bluuebunny/crossref_metadata_2025_split huggingface dataset:
Modeling Substrate Coordination to Zn-Bound Angiotensin Converting Enzyme 2
Authors: Fatouros Peter R. , Roy Urmi , Sur Shantanu 
Published: March 2021

ABSTRACTThe spike protein in the envelope of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) interacts with the receptor Angiotensin Converting Enzyme 2 (ACE2) on the host cell to facilitate the viral uptake. Angiotensin II (Ang II) peptide, which has a naturally high affinity for ACE2, may be useful in inhibiting this interaction. In this study, we computationally designed several Ang II mutants to find a strong binding sequence to ACE2 receptor and examined the role of ligand substitution in the docking of native as well as mutant Ang II to the ACE2 receptor. The peptide in the ACE2-peptide complex was coordinated to zinc in the ACE2 cleft. Exploratory molecular dynamics (MD) simulations were used to measure the time-based stability of the native and mutant peptides and their receptor complexes. The MD-generated root-mean-square deviation (RMSD) values are mostly similar between the native and seven mutant peptides considered in this work, although the values for free peptides demonstrated higher variation, and often were higher in amplitude than peptides associated with the ACE2 complex. An observed lack of a strong secondary structure in the short peptides is attributed to the latter’s greater flexibility and movement. The strongest binding energies within the ACE2-peptide complexes were observed in the native Ang II and only one of its mutant variants, suggesting ACE2 cleft is designed to provide optimal binding to the native sequence. An examination of the S1 binding site on ACE2 suggests that complex formation alone with these peptides may not be sufficient to allosterically inhibit the binding of SARS-CoV-2 spike proteins. However, it opens up the potential for utilizing AngII-ACE2 binding in the future design of molecular and supramolecular structures to prevent spike protein interaction with the receptor through creation of steric hindrance.
The link between static and dynamic brain functional network connectivity and genetic risk of Alzheimer’s disease
Authors: Sendi Mohammad S. E. , Zendehrouh Elaheh , Ellis Charles A. , Chen Jiayu , Miller Robyn L. , Mormino Elizabeth , Salat David H. , Calhoun Vince D. 
Published: March 2021

AbstractApolipoprotein E (APOE) polymorphic alleles are genetic factors associated with Alzheimer’s disease (AD) risk. Although previous studies have explored the link between AD genetic risk and static functional network connectivity (sFNC), to the best of our knowledge, no previous studies have evaluated the association between dynamic FNC (dFNC) and AD genetic risk. Here, we examined the link between sFNC, dFNC, and AD genetic risk with a reproducible, data-driven approach. We used rs-fMRI, demographic, and APOE data from cognitively normal individuals (N=894) between 42 to 95 years of age (mean = 70 years). We divided individuals into low, moderate, and high-risk groups. Using Pearson correlation, we calculated sFNC across seven brain networks. We also calculated dFNC with a sliding window and Pearson correlation. The dFNC windows were partitioned into three distinct states with k-means clustering. Next, we calculated the amount of time each subject spent in each state, called occupancy rate or OCR. We compared both sFNC and OCR, estimated from dFNC, across individuals with different genetic risk and found that both sFNC and dFNC are related to AD genetic risk. We found that higher AD risk reduces within-visual sensory network (VSN) sFNC and that individuals with higher AD risk spend more time in a state with lower within-VSN dFNC. Additionally, we found that AD genetic risk affects whole-brain sFNC and dFNC in women but not in men. In conclusion, we presented novel insights into the links between sFNC, dFNC, and AD genetic risk.
Effects of sequence motifs in the yeast 3′ untranslated region determined from massively-parallel assays of random sequences
Authors: Savinov Andrew , Brandsen Benjamin M. , Angell Brooke E. , Cuperus Josh T. , Fields Stanley 
Published: March 2021

AbstractThe 3′ untranslated region (UTR) plays critical roles in determining the level of gene expression, through effects on activities such as mRNA stability and translation. The underlying functional elements within this region have largely been identified through analyses of the limited number of native genes. To explore the effects of sequence elements when not present in biologically evolved sequence backgrounds, we analyzed hundreds of thousands of random 50-mers inserted into the 3′ UTR of a reporter gene in the yeastSaccharomyces cerevisiae. We determined relative protein expression levels from the fitness of a library of transformants in a growth selection. We find that the consensus 3′ UTR efficiency element significantly boosts expression, independent of sequence context; on the other hand, the consensus positioning element has only a small effect on expression. Some sequence motifs that are binding sites for Puf proteins substantially increase expression in this random library, despite these proteins generally being associated with post-transcriptional downregulation when bound to native mRNAs. Thus, the regulatory effects of 3′ UTR sequence features like the positioning element and Puf binding sites appear to be strongly dependent on their context within native genes, where they exist alongside co-evolved sequence features. Our measurements also allowed a systematic examination of the effects of point mutations within efficiency element motifs across diverse sequence backgrounds. These mutational scans reveal the relativein vivoimportance of individual bases in the efficiency element, which likely reflects their roles in binding the Hrp1 protein involved in cleavage and polyadenylation.
High-dimensional profiling demonstrates complexity, tissue imprinting, and lineage-specific precursors within the mononuclear phagocyte compartment of the human intestine
Authors: Fenton Thomas M. , Wulff Line , Jones Gareth-Rhys , Vandamme Julien , Jørgensen Peter B. , Bain Calum C. , Lee Julie , Izarzugaza Jose MG. , Belling Kirstine G. , Ho Gwo-Tzer , Nielsen Ole H. , Riis Lene B. , Pers Tune H. , Jakobsen Henrik L. , Mowat Allan M. , Brunak Søren , Agace William W. 
Published: March 2021

AbstractMononuclear phagocytes (MNP), including macrophages and classical dendritic cells (cDC), are highly heterogeneous cells with distinct functions. Understanding MNP complexity in the intestinal lamina propria (LP), particularly in humans, has proved difficult due to the expression of overlapping phenotypic markers and the inability to isolate these cells without contamination from gut-associated lymphoid tissues (GALT). Here, we exploited our novel method for isolation of human GALT-free LP to carry out single-cell (sc)RNA-seq, CITE-seq and flow cytometry analysis of human ileal and colonic LP MNPs. As well as classical monocytes, non-classical monocytes, mature macrophage subsets, cDC1s, and cDC2s, we identified a CD1c+cDC subset with features of both cDC2 and monocytes, which were transcriptionally similar to the recently described cDC3. While similar MNP subsets were present in both ileal and colonic LP, the proportions and transcriptional profiles of these populations differed between these sites and in diseased states, indicating local specialization and environmental imprinting. Using computational trajectory tools, we identified putative early committed pre-cDC subsets and developmental intermediates of mature cDC1, cDC2 and cDC3, as well as monocyte–to-macrophage trajectories. Collectively, our results provide novel insights into the heterogeneity and development of intestinal LP MNP and an important framework for studying the role of these populations in intestinal homeostasis and disease.One sentence summaryFenton and Wulffet al. use single-cell methods to explore the complexity of the mononuclear phagocyte compartment of the human intestinal lamina propria, identifying distinct dendritic cell and macrophage subsets, site-specific transcriptional signatures, and lineage-specific precursors.
Functional expression of the ATP-gated P2X7 receptor in human iPSC-derived neurons and astrocytes
Authors: Kesavan Jaideep , Watters Orla , Dinkel Klaus , Hamacher Michael , Prehn Jochen H.M. , Henshall David C. , Engel Tobias 
Published: March 2021

AbstractThe P2X7 receptor (P2X7R) is a cation membrane channel activated by extracellular adenosine 5′-triphosphate. Activation of this receptor results in numerous downstream events including the modulation of neurotransmission, release of pro-inflammatory mediators, cell proliferation or cell death. While the expression of P2X7Rs is well documented on microglia and oligodendrocytes, the presence of functional P2X7Rs on neurons and astrocytes remains debated. Furthermore, to date, functional studies on the P2X7R are mostly limited to studies in cells from rodents and immortalised cell lines expressing human P2X7Rs. To assess the functional expression of P2X7Rs in human neurons and astrocytes, we differentiated human-induced pluripotent stem cells (hiPSCs) into forebrain cortical neurons that co-express FOXG1 and βIII-tubulin as well as S100 β-expressing astrocytes. Immunostaining revealed prominent punctate P2X7R staining on the soma and processes of hiPSC-derived neurons and astrocytes. In addition, our data show that stimulation with the potent nonselective P2X7R agonist BzATP induces robust calcium rises in hiPSC-derived neurons and astrocytes, which were blocked by the selective P2X7R antagonist AFC-5128. Together, our findings provide evidence for the functional expression of P2X7Rs in hiPSC-derived forebrain cortical neurons and astrocytes demonstrating that these cells offer the potential for investigating P2X7R-mediated pathophysiology and drug screening in vitro.
The Effect of Attention Load on Balance Control Performance
Authors: Mirloo Sheida , Parpanchi Behzad , Baghdadi Golnaz 
Published: March 2021

AbstractPosture balance control is an essential ability that is affected by the attention load. We investigated the effect of attention load on posture balance control experimentally and computationally. Fifteen young individuals participated in an experiment containing simultaneous performing of a balance control task and an auditory task. A previous computational model was extended by introducing the effect of attention load as a gain in a Proportional-Integral-Derivative (PID) controller. Results demonstrated that the sensitivity of the posture balance control to the attention load should be considered besides other influential factors in designing sport or physical rehabilitation exercises. Simulations suggested that the issues of joint impedance stiffness or viscosity might also be compensated by changing the attention load.
Combining evolutionary and assay-labelled data for protein fitness prediction
Authors: Hsu Chloe , Nisonoff Hunter , Fannjiang Clara , Listgarten Jennifer 
Published: March 2021

AbstractPredictive modelling of protein properties has become increasingly important to the field of machine-learning guided protein engineering. In one of the two existing approaches, evolutionarily-related sequences to a query protein drive the modelling process, without any property measurements from the laboratory. In the other, a set of protein variants of interest are assayed, and then a supervised regression model is estimated with the assay-labelled data. Although a handful of recent methods have shown promise in combining the evolutionary and supervised approaches, this hybrid problem has not been examined in depth, leaving it unclear how practitioners should proceed, and how method developers should build on existing work. Herein, we present a systematic assessment of methods for protein fitness prediction when evolutionary and assay-labelled data are available. We find that a simple baseline approach we introduce is competitive with and often outperforms more sophisticated methods. Moreover, our simple baseline is plug-and-play with a wide variety of established methods, and does not add any substantial computational burden. Our analysis highlights the importance of systematic evaluations and sufficient baselines.
Strain diversity of plant-associated Lactiplantibacillus plantarum
Authors: Yu Annabelle O. , Goldman Elissa A. , Brooks Jason T. , Golomb Benjamin L. , Yim Irene S. , Gotcheva Velitchka , Angelov Angel , Kim Eun Bae , Marco Maria L. 
Published: March 2021

AbstractThe intraspecific phenotypic and genetic diversity of Lactiplantibacillus plantarum (formerly Lactobacillus plantarum) was examined for five strains isolated from fermented olives and eight strains from cactus fruit, fermented tomatoes, teff injera, wheat boza, and wheat sourdough starter sources. Carbohydrate utilization and stress tolerance characteristics showed that the olive isolates grew more robustly in galactose and raffinose, showed higher tolerance to 12% v/v EtOH, and exhibited a greater capacity to inhibit an olive spoilage strain of Saccharomyces cerevisiae than L. plantarum from the other plant sources. Certain traits were variable between fermented olive isolates such as the capacity for biofilm formation and survival at pH 2 or 50 °C. By comparison, all L. plantarum from fruit sources grew better at a pH of 3.5 than the strains from fermented grains. Multi-locus sequence typing and genome sequencing indicated that strains from the same source type tended to be genetically related. Comparative genomics was unable to resolve strain differences, with the exception of the most phenotypically impaired and robust isolates. The findings show that L. plantarum is adapted for growth on specific plants or plant food types, but that intraspecific variation may be important for ecological fitness of L. plantarum within individual habitats.
Whole genome duplications and the diversification of the Globin-X genes of vertebrates
Authors: Hoffmann Federico G. , Storz Jay F. , Kuraku Shigehiro , Vandewege Mike W. , Opazo Juan C. 
Published: March 2021

AbstractThe globin superfamily of vertebrate genes is a textbook example of how the interplay between local gene duplications, whole-genome duplications, and regulatory changes can facilitate the evolution of novel protein functions. Almost every vertebrate examined possesses copies of hemoglobin and myoglobin in their genomes, and both cytoglobin and neuroglobin are present in the vast majority of vertebrate genomes surveyed as well. The phylogenetic distribution of globin-E, globin-Y and globin-X (GbX), however, is more spotty, suggesting multiple independent gene losses. Globin-X is an enigmatic globin with a wide phyletic distribution that spans protostomes and deuterostomes. Unlike canonical globins such as hemoglobins and myoglobins, functional data suggest that GbX does not have a primary respiratory function. Instead, available evidence suggests that GbX may play a role in protecting cells from oxidative damage and in reducing nitrite and it is predicted to be bound to the cell membrane. Recently released genomes from key vertebrate taxa provide an excellent opportunity to address questions about the early stages of evolution of these genes in vertebrates. In the current study, we integrate bioinformatic, synteny and phylogenetic analyses to characterize the diversity of GbX genes in non-teleost ray-finned fishes, resolve relationships between the GbX genes of cartilaginous fish and the GbX genes of bony vertebrates, and demonstrate that the GbX genes of cyclostomes and gnathostomes have independent duplicative histories. Our study highlights the role that whole genome duplications (WGDs) have played in expanding the repertoire of genes in vertebrate genomes. Our results indicate that GbX paralogs have a remarkably high rate of retention following WGDs in comparison to other globin genes, and also provide an evolutionary framework for interpreting results of experiments that examine functional properties of GbX and patterns of tissue-specific expression. By identifying GbX genes products of different WGDs in the vertebrate tree of life, our results can guide the design of experimental work to explore whether gene duplicates that originate via WGDs have evolved novel functional properties or expression profiles relative to singleton or tandemly duplicated copies of GbX.
Unravelling the shared genetic mechanisms underlying 18 autoimmune diseases using a systems approach
Authors: Gokuladhas Sreemol , Schierding William , Golovina Evgeniia , Fadason Tayaza , O’Sullivan Justin 
Published: March 2021

AbstractAutoimmune diseases (AiDs) are complex heterogeneous diseases characterized by hyperactive immune responses against self. Genome-wide association studies have identified thousands of single nucleotide polymorphisms (SNPs) associated with several AiDs. While these studies have identified a handful of pleiotropic loci that confer risk to multiple AiDs, they lack the power to detect shared genetic factors residing outside of these loci. Here, we integrated chromatin contact, expression quantitative trait loci and protein-protein interaction (PPI) data to identify genes that are regulated by both pleiotropic and non-pleiotropic SNPs. The PPI analysis revealed complex interactions between the shared and disease-specific genes. Furthermore, pathway enrichment analysis demonstrated that the shared genes co-occur with disease-specific genes within the same biological pathways. In conclusion, our results are consistent with the hypothesis that genetic risk loci associated with multiple AiDs converge on a core set of biological processes that potentially contribute to the emergence of polyautoimmunity.
Pulse labeling reveals the tail end of protein folding by proteome profiling
Authors: Zhu Mang , Kuechler Erich R. , Stoynov Nikolay , Gsponer Joerg , Mayor Thibault 
Published: March 2021

SummaryAccurate and efficient folding of nascent protein sequences into their native state requires support from the protein homeostasis network. Herein we probed which newly translated proteins are less thermostable to infer which polypeptides require more time to fold within the proteome. Specifically, we determined which of these proteins were more susceptible to misfolding and aggregation under heat stress using pulse SILAC coupled mass spectrometry. These proteins are abundant, short, and highly structured. Notably these proteins display a tendency to form β-sheet structures, a configuration which typically requires more time for folding, and were enriched for Hsp70/Ssb and TRiC/CCT binding motifs, suggesting a higher demand for chaperone-assisted folding. These polypeptides were also more often components of stable protein complexes in comparison to other proteins. All evidence combined suggests that a specific subset of newly translated proteins requires more time following synthesis to reach a thermostable native state in the cell.
OpenCell: proteome-scale endogenous tagging enables the cartography of human cellular organization
Authors: Cho Nathan H. , Cheveralls Keith C. , Brunner Andreas-David , Kim Kibeom , Michaelis André C. , Raghavan Preethi , Kobayashi Hirofumi , Savy Laura , Li Jason Y. , Canaj Hera , Kim James Y.S. , Stewart Edna M. , Gnann Christian , McCarthy Frank , Cabrera Joana P. , Brunetti Rachel M. , Chhun Bryant B. , Dingle Greg , Hein Marco Y. , Huang Bo , Mehta Shalin B. , Weissman Jonathan S. , Gómez-Sjöberg Rafael , Itzhak Daniel N. , Royer Loic A. , Mann Matthias , Leonetti Manuel D. 
Published: March 2021

AbstractElucidating the wiring diagram of the human cell is a central goal of the post-genomic era. We combined genome engineering, confocal live-cell imaging, mass spectrometry and data science to systematically map the localization and interactions of human proteins. Our approach provides a data-driven description of the molecular and spatial networks that organize the proteome. Unsupervised clustering of these networks delineates functional communities that facilitate biological discovery, and uncovers that RNA-binding proteins form a specific sub-group defined by unique interaction and localization properties. Furthermore, we discover that remarkably precise functional information can be derived from protein localization patterns, which often contain enough information to identify molecular interactions. Paired with a fully interactive website opencell.czbiohub.org, we provide a resource for the quantitative cartography of human cellular organization.
The CTEXT complex inSaccharomyces cerevisiaeplays a crucial role in degrading distinct sets of aberrant mRNAs by the nuclear exosome
Authors: Saha Upasana , Gaine Rajlaxmi , Paira Sunirmal , Das Satarupa , Das Biswadip 
Published: March 2021

AbstractInSaccharomyces cerevisiae, DRN (Decay ofRNA in theNucleus) requiring Cbc1/2p, Tif4631p, and Upf3p promotes the exosomal degradation of aberrantly long 3′-extended-, export-defective transcripts and a small group of normal (special) mRNAs. In this study, using a systematic proteomic analysis we show that each of the known components interacts with one another and they exist as a separate complex, which was dubbed CTEXT (CBC-Tif4631p-dependentEXosomeTargeting). We also identified a DEAD-box RNA helicase Dbp2p as an additional novel component of CTEXT during this analysis which was further bolstered by the finding that genomic deletions of Dbp2p led to the stabilization of all the signature nuclear messages. Interestingly, the RRM domain of Tif4631p located at the extreme N-termini of this polypeptide was found to play a vital role in in mediating the interaction of the CTEXT with the core exosome complex. These inferences were substantiated by the finding that deletion of this domain led to the functional impairment of the CTEXT complex. Thus, the CTEXT constitutes an independent complex that assists the nuclear exosome in degrading the select classes of nuclear transcripts inSaccharomyces cerevisiae.
Phosphorylation of myosin A regulatesPlasmodiumsporozoite motility and is essential for efficient malaria transmission
Authors: Ripp Johanna , Smyrnakou Xanthoula , Neuhoff Marie-Therese , Frischknecht Friedrich 
Published: March 2021

AbstractMalaria-causing parasites rely on an actin-myosin based motor for the invasion of different host cells as well as tissue traversal in mosquitoes and vertebrates. The unusual myosin A ofPlasmodiumspp. has a unique N-terminal extension which is important for red blood cell invasion byP. falciparummerozoitesin vitroand harbors a phosphorylation site at serine 19. Here, using the rodent-infectingP. bergheiwe show that serine 19 is essential for efficient transmission ofPlasmodiumby mosquitoes as S19A mutants show defects in mosquito salivary gland entry and migration of salivary gland sporozoites in both 2D and 3D environments. Our data suggests that entry into salivary glands represents the strongest barrier in parasite transmission and hence is the key determinant for evolution of the motility and invasion machinery of these parasites.HighlightsThe unusual N-terminal extension ofPlasmodiummyosin A is important for efficient gliding motilityAltering the kinetics of the myosin A power stroke impactsPlasmodiumlife cycle progression and sporozoite motilityMyosin A phosphorylation at serine 19 is important for malaria transmission by mosquitoesSalivary gland invasion emerges as key selection step for evolution of the parasite motor