retina.

Correlation of single-cell DNA accessibility between human retina and retinal organoids.

Association of disease risk loci with cell-class-specific accessibility.

Modeling of enhancer function at the 5q14.3 retinal disease-risk locus.
Selective ablation of adult GFAP-expressing tanycytes leads to hypogonadotropic hypogonadism in males
Authors: Butruille Lucile , Batailler Martine , Cateau Marie-Line , Sharif Ariane , Leysen Valérie , Prévot Vincent , Vaudin Pascal , Pillon Delphine , Migaud Martine
Published: August 2021

In adult mammals, neural stem cells emerge in three neurogenic regions, the subventricular zone of the lateral ventricle (SVZ), the subgranular zone of the dentate gyrus of the hippocampus (SGZ) and the hypothalamus. In the SVZ and the SGZ, neural stem/progenitor cells (NSPCs) express the glial fibrillary acidic protein (GFAP) and selective ablation of these NSPCs drastically decreases cell proliferation in vitro and in vivo. In the hypothalamus, GFAP is expressed by α-tanycytes, which are specialized radial glia-like cells in the wall of the third ventricle. To explore the role of these hypothalamic GFAP-positive tanycytes, we used transgenic mice expressing herpes simplex virus thymidine kinase (HSV-Tk) under the control of the mouse Gfap promoter and 4-week intracerebroventricular infusion of the antiviral agent ganciclovir (GCV) that kills dividing cells expressing Tk. While GCV drastically reduced the number and growth of hypothalamus-derived neurospheres from adult transgenic mice in vitro, it caused hypogonadism in vivo. The selective death of dividing tanycytes expressing GFAP indeed caused a marked decrease in testosterone levels and testicular weight, as well as vacuolization of the seminiferous tubules and loss of spermatogenesis. In addition, GCV-treated GFAP-Tk mice showed impaired sexual behavior, but no alteration in food intake or body weight. Our results also show that the selective ablation of GFAP-expressing tanycytes leads to a sharp decrease in the number of gonadotropin-releasing hormone (GnRH)-immunoreactive neurons and blunted LH secretion. Altogether, our data show that GFAP-expressing tanycytes play a central role in the regulation of male reproductive function.

Main points

Killing adult hypothalamic GFAP-expressing cells blunts neurosphere formation in vitro and leads to GnRH deficiency and hypogonadism in vivo. This work pinpoints an unreported role of dividing GFAP-expressing tanycytes in reproductive function.
Deep learning-enhanced morphological profiling predicts cell fate dynamics in real-time in hPSCs
Authors: Ren Edward , Kim Sungmin , Mohamad Saad , Huguet Samuel F. , Shi Yulin , Cohen Andrew R. , Piddini Eugenia , Salas Rafael Carazo
Published: August 2021

Predicting how stem cells become patterned and differentiated into target tissues is key for optimising human tissue design. Here, we established DEEP-MAP - for deep learning-enhanced morphological profiling - an approach that integrates single-cell, multi-day, multi-colour microscopy phenomics with deep learning and allows to robustly map and predict cell fate dynamics in real-time without a need for cell state-specific reporters. Using human pluripotent stem cells (hPSCs) engineered to co-express the histone H2B and two-colour FUCCI cell cycle reporters, we used DEEP-MAP to capture hundreds of morphological- and proliferation-associated features for hundreds of thousands of cells and used this information to map and predict spatiotemporally single-cell fate dynamics across germ layer cell fates. We show that DEEP-MAP predicts fate changes as early or earlier than transcription factor-based fate reporters, reveals the timing and existence of intermediate cell fates invisible to fixed-cell technologies, and identifies proliferative properties predictive of cell fate transitions. DEEP-MAP provides a versatile, universal strategy to map tissue evolution and organisation across many developmental and tissue engineering contexts.
Genes used together are more likely to be fused together in evolution by mutational mechanisms: A bioinformatic test of the used-fused hypothesis
Authors: Bolotin Evgeni , Melamed Daniel , Livnat Adi
Published: August 2021

Cases of parallel or recurrent gene fusions, whether in evolution or in cancer and genetic disease, are difficult to explain, as they require multiple of the same or similar breakpoints to repeat. The used-together-fused-together hypothesis holds that genes that are used together repeatedly and persistently in a certain context are more likely than otherwise to undergo a fusion mutation in the course of evolution—reminiscent of the Hebbian learning rule where neurons that fire together wire together. This mutational hypothesis offers to explain both evolutionary parallelism and recurrence in disease of gene fusions under one umbrella. Here, we test this hypothesis using bioinformatic data. Various measures of gene interaction, including co-expression, co-localization, same-TAD presence and semantic similarity of GO terms show that human genes whose homologs are fused in one or more other organisms are significantly more likely to interact together than random genes, controlling for genomic distance between genes. In addition, we find a statistically significant overlap between pairs of genes that fused in the course of evolution in non-human species and pairs that undergo fusion in human cancers. These results provide support for the used-together-fused-together hypothesis over several alternative hypotheses, including that all gene pairs can fuse by random mutation, but among pairs that have thus fused, those that have interacted previously are more likely to be favored by selection. Multiple consequences are discussed, including the relevance of mutational mechanisms to exon shuffling, to the distribution of fitness effects of mutation and to parallelism.
Three conserved hydrophobic residues in the CC domain of Pit contribute to its plasma membrane localization and immune induction
Authors: Wang Qiong , Li Yuying , Kosami Ken-ichi , Liu Chaochao , Li Jing , Zhang Dan , Miki Daisuke , Kawano Yoji
Published: August 2021

Nucleotide-binding leucine-rich repeat (NLR) proteins work as crucial intracellular immune receptors. N-terminal domains of NLRs fall into two groups, namely coiled-coil (CC) and Toll-interleukin 1 receptor (TIR) domains, which play critical roles in signal transduction and disease resistance. However, the activation mechanisms of NLRs, and how their N-termini are involved in immune induction, remain largely unknown. Here, we revealed that the rice NLR Pit self-associates through its CC domain. The CC domain of Pit possesses three conserved hydrophobic residues that are known to be involved in homodimer formation in two NLRs, barley MLA10 and Arabidopsis RPM1. Interestingly, the function of these residues in Pit is different from that in MLA10 and RPM1. Although the three hydrophobic residues are important for Pit-induced disease resistance against rice blast fungus, they do not participate in self-association or in binding to downstream signaling molecules. Based on homology modeling of Pit using the structure of the Arabidopsis NLR ZAR1, we tried to clarify the role of the three conserved hydrophobic residues and found that they are involved in the plasma membrane localization. Our findings provide novel insights for understanding the mechanisms of NLR activation as well as the relationship between subcellular localization and immune induction.
Transcriptomic analysis of ribosome biogenesis and pre-rRNA processing during growth stress in Entamoeba histolytica
Authors: Naiyer Sarah , Singh Shashi Shekhar , Kaur Devinder , Singh Yatendra Pratap , Mukherjee Amartya , Bhattacharya Alok , Bhattacharya Sudha
Published: August 2021

Ribosome biogenesis, a multi-step process involving the transcription, modification, folding and processing of rRNA is the major consumer of cellular energy. It involves the sequential assembly of ribosomal proteins (RP)s via more than 200 ribogenesis factors. Unlike model organisms where transcription of rRNA and RP genes slows down during stress, in Entamoeba histolytica, pre-rRNA synthesis continues, and unprocessed pre-rRNA accumulates. To gain insight into the vast repertoire of ribosome biogenesis factors and understand the major components playing role during stress we computationally identified the ribosome biogenesis factors in E. histolytica. Of the total ∼279 S. cerevisiae proteins, we could only find 188 proteins in E. histolytica. Some of the proteins missing in E. histolytica were also missing in humans. A number of proteins represented by multiple genes in S. cerevisiae had only a single copy in E. histolytica. It was interesting to note that E. histolytica lacked mitochondrial ribosome biogenesis factors and had far less RNase components as compared to S. cerevisiae. Northern hybridization using probes from different spacer regions depicted the accumulation of unprocessed intermediates during stress. Transcriptomic studies revealed the differential regulation of a number of ribosomal factors both in serum-starved and RRP6KD conditions. The ARB1 protein involved at multiple steps of ribosome biogenesis and NEP1 and TSR3 involved in chemical modification of 18S rRNA previously shown to accumulate pre-rRNA precursors upon downregulation in S. cerevisiae and humans were included. The data reveals the importance of some of the major factors required for regulating pre-rRNA processing during stress. This is the first report on the complete repertoire of ribosome biogenesis factors in E. histolytica.
Connectome-based predictions reveal developmental change in the functional architecture of sustained attention and working memory
Authors: Kardan Omid , Stier Andrew J. , Cardenas-Iniguez Carlos , Pruin Julia C. , Schertz Kathryn E. , Deng Yuting , Chamberlain Taylor , Meredith Wesley J. , Zhang Xihan , Bowman Jillian E. , Lakhtakia Tanvi , Tindel Lucy , Avery Emily W. , Lin Qi , Yoo Kwangsun , Chun Marvin M. , Berman Marc G. , Rosenberg Monica D.
Published: August 2021

Sustained attention (SA) and working memory (WM) are critical processes, but the brain networks supporting these abilities in development are unknown. We characterized the functional brain architecture of SA and WM in 9–11-year-old children and adults. First, we found that adult network predictors of SA generalized to predict individual differences and fluctuations in SA in youth. A WM network model predicted WM performance both across and within children—and captured individual differences in later recognition memory—but underperformed in youth relative to adults. We next characterized functional connections differentially related to SA and WM in youth compared to adults. Results revealed two network configurations: a dominant architecture predicting performance in both age groups and a secondary architecture, more prominent for WM than SA, predicting performance in one. Thus, functional connectivity predicts SA and WM in youth, with networks predicting WM changing more from preadolescence to adulthood than those predicting SA.
Multidimensional encoding of movement and contextual variables by rat globus pallidus neurons during a novel environment exposure task
Authors: Peer Noam D. , Yamin Hagar G. , Cohen Dana
Published: August 2021

The basal ganglia (BG) play a critical role in a variety of functions that are essential for animal survival. Information from different cortical areas propagates through the BG in anatomically segregated circuits along the parallel direct and indirect pathways. We examined how the globus pallidus (GP), a central nucleus within the indirect pathway, encodes input from the motor and cognitive domains. We chronically recorded and analyzed neuronal activity in the GP of rats engaged in a novel environment exposure task. GP neurons displayed multidimensional responses to movement and contextual information. A model predicting single unit activity required many task-related variables, thus confirming the multidimensionality of GP neurons. In addition, populations of GP neurons, but not single units, reliably encoded the animals’ locomotion speed and the environmental novelty. We posit that the GP independently processes information from different domains, effectively compresses it and collectively conveys it to successive nuclei.
Evolutionary conservation of maternal RNA localization in fishes and amphibians revealed by TOMO-Seq
Authors: Naraine Ravindra , Iegorova Viktoriia , Abaffy Pavel , Franek Roman , Soukup Vladimír , Psenicka Martin , Sindelka Radek
Published: August 2021

Asymmetrical localization of biomolecules inside the egg, results in uneven cell division and establishment of many biological processes, cell types and the body plan. However, our knowledge about evolutionary conservation of localized mRNAs is still limited to a few candidates. Our goal was to compare localization profiles along the animal-vegetal axis of mature eggs from four models, Xenopus laevis, Danio rerio, Ambystoma mexicanum and Acipenser ruthenus using the spatial expression method called TOMO-Seq. We revealed that RNAs of many known important genes such as germ layer determinants, germ plasm factors and members of key signalling pathways, are localized in completely different profiles among the models. There was also a poor correlation between vegetally localized genes but a relatively good correlation between animally localized genes. These findings indicate that the regulation of embryonic development within the animal kingdom is highly diverse and cannot be deduced based on a single model.
Naked Mole-Rat Hematopoietic Stem and Progenitors are Highly Quiescent with an Inherent Myeloid Bias
Authors: Emmrich Stephan , Trapp Alexandre , Zakusilo Frances Tolibzoda , Mariotti Marco , Straight Maggie E. , Zhang Zhihui , Gray Spencer , Drage Michael G. , Ke Zhonghe , Takasugi Masaki , Klusmann Jan-Henning , Gladyshev Vadim N. , Seluanov Andrei , Gorbunova Vera
Published: August 2021

Naked mole-rats (NMRs) are the longest-lived rodents yet their stem cell characteristics remain enigmatic. Here we comprehensively mapped the NMR hematopoietic landscape and identified unique features likely contributing to longevity. Adult NMRs form red blood cells in spleen and marrow, which is a neotenic trait. A myeloid bias towards granulopoiesis in concert with decreased B-lymphopoiesis defines the marrow composition, resembling fetal leukopoiesis. Very similar to primates, the primitive stem cell compartment is marked by CD34 and THY1. Remarkably, stem and progenitor respiration rates are as low as in human cells, while NMR cells show a strong expression signature for fatty acid metabolism. The pool of quiescent stem cells is higher than in mice, and the cell cycle of hematopoietic cells is prolonged. Our work provides a platform to study immunology and stem cell biology in an animal model of exceptional longevity.

Teaser

Juvenile features of hematopoiesis shape the blood system of the longest-lived rodent.
Harnessing protein folding neural networks for peptide-protein docking
Authors: Tsaban Tomer , Varga Julia , Avraham Orly , Ben-Aharon Ziv , Khramushin Alisa , Schueler-Furman Ora
Published: August 2021

Highly accurate protein structure predictions by the recently published deep neural networks such as AlphaFold2 and RoseTTAFold are truly impressive achievements, and will have a tremendous impact far beyond structural biology. If peptide-protein binding can be seen as a final complementing step in the folding of a protein monomer, we reasoned that these approaches might be applicable to the modeling of such interactions. We present a simple implementation of AlphaFold2 to model the structure of peptide-protein interactions, enabled by linking the peptide sequence to the protein c-terminus via a poly glycine linker. We show on a large non-redundant set of 162 peptide-protein complexes that peptide-protein interactions can indeed be modeled accurately. Importantly, prediction is fast and works without multiple sequence alignment information for the peptide partner. We compare performance on a smaller, representative set to the state-of-the-art peptide docking protocol PIPER-FlexPepDock, and describe in detail specific examples that highlight advantages of the two approaches, pointing to possible further improvements and insights in the modeling of peptide-protein interactions. Peptide-mediated interactions play important regulatory roles in functional cells. Thus the present advance holds much promise for significant impact, by bringing into reach a wide range of peptide-protein complexes, and providing important starting points for detailed study and manipulation of many specific interactions.
Hemangiosarcoma cells induce M2 polarization and PD-L1 expression in macrophages
Authors: Gulay Kevin Christian M. , Aoshima Keisuke , Maekawa Naoya , Konnai Satoru , Kobayashi Atsushi , Kimura Takashi
Published: August 2021

Hemangiosarcoma (HSA) is a malignant tumor derived from endothelial cells. Tumor-associated macrophages are one of the major components of tumor microenvironment and crucial for cancer development. The presence and function of macrophages in HSA have not been studied because there is no syngeneic model for HSA. In this study, we evaluated two mouse HSA cell lines and one immortalized mouse endothelial cells for their usefulness as syngeneic models for canine HSA. Our results show that the ISOS-1 cell line develops tumors with similar morphology to canine HSA. ISOS-1 cells highly express KDM2B and have similar KDM2B target expression patterns with canine HSA. Moreover, we determine that in both ISOS-1 and canine HSA tumors, macrophages are present as a major constituent of the tumor microenvironment. These macrophages are positive for CD204, an M2 macrophage marker, and express PD-L1. ISOS-1-conditioned medium can induce M2 polarization and PD-L1 expression in RAW264.7 mouse macrophage cell line. These results show that ISOS-1 can be used as a syngenic model for canine HSA and suggest that macrophages play an important role in immune evasion in HSA. Using the syngeneic mouse model for canine HSA, we can further study the role of immune cells in the pathology of HSA.
Epigenetic reprogramming of DCCs into dormancy suppresses metastasis via restored TGFβ–SMAD4 signaling
Authors: Singh Deepak K. , Farias Eduardo , Carcamo Saul , Hasson Dan , Sun Dan , Cheung Julie , Nobre Ana Rita , Kale Nupura , Sosa Maria Soledad , Bernstein Emily , Aguirre-Ghiso Julio A.
Published: August 2021

Disseminated cancer cells (DCCs) identified in secondary organs, sometimes before the primary tumor becomes detectable and treated, can remain dormant for years to decades before manifesting. Microenvironmental and epigenetic mechanisms may control the onset and escape from dormancy, and here we reveal how a combination of the DNA methylation inhibitor 5-azacytidine (AZA) and retinoic acid receptor ligands all-trans retinoic acid (atRA), orchestrate a novel program of stable dormancy. Treatment of HNSCC tumor cells with AZA+atRA induced a SMAD2/3/4 dependent regulation of downstream transcriptional program that restored the anti-proliferative function of TGFβ signaling. Significantly, AZA+atRA or AZA+AM80, an RARα specific agonist, strongly suppresses lung metastasis formation. The metastatic suppression occurs via the induction and maintenance of phenotypically homogenous dormant SMAD4+/NR2F1+ non-proliferative DCCs. These findings suggest that strategies that maintain or induce dormancy programs may be a viable alternative strategy to improve patient outcomes by preventing or significantly delaying metastasis development.
Functional specialization of monocot DCL3 and DCL5 proteins through the evolution of the PAZ domain
Authors: Chen Shirui , Liu Wei , Naganuma Masahiro , Tomari Yukihide , Iwakawa Hiro-oki
Published: August 2021

Monocot DICER-LIKE3 (DCL3) and DCL5 produce distinct 24-nt heterochromatic small interfering RNAs (hc-siRNAs) and phased secondary siRNAs (phasiRNAs). The former small RNAs are linked to plant heterochromatin, and the latter to reproductive processes. It is assumed that these DCLs evolved from an ancient “eudicot-type” DCL3 ancestor, which may have produced both types of siRNAs. However, how functional differentiation was achieved after gene duplication remains elusive. Here, we find that monocot DCL3 and DCL5 exhibit biochemically distinct preferences for 3′ overhangs and 5′ phosphates, consistent with the structural properties of their in vivo double-stranded RNA substrates. Importantly, these distinct substrate specificities are determined by the PAZ domains of DCL3 and DCL5 which have accumulated mutations during the course of evolution. These data explain the mechanism by which these DCLs cleave their cognate substrates from a fixed end, ensuring the production of functional siRNAs. Our study also indicates how plants have diversified and optimized RNA silencing mechanisms during evolution.
Cytokinin- microbiome interactions regulate developmental functions
Authors: Gupta Rupali , Elkabetz Dorin , Leibman-Markus Meirav , Jami Elie , Bar Maya
Published: August 2021

The interaction of plants with the complex microbial networks that inhabit them is important for plant health. While the reliance of plants on their microbial inhabitants for defense against invading pathogens is well documented, the acquisition of data concerning the relationships between plant developmental stage or aging, and microbiome assembly, is still underway. In this work, we observed developmental-age dependent changes in the phyllopshere microbiome of tomato. The plant hormone cytokinin (CK) regulates various plant growth and developmental processes. Here, we show that age-related shifts in microbiome content vary based on content of, or sensitivity to, CK. We observed a developmental age associated decline in microbial richness and diversity, accompanied by a decline in the presence of growth promoting and resistance inducing bacilli in the phyllosphere. This decline was absent from CK-rich or CK-hypersensitive genotypes. Bacillus isolates we obtained from CK rich genotypes were found to re-program the transcriptome to support morphogenesis and alter the leaf developmental program when applied to seedlings, and enhance yield and agricultural productivity when applied to mature plants. Our results support the notion that CK-dependent effects on microbiome content support developmental functions, suggesting that these are mediated by CK in part via the bacterial community.
Solving the chromosome puzzle of aneuploidy in cancer
Authors: Chiarle Roberto
Published: August 2021

Chromosome instability (CIN) and aneuploidy are hallmarks of cancer cells, typically associated with aggressiveness and poor outcomes. Historically, the causative link between aneuploidy and cancer has been difficult to study due to its intrinsic complexity and the poor fitness of aneuploid cells. In this issue of Genes & Development, two companion papers (Trakala and colleagues [pp. 1079–1092] and Shoshani and colleagues [pp. 1093–1108]) exploited sophisticated mouse models to study the progression of aneuploidy from early phases to established tumors. Both groups observed that, while in the early nontumoral cells aneuploidy is characterized by random chromosomal gains, established tumors display a stereotypic karyotype with recurrent gains of only a few chromosomes. Thus, aneuploidy in tumors is not random but shows reproducible patterns of chromosomal changes induced by mechanisms that these two studies are beginning to unveil.
Preparing Live Cells for Immunization
Authors: Greenfield Edward A. , DeCaprio James , Brahmandam Mohan
Published: August 2021

Generating monoclonal antibodies against cell-surface (i.e., membrane) proteins can be challenging because membrane and membrane-associated proteins often lose their native conformation during the purification process. This also makes fusion screening very difficult. One widely used technique to overcome this issue is to overexpress the target protein in HEK 293T cells and then immunize the host with these cells. The advantage of immunizing with native cells is that the target protein is expressed and presented to the immune system in a correctly folded form with all of its secondary posttranslational structure in place. This is essential for conformational or discontinuous epitopes, and for transmembrane proteins that weave in and out of the cell membrane multiple times. Transient or stable transfectants can be used for immunization and for screening using fluorescence-activated cell sorting, western blot, or immunoprecipitation. Although transfectants often have higher expression levels than do native cells, care should be taken to ensure that the transfectant expresses a functionally active version of the target protein, as otherwise minor folding issues or modifications in structure can result in antibodies that recognize the transfected, but not the native, protein. Care must also be taken when using cells as immunogens because numerous antigenic proteins coimmunize with the target protein. Screening hybridomas using the same cells and counterscreening them on untransfected cells will enable the selection of specific hybridomas.
Accounting, microfoundations, hybridization and longitudinal conflict in a Finnish health care organization
Authors: Rautiainen Antti , Mättö Toni , Sippola Kari , Pellinen Jukka O.
Published: August 2021

Purpose

This article analyzes the cognitive microfoundations, conflicting institutional logics and professional hybridization in a case characterized by conflict.

Design/methodology/approach

In contrast to the majority of earlier studies focusing on special health care, the study was conducted in a Finnish basic health care organization. The empirical data include 36 interviews, accounting reports, budgets, newspaper articles and meeting notes collected 2013–2018.

Findings

The use of accounting techniques in this case did not offer professionals sufficient support under conditions of conflict. The authors suggest that this perceived lack of support intensified the negative emotions toward accounting techniques. These negative emotions aggregated into incompatible professional-level institutional logics, which contributed to the lack of hybridization between such logics. The authors highlight the importance of the cognitive microfoundations, that is, the individual-level interpretations and emotional responses, in the analysis of conflicting institutional logics.

Practical implications

Managerial attention needs to be directed to accounting practices perceived as frustrating or threatening, a perception that can prevent the use of accounting techniques in the creation of professional hybrids. The Finnish basic health care context involves inconsistent political decision-making, multiple tasks, three institutional logics and individual interpretations and emotions in various decision-making situations.

Originality/value

This study develops microfoundational accounting research by illustrating how individual-level cognitive microfoundations such as dissatisfaction with budgeting, aggregate into professional-level institutional logics, and in our case, prevent professional hybridization in a basic health care setting characterized by conflict and three separate institutional logics.