bluuebunny/crossref_metadata_2025_split huggingface dataset:
Quantitative single-cell interactomes in normal and virus-infected mouse lungs
Authors: Cain Margo P , Hernandez Belinda J , Chen Jichao 
Published: February 2020

ABSTRACTMammalian organs consist of diverse, intermixed cell types that signal to each other via ligand-receptor interactions – an interactome – to ensure development, homeostasis, and injury-repair. Dissecting such intercellular interactions is facilitated by rapidly growing single-cell RNA-seq (scRNA-seq) data; however, existing computational methods are often not sufficiently quantitative nor readily adaptable by bench scientists without advanced programming skills. Here we describe a quantitative intuitive algorithm, coupled with an optimized experimental protocol, to construct and compare interactomes in control and Sendai virus-infected mouse lungs. A minimum of 90 cells per cell type compensates for the known gene dropout issue in scRNA-seq and achieves comparable sensitivity to bulk RNA-seq. Cell lineage normalization after cell sorting allows cost-efficient representation of cell types of interest. A numeric representation of ligand-receptor interactions identifies, as outliers, known and potentially new interactions as well as changes upon viral infection. Our experimental and computational approaches can be generalized to other organs and human samples.Summary statementAn intuitive method to construct quantitative ligand-receptor interactomes using single-cell RNA-seq data and its application to normal and Sendai virus-infected mouse lungs.
Principles of dengue virus evolvability derived from genotype-fitness maps in human and mosquito cells
Authors: Dolan Patrick T. , Taguwa Shuhei , Rangel Mauricio Aguilar , Acevedo Ashley , Hagai Tzachi , Andino Raul , Frydman Judith 
Published: February 2020

ABSTRACTDengue virus (DENV), an arbovirus infecting over 100 million annually, cycles between human and mosquito hosts1. Examining how DENV adapts to such different host environments could uncover principles of arbovirus transmission and emergence. Here we combine sequential passaging and ultra-deep sequencing to examine the sequence dynamics and fitness changes of DENV populations adapting to human and mosquito cells, identifying the contributions of beneficial and deleterious mutations in shaping the fitness landscape driving host-specific paths of viral adaptation. We find DENV phenotypic adaptation is best described by the collective fitness contributions of all the alleles present in the population. Accordingly, while increased fitness during adaptation to each host is driven by host-specific beneficial mutations, it is reduced by the consistently replenished genetic load of deleterious mutations. Of note, host-specific beneficial mutations are in discrete regions across the genome, revealing molecular mechanisms of adaptation. Some of these clusters comprise phenotypically redundant mutations that may provide evolutionary robustness to transmission bottlenecks. Our results also suggest DENV adaptation is facilitated through variation in intrinsically disordered protein regions while transmembrane and structured domains evolve under stronger biophysical constraints. Importantly, the adaptation strategies uncovered in our simple system mirror macro-evolutionary changes observed across DENV serotypes and Zika virus and may suggest general principles of evolvability in arbovirus evolution.
Phenotypic and genotypic parallel evolution in parapatric ecotypes ofSenecio
Authors: James Maddie E. , Wilkinson Melanie J. , Bernal Diana M. , Liu Huanle , North Henry L. , Engelstädter Jan , Ortiz-Barrientos Daniel 
Published: February 2020

AbstractThe independent and repeated adaptation of populations to similar environments often results in the evolution of similar forms. This phenomenon creates a strong correlation between phenotype and environment and is referred to as parallel evolution. However, we are still largely unaware of the dynamics of parallel evolution, as well as the interplay between phenotype and genotype within natural systems. Here, we examined phenotypic and genotypic parallel evolution in multiple parapatric Dune-Headland coastal ecotypes of an Australian wildflower,Senecio lautus. We observed a clear trait-environment association within the system, with all replicate populations having evolved along the same phenotypic evolutionary trajectory. Similar phenotypes have arisen via mutational changes occurring in different genes, although many share the same biological functions. Our results shed light on how replicated adaptation manifests at the phenotypic and genotypic levels within populations, and highlightsS. lautusas one of the most striking cases of phenotypic parallel evolution in nature.
Transcranial magnetic stimulation language mapping analysis revisited: Machine learning classification of 90 patients reveals distinct reorganization pattern in aphasic patients
Authors: Wang Ziqian , Fekonja Lucius , Dreyer Felix , Vajkoczy Peter , Picht Thomas 
Published: February 2020

AbstractRepetitive TMS (rTMS) allows to non-invasively and transiently disrupt local neuronal functioning. Its potential for mapping of language function is currently explored. Given the inter-individual heterogeneity of tumor impact on the language network and resulting rTMS derived functional mapping, we propose to use machine learning strategies to classify potential patterns of functional reorganization. We retrospectively included 90 patients with left perisylvian glioma tumors, world health organization (WHO) grade II-IV, affecting the language network. All patients underwent navigated rTMS language mappings. The severity of aphasia was assessed preoperatively using the Berlin Aphasia Score (BAS), which is adapted to the Aachener Aphasia Test (AAT). After spatial normalization to MNI 152 of all rTMS spots, we calculated the error rate (ER) in each cortical area by automated anatomical labeling parcellation (AAL) and used support vector machine (SVM) as a classifier for significant areas in relation to aphasia. 29 of 90 (32.2%) patients suffered from aphasia. Univariate analysis revealed 11 perisylvian AVOIs’ ERs (eight left, three right hemispheric) that were significantly higher in the aphasic than non-aphasic group (p < 0.05), depicting a broad, bihemispheric language network. After feeding the significant AVOIs into the SVM model, it showed that additional to age (w = 2.95), the ERs of right Frontal_Inf_Tri (w = 2.06) and left SupraMarginal (w = 2.05) and Parietal_Inf (w= 1.80) contributed more than other features to the model. The model’s sensitivity was 89.7%, the specificity was 82.0%, the overall accuracy was 81.1% and AUC was 88.7%. Our results demonstrate an increased vulnerability of the right inferior frontal gyrus to rTMS in patients suffering from aphasia due to left perisylvian gliomas. This confirms a functional relevant involvement of the right frontal area in relation to aphasia. While age as a feature improved our SVM model the most, the tumor location feature didn’t affect the SVM model. This finding indicates that general tumor induced network disconnection is relevant to aphasia and not necessarily related to specific lesion locations. Additionally, our results emphasize the decreasing potential for neuroplasticity with age.
The Cognitive-Functional Composite is sensitive to clinical progression in early dementia: longitudinal findings from the Catch-Cog study cohort
Authors: Jutten Roos J. , Harrison John E. , Brunner A. , Vreeswijk R. , van Deelen R.A.J. , de Jong Frank Jan , Opmeer Esther M. , Ritchie Craig W. , Aleman André , Scheltens Philip , Sikkes Sietske A.M. 
Published: February 2020

AbstractIntroductionIn an attempt to capture clinically meaningful cognitive decline in early dementia, we developed the Cognitive-Functional Composite (CFC). We investigated the CFC’s sensitivity to decline in comparison to traditional clinical endpoints.MethodsThis longitudinal construct validation study included 148 participants with subjective cognitive decline, mild cognitive impairment or mild dementia. The CFC and traditional tests were administered at baseline, 3, 6 and 12 months. Sensitivity to change was investigated using linear mixed models andr2effect-sizes.ResultsCFC scores declined over time (β=−.16,p<.001), with steepest decline observed in mild Alzheimer’s dementia (β=−.25,p<.001). The CFC showed medium-to-large effect-sizes at succeeding follow-up points (r2=.08–.42), exhibiting greater change than the Clinical Dementia Rating scale (r2=.02–.12). Moreover, change on the CFC was significantly associated with informant reports of cognitive decline (β=.38,p<.001).DiscussionBy showing sensitivity to decline, the CFC could enhance the monitoring of disease progression in dementia research and clinical practice.
Oxytocin enhances the recovery of eye-contact induced autonomic arousal: A treatment mechanism study with placebo-controlled design
Authors: Daniels Nicky , Prinsen Jellina , Soriano Javier R. , Alaerts Kaat 
Published: February 2020

AbstractThe neuropeptide oxytocin (OT) is suggested to exert a pivotal role in a variety of complex human behaviors, including trust, attachment, social perception and fear-regulation. Previous studies have demonstrated that intranasal administration of OT reduces subjective and neuroendocrine stress responses and dampens amygdala reactivity. Moreover, OT has been proposed to modulate activity of the autonomic nervous system.Here, we conducted a double-blind, placebo-controlled study with 56 men, to investigate whether a single-dose of OT (24 IU) modulates sympathetic autonomic arousal upon live dyadic gaze interactions. To do so, electro-dermal recordings of skin conductance were performed during the engagement of eye contact with a live model in a naturalistic two-person social context.In accordance to prior research, direct eye gaze elicited a significant enhancement in skin conductance responses, but OT did not specifically enhance or dampen the overall magnitude (amplitude) of the autonomic arousal response. Administration of OT did facilitate the recovery of skin conductance responses back to baseline (increased steepness of recovery slope), indicating a role of OT in restoring homeostatic balance. Notably, the treatment-effect on autonomic recovery was most prominent in participants with low self-reported social responsiveness and high attachment avoidance, indicating that person-dependent factors play a pivotal role in determining OT treatment-responses. Behaviorally, OT significantly reduced self-reported feelings of tension and (at trend-level) worrying about how one presents oneself.Together, these observations add further evidence to a role of OT in reducing subjective and autonomic stress responses, primarily by facilitating restoration of homeostatic balance after (social) stress-induced perturbation.
Memo1gene expression in kidney and bone is unaffected by dietary mineral load and calciotropic hormones
Authors: Moor Matthias B. , Bonny Olivier 
Published: February 2020

AbstractMediator of Cell Motility 1 (MEMO1) is an ubiquitously expressed modulator of cellular responses to growth factors including FGF23 signaling, andMemo1-deficient mice share some phenotypic traits withFgf23- orKlotho-deficient mouse models. Here, we tested whetherMemo1gene expression is regulated by calciotropic hormones or by changing the dietary mineral load.MLO-Y4 osteocyte-like cells were cultured and treated with 1,25(OH)2-vitamin D3. Wildtype C57BL/6N mice underwent treatments with 1,25(OH)2-vitamin D3, parathyroid hormone (PTH), 17β-estradiol or vehicle. Other cohorts of C57BL/6N mice were fed diets varying in calcium or phosphate content. Expression ofMemo1and control genes was assessed by qPCR.1,25(OH)2-vitamin D3caused an acute decrease inMemo1transcript levels in vitro, but not in vivo. None of the hormones tested had an influence onMemo1transcripts, whereas the assessed control genes reacted the expected way. Dietary interventions with calcium and phosphate did not affectMemo1transcripts but altered the chosen control genes’ expression.We observed thatMemo1was not regulated by calciotropic hormones or change in mineral load, suggesting major differences between the regulation and physiological roles ofKlotho, Fgf23andMemo1.
Enterococcus faecalismanganese exporter MntE alleviates manganese toxicity and is required for mouse gastrointestinal colonization
Authors: Lam Ling Ning , Wong Jun Jie , Long Chong Kelvin Kian , Kline Kimberly A. 
Published: February 2020

AbstractBacterial pathogens encounter a variety of nutritional environments in the human host, including nutrient metal restriction and overload. Uptake of manganese (Mn) is essential forEnterococcus faecalisgrowth and virulence; however, it is not known how this organism prevents Mn toxicity. In this study, we examine the role of the highly conserved MntE transporter inE. faecalisMn homeostasis and virulence. We show that inactivation ofmntEresults in growth restriction in the presence of excess Mn, but not other metals, demonstrating its specific role in Mn detoxification. Upon growth in the presence of excess Mn, anmntEmutant accumulates intracellular Mn, iron (Fe), and magnesium (Mg), supporting a role for MntE in Mn and Fe export, and a role for Mg in offsetting Mn toxicity. Growth of themntEmutant in excess Fe also results in increased levels of intracellular Fe, but not Mn or Mg, providing further support for MntE in Fe efflux. Inactivation ofmntEin the presence of excess iron also results in the upregulation of glycerol catabolic genes and enhanced biofilm growth, and addition of glycerol is sufficient to augment biofilm growth for both themntEmutant and its wild type parental strain, demonstrating that glycerol availability significantly enhances biofilm formation. Finally, we show thatmntEcontributes to infection of the antibiotic-treated mouse gastrointestinal (GI) tract, suggesting thatE. faecalisencounters excess Mn in this niche. Collectively, these findings demonstrate that the manganese exporter MntE plays a crucial role inE. faecalismetal homeostasis and virulence.
Lateral gene transfer drives metabolic flexibility in the anaerobic methane oxidising archaeal familyMethanoperedenaceae
Authors: Leu Andy O. , McIlroy Simon J. , Ye Jun , Parks Donovan H. , Orphan Victoria J. , Tyson Gene W. 
Published: February 2020

AbstractAnaerobic oxidation of methane (AOM) is an important biological process responsible for controlling the flux of methane into the atmosphere. Members of the archaeal familyMethanoperedenaceae(formerly ANME-2d) have been demonstrated to couple AOM to the reduction of nitrate, iron, and manganese. Here, comparative genomic analysis of 16Methanoperedenaceacemetagenome-assembled genomes (MAGs), recovered from diverse environments, revealed novel respiratory strategies acquired through lateral gene transfer (LGT) events from diverse archaea and bacteria. Comprehensive phylogenetic analyses suggests that LGT has allowed members of theMethanoperedenaceaeto acquire genes for the oxidation of hydrogen and formate, and the reduction of arsenate, selenate and elemental sulfur. Numerous membrane-bound multi-hemectype cytochrome complexes also appear to have been laterally acquired, which may be involved in the direct transfer of electrons to metal oxides, humics and syntrophic partners.ImportanceAOM by microorganisms limits the atmospheric release of the potent greenhouse gas methane and has consequent importance to the global carbon cycle and climate change modelling. While the oxidation of methane coupled to sulphate by consortia of anaerobic methanotrophic (ANME) archaea and bacteria is well documented, several other potential electron acceptors have also been reported to support AOM. In this study we identify a number of novel respiratory strategies that appear to have been laterally acquired by members of theMethanoperedenaceaeas they are absent in related archaea and other ANME lineages. Expanding the known metabolic potential for members of theMethanoperedenaceaeprovides important insight into their ecology and suggests their role in linking methane oxidation to several global biogeochemical cycles.
An integrated model system to gain mechanistic insights into biofilm formation and antimicrobial resistance development inPseudomonas aeruginosaMPAO1
Authors: Varadarajan Adithi R. , Allan Raymond N. , Valentin Jules D. P. , Castañeda Ocampo Olga E. , Somerville Vincent , Pietsch Franziska , Buhmann Matthias T. , West Jonathan , Skipp Paul J. , van der Mei Henny C. , Ren Qun , Schreiber Frank , Webb Jeremy S. , Ahrens Christian H. 
Published: February 2020

AbstractPseudomonas aeruginosaMPAO1 is the parental strain of the widely utilized transposon mutant collection for this important clinical pathogen. Here, we validate a model system to identify genes involved in biofilm growth and antibiotic resistance.Our model employs a genomics-driven workflow to assemble the complete MPAO1 genome, identify unique and conserved genes by comparative genomics with the PAO1 reference strain and missed genes by proteogenomics. Among over 200 unique MPAO1 genes, we identified six general essential genes that were overlooked when mapping public Tn-seq datasets against PAO1, including an antitoxin. Genomic data were integrated with phenotypic data from an experimental workflow using a user-friendly, soft lithography-based microfluidic flow chamber for biofilm growth. Experiments conducted across three laboratories delivered reproducible data onP. aeruginosabiofilms and validated both known and novel genes involved in biofilm growth and antibiotic resistance identified in screens of the mutant collection. Differential protein expression data from planktonic cells versus biofilm confirmed upregulation of candidates known to affect biofilm formation, of structural and secreted proteins of type six secretion systems, and provided proteogenomic evidence for some missed MPAO1 genes. This integrated, broadly applicable model promises to improve the mechanistic understanding of biofilm formation, antimicrobial tolerance and resistance evolution.
A biodiverse package of southwest Asian grain crops facilitated high-elevation agriculture in the central Tien Shan during the mid-third millennium BCE
Authors: Matuzeviciute Giedre Motuzaite , Hermes Taylor R. , Mir-Makhamad Basira , Tabaldiev Kubatbek 
Published: February 2020

AbstractWe report the earliest and the most abundant archaeobotanical assemblage of southwest Asian grain crops from Early Bronze Age Central Asia, recovered from the Chap II site in Kyrgyzstan. The archaeobotanical remains consist of thousands of cultivated grains dating to the mid-late 3rdmillennium BCE. The recovery of cereal chaff, which is rare in archaeobotanical samples from Central Asia, allows for the identification of some crops to species and indicates local cultivation at 2000 m.a.s.l., as crop first spread to the mountains of Central Asia. The site’s inhabitants cultivated two types of free-threshing wheats, glume wheats, and hulled and naked barleys. Highly compact morphotypes of wheat and barley grains represent a special variety of cereals adopted to highland environments. Moreover, glume wheats recovered at Chap II represent their most eastern distribution in Central Asia so far identified. Based on the presence of weed species, we argue that the past environment of Chap II was characterized by an open mountain landscape, where animal grazing likely took place, which may have been further modified by people irrigating agricultural fields. This research suggests that early farmers in the mountains of Central Asia cultivated a high diversity of southwest Asian crops during the initial eastward dispersal of agricultural technologies, which likely played a critical role in shaping montane adaptations and dynamic interaction networks between farming societies across highland and lowland cultivation zones.
Fluctuation, correlation and perturbation-response behavior of nature-made and artificial nanobodies
Authors: Hacisuleyman Aysima , Erman Batu , Erkip Albert , Erman Burak 
Published: February 2020

AbstractNanobodies, like other antibodies bind their targets through complementarity determining regions (CDR’s). Improving nanobody-antigen binding affinities by introducing mutations in these CDR’s is critical for biotechnological applications. However, any mutation is expected to introduce changes in the behavior of the protein, such as fluctuations of residues, correlation of fluctuations of residue pairs, response of a residue to perturbation of another. Most importantly, the nanoscale dynamics of the protein may change. In these respects, the problem is similar to the general problem of dynamic allostery, a perturbation at one site affecting the response at another site. Using the Gaussian Network Model of proteins, we show that CDR mutations indeed modify the fluctuation profile and dynamics of the nanobody. Effects are not confined to CDR regions but extend throughout the full structure. We introduce a computational scheme where fluctuations of a residue are perturbed by a force and response amplitude and response time of the remaining residues are determined. Response to a perturbation of a residue shows a synchronous and an asynchronous component. The model is used to quantify the effects of mutation on protein dynamics: highly perturbable residues and highly responsive residues of the nanobody are determined. Residues whose perturbation has no effect on protein behavior may also be determined with the present model. Three known nanobodies produced by nature are used as an illustrative example and their various modifications which we generated by CDR residue mutations are analyzed.
dyngen: a multi-modal simulator for spearheading new single-cell omics analyses
Authors: Cannoodt Robrecht , Saelens Wouter , Deconinck Louise , Saeys Yvan 
Published: February 2020

AbstractWe present dyngen, a novel, multi-modal simulation engine for studying dynamic cellular processes at single-cell resolution. dyngen is more flexible than current single-cell simulation engines, and allows better method development and benchmarking, thereby stimulating development and testing of novel computational methods. We demonstrate its potential for spearheading novel computational methods on three novel applications: aligning cell developmental trajectories, single-cell regulatory network inference and estimation of RNA velocity.
Single-cell sequencing of developing human gut reveals transcriptional links to childhood Crohn’s disease
Authors: Elmentaite Rasa , Ross Alexander , James Kylie R. , Ortmann Daniel , Gomes Tomas , Roberts Kenny , Nayak Komal , Tuck Liz , Bayraktar Omer Ali , Heuschkel Robert , Vallier Ludovic , Teichmann Sarah A. , Zilbauer Matthias 
Published: February 2020

SummaryHuman gut development requires the orchestrated interaction of various differentiating cell types. Here we generate an in-depth single-cell map of the developing human intestine at 6–10 weeks post-conception, a period marked by crypt-villus formation. Our analysis reveals the transcriptional profile of cycling epithelial precursor cells, which are distinct from LGR5-expressing cells. We use computational analyses to show that these cells contribute to differentiated cell subsets directly and indirectly via the generation of LGR5-expressing stem cells and receive signals from the surrounding mesenchymal cells. Furthermore, we draw parallels between the transcriptomes ofex vivotissues andin vitrofetal organoids, revealing the maturation of organoid cultures in a dish. Lastly, we compare scRNAseq profiles from paediatric Crohn’s disease epithelium alongside matched healthy controls to reveal disease associated changes in epithelial composition. Contrasting these with the fetal profiles reveals re-activation of fetal transcription factors in Crohn’s disease epithelium. Our study provides a unique resource, available atwww.gutcellatlas.org, and underscores the importance of unravelling fetal development in understanding disease.