bluuebunny/crossref_metadata_2025 huggingface dataset:
Staphylococcal phages and pathogenicity islands drive plasmid evolution
Authors: Humphrey Suzanne , San Millán Álvaro , Toll-Riera Macarena , Connolly John , Flor-Duro Alejandra , Chen John , Ubeda Carles , MacLean R. Craig , Penadés José R.
Published: October 2021

Conjugation has classically been considered the main mechanism driving plasmid transfer in nature. Yet bacteria frequently carry so-called non-transmissible plasmids, raising questions about how these plasmids spread. Interestingly, the size of many mobilisable and non-transmissible plasmids coincides with the average size of phages (~40 kb) or that of a family of pathogenicity islands, the phage-inducible chromosomal islands (PICIs, ~11 kb). Here, we show that phages and PICIs from Staphylococcus aureus can mediate intra- and inter-species plasmid transfer via generalised transduction, potentially contributing to non-transmissible plasmid spread in nature. Further, staphylococcal PICIs enhance plasmid packaging efficiency, and phages and PICIs exert selective pressures on plasmids via the physical capacity of their capsids, explaining the bimodal size distribution observed for non-conjugative plasmids. Our results highlight that transducing agents (phages, PICIs) have important roles in bacterial plasmid evolution and, potentially, in antimicrobial resistance transmission.
A proteomics sample metadata representation for multiomics integration and big data analysis
Authors: Dai Chengxin , Füllgrabe Anja , Pfeuffer Julianus , Solovyeva Elizaveta M. , Deng Jingwen , Moreno Pablo , Kamatchinathan Selvakumar , Kundu Deepti Jaiswal , George Nancy , Fexova Silvie , Grüning Björn , Föll Melanie Christine , Griss Johannes , Vaudel Marc , Audain Enrique , Locard-Paulet Marie , Turewicz Michael , Eisenacher Martin , Uszkoreit Julian , Van Den Bossche Tim , Schwämmle Veit , Webel Henry , Schulze Stefan , Bouyssié David , Jayaram Savita , Duggineni Vinay Kumar , Samaras Patroklos , Wilhelm Mathias , Choi Meena , Wang Mingxun , Kohlbacher Oliver , Brazma Alvis , Papatheodorou Irene , Bandeira Nuno , Deutsch Eric W. , Vizcaíno Juan Antonio , Bai Mingze , Sachsenberg Timo , Levitsky Lev I. , Perez-Riverol Yasset
Published: October 2021

The amount of public proteomics data is rapidly increasing but there is no standardized format to describe the sample metadata and their relationship with the dataset files in a way that fully supports their understanding or reanalysis. Here we propose to develop the transcriptomics data format MAGE-TAB into a standard representation for proteomics sample metadata. We implement MAGE-TAB-Proteomics in a crowdsourcing project to manually curate over 200 public datasets. We also describe tools and libraries to validate and submit sample metadata-related information to the PRIDE repository. We expect that these developments will improve the reproducibility and facilitate the reanalysis and integration of public proteomics datasets.
Calibrated rare variant genetic risk scores for complex disease prediction using large exome sequence repositories
Authors: Lali Ricky , Chong Michael , Omidi Arghavan , Mohammadi-Shemirani Pedrum , Le Ann , Cui Edward , Paré Guillaume
Published: October 2021

Rare variants are collectively numerous and may underlie a considerable proportion of complex disease risk. However, identifying genuine rare variant associations is challenging due to small effect sizes, presence of technical artefacts, and heterogeneity in population structure. We hypothesize that rare variant burden over a large number of genes can be combined into a predictive rare variant genetic risk score (RVGRS). We propose a method (RV-EXCALIBER) that leverages summary-level data from a large public exome sequencing database (gnomAD) as controls and robustly calibrates rare variant burden to account for the aforementioned biases. A calibrated RVGRS strongly associates with coronary artery disease (CAD) in European and South Asian populations by capturing the aggregate effect of rare variants through a polygenic model of inheritance. The RVGRS identifies 1.5% of the population with substantial risk of early CAD and confers risk even when adjusting for known Mendelian CAD genes, clinical risk factors, and a common variant genetic risk score.
NLRP3 phosphorylation in its LRR domain critically regulates inflammasome assembly
Authors: Niu Tingting , De Rosny Charlotte , Chautard Séverine , Rey Amaury , Patoli Danish , Groslambert Marine , Cosson Camille , Lagrange Brice , Zhang Zhirong , Visvikis Orane , Hacot Sabine , Hologne Maggy , Walker Olivier , Wong Jeimin , Wang Ping , Ricci Roméo , Henry Thomas , Boyer Laurent , Petrilli Virginie , Py Bénédicte F.
Published: October 2021

NLRP3 controls the secretion of inflammatory cytokines IL-1β/18 and pyroptosis by assembling the inflammasome. Upon coordinated priming and activation stimuli, NLRP3 recruits NEK7 within hetero-oligomers that nucleate ASC and caspase-1 filaments, but the apical molecular mechanisms underlying inflammasome assembly remain elusive. Here we show that NEK7 recruitment to NLRP3 is controlled by the phosphorylation status of NLRP3 S803 located within the interaction surface, in which NLRP3 S803 is phosphorylated upon priming and later dephosphorylated upon activation. Phosphomimetic substitutions of S803 abolish NEK7 recruitment and inflammasome activity in macrophages in vitro and in vivo. In addition, NLRP3-NEK7 binding is also essential for NLRP3 deubiquitination by BRCC3 and subsequently inflammasome assembly, with NLRP3 phosphomimetic mutants showing enhanced ubiquitination and degradation than wildtype NLRP3. Finally, we identify CSNK1A1 as the kinase targeting NLRP3 S803. Our findings thus reveal NLRP3 S803 phosphorylation status as a druggable apical molecular mechanism controlling inflammasome assembly.
Pig genome functional annotation enhances the biological interpretation of complex traits and human disease
Authors: Pan Zhangyuan , Yao Yuelin , Yin Hongwei , Cai Zexi , Wang Ying , Bai Lijing , Kern Colin , Halstead Michelle , Chanthavixay Ganrea , Trakooljul Nares , Wimmers Klaus , Sahana Goutam , Su Guosheng , Lund Mogens Sandø , Fredholm Merete , Karlskov-Mortensen Peter , Ernst Catherine W. , Ross Pablo , Tuggle Christopher K. , Fang Lingzhao , Zhou Huaijun
Published: October 2021

The functional annotation of livestock genomes is crucial for understanding the molecular mechanisms that underpin complex traits of economic importance, adaptive evolution and comparative genomics. Here, we provide the most comprehensive catalogue to date of regulatory elements in the pig (Sus scrofa) by integrating 223 epigenomic and transcriptomic data sets, representing 14 biologically important tissues. We systematically describe the dynamic epigenetic landscape across tissues by functionally annotating 15 different chromatin states and defining their tissue-specific regulatory activities. We demonstrate that genomic variants associated with complex traits and adaptive evolution in pig are significantly enriched in active promoters and enhancers. Furthermore, we reveal distinct tissue-specific regulatory selection between Asian and European pig domestication processes. Compared with human and mouse epigenomes, we show that porcine regulatory elements are more conserved in DNA sequence, under both rapid and slow evolution, than those under neutral evolution across pig, mouse, and human. Finally, we provide biological insights on tissue-specific regulatory conservation, and by integrating 47 human genome-wide association studies, we demonstrate that, depending on the traits, mouse or pig might be more appropriate biomedical models for different complex traits and diseases.
Tcf1 and Lef1 provide constant supervision to mature CD8+ T cell identity and function by organizing genomic architecture
Authors: Shan Qiang , Li Xiang , Chen Xia , Zeng Zhouhao , Zhu Shaoqi , Gai Kexin , Peng Weiqun , Xue Hai-Hui
Published: October 2021

T cell identity is established during thymic development, but how it is maintained in the periphery remains unknown. Here we show that ablating Tcf1 and Lef1 transcription factors in mature CD8+ T cells aberrantly induces genes from non-T cell lineages. Using high-throughput chromosome-conformation-capture sequencing, we demonstrate that Tcf1/Lef1 are important for maintaining three-dimensional genome organization at multiple scales in CD8+ T cells. Comprehensive network analyses coupled with genome-wide profiling of chromatin accessibility and Tcf1 occupancy show the direct impact of Tcf1/Lef1 on the T cell genome is to promote formation of extensively interconnected hubs through enforcing chromatin interaction and accessibility. The integrative mechanisms utilized by Tcf1/Lef1 underlie activation of T cell identity genes and repression of non-T lineage genes, conferring fine control of various T cell functionalities. These findings suggest that Tcf1/Lef1 control global genome organization and help form intricate chromatin-interacting hubs to facilitate promoter-enhancer/silencer contact, hence providing constant supervision of CD8+ T cell identity and function.
Integrated omics networks reveal the temporal signaling events of brassinosteroid response in Arabidopsis
Authors: Clark Natalie M. , Nolan Trevor M. , Wang Ping , Song Gaoyuan , Montes Christian , Valentine Conner T. , Guo Hongqing , Sozzani Rosangela , Yin Yanhai , Walley Justin W.
Published: October 2021

Brassinosteroids (BRs) are plant steroid hormones that regulate cell division and stress response. Here we use a systems biology approach to integrate multi-omic datasets and unravel the molecular signaling events of BR response in Arabidopsis. We profile the levels of 26,669 transcripts, 9,533 protein groups, and 26,617 phosphorylation sites from Arabidopsis seedlings treated with brassinolide (BL) for six different lengths of time. We then construct a network inference pipeline called Spatiotemporal Clustering and Inference of Omics Networks (SC-ION) to integrate these data. We use our network predictions to identify putative phosphorylation sites on BES1 and experimentally validate their importance. Additionally, we identify BRONTOSAURUS (BRON) as a transcription factor that regulates cell division, and we show that BRON expression is modulated by BR-responsive kinases and transcription factors. This work demonstrates the power of integrative network analysis applied to multi-omic data and provides fundamental insights into the molecular signaling events occurring during BR response.
Regio- and sequence-controlled conjugated topological oligomers and polymers via boronate-tag assisted solution-phase strategy
Authors: Xu Chaoran , He Congze , Li Ning , Yang Shicheng , Du Yuxuan , Matyjaszewski Krzysztof , Pan Xiangcheng
Published: October 2021

The regulation of polymer topology and the precise control over the monomer sequence is crucial and challenging in polymer science. Herein, we report an efficient solution-phase synthetic strategy to prepare regio- and sequence-controlled conjugated polymers with topological variations via the usage of methyliminodiacetic acid (MIDA) boronates. Based on the solubility of MIDA boronates and their unusual binary affinity for silica gel, the synthesized regio- and sequence-defined conjugated oligomers can be rapidly purified via precipitation or automatic liquid chromatography. These synthesized discrete oligomers can be used for iterative exponential and sequential growth to obtain linear and dendrimer-like star polymers. Moreover, different topological sequence-controlled conjugated polymers are conveniently prepared from these discrete oligomers via condensation polymerization. By investigating the structure-property relationship of these polymers, we find that the optical properties are strongly influenced by the regiochemistry, which may give inspiration to the design of optoelectronic polymeric materials.
SOIL-WATERGRIDS, mapping dynamic changes in soil moisture and depth of water table from 1970 to 2014
Authors: Guglielmo Magda , Tang Fiona H. M. , Pasut Chiara , Maggi Federico
Published: October 2021

We introduce here SOIL-WATERGRIDS, a new dataset of dynamic changes in soil moisture and depth of water table over 45 years from 1970 to 2014 globally resolved at 0.25 × 0.25 degree resolution (about 30 × 30 km at the equator) along a 56 m deep soil profile. SOIL-WATERGRIDS estimates were obtained using the BRTSim model instructed with globally gridded soil physical and hydraulic properties, land cover and use characteristics, and hydrometeorological variables to account for precipitation, ecosystem-specific evapotranspiration, snowmelt, surface runoff, and irrigation. We validate our estimates against independent observations and re-analyses of the soil moisture, water table depth, wetland occurrence, and runoff. SOIL-WATERGRIDS brings into a single product the monthly mean water saturation at three depths in the root zone and the depth of the highest and lowest water tables throughout the reference period, their long-term monthly averages, and data quality. SOIL-WATERGRIDS can therefore be used to analyse trends in water availability for agricultural abstraction, assess the water balance under historical weather patterns, and identify water stress in sensitive managed and unmanaged ecosystems.
A scalable open-source MATLAB toolbox for reconstruction and analysis of multispectral optoacoustic tomography data
Authors: O’Kelly Devin , Campbell James , Gerberich Jeni L. , Karbasi Paniz , Malladi Venkat , Jamieson Andrew , Wang Liqiang , Mason Ralph P.
Published: October 2021

Multispectral photoacoustic tomography enables the resolution of spectral components of a tissue or sample at high spatiotemporal resolution. With the availability of commercial instruments, the acquisition of data using this modality has become consistent and standardized. However, the analysis of such data is often hampered by opaque processing algorithms, which are challenging to verify and validate from a user perspective. Furthermore, such tools are inflexible, often locking users into a restricted set of processing motifs, which may not be able to accommodate the demands of diverse experiments. To address these needs, we have developed a Reconstruction, Analysis, and Filtering Toolbox to support the analysis of photoacoustic imaging data. The toolbox includes several algorithms to improve the overall quantification of photoacoustic imaging, including non-negative constraints and multispectral filters. We demonstrate various use cases, including dynamic imaging challenges and quantification of drug effect, and describe the ability of the toolbox to be parallelized on a high performance computing cluster.
Transcriptomic profiling and functional prediction reveal aberrant expression of circular RNAs during osteogenic differentiation in human umbilical cord mesenchymal stromal cells
Authors: Su Cheng , Zheng Xiao , He Yanjin , Long Li , Chen Wenchuan
Published: October 2021

Circular RNAs (circRNAs) are crucial elements of non-coding RNA, that regulate various biological processes. To date, expression patterns and functional roles of circRNAs during osteogenic differentiation of human umbilical cord mesenchymal stromal cells (hUCMSCs) remain unknown. In this study, we analyzed RNA-sequence data to reveal expression profiles of circRNAs during osteogenesis of hUCMSCs, then elucidated the underlying mechanisms of action. We identified a total of 5457 circRNAs in hUCMSCs, of which 34 and 33 were upregulated and downregulated, respectively. We applied Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses to determine functions and related pathways of differentially expressed circRNAs. Moreover, we applied bioinformatics tools to construct competing endogenous RNA networks, comprising 10 circRNAs, 46 micro RNAs and 413 mRNAs. Furthermore, we predicted protein-coding potential of the upregulated circRNAs then constructed a co-expression network comprising the top 5 upregulated circRNAs and 75 RNA-binding proteins. Next, we validated 6 differentially-expressed circRNAs and found that overexpressing circ‐CTTN could promote osteogenesis of hUCMSCs. Overall, our findings indicate that clusters of circRNAs are aberrantly expressed in hUCMSCs during osteogenic differentiation, hence lay a foundation for future research into promoting hUCMSCs osteogenic differentiation and bone regeneration.
Activators of alpha synuclein expression identified by reporter cell line-based high throughput drug screen
Authors: Stahl Fabian , Denner Philip , Piston Dominik , Evert Bernd O. , de Boni Laura , Schmitt Ina , Breuer Peter , Wüllner Ullrich
Published: October 2021

Multiplications, mutations and dysregulation of the alpha synuclein gene (SNCA) are associated with the demise of dopaminergic neurons and are considered to play important roles in the pathogenesis of familial and sporadic forms of Parkinson’s disease. Regulation of SNCA expression might thus be an appropriate target for treatment. We aimed to identify specific modulators of SNCA transcription, generated CRISPR/Cas9 modified SNCA-GFP-luciferase (LUC) genomic fusion- and control cell lines and screened a library of 1649 bioactive compounds, including the FDA approved drugs. We found no inhibitors but three selective activators which increased SNCA mRNA and protein levels.
Music video emotion classification using slow–fast audio–video network and unsupervised feature representation
Authors: Pandeya Yagya Raj , Bhattarai Bhuwan , Lee Joonwhoan
Published: October 2021

Affective computing has suffered by the precise annotation because the emotions are highly subjective and vague. The music video emotion is complex due to the diverse textual, acoustic, and visual information which can take the form of lyrics, singer voice, sounds from the different instruments, and visual representations. This can be one reason why there has been a limited study in this domain and no standard dataset has been produced before now. In this study, we proposed an unsupervised method for music video emotion analysis using music video contents on the Internet. We also produced a labelled dataset and compared the supervised and unsupervised methods for emotion classification. The music and video information are processed through a multimodal architecture with audio–video information exchange and boosting method. The general 2D and 3D convolution networks compared with the slow–fast network with filter and channel separable convolution in multimodal architecture. Several supervised and unsupervised networks were trained in an end-to-end manner and results were evaluated using various evaluation metrics. The proposed method used a large dataset for unsupervised emotion classification and interpreted the results quantitatively and qualitatively in the music video that had never been applied in the past. The result shows a large increment in classification score using unsupervised features and information sharing techniques on audio and video network. Our best classifier attained 77% accuracy, an f1-score of 0.77, and an area under the curve score of 0.94 with minimum computational cost.
Neurocognitive development of novelty and error monitoring in children and adolescents
Authors: Kang Kathleen , Alexander Nina , Wessel Jan R. , Wimberger Pauline , Nitzsche Katharina , Kirschbaum Clemens , Li Shu-Chen
Published: October 2021

The abilities to monitor one’s actions and novel information in the environment are crucial for behavioural and cognitive control. This study investigated the development of error and novelty monitoring and their electrophysiological correlates by using a combined flanker with novelty-oddball task in children (7–12 years) and adolescents (14–18 years). Potential moderating influences of prenatal perturbation of steroid hormones on these performance monitoring processes were explored by comparing individuals who were prenatally exposed and who were not prenatally exposed to synthetic glucocorticoids (sGC). Generally, adolescents performed more accurately and faster than children. However, behavioural adaptations to error or novelty, as reflected in post-error or post-novelty slowing, showed different developmental patterns. Whereas post-novelty slowing could be observed in children and adolescents, error-related slowing was absent in children and was marginally significant in adolescents. Furthermore, the amplitude of error-related negativity was larger in adolescents, whereas the amplitude of novelty-related N2 was larger in children. These age differences suggest that processes involving top-down processing of task-relevant information (for instance, error monitoring) mature later than processes implicating bottom-up processing of salient novel stimuli (for instance, novelty monitoring). Prenatal exposure to sGC did not directly affect performance monitoring but initial findings suggest that it might alter brain-behaviour relation, especially for novelty monitoring.
Identification of splice regulators of fibronectin-EIIIA and EIIIB by direct measurement of exon usage in a flow-cytometry based CRISPR screen
Authors: Hensel Jessica A. , Heineman Brent D. , Kimble Amy L. , Jellison Evan R. , Reese Bo , Murphy Patrick A.
Published: October 2021

The extracellular matrix protein fibronectin (FN) is alternatively spliced in a variety of inflammatory conditions, resulting in increased inclusion of alternative exons EIIIA and EIIIB. Inclusion of these exons affects fibril formation, fibrosis, and inflammation. To define upstream regulators of alternative splicing in FN, we have developed an in vitro flow-cytometry based assay, using RNA-binding probes to determine alternative exon inclusion level in aortic endothelial cells. This approach allows us to detect exon inclusion in the primary transcripts themselves, rather than in surrogate splicing reporters. We validated this assay in cells with and without FN-EIIIA and -EIIIB expression. In a small-scale CRISPR KO screen of candidate regulatory splice factors, we successfully detected known regulators of EIIIA and EIIIB splicing, and detected several novel regulators. Finally, we show the potential in this approach to broadly interrogate upstream signaling pathways in aortic endothelial cells with a genome-wide CRISPR-KO screen, implicating the TNFalpha and RIG-I-like signaling pathways and genes involved in the regulation of fibrotic responses. Thus, we provide a novel means to screen the regulation of splicing of endogenous transcripts, and predict novel pathways in the regulation of FN-EIIIA inclusion.
Mapping thalamocortical functional connectivity with large-scale brain networks in patients with first-episode psychosis
Authors: Kwak Yoo Bin , Cho Kang Ik Kevin , Hwang Wu Jeong , Kim Ahra , Ha Minji , Park Hyungyou , Lee Junhee , Lee Tae Yong , Kim Minah , Kwon Jun Soo
Published: October 2021

Abnormal thalamocortical networks involving specific thalamic nuclei have been implicated in schizophrenia pathophysiology. While comparable topography of anatomical and functional connectivity abnormalities has been reported in patients across illness stages, previous functional studies have been confined to anatomical pathways of thalamocortical networks. To address this issue, we incorporated large-scale brain network dynamics into examining thalamocortical functional connectivity. Forty patients with first-episode psychosis and forty healthy controls underwent T1-weighted and resting-state functional magnetic resonance imaging. Independent component analysis of voxelwise thalamic functional connectivity maps parcellated the cortex into thalamus-related networks, and thalamic subdivisions associated with these networks were delineated. Functional connectivity of (1) networks with the thalamus and (2) thalamic subdivision seeds were examined. In patients, functional connectivity of the salience network with the thalamus was decreased and localized to the ventrolateral (VL) and ventroposterior (VP) thalamus, while that of a network comprising the cerebellum, temporal and parietal regions was increased and localized to the mediodorsal (MD) thalamus. In patients, thalamic subdivision encompassing the VL and VP thalamus demonstrated hypoconnectivity and that encompassing the MD and pulvinar regions demonstrated hyperconnectivity. Our results extend the implications of disrupted thalamocortical networks involving specific thalamic nuclei to dysfunctional large-scale brain network dynamics in schizophrenia pathophysiology.
Cardiac tyrosine hydroxylase activation and MB-COMT in dyskinetic monkeys
Authors: Cuenca-Bermejo Lorena , Almela Pilar , Gallo-Soljancic Pablo , Yuste José E. , de Pablos Vicente , Bautista-Hernández Víctor , Fernández-Villalba Emiliano , Laorden María-Luisa , Herrero María-Trinidad
Published: October 2021

The impact of age-associated disorders is increasing as the life expectancy of the population increments. Cardiovascular diseases and neurodegenerative disorders, such as Parkinson’s disease, have the highest social and economic burden and increasing evidence show interrelations between them. Particularly, dysfunction of the cardiovascular nervous system is part of the dysautonomic symptoms of Parkinson’s disease, although more studies are needed to elucidate the role of cardiac function on it. We analyzed the dopaminergic system in the nigrostriatal pathway of Parkinsonian and dyskinetic monkeys and the expression of some key proteins in the metabolism and synthesis of catecholamines in the heart: total and phosphorylated (phospho) tyrosine hydroxylase (TH), and membrane (MB) and soluble (S) isoforms of catechol-O-methyl transferase (COMT). The dopaminergic system was significantly depleted in all MPTP-intoxicated monkeys. MPTP- and MPTP + L-DOPA-treated animals also showed a decrease in total TH expression in both right (RV) and left ventricle (LV). We found a significant increase of phospho-TH in both groups (MPTP and MPTP + L-DOPA) in the LV, while this increase was only observed in MPTP-treated monkeys in the RV. MB-COMT analysis showed a very significant increase of this isoform in the LV of MPTP- and MPTP + L-DOPA-treated animals, with no significant differences in S-COMT levels. These data suggest that MB-COMT is the main isoform implicated in the cardiac noradrenergic changes observed after MPTP treatment, suggesting an increase in noradrenaline (NA) metabolism. Moreover, the increase of TH activity indicates that cardiac noradrenergic neurons still respond despite MPTP treatment.
Peripheral blood microbial signatures in current and former smokers
Authors: Morrow Jarrett D. , Castaldi Peter J. , Chase Robert P. , Yun Jeong H. , Lee Sool , Liu Yang-Yu , Hersh Craig P.
Published: October 2021

The human microbiome has a role in the development of multiple diseases. Individual microbiome profiles are highly personalized, though many species are shared. Understanding the relationship between the human microbiome and disease may inform future individualized treatments. We hypothesize the blood microbiome signature may be a surrogate for some lung microbial characteristics. We sought associations between the blood microbiome signature and lung-relevant host factors. Based on reads not mapped to the human genome, we detected microbial nucleic acids through secondary use of peripheral blood RNA-sequencing from 2,590 current and former smokers with and without chronic obstructive pulmonary disease (COPD) from the COPDGene study. We used the Genome Analysis Toolkit (GATK) microbial pipeline PathSeq to infer microbial profiles. We tested associations between the inferred profiles and lung disease relevant phenotypes and examined links to host gene expression pathways. We replicated our analyses using a second independent set of blood RNA-seq data from 1,065 COPDGene study subjects and performed a meta-analysis across the two studies. The four phyla with highest abundance across all subjects were Proteobacteria, Actinobacteria, Firmicutes and Bacteroidetes. In our meta-analysis, we observed associations (q-value < 0.05) betweenAcinetobacter,Serratia,StreptococcusandBacillusinferred abundances and Modified Medical Research Council (mMRC) dyspnea score. Current smoking status was associated (q < 0.05) withAcinetobacter,SerratiaandCutibacteriumabundance. All 12 taxa investigated were associated with at least one white blood cell distribution variable. Abundance for nine of the 12 taxa was associated with sex, and seven of the 12 taxa were associated with race. Host-microbiome interaction analysis revealed clustering of genera associated with mMRC dyspnea score and smoking status, through shared links to several host pathways. This study is the first to identify a bacterial microbiome signature in the peripheral blood of current and former smokers. Understanding the relationships between systemic microbial signatures and lung-related phenotypes may inform novel interventions and aid understanding of the systemic effects of smoking.
Loading equine oocytes with cryoprotective agents captured with a finite element method model
Authors: Içli Sercan , Soleimani Meisam , Oldenhof Harriëtte , Sieme Harald , Wriggers Peter , Wolkers Willem F.
Published: October 2021

Cryopreservation can be used to store equine oocytes for extended periods so that they can be used in artificial reproduction technologies at a desired time point. It requires use of cryoprotective agents (CPAs) to protect the oocytes against freezing injury. The intracellular introduction of CPAs, however, may cause irreversible osmotic damage. The response of cells exposed to CPA solutions is governed by the permeability of the cellular membrane towards water and the CPAs. In this study, a mathematical mass transport model describing the permeation of water and CPAs across an oocyte membrane was used to simulate oocyte volume responses and concomitant intracellular CPA concentrations during the exposure of oocytes to CPA solutions. The results of the analytical simulations were subsequently used to develop a phenomenological finite element method (FEM) continuum model to capture the response of oocytes exposed to CPA solutions with spatial information. FEM simulations were used to depict spatial differences in CPA concentration during CPA permeation, namely at locations near the membrane surface and towards the middle of the cell, and to capture corresponding changes in deformation and hydrostatic pressure. FEM simulations of the multiple processes occurring during CPA loading of oocytes are a valuable tool to increase our understanding of the mechanisms underlying cryopreservation outcome.
Possible vertebral brucellosis infection in a Neanderthal
Authors: Rothschild Bruce , Haeusler Martin
Published: October 2021

The La Chapelle-aux-Saints 1 skeleton of an old (>60-year-old) male Neanderthal is renowned for the advanced osteoarthritis of its spinal column and hip joint, and their implications for posture and lifestyle in these Mid- to Late Pleistocene humans. Reassessment of the pathologic lesions reveals erosions at multiple non-contiguous vertebrae and reactive bone formation extending far beyond the left hip joint, which suggests the additional diagnosis of brucellosis. This implies the earliest secure evidence of this zoonotic disease in hominin evolution. Brucellosis might have been transmitted via butchering or eating raw meat and is well compatible with the range of prey animals documented for Neanderthals. The associated infertility could have represented an important aspect of health in these late archaic humans.
Demography of a Eurasian lynx (Lynx lynx) population within a strictly protected area in Central Europe
Authors: Palmero Stefano , Belotti Elisa , Bufka Luděk , Gahbauer Martin , Heibl Christoph , Premier Joe , Weingarth-Dachs Kirsten , Heurich Marco
Published: October 2021

Large carnivores promote crucial ecosystem processes but are increasingly threatened by human persecution and habitat destruction. Successful conservation of this guild requires information on long-term population dynamics obtained through demographic surveys. We used camera traps to monitor Eurasian lynx between 2009 and 2018 in a strictly protected area in the Bohemian Forest Ecosystem, located in the core of the distribution of the Bohemian–Bavarian–Austrian lynx population. Thereby, we estimated sex-specific demographic parameters using spatial capture–recapture (SCR) models. Over 48,677 trap nights, we detected 65 unique lynx individuals. Density increased from 0.69 to 1.33 and from 1.09 to 2.35 individuals/100 km2for open and closed population SCR models, respectively, with corresponding positive population growth rates (mean = 1.06). Estimated yearly sex-specific survival probabilities for the entire monitoring period were high (females 82%, males 90%) and per capita recruitment rate was low (females 12%, males 9%), indicating a low yearly population turnover. We ascertained an average number of recruits of 1.97 and a generation time of 2.64 years when considering resident reproducing females. We confirmed that reproduction in the study area took place successfully every year. Despite the overall increase in local lynx densities, the number of detected family groups remained constant throughout the study period. These results indicated that the strictly protected study area acts as a source for the multi-use landscapes in its surroundings. In this first open population SCR study on lynx, we provide sex-specific demographic parameters that are fundamental information for lynx management in the study area as well as in similar contexts Europe-wide.
Generation of knock-in lampreys by CRISPR-Cas9-mediated genome engineering
Authors: Suzuki Daichi G. , Wada Hiroshi , Higashijima Shin-ichi
Published: October 2021

The lamprey represents the oldest group of living vertebrates and has been a key organism in various research fields such as evolutionary developmental biology and neuroscience. However, no knock-in technique for this animal has been established yet, preventing application of advanced genetic techniques. Here, we report efficient generation of F0 knock-in lampreys by CRISPR-Cas9-mediated genome editing. A donor plasmid containing a heat-shock promoter was co-injected with a short guide RNA (sgRNA) for genome digestion, a sgRNA for donor plasmid digestion, and Cas9 mRNA. Targeting different genetic loci, we succeeded in generating knock-in lampreys expressing photoconvertible protein Dendra2 as well as those expressing EGFP. With its simplicity, design flexibility, and high efficiency, we propose that the present method has great versatility for various experimental uses in lamprey research and that it can also be applied to other “non-model” organisms.
Optogenetic stimulation of striatal patches modifies habit formation and inhibits dopamine release
Authors: Nadel J. A. , Pawelko S. S. , Scott J. R. , McLaughlin R. , Fox M. , Ghanem M. , van der Merwe R. , Hollon N. G. , Ramsson E. S. , Howard C. D.
Published: October 2021

Habits are inflexible behaviors that develop after extensive repetition, and overreliance on habits is a hallmark of many pathological states. The striatum is involved in the transition from flexible to inflexible responding, and interspersed throughout the striatum are patches, or striosomes, which make up ~15% of the volume of the striatum relative to the surrounding matrix compartment. Previous studies have suggested that patches are necessary for normal habit formation, but it remains unknown exactly how patches contribute to habit formation and expression. Here, using optogenetics, we stimulated striatal patches in Sepw1-NP67 mice during variable interval training (VI60), which is used to establish habitual responding. We found that activation of patches at reward retrieval resulted in elevated responding during VI60 training by modifying the pattern of head entry and pressing. Further, this optogenetic manipulation reduced subsequent responding following reinforcer devaluation, suggesting modified habit formation. However, patch stimulation did not generally increase extinction rates during a subsequent extinction probe, but did result in a small ‘extinction burst’, further suggesting goal-directed behavior. On the other hand, this manipulation had no effect in omission trials, where mice had to withhold responses to obtain rewards. Finally, we utilized fast-scan cyclic voltammetry to investigate how patch activation modifies evoked striatal dopamine release and found that optogenetic activation of patch projections to the substantia nigra pars compacta (SNc) is sufficient to suppress dopamine release in the dorsal striatum. Overall, this work provides novel insight into the role of the patch compartment in habit formation, and provides a potential mechanism for how patches modify habitual behavior by exerting control over dopamine signaling.
One-pot three-component tandem annulation of 4-hydroxycoumarine with aldehyde and aromatic amines using graphene oxide as an efficient catalyst
Authors: Singha Rabindranath , Islam Aminul , Ghosh Pranab
Published: October 2021

A convenient and efficient solvent-free, facile, one-pot three-component graphene oxide catalysed approach has been described for the synthesis of chromeno-[4,3-b]quinolin-6-one derivatives from 4-hydroxycoumarin with aldehydes and aromatic amines. Graphene oxide (GO) has proved to be a new class of heterogeneous carbocatalyst which could be easily recovered and reused up to 5th run without significant loss of its catalytic activity. A broad scope of substrate applicability is offered and a plausible mechanism is also suggested for this developed protocol.
Influence of normal tide and the Great Tsunami as recorded through hourly-resolution micro-analysis of a mussel shell
Authors: Sano Yuji , Okumura Tomoyo , Murakami-Sugihara Naoko , Tanaka Kentaro , Kagoshima Takanori , Ishida Akizumi , Hori Masako , Snyder Glen T. , Takahata Naoto , Shirai Kotaro
Published: October 2021

We report here hourly variations of Mg/Ca, Sr/Ca, and Ba/Ca ratios in a Mediterranean mussel shell (Mytilus galloprovincialis) collected at the Otsuchi bay, on the Pacific coast of northeastern Japan. This bivalve was living in the intertidal zone, where such organisms are known to form a daily or bidaily growth line comprised of abundant organic matter. Mg/Ca ratios of the inner surface of the outer shell layer, corresponding to the most recent date, show cyclic changes at 25–90 μm intervals, while no interpretable variations are observed in Sr/Ca and Ba/Ca ratios. High Mg/Ca ratios were probably established by (1) cessation of the external supply of Ca and organic layer forming when the shell is closed at low tide, and (2) the strong binding of Mg to the organic layer, but not of Sr and Ba. Immediately following the great tsunami induced by the 2011 Tohoku earthquake, Mg/Ca enrichment occurred, up to 10 times that of normal low tide, while apparent Ba/Ca enrichment was observed for only a few days following the event, therefore serving a proxy of the past tsunami. Following the tsunami, periodic peaks and troughs in Mg/Ca continued, perhaps due to a biological memory effect as an endogenous clock.
Combining experiments and in silico modeling to infer the role of adhesion and proliferation on the collective dynamics of cells
Authors: Melo Hygor P. M. , Maia F. Raquel , Nunes André S. , Reis Rui L. , Oliveira Joaquim M. , Araújo Nuno A. M.
Published: October 2021

The collective dynamics of cells on surfaces and interfaces poses technological and theoretical challenges in the study of morphogenesis, tissue engineering, and cancer. Different mechanisms are at play, including, cell–cell adhesion, cell motility, and proliferation. However, the relative importance of each one is elusive. Here, experiments with a culture of glioblastoma multiforme cells on a substrate are combined with in silico modeling to infer the rate of each mechanism. By parametrizing these rates, the time-dependence of the spatial correlation observed experimentally is reproduced. The obtained results suggest a reduction in cell–cell adhesion with the density of cells. The reason for such reduction and possible implications for the collective dynamics of cancer cells are discussed.
miR-27b antagonizes BMP signaling in early differentiation of human induced pluripotent stem cells
Authors: Lim Jaeeun , Sakai Eiko , Sakurai Fuminori , Mizuguchi Hiroyuki
Published: October 2021

Human induced pluripotent stem (hiPS) cells are feasible materials for studying the biological mechanisms underlying human embryogenesis. In early embryogenesis, definitive endoderm and mesoderm are differentiated from their common precursor, mesendoderm. Bone morphogenetic protein (BMP) signaling is responsible for regulating mesendoderm and mesoderm formation. Micro RNAs (miRNAs), short non-coding RNAs, broadly regulate biological processes via post-transcriptional repression. The expression of miR-27b, which is enriched in somatic cells, has been reported to increase through definitive endoderm and hepatic differentiation, but little is known about how miR-27b acts during early differentiation. Here, we used miR-27b-inducible hiPS cells to investigate the roles of miR-27b in the undifferentiated and early-differentiated stages. In undifferentiated hiPS cells, miR-27b suppressed the expression of pluripotency markers [alkaline phosphatase (AP) and nanog homeobox (NANOG)] and cell proliferation. Once differentiation began, miR-27b expression repressed phosphorylated SMAD1/5, the mediators of the BMP signaling, throughout definitive endoderm differentiation. Consistent with the above findings, miR-27b overexpression downregulated BMP-induced mesendodermal marker genes [Brachyury, mix paired-like homeobox 1 (MIXL1) and eomesodermin (EOMES)], suggesting that miR-27b had an inhibitory effect on early differentiation. Collectively, our findings revealed a novel antagonistic role of miR-27b in the BMP signaling pathway in the early differentiation of hiPS cells.
Effect of gamma irradiation on filtering facepiece respirators and SARS-CoV-2 detection
Authors: Al-Hadyan Khaled , Alsbeih Ghazi , Al-Harbi Najla , Judia Sara Bin , Al-Ghamdi Maha , Almousa Akram , Alsharif Ibtihaj , Bakheet Razan , Al-Romaih Khaldoun , Al-Mozaini Maha , Al-Ghamdi Salem , Moftah Belal , Alhmaid Rashed
Published: October 2021

To cope with the shortage of filtering facepiece respirators (FFRs) during the coronavirus (COVID-19) pandemic, healthcare institutions were forced to reuse FFRs after applying different decontamination methods including gamma-irradiation (GIR). The aim of this study was to evaluate the effect of GIR on the filtration efficiency (FE) of FFRs and on SARS-CoV-2 detection. The FE of 2 FFRs types (KN95 and N95-3 M masks) was assessed at different particle sizes (0.3–5 µm) following GIR (0–15 kGy) delivered at either typical (1.65 kGy/h) or low (0.5088 kGy/h) dose rates. The detection of two SARS-CoV-2 RNA genes (E and RdRp4) following GIR (0–50 kGy) was carried out using RT-qPCR assay. Both masks showed an overall significant (P < 0.001) reduction in FE with increased GIR doses. No significant differences were observed between GIR dose rates on FE. The GIR exhibited significant increases (P ≤ 0.001) in the cycle threshold values (ΔCt) of both genes, with no detection following high doses. In conclusion, complete degradation of SARS-CoV-2 RNA can be achieved by high GIR (≥ 30 kGy), suggesting its potential use in FFRs decontamination. However, GIR exhibited adverse effects on FE in dose- and particle size-dependent manners, rendering its use to decontaminate FFRs debatable.
Intention-based and sensory-based predictions
Authors: Darriba Álvaro , Hsu Yi-Fang , Van Ommen Sandrien , Waszak Florian
Published: October 2021

We inhabit a continuously changing world, where the ability to anticipate future states of the environment is critical for adaptation. Anticipation can be achieved by learning about the causal or temporal relationship between sensory events, as well as by learning to act on the environment to produce an intended effect. Together, sensory-based and intention-based predictions provide the flexibility needed to successfully adapt. Yet it is currently unknown whether the two sources of information are processed independently to form separate predictions, or are combined into a common prediction. To investigate this, we ran an experiment in which the final tone of two possible four-tone sequences could be predicted from the preceding tones in the sequence and/or from the participants’ intention to trigger that final tone. This tone could be congruent with both sensory-based and intention-based predictions, incongruent with both, or congruent with one while incongruent with the other. Trials where predictions were incongruent with each other yielded similar prediction error responses irrespectively of the violated prediction, indicating that both predictions were formulated and coexisted simultaneously. The violation of intention-based predictions yielded late additional error responses, suggesting that those violations underwent further differential processing which the violations of sensory-based predictions did not receive.
Comparison of mitral regurgitation severity assessments based on magnetic resonance imaging and echocardiography in patients with hypertrophic cardiomyopathy
Authors: Śpiewak Mateusz , Kłopotowski Mariusz , Kowalik Ewa , Mazurkiewicz Łukasz , Kożuch Katarzyna , Petryka-Mazurkiewicz Joanna , Miłosz-Wieczorek Barbara , Witkowski Adam , Klisiewicz Anna , Marczak Magdalena
Published: October 2021

Mitral regurgitation (MR), which is one of the factors responsible for heart failure symptoms and the development of atrial fibrillation, is an important feature of hypertrophic cardiomyopathy (HCM), and its presence affects which treatment options are chosen. Although cardiac magnetic resonance imaging (MRI) is considered the reference standard for assessing the regurgitant volume (RV) and fraction (RF), echocardiography is the most common method for assessing MR severity. Accordingly, the aim of this study was to compare the results of echocardiography and cardiac MRI for assessing MR severity in a cohort of patients with HCM. MR severity was assessed in 53 patients using cardiac MRI by determining the mitral RV (MRV) and mitral RF (MRF). The results were graded according to thresholds recommended in current guidelines. MR severity assessed by echocardiography was graded by integrating indices of severity. Greater than mild MR, as assessed using echocardiography, was present in 22 patients (41.5%) with HCM and in none of the control patients (p = 0.001). In all, 31 patients (58.5%) had no more than mild MR. When MR severity was assessed using different methods, either moderate (kappa = 0.44, 95% confidence interval = 0.21–0.67), poor or no agreement was found between MRI-derived and echocardiography-derived grades. HCM patients with echocardiography-derived moderate and severe MR had similar median MRVs and MRFs (p = 0.59 and p = 0.11, respectively). In HCM patients, cardiac MRI and echocardiography were at most in modest agreement in assessing MR severity. Importantly, echocardiography-derived moderate and severe MR were not distinguishable by either MRV or MRF.