bluuebunny/crossref_metadata_2025 huggingface dataset:
An adaptive teosintemexicanaintrogression modulates phosphatidylcholine levels and is associated with maize flowering time
Authors: Barnes Allison C , Rodríguez-Zapata Fausto , Blöcher-Juárez Karla A , Gates Daniel J , Janzen Garrett M , Kur Andi , Wang Li , Jensen Sarah E , Estévez-Palmas Juan M , Crow Taylor M , Kavi Heli S , Pil Hannah D , Stokes Ruthie L , Knizner Kevan T , Aguilar-Rangel Maria R , Demesa-Arévalo Edgar , Skopelitis Tara , Pérez-Limón Sergio , Stutts Whitney L , Thompson Peter , Chiu Yu-Chun , Jackson David , Muddiman David C , Fiehn Oliver , Runcie Daniel , Buckler Edward S , Ross-Ibarra Jeffrey , Hufford Matthew B , Sawers Ruairidh JH , Rellán-Álvarez Rubén
Published: January 2021

Native Americans domesticated maize (Zea maysssp.mays) from lowland teosinteparviglumis(Zea maysssp.parviglumis) in the warm Mexican southwest and brought it to the highlands of México and South America where it was exposed to lower temperatures that imposed strong selection on flowering time. Phospholipids are important metabolites in plant responses to low-temperature and phosphorus availability, and have been suggested to influence flowering time. Here, we combined linkage mapping with genome scans to identifyHigh PhosphatidylCholine 1(HPC1), a gene that encodes a phospholipase A1 enzyme, as a major driver of phospholipid variation in highland maize. Common garden experiments demonstrated strong genotype-by-environment interactions associated with variation atHPC1, with the highlandHPC1allele leading to higher fitness in highlands, possibly by hastening flowering. The highland maizeHPC1variant resulted in impaired function of the encoded protein due to a polymorphism in a highly conserved sequence. A meta-analysis across HPC1 orthologs indicated a strong association between the identity of the amino acid at this position and optimal growth in prokaryotes. Mutagenesis ofHPC1via genome editing validated its role in regulating phospholipid metabolism. Finally, we showed that the highlandHPC1allele entered cultivated maize by introgression from the wild highland teosinteZea maysssp.mexicanaand has been maintained in maize breeding lines from the Northern US, Canada and Europe. Thus,HPC1introgressed from teosintemexicanaunderlies a large metabolic QTL that modulates phosphatidylcholine levels and has an adaptive effect at least in part via induction of early flowering time.
An Alternative, Cas12a-based CRISPR Interference System for Mycobacteria
Authors: Fleck Neil , Grundner Christoph
Published: January 2021

The introduction of CRISPR interference (CRISPRi) has made gene repression in mycobacteria much more efficient, but technical challenges of the prototypical Cas9-based platform, for example in multigene regulation, remain. Here, we introduce an alternative CRSPRi platform that uses the minimal Cas12a enzyme in combination with synthetic CRISPR arrays. This system is simple, tunable, and can regulate multiple genes simultaneously, providing a new tool to probe higher-order genetic interactions in mycobacteria includingMycobacterium tuberculosis(Mtb).
Spatiotemporal Trajectories in Resting-state FMRI Revealed by Convolutional Variational Autoencoder
Authors: Zhang Xiaodi , Maltbie Eric , Keilholz Shella
Published: January 2021

Recent resting-state fMRI studies have shown that brain activity exhibits temporal variations in functional connectivity by using various approaches including sliding window correlation, co-activation patterns, independent component analysis, quasi-periodic patterns, and hidden Markov models. These methods often model the brain activity as a discretized hopping among several brain states that are defined by the spatial configurations of network activity. However, the discretized states are merely a simplification of what is likely to be a continuous process, where each network evolves over time following its unique path. To model these characteristic spatiotemporal trajectories, we trained a variational autoencoder using rs-fMRI data and evaluated the spatiotemporal features of the latent variables obtained from the trained networks. Our results suggest that there are a relatively small number of approximately orthogonal whole-brain spatiotemporal patterns that capture the most prominent features of rs-fMRI data, which can serve as the building blocks to construct all possible spatiotemporal dynamics in resting state fMRI. These spatiotemporal patterns provide insight into how activity flows across the brain in concordance with known network structures and functional connectivity gradients.
SARS-CoV-2 receptor binding mutations and antibody mediated immunity
Authors: Mejdani Marios , Haddadi Kiana , Pham Chester , Mahadevan Radhakrishnan
Published: January 2021

SARS-CoV-2 mutations can impact infectivity, viral load, and overall morbidity/mortality during infection. In this analysis, we look at the mutational landscape of the SARS-CoV-2 receptor binding domain, a structure that is antigenic and allows for viral binding to the host. We analyze 104193 GISAID sequences acquired on October 15th, 2020 with a majority of sequences (96%) containing point mutations. We report high frequency mutations with improved binding affinity to ACE2 including S477N, N439K, V367F, and N501Y and address the potential impact of RBD mutations on antibody binding. The high frequency S477N mutation is present in 6.7% of all SARS-CoV-2 sequences, co-occurs with D614G, and is currently present in 14 countries. To address RBD-antibody interactions we take a subset of human derived antibodies and define their interacting residues using PDBsum. Our analysis shows that adaptive immunity against SARS-CoV-2 enlists broad coverage of the RBD suggesting that antibody mediated immunity should be sufficient to resolve infection in the presence of RBD point mutations that conserve structure.
Surface-based Single-subject Morphological Brain Networks: Effects of Morphological Index, Brain Parcellation and Similarity Measure, Sample Size-varying Stability and Test-retest Reliability
Authors: Li Yinzhi , Wang Ningkai , Wang Hao , Lv Yating , Zou Qihong , Wang Jinhui
Published: January 2021

Morphological brain networks, in particular those at the individual level, have become an important approach for studying the human brain connectome; however, relevant methodology is far from being well-established in their formation, description and reproducibility. Here, we extended our previous study by constructing and characterizing single-subject morphological similarity networks from brain volume to surface space and systematically evaluated their reproducibility with respect to effects of different choices of morphological index, brain parcellation atlas and similarity measure, sample size-varying stability and test-retest reliability. Using the Human Connectome Project dataset, we found that surface-based single-subject morphological similarity networks shared common small-world organization, high parallel efficiency, modular architecture and bilaterally distributed hubs regardless of different analytical strategies. Nevertheless, quantitative values of all interregional similarities, global network measures and nodal centralities were significantly affected by choices of morphological index, brain parcellation atlas and similarity measure. Moreover, the morphological similarity networks varied along with the number of participants and approached stability until the sample size exceeded ∼70. Using an independent test-retest dataset, we found fair to good, even excellent, reliability for most interregional similarities and network measures, which were also modulated by different analytical strategies, in particular choices of morphological index. Specifically, fractal dimension and sulcal depth outperformed gyrification index and cortical thickness, higher-resolution atlases outperformed lower-resolution atlases, and Jensen-Shannon divergence-based similarity outperformed Kullback-Leibler divergence-based similarity. Altogether, our findings propose surface-based single-subject morphological similarity networks as a reliable method to characterize the human brain connectome and provide methodological recommendations and guidance for future research.
Nigrostriatal Dopamine Signals Sequence-Specific Action-Outcome Prediction Errors
Authors: Hollon Nick G. , Williams Elora W. , Howard Christopher D. , Li Hao , Traut Tavish I. , Jin Xin
Published: January 2021

Dopamine has been suggested to encode cue-reward prediction errors during Pavlovian conditioning. While this theory has been widely applied to reinforcement learning concerning instrumental actions, whether dopamine represents action-outcome prediction errors and how it controls sequential behavior remain largely unknown. Here, by training mice to perform optogenetic intracranial self-stimulation, we examined how self-initiated goal-directed behavior influences nigrostriatal dopamine transmission during single as well as sequential instrumental actions. We found that dopamine release evoked by direct optogenetic stimulation was dramatically reduced when delivered as the consequence of the animal’s own action, relative to non-contingent passive stimulation. This action-induced dopamine suppression was specific to the reinforced action, temporally restricted to counteract the expected outcome, and exhibited sequence-selectivity consistent with hierarchical control of sequential behavior. Together these findings demonstrate that nigrostriatal dopamine signals sequence-specific prediction errors in action-outcome associations, with fundamental implications for reinforcement learning and instrumental behavior in health and disease.
Global analysis of protein arginine methylation
Authors: Zhang Fangrong , Kerbl-Knapp Jakob , Rodriguez Colman Maria J. , Macher Therese , Vujić Nemanja , Fasching Sandra , Jany-Luig Evelyne , Korbelius Melanie , Kuentzel Katharina B. , Mack Maximilian , Akhmetshina Alena , Paar Margret , Rinner Beate , Hörl Gerd , Steyrer Ernst , Stelzl Ulrich , Burgering Boudewijn , Eisenberg Tobias , Pertschy Brigitte , Kratky Dagmar , Madl Tobias
Published: January 2021

Quantitative information about the levels and dynamics of post-translational modifications (PTMs) is critical for an understanding of cellular functions. Protein arginine methylation (ArgMet) is an important subclass of PTMs and is involved in a plethora of (patho)physiological processes. However, due to the lack of methods for global analysis of ArgMet, the link between ArgMet levels, dynamics and (patho)physiology remains largely unknown. We utilized the high sensitivity and robustness of Nuclear Magnetic Resonance (NMR) spectroscopy to develop a general method for the quantification of global protein ArgMet. Our NMR-based approach enables the detection of protein ArgMet in purified proteins, cells, organoids, and mouse tissues. We demonstrate that the process of ArgMet is a highly prevalent PTM and can be modulated by small-molecule inhibitors and metabolites and changes in cancer and during ageing. Thus, our approach enables to address a wide range of biological questions related to ArgMet in health and disease.

Graphical Abstract
Trophic position derived from amino-acid nitrogen isotopes reflect physiological status of both predator and prey over four decades
Authors: Karlson Agnes ML , Ek Caroline , Jones Douglas
Published: January 2021

Nitrogen isotope analyses of amino-acids (δ15N-AA) are increasingly used to decipher food webs. Interpretation of δ15N-AA in consumers relies on the assumption that physiological status has a negligible influence on the trophic enrichment factor (TEF). Recent experiments have shown that this is not always the case and there is a need to validate derived trophic position (TP) estimates using ecological data. We analyzed δ15N-AA in cod and herring (1980-2019) from the Baltic Sea, a species-poor system where dramatic reduction in condition status of cod has occurred. We expected that TEFcod-herringin trophic AAs would increase during periods of poor cod growth, resulting in inflated TP estimates. We found that TEF and TP estimates were negatively linked to individual condition status, prey fat content and the hypoxic state of the ecosystem. Statistically adjusting for these variables resulted in lower cod TP, highlighting the importance of including ecological knowledge when interpreting TP.

Scientific Significance Statement

Nitrogen stable isotope analyses in amino acids are increasingly used in ecology to understand how environmental change impacts food-webs. Specifically, it is used to more accurately calculate trophic position (TP) of consumers. Controlled experiments have shown that physiological status can alter amino acid isotope composition and TP interpretation, but field studies are lacking. We use 40 years of archived material to demonstrate that TP estimates in Baltic Sea cod and its prey herring are directly related to physiological status. This has important implications for interpreting the real trophic ecology of consumers under environmental stress. By simultaneously measuring condition status in both predator and prey it is possible to adjust for them as confounding variables and decipher actual consumer TP.
martini: an R package for genome-wide association studies using SNP networks
Authors: Climente-González Héctor , Azencott Chloé-Agathe
Published: January 2021

Systems biology shows that genes related to the same phenotype are often functionally related. We can take advantage of this to discover new genes that affect a phenotype. However, the natural unit of analysis in genome-wide association studies (GWAS) is not the gene, but the single nucleotide polymorphism, or SNP. We introducemartini, an R package to build SNP co-function networks and use them to conduct GWAS. In SNP networks, two SNPs are connected if there is evidence they jointly contribute to the same biological function. By leveraging such information in GWAS, we search SNPs that are not only strongly associated with a phenotype, but also functionally related. This, in turn, boosts discovery and interpretability.Martinibuilds such networks using three sources of information: genomic position, gene annotations, and gene-gene interactions. The resulting SNP networks involve hundreds of thousands of nodes and millions of edges, making their exploration computationally intensive.Martiniimplements two network-guided biomarker discovery algorithms based on graph cuts that can handle such large networks: SConES and SigMod. They both seek a small subset of SNPs with high association scores with the phenotype of interest and densely interconnected in the network. Both algorithms use parameters that control the relative importance of the SNPs’ association scores, the number of SNPs selected, and their interconnection.Martiniincludes a cross-validation procedure to set these parameters automatically. Lastly,martiniincludes tools to visualize the selected SNPs’ network and association properties.Martiniis available on GitHub (hclimente/martini) and Bioconductor (martini).
Haploflow: Strain-resolvedde novoassembly of viral genomes
Authors: Fritz A. , Bremges A. , Deng Z.-L. , Lesker T.-R. , Götting J. , Ganzenmüller T. , Sczyrba A. , Dilthey A. , Klawonn F. , McHardy A.C.
Published: January 2021

In viral infections often multiple related viral strains are present, due to coinfection or within-host evolution. We describe Haploflow, a de Bruijn graph-based assembler forde novogenome assembly of viral strains from mixed sequence samples using a novel flow algorithm. We assessed Haploflow across multiple benchmark data sets of increasing complexity, showing that Haploflow is faster and more accurate than viral haplotype assemblers and generic metagenome assemblers not aiming to reconstruct strains. Haplotype reconstructed high-quality strain-resolved assemblies from clinical HCMV samples and SARS-CoV-2 genomes from wastewater metagenomes identical to genomes from clinical isolates.
Improved DNA-versus-Protein Homology Search for Protein Fossils
Authors: Yao Yin , Frith Martin C.
Published: January 2021

Protein fossils, i.e. noncoding DNA descended from coding DNA, arise frequently from transposable elements (TEs), decayed genes, and viral integrations. They can reveal, and mislead about, evolutionary history and relationships. They have been detected by comparing DNA to protein sequences, but current methods are not optimized for this task. We describe a powerful DNA-protein homology search method. We use a 64×21 substitution matrix, which is fitted to sequence data, automatically learning the genetic code. We detect subtly homologous regions by considering alternative possible alignments between them, and calculate significance (probability of occurring by chance between random sequences). Our method detects TE protein fossils much more sensitively thanblastx, and > 10× faster. Of the ~7 major categories of eukaryotic TE, three have not been found in mammals: we find two of them in the human genome, polinton and DIRS/Ngaro. This method increases our power to find ancient fossils, and perhaps to detect non-standard genetic codes. The alternative-alignments and significance paradigm is not specific to DNA-protein comparison, and could benefit homology search generally.
Regulatory Modules of Human Thermogenic Adipocytes: Functional Genomics of Meta-Analyses Derived Marker-Genes
Authors: Tóth Beáta B. , Barta Zoltán , Fésüs László
Published: January 2021

Recently, ProFAT and BATLAS scores have been offered to determine thermogenic status of adipocytes using expression pattern of brown and white marker-genes. In this work, we investigated the functional context of these genes. Although the two meta-analyses based marker-gene lists have little overlap, their enriched pathways show strong coincides suggesting they may better characterize adipocytes. We demonstrate that functional genomics of the annotated genes in common pathways enables an extended analysis of thermogenesis regulation, generates testable hypotheses supported by experimental results in human adipocytes with different browning potential and may lead to more global conclusions than single-state studies. Our results imply that different biological processes shape brown and white adipocytes with presumed transitional states. We propose that the thermogenic adipocyte phenotype require both repression of whitening and induction of browning. These simultaneous actions and hitherto unnoticed regulatory modules, such as the exemplified HIF1A that may directly act atUCP1promoter, can set new direction in obesity research.

Highlights

Integrated pathways better characterize brown adipocytes than marker-genes

Different processes shape the brown and white adipocyte phenotypes

Thermogenic phenotype may require simultaneous repression of whitening and induction of browning

Protein network analyses reveals unnoticed regulatory modules of adipocyte phenotype

HIF1A may regulate thermogenesis by direct control ofUCP1gene-expression

Graphical Abstract
AMMI and GGE biplot analysis of yield of different elite Wheat line under terminal heat stress and irrigated environment
Authors: K. C. Bishwas , Poudel Mukti Ram , Regmi Dipendra
Published: January 2021

Wheat crop in Nepal faces terminal heat stress which accelerates the gain filling rate and shortens the filling period which leads to reduced grain weight, size, number, quality that is yield loss. For minimization of this loss, genotypic selection of high yielding lines should be performed understanding the gene-environment interaction. With the view to obtain a high yielding line with stable performance across the environments an experiment was conducted using 18 elite wheat line and 2 check varieties in alpha lattice design (2 replication and 5 blocks per replication) in different environments viz. irrigated and terminal heat stressed environment. The analysis of variance revealed that genotype, environment and their interaction had highly significant effect on the yield. Furthermore, which-won–where model indicated specific adaptation of elite lines NL-1179, NL-1420, BL-4407, NL-1368 to irrigated environment and BL-4919 and NL-1350 to terminal heat-stressed environment. Similarly, Mean-versus-stability study indicated that elite line BL-4407, NL-1368, BL-4919, NL-1350 and NL-1420 had above average yield and higher stability whereas elite lines Gautam, NL-1412, NL-1376, NL-1387, NL-1404 and N-1381 had below average yield and lower stability. Also, ranking elite lines biplot, PCA1 explaining 73.6% and PCA2 explaining 26.4% of the interaction effect, showed the rank of elite line, NL-1420 > NL-1368> NL-1350 > other lines, close to ideal line. From these findings, NL-1420 with high yield and stability can be recommended across both the environment while NL-1179 is adapted specifically for irrigated and NL-1350 adapted specifically for terminal heat-stressed environment.
Comparison of Two Illumina Whole Transcriptome RNA Sequencing Library Preparation Methods Using Human FFPE Specimens
Authors: Wang Danyi , Rolfe P. Alexander , Foernzler Dorothee , O’Rourke Dennis , Zhao Sheng , Scheuenpflug Juergen , Feng Zheng
Published: January 2021

RNA extraction and library preparation from formalin-fixed, paraffin-embedded (FFPE) samples are crucial pre-analytical steps towards achieving optimal downstream RNA Sequencing (RNASeq) results. We assessed the Illumina TruSeq Stranded Total RNA library preparation method and the Illumina TruSeq RNA Access library preparation method for RNA-Seq analysis using 25 FFPE samples from human cancer indications (NSCLC, CRC, RC, BC and HCC) at two independent vendors. These FFPE samples covered a wide range of sample storage durations (3-25 years-old), sample qualities, and specimen types (resection vs. core needle biopsy). Our data showed that TruSeq RNA Access libraries yield over 80% exonic reads across different quality samples, indicating higher selectivity of the exome pull down by the capture approach compared to the random priming of the TruSeq Stranded Total kit. The overall QC data for FFPE RNA extraction, library preparation, and sequencing generated by the two vendors are comparable, and downstream gene expression quantification results show high concordance as well. With the TruSeq Stranded Total kit, the average Spearman correlation between vendors was 0.87 and the average Pearson correlation was 0.76. With the TruSeq RNA Access kit, the average Spearman correlation between vendors was 0.89 and the average Pearson correlation was 0.73. Interestingly, examination of the crossvendor correlations compared to various common QC statistics suggested that library concentration is better correlated with consistency between vendors than is the RNA quantity. Our analyses provide evidence to guide selection of sequencing methods for FFPE samples in which the sample quality may be severely compromised.
Hemagglutination Inhibition (HAI) Antibody Landscapes after Vaccination with diverse H7 hemagglutinin (HA) proteins
Authors: Jang Hyesun , Ross Ted M
Published: January 2021

Background

A systemic evaluation of the antigenic differences of the H7 influenza hemagglutinin (HA) proteins, especially for the viruses isolated after 2016, are limited. The purpose of this study was to investigate the antigenic differences of major H7 strains with an ultimate aim to discover H7 HA proteins that can elicit protective receptor-blocking antibodies against co-circulating H7 influenza strains.

Method

A panel of nine H7 influenza strains were selected from 3,633 H7 HA amino acid sequences identified over the past two decades (2000-2018). The sequences were expressed on the surface of virus like particles (VLPs) and used to vaccinate C57BL/6 mice. Serum samples were collected and tested for hemagglutination-inhibition (HAI) activity. The vaccinated mice were challenged with lethal dose of H7N9 virus, A/Anhui/1/2013.

Results

VLPs expressing the H7 HA antigens elicited broadly reactive antibodies each of the selected H7 HAs, except the A/Turkey/Italy/589/2000 (Italy/00) H7 HA. A putative glycosylation due to an A169T substitution in antigenic site B was identified as a unique antigenic profile of Italy/00. Introduction of the putative glycosylation site (H7 HA-A169T) significantly altered the antigenic profile of HA of the A/Anhui/1/2013 (H7N9) strain.

Conclusion

This study identified key amino acid mutations that result in severe vaccine mismatches for future H7 epidemics. Future universal influenza vaccine candidates will need to focus on viral variants with these key mutations.
NOMIS: Quantifying morphometric deviations from normality over the lifetime of the adult human brain
Authors: Potvin Olivier , Dieumegarde Louis , Duchesne Simon ,   the Alzheimer’s Disease Neuroimaging Initiative,   the CIMA-Q,   the CCNA groups
Published: January 2021

We present NOMIS (https://github.com/medicslab/NOMIS), a comprehensive open MRI tool to assess morphometric deviation from normality in the adult human brain. Based on MR anatomical images from 6,909 cognitively healthy individuals aged 18-100 years, we modeled 1,344 measures computed using the open accessFreeSurferpipeline, considering account personal characteristics (age, sex, intracranial volume) and image quality (resolution, contrast-to-noise ratio and surface reconstruction defect holes), and providing expected values for any new individual. Then, for each measure, the NOMIS tool was built to generate Z-score effect sizes denoting the extent of deviation from the normative sample. Depending on the user need, NOMIS offers four versions of Z-score adjusted on different sets of variables. While all versions consider head size and image quality, they can also incorporate age and/or sex, thereby facilitating multi-site neuromorphometric research across adulthood.
Deciphering the transcriptomic regulation of heat stress responses inNothofagus pumilio
Authors: Estravis-Barcala Maximiliano , Heer Katrin , Marchelli Paula , Ziegenhagen Birgit , Arana María Verónica , Bellora Nicolás
Published: January 2021

Global warming is predicted to exert negative impacts on plant growth due to the damaging effect of high temperatures on plant physiology. Revealing the genetic architecture underlying the heat stress response is therefore crucial for the development of conservation strategies, and for breeding heat-resistant plant genotypes. Here we investigated the transcriptional changes induced by heat inNothofagus pumilio, an emblematic tree species of the sub-Antarctic forests of South America. Through the performance of RNA-seq of leaves of plants exposed to 20°C (control) or 34°C (heat shock), we generated the first transcriptomic resource for the species. We also studied the changes in protein-coding transcripts expression in response to heat. We found 5,214 contigs differentially expressed between temperatures. The heat treatment resulted in a down-regulation of genes related to photosynthesis and carbon metabolism, whereas secondary metabolism, protein re-folding and response to stress were up-regulated. Moreover, several transcription factor families like WRKY or ERF were promoted by heat, alongside spliceosome machinery and hormone signaling pathways. Through a comparative analysis of gene regulation in response to heat inArabidopsis thaliana, Populus tomentosaandN. pumiliowe provide evidence of the existence of shared molecular features of heat stress responses across angiosperms, and identify genes of potential biotechnological application.
Ecological habitat partitioning and feeding specialisations of coastal minke whales (Balaenoptera acutorostrata) using a designated MPA in northeast Scotland
Authors: Robinson Kevin P. , Bamford Connor C.G. , Brown William J. , Culloch Ross M. , Dolan Ciaran J. , Hall Rebecca , Russell Grace , Sidiropoulos Theofilos , Spinou Evgenia , Sim Texa M.C. , Stroud Elice , Williams Genevieve , Haskins Gary N.
Published: January 2021

In the design of protected areas for cetaceans, spatial maps rarely take account of the life-history and behaviour of protected species relevant to their spatial ambit, which may be important when modelling population trends or assessing susceptibility to anthropogenic threats. In the present study, we examined the distribution and feeding behaviours of minke whales by age-class (adultsversusjuveniles) from long-term studies in the Moray Firth in northeast Scotland, where a Marine Protected Area (MPA) has recently been designated. Data were collected from dedicated boat surveys between 2000 and 2019, during which 657 encounters with 774 whales of confirmed age-class (444 juveniles and 330 adults) were recorded from 50,041 km of survey effort, resulting in 224 individual follows. Feeding/foraging whales were documented in 84% of the encounters. Adults and juveniles were occasionally seen together, but their distributions were not statistically correlated, and GIS revealed spatial separation by age-class―with juveniles preferring shallow, inshore waters with sandy-gravel sediments and adults preferring deeper, offshore waters with steep benthic slope. Whilst adult minkes employed a range of “active” prey-entrapment specialisations, showing seasonal flexibility in their targeted prey with interindividual variation, juveniles almost exclusively used “passive” (low energy) feeding methods, targeting low-density patches of inshore prey. These findings corroborate the need to incorporate demographic/behavioural data into spatial models when identifying priority areas for protected cetaceans and may be important to adaptive management objectives for the species in the Moray Firth MPA.
Induction of peri-implantation stage synthetic embryos using reprogramming paradigms in ESCs
Authors: Langkabel Jan , Horne Arik , Bonaguro Lorenzo , Hesse Tatiana , Knaus Alexej , Riedel Yannick , Händler Kristian , Bassler Kevin , Reusch Nico , Yeghiazarian Leon Harootoonovtch , Pecht Tal , Aschenbrenner Anna C. , Kaiser Franziska , Kubaczka Caroline , Schultze Joachim L. , Schorle Hubert
Published: January 2021

Blastocyst-derived stem cell lines were shown to self-organize into embryo-like structures in 3D cell culture environments. Here, we provide evidence that synthetic embryo-like structures are generated solely based on transcription factor-mediated molecular reprogramming of embryonic stem cells in a simple 3D co-culture system. ESCs in these cultures self-organize into elongated, compartmentalized synthetic embryo-like structures over the course of reprogramming exhibiting anterior visceral endoderm formation and symmetry breaking. Single-cell RNA-Seq reveals transcriptional profiles resembling epiblast, visceral endoderm, and extraembryonic ectoderm of early murine embryos around E4.5–E5.5. Within the epiblast, compartment marker gene expression supports primordial germ cell specification. After transplantation, synthetic embryo-like structures implantin uteriand initiate the formation of decidual tissues. This system allows for fast and reproducible generation of synthetic embryo-like structures, providing further insights into synthetic embryology.
miR-24:Prdx6 interactions regulate oxidative stress and viability of myogenic progenitors during ageing
Authors: Soriano-Arroquia Ana , Gostage John , Bardell David , McCloskey Eugene , Bellantuono Ilaria , Clegg Peter , McDonagh Brian , Goljanek-Whysall Katarzyna
Published: January 2021

microRNAs regulate a myriad of physiological processes, including skeletal muscle regeneration and homeostasis. During ageing, changes in muscle fibre microenvironment contribute to the capability of satellite cells to regenerate the muscle in response to injury and loading stressors. In this study, we isolated murine satellite cells and primary myogenic progenitors from mice and humans to demonstrate that the microRNA miR-24-3p and its target peroxiredoxin 6 (Prdx6) play an important role in muscle regeneration during ageing, regulating satellite cell viability and their differentiation potential. Our results show upregulation of miR-24 during early stages of muscle regenerationin vivoin adult mice, suggesting a potential role of miR-24 at the early stages of muscle injury. On contrary, miR-24 was downregulated during regeneration of muscle of old mice. miR-24 was also downregulated, whereas its target gene Prdx6 was upregulated, in satellite cells isolated from old mice. miR-24 consistently regulated viability and myogenic potential of myogenic progenitors from both humans and old mice, suggesting that changes in miR-24 levels during ageing may contribute to defective early stages of muscle regeneration during ageing through affecting satellite cell viability and myogenic potential. This regulation likely occursviamiR-24 counteracting the generation of reactive oxygen species through Prdx6 de-repression in primary myogenic progenitors isolated from humans and old mice. We propose that downregulation of miR-24 in muscle of old mice following injury may be a protective mechanism against elevated ROS levels to maintain satellite cell viability and myogenic potential, acting through Prdx6 upregulation. However, as miR-24 is a regulator of p16 and p21, this downregulation may lead to increased satellite cell senescence, therefore representing an age-related failed compensatory mechanism.
A preliminary study on the cistrome of human postsynaptic density from an evolutionary and network-based perspective
Authors: Kalman Zsofia E. , Gáspári Zoltán
Published: January 2021

The postsynaptic density (PSD) is a neuronal organelle that consists of thousands of protein complexes, having a role in signal transduction. The emergence of the complexes is dependent on the presence of proteins provided by gene expression. In this research we used Chip-seq data supported by protein level information. We developed a pipeline using data from five neuronal transcription factors, which reduces the false-positive hits of identified binding sites. In addition we found correlation between co-regulation and protein complex formation. The developed method paves the way for a future for large scale analysis utilizing a more comprehensive set of transcription factors.
Modeling Protein Association from Homogeneous to Mixed Environments: A Reaction-Diffusion Dynamics Approach
Authors: Sahu Suraj Kumar , Biswas Mithun
Published: January 2021

Protein-protein associationin vivooccur in a crowded and complex environment. Theoretical models based on hard-core repulsion predict stabilization of the product under crowded conditions. Soft interactions, on the contrary, can either stabilize or destabilize the product formation. Here we modeled protein association in presence of crowders of varying size, shape, interaction potential and used different mixing parameters for constituent crowders to study the influence on the association reaction. It was found that size a more dominant factor in crowder-induced stabilization than the shape. Furthermore, in a mixture of crowders having different sizes but identical interaction potential, the change of free energy is additive of the free energy changes produced by individual crowders. However, the free energy change is not additive if two crowders of same size interact via different interaction potentials. These findings provide a systematic understanding of crowding influences in heterogeneous medium.
Small proteins modulate ion channel-like ACD6 to regulate immunity inArabidopsis thaliana
Authors: Chen Junbin , Li Lei , Kim Jong Hum , Neuhäuser Benjamin , Wang Mingyu , Thelen Michael , Hilleary Richard , Chi Yuan , Wei Luyang , Venkataramani Kavita , Exposito-Alonso Moises , Liu Chang , Keck Jakob , Barragan A. Cristina , Schwab Rebecca , Lutz Ulrich , Pei Zhen-Ming , He Sheng-Yang , Ludewig Uwe , Weigel Detlef , Zhu Wangsheng
Published: January 2021

ACCELERATED CELL DEATH 6 (ACD6) mediates a trade-off between growth and defense inArabidopsis thaliana. However, the precise biochemical mechanism by which ACD6 and related proteins in plants act remains enigmatic. Here, we identified two loci,MODULATOR OF HYPERACTIVE ACD6 1(MHA1) and its paralogMHA1-LIKE(MHA1L), that code for ∼7 kDa proteins that differentially interact with specific ACD6 variants. MHA1L enhances accumulation of an ACD6 complex, thereby increasing activity of theACD6standard allele for regulating plant growth and defenses. ACD6 is a multipass transmembrane protein with intracellular ankyrin repeats that are structurally similar to those found in mammalian ion channels. Several lines of evidence link increased ACD6 activity to enhanced calcium influx, likely mediated by ACD6 itself and with MHA1L as a direct regulator of ACD6.
HIV-1 Vpr drives a tissue residency-like phenotype during selective infection of resting memory T cells
Authors: Reuschl Ann-Kathrin , Shivkumar Maitreyi , Mesner Dejan , Pallett Laura J. , Guerra-Assunção José Afonso , Madansein Rajhmun , Dullabh Kaylesh J , Sigal Alex , Thornhill John P. , Herrera Carolina , Fidler Sarah , Noursadeghi Mahdad , Maini Mala K. , Jolly Clare
Published: January 2021

Human immunodeficiency virus type 1 (HIV-1) replicates in CD4+ T cells leading to profound T cell loss, immunological dysfunction and AIDS. Determining how HIV-1 shapes the immunological niche in which it resides to create a permissive environment is central to informing efforts to limit pathogenesis, disturb viral reservoirs and achieve a cure. A key roadblock in understanding HIV-T cell interactions is the requirement to activate CD4+ T cellsin vitroin order to make them permissive to infection. This dramatically alters T cell biology, obscuring native virus-host interactions. Here we show that HIV-1 cell-to-cell spread permits efficient and productive infection of resting CD4+ T cells without the need for prior activation. Infection is preferential for resting memory T cells, is observed with both CXCR4-tropic virus and CCR5-tropic transmitter-founder viruses and results in virus production and onward spreading infection. Strikingly, we find that HIV-1 infection of resting memory CD4+ T cells primes for induction of a tissue-resident memory (TRM)-like phenotype evidenced by upregulation of TRMmarkers CD69/CXCR6 alongside co-expression of CD49a, PD-1, CD101 as well as transcription factor Blimp-1. Furthermore, we reveal that HIV-1 initiates a transcriptional program that overlaps with the core TRMtranscriptional signature. This reprograming depends on the HIV-1 accessory protein Vpr. We propose that HIV-1 infection drives a CD4+ TRM-phenotype potentially sequestering infected cells within tissues to support viral replication and persistence.
Shifts in marine invertebrate bacterial assemblages associated with tissue necrosis during a heatwave
Authors: Rubio-Portillo Esther , Ramos Esplá Alfonso A. , Antón Josefa
Published: January 2021

Marine heatwaves (MHWs) are periods of extremely high seawater temperature that affect marine ecosystems in several ways. Anthozoans (corals and gorgonians) and Porifera (sponges) are usually among the taxa most affected by MHWs. Both are holobiont entities that form complex interactions with a wide range of microbes, which are an essential part of these organisms and play key roles in their health status. Here, we determine microbial community changes suffered in two corals (Cladocora caespitosaandOculina patagonica), one gorgonian (Leptogorgia sarmentosa), and one sponge (Sarcotragus fasciculatus) during the 2015 MHW. The microbial communities were different among hosts and displayed shifts related to host health status, with a higher abundance in necrosed tissues ofRuegeriaspecies or of potential pathogens likeVibrio.We also carry out a meta-analysis using 93 publicly accessible 16S rRNA gene libraries fromO. patagonica,C. caespitosaandL. sarmentosato establish a Mediterranean core microbiome in these species. We have identified oneRuegeriaOTU that maintained a stable and consistent association with these species, which was also related with tissue necrosis in their hosts. Therefore,Ruegeriasp. could play an important and still underexplored role in the health status of its hosts.
Longitudinal analysis of humoral immunity against SARS-CoV-2 Spike in convalescent individuals up to 8 months post-symptom onset
Authors: Anand Sai Priya , Prévost Jérémie , Nayrac Manon , Beaudoin-Bussières Guillaume , Benlarbi Mehdi , Gasser Romain , Brassard Nathalie , Laumaea Annemarie , Gong Shang Yu , Bourassa Catherine , Brunet-Ratnasingham Elsa , Medjahed Halima , Gendron-Lepage Gabrielle , Goyette Guillaume , Gokool Laurie , Morrisseau Chantal , Bégin Philippe , Martel-Laferrière Valérie , Tremblay Cécile , Richard Jonathan , Bazin Renée , Duerr Ralf , Kaufmann Daniel E. , Finzi Andrés
Published: January 2021

Functional and lasting immune responses to the novel coronavirus (SARS-CoV-2) are currently under intense investigation as antibody titers in plasma have been shown to decline during convalescence. Since the absence of antibodies does not equate to absence of immune memory, we sought to determine the presence of SARS-CoV-2-specific memory B cells in COVID-19 convalescent patients. In this study, we report on the evolution of the overall humoral immune responses on 101 blood samples obtained from 32 COVID-19 convalescent patients between 16 and 233 days post-symptom onset. Our observations indicate that anti-Spike and anti-RBD IgM in plasma decay rapidly, whereas the reduction of IgG is less prominent. Neutralizing activity in convalescent plasma declines rapidly compared to Fc-effector functions. Concomitantly, the frequencies of RBD-specific IgM+ B cells wane significantly when compared to RBD-specific IgG+ B cells, which increase over time, and the number of IgG+ memory B cells which remain stable thereafter for up to 8 months after symptoms onset. With the recent approval of highly effective vaccines for COVID-19, data on the persistence of immune responses are of central importance. Even though overall circulating SARS-CoV-2 Spike-specific antibodies contract over time during convalescence, we demonstrate that RBD-specific B cells increase and persist up to 8 months post symptom onset. We also observe modest increases in RBD-specific IgG+ memory B cells and importantly, detectable IgG and sustained Fc-effector activity in plasma over the 8-month period. Our results add to the current understanding of immune memory following SARS-CoV-2 infection, which is critical for the prevention of secondary infections, vaccine efficacy and herd immunity against COVID-19.
Electrophysiological evidence of synergistic auxin transport by interacting Arabidopsis ABCB4 and PIN2 proteins
Authors: Deslauriers Stephen D. , Spalding Edgar P.
Published: January 2021

To understand why both ATP-binding cassette B (ABCB) and PIN-FORMED (PIN) proteins are required for polar auxin transport through tissues, even though only the latter is polarly localized, we biophysically studied their transport characteristics separately and together by whole-cell patch clamping. ABCB4 and PIN2 fromArabidopsis thalianaexpressed in human embryonic kidney cells displayed electrogenic activity when CsCl-based electrolytes were used. Current-voltage (I-V) analysis of the activities and modeling the effects of adding the auxin anion (IAA−) as a potential substrate with the Goldman-Hodgkin-Katz equation, demonstrated that ABCB4 and PIN2 were 9-fold and 10-fold more selective for IAA−than Cl−, respectively. Thus, these proteins directly transport IAA−, which was not unequivocally established by previous auxin retention assays. Co-expression of ABCB4 and PIN2 produced an especially significant result. Co-expression synergistically doubled the selectivity for IAA−. An area of two-fold higher selectivity for IAA−that this result indicates will occur in cells with asymmetric PIN2 and symmetric ABCB4 matches what early models found to be necessary to create observed levels of polar auxin transport through tissues. Thus, the requirement for two different proteins appears to be explained by a synergistic effect on selectivity. More substrate details and important pharmacological results are reported.
Neuronal post-developmentally acting SAX-7S/L1CAM can function as cleaved fragments to maintain neuronal architecture inC. elegans
Authors: Desse V.E. , Blanchette C.R. , Perrat P. , Bénard C.Y.
Published: January 2021

Whereas remarkable advances have uncovered mechanisms that drive nervous system assembly, the processes responsible for the lifelong maintenance of nervous system architecture remain poorly understood. Subsequent to its establishment during embryogenesis, neuronal architecture is maintained throughout life in the face of the animal’s growth, maturation processes, the addition of new neurons, body movements, and aging. TheC. elegansprotein SAX-7, homologous to the vertebrate L1 protein family, is required for maintaining the organization of neuronal ganglia and fascicles after their successful initial embryonic development. To dissect the function ofsax-7in neuronal maintenance, we generated a null allele andsax-7S-isoform-specific alleles. We find that the nullsax-7(qv30)is, in some contexts, more severe than previously described mutant alleles, and that the loss ofsax-7Slargely phenocopies the null, consistent withsax-7Sbeing the key isoform in neuronal maintenance. Using a sfGFP::SAX-7S knock-in, we observesax-7Sto be predominantly expressed across the nervous system, from embryogenesis to adulthood. Yet, its role in maintaining neuronal organization is ensured by post-developmentally acting SAX-7S, as larval transgenicsax-7S(+) expression alone is sufficient to profoundly rescue the null mutants’ neuronal maintenance defects. Moreover, the majority of the protein SAX-7 appears to be cleaved, and we show that these cleaved SAX-7S fragments together, not individually, can fully support neuronal maintenance. These findings contribute to our understanding of the role of the conserved protein SAX-7/L1CAM in long-term neuronal maintenance, and may help decipher processes that go awry in some neurodegenerative conditions.
Profiling transcription factor sub-networks in type I interferon signaling and in response to SARS-CoV-2 infection
Authors: Ramana Chilakamarti V.
Published: January 2021

Type I interferons (IFN α/β) play a central role in innate immunity to respiratory viruses, including coronaviruses. Genetic defects in type I interferon signaling were reported in a significant proportion of critically ill COVID-19 patients. Extensive studies on interferon-induced intracellular signal transduction pathways led to the elucidation of the Jak-Stat pathway. Furthermore, advances in gene expression profiling by microarrays have revealed that type I interferon rapidly induced multiple transcription factor mRNA levels. In this study, transcription factor profiling in the transcriptome was used to gain novel insights into the role of inducible transcription factors in response to type I interferon signaling in immune cells and in lung epithelial cells after SARS-CoV-2 infection. Modeling the interferon-inducible transcription factor mRNA data in terms of distinct sub-networks based on biological functions such as antiviral response, immune modulation, and cell growth revealed enrichment of specific transcription factors in mouse and human immune cells. The evolutionarily conserved core type I interferon gene expression consists of the inducible transcriptional factor mRNA of the antiviral response sub-network and enriched in granulocytes. Analysis of the type I interferon-inducible transcription factor sub-networks as distinct protein-protein interaction pathways revealed insights into the role of critical hubs in signaling. Interrogation of multiple microarray datasets revealed that SARS-CoV-2 induced high levels of IFN-beta and interferon-inducible transcription factor mRNA in human lung epithelial cells. Transcription factor mRNA of the three major sub-networks regulating antiviral, immune modulation, and cell growth were differentially regulated in human lung epithelial cell lines after SARS-CoV-2 infection and in the tissue samples of COVID-19 patients. A subset of type I interferon-inducible transcription factors and inflammatory mediators were specifically enriched in the lungs and neutrophils of COVID-19 patients. The emerging complex picture of type I IFN transcriptional regulation consists of a rapid transcriptional switch mediated by the Jak-Stat cascade and a graded output of the inducible transcription factor activation that enables temporal regulation of gene expression.