bluuebunny/crossref_metadata_2025_split huggingface dataset:
Atf3 defines a population of pulmonary endothelial cells essential for lung regeneration
Authors: Niethamer Terren K. , Levin Lillian I. , Morley Michael P. , Babu Apoorva , Zhou Su , Morrisey Edward E. 
Published: October 2022

AbstractFollowing acute injury, the capillary vascular bed in the lung must be repaired to reestablish gas exchange with the external environment. Little is known about the transcriptional and signaling factors that drive pulmonary endothelial cell (EC) proliferation and subsequent regeneration of pulmonary capillaries, as well as their response to stress. Here, we show that the transcription factor Atf3 is essential for the regenerative response of the mouse pulmonary endothelium after influenza infection.Atf3expression defines a subpopulation of capillary ECs enriched in genes involved in endothelial development, differentiation, and migration. During lung alveolar regeneration, this EC population expands and increases expression of genes involved in angiogenesis, blood vessel development, and cellular response to stress. Importantly, endothelial cell-specific loss of Atf3 results in defective alveolar regeneration, in part through increased apoptosis and decreased proliferation in the endothelium. This leads to the general loss of alveolar endothelium and persistent morphological changes to the alveolar niche, including an emphysema-like phenotype with enlarged alveolar airspaces lined with regions that lack vascular investment. Taken together, these data implicate Atf3 as an essential component of the vascular response to acute lung injury that is required for successful lung alveolar regeneration.
Structural analysis shows that the BIR2 domain of E3 ligase XIAP binds across the RIP2 kinase dimer interface
Authors: Lethier Mathilde , Hons Michael , Favier Adrien , Brutscher Bernhard , Erba Elisabetta Boeri , Cusack Stephen , Pellegrini Erika 
Published: October 2022

AbstractNOD1 and NOD2 are innate immune system pattern recognition receptors that play a key role in the protection from bacterial infections and in the maintenance of gastro-intestinal homeostasis. Dysregulation of NOD signalling pathways promotes chronic inflammatory diseases such as inflammatory bowel disease. RIP2, which contains a kinase domain (RIP2K) and a CARD domain, is the immediate downstream signalling partner in the NOD pathway and inhibition of its kinase activity and ubiquitination are promising strategies to address these inflammatory diseases. However, recent work indicates that the phosphorylation activity of RIP2K is dispensable for signalling and that inhibitors of both RIP2K activity and RIP2 ubiquitination prevent the essential interaction between RIP2K and the BIR2 domain of XIAP, the key RIP2 ubiquitin E3 ligase. Moreover, XIAP BIR2 antagonists also block this interaction. To reveal the molecular mechanisms involved, we combined Native mass spectrometry, NMR, cryo-electron microscopy and Alphafold2 predictions to determine the structure of the RIP2K-XIAP BIR2 complex with 2:1 stoichiometry. The structure shows that complex formation requires that the kinase is in an active-like (i.e. αC-helix IN) and dimeric conformation and explains both inhibitory mechanisms. It also shows why phosphorylation of the kinase activation loop is dispensable for signalling and reveals the structural role of RIP2K-K209 residue in the RIP2K-XIAP BIR2 interaction. Importantly, our results clarify the features of the RIP2K conformation essential for its role as a scaffold protein for ubiquitination.
Phylogenomics reveals the relationships of butterflies and moths (Lepidoptera): providing the potential landscape using universal single copy orthologues
Authors: Chen Qi , Deng Min , Wang Wei , Wang Xing , Chen Liu-Sheng , Huang Guo-Hua 
Published: October 2022

AbstractBackgroundA robust and stable phylogenetic framework is a fundamental goal of evolutionary biology. As the third largest insect order following by Diptera and Coleoptera in the world, lepidoptera (butterflies and moths) play a central role in almost every terrestrial ecosystem as the indicators of environmental change and serve as important models for biologists exploring questions related to ecology and evolutionary biology. However, for such charismatic insect group, the higher-level phylogenetic relationships among its superfamilies are still poorly unresolved.Resultswe increased taxon sampling among Lepidoptera (40 superfamilies and 76 families contained 286 taxa) and filtered the unqualified samples, then acquired a series of large amino-acid datasets from 69,680 to 400,330 for phylogenomic reconstructions. Using these datasets, we explored the effect of different taxon sampling on tree topology by considering a series of systematic errors using ML and BI methods. Moreover, we also tested the effectiveness in topology robustness among the three ML-based models. The results showed that taxon sampling is an important determinant in tree robustness of accurate lepidopteran phylogenetic estimation. Long-branch attraction (LBA) caused by site-wise heterogeneity is a significant source of bias given rise to topologies divergence of ditrysia in phylogenomic reconstruction. Phylogenetic inference showed a most comprehensive framework by far to reveal the relationships among lepidopteran superfamilies, but limited by taxon sampling, it could only represent the current understanding of the lepidopteran tree of life. The relationships within the species-rich and relatively rapid radiation Ditrysia and especially Apoditrysia remain poorly unresolved, which need to increase taxon sampling and adopt lineage-specific genes for further phylogenomic reconstruction.ConclusionsThe present study further expands the taxon sampling of lepidopteran phylogeny and provides a potential phylogenomic foundation for further understanding its current higher-level relationships.
The soluble N-termini of mechanosensitive ion channels MSL8, MSL9, and MSL10 are environmentally sensitive intrinsically disordered regions with distinct biophysical characteristics
Authors: Flynn Aidan J. , Miller Kari , Codjoe Jennette M. , King Matthew R. , Posey Ammon E. , Haswell Elizabeth S. 
Published: October 2022

ABSTRACTIntrinsically disordered protein regions (IDRs) are highly dynamic sequences that rapidly sample a collection of conformations. In the past several decades, IDRs have emerged as a core component of many proteomes, comprising ∼30% of all eukaryotic protein sequences. IDRs are ubiquitous throughout different biological pathways, with a notable enrichment in responses to environmental stimuli such as abiotic stress. However, the diversity of IDR-based systems that biology has evolved to respond to different stimuli is expansive, warranting the exploration of IDRs present in unique molecular contexts. Here, we identify and characterize intrinsic disorder in the soluble, cytoplasmic N-terminal domains of three members of the MscS-Like (MSL) family of mechanosensitive ion channels, MSL8, MSL9 and MSL10. In plants, MSL channels are proposed to mediate the reactions to cell swelling, pathogenic invasion, and touch. A series of bioinformatic tools unanimously predicted that the cytosolic N-termini of MSLs are intrinsically disordered. We confirmed this prediction for the N-terminus of MSL10 (MSL10N) via circular dichroism spectroscopy. MSL10Nadopted a predominately helical structure when exposed to the helix-inducing compound trifluoroethanol (TFE) and underwent structural changes and alterations to homotypic interaction favorability in the presence of molecular crowding agents. Lastly,in vitroimaging of condensates indicated that MSL8N, MSL9Nand MSL10Nhave sharply differing propensities for condensate formation both inherently and in response to salt, temperature, and molecular crowding. Altogether, these data establish the N-termini of MSL channels as intrinsically disordered regions with distinct biophysical properties and the potential to respond disparately to changes in their physiochemical environment.
Phylogeographic reconstruction of the emergence and spread of Powassan virus in the northeastern United States
Authors: Vogels Chantal B.F. , Brackney Doug E. , Dupuis Alan P. , Robich Rebecca M. , Fauver Joseph R. , Brito Anderson F. , Williams Scott C. , Anderson John F. , Lubelczyk Charles B. , Lange Rachel E. , Prusinski Melissa A. , Kramer Laura D. , Gangloff-Kaufmann Jody L. , Goodman Laura B. , Baele Guy , Smith Robert P. , Armstrong Philip M. , Ciota Alexander T. , Dellicour Simon , Grubaugh Nathan D. 
Published: October 2022

AbstractPowassan virus is an emerging tick-borne virus of concern for public health, but very little is known about its transmission patterns and ecology. Here, we expanded the genomic dataset by sequencing 279 Powassan viruses isolated fromIxodes scapularisticks from the northeastern United States. Our phylogeographic reconstructions revealed that Powassan virus lineage II was likely introduced or emerged from a relict population in the Northeast between 1940-1975. Sequences strongly clustered by sampling location, suggesting a highly focal geographical distribution. Our analyses further indicated that Powassan virus lineage II emerged in the northeastern U.S. mostly following a south to north pattern, with a weighted lineage dispersal velocity of ~3 km/year. Since the emergence in the Northeast, we found an overall increase in the effective population size of Powassan virus lineage II, but with growth stagnating during recent years. The cascading effect of population expansion of white-tailed deer andI. scapularispopulations likely facilitated the emergence of Powassan virus in the northeastern U.S.Significance statementOur work provides important fundamental insights in the local transmission dynamics of an emerging tick-borne pathogen of public health concern. Without the availability of vaccines or specific treatments, prevention of Powassan virus infection is dependent on education and control. We identified that Powassan virus is maintained in highly localized transmission foci that have been maintained for several years, without introductions of new virus clades. This provides both opportunities for better education about high risk areas and effective targeted control in Powassan virus foci with a long lasting impact.
The tendon interfascicular basement membrane provides a vascular niche for CD146+pericyte cell subpopulations
Authors: Marr Neil , Zamboulis Danae E. , Werling Dirk , Felder Alessandro A. , Dudhia Jayesh , Pitsillides Andrew A. , Thorpe Chavaunne T. 
Published: October 2022

AbstractThe interfascicular matrix (IFM) is critical to the mechanical adaptations and response to load in energy-storing tendons, such as the human Achilles and equine superficial digital flexor tendon (SDFT). We hypothesized that the IFM is a tendon progenitor cell niche housing an exclusive cell subpopulation. Immunolabelling of equine SDFT was used to identify the IFM niche, localising expression patterns of CD31 (endothelial cells), CD146 (IFM cells) and LAMA4 (IFM basement membrane marker). Magnetic-activated cell sorting was employed to isolate and comparein vitroproperties of CD146+and CD146-subpopulations. CD146 demarcated an exclusive interfascicular cell subpopulation that resides in proximity to a basal lamina which forms interconnected vascular networks. Isolated CD146+cells exhibited limited mineralization (osteogenesis) and lipid production (adipogenesis). This study demonstrates that the IFM is a unique tendon cell niche, containing a vascular-rich network of basement membrane, CD31+endothelial cells and CD146+cell populations that are likely essential to tendon structure- and/or function. Interfascicular CD146+subpopulations did not exhibit stem cell-like phenotypes and are more likely to represent a pericyte lineage. Previous work has shown that tendon CD146 cells migrate to sites of injury, therefore mobilisation of endogenous tendon IFM cell populations may promote intrinsic repair.
Discovering cryptic splice mutations in cancers via a deep neural network framework
Authors: Teboul Raphaël , Grabias Michalina , Zucman-Rossi Jessica , Letouzé Eric 
Published: October 2022

ABSTRACTSomatic mutations can disrupt splicing regulatory elements and have dramatic effects on cancer genes, yet the functional consequences of mutations located in extended splice regions is difficult to predict. Here, we use a deep neural network (SpliceAI) to characterize the landscape of splice-altering mutations in cancer. In our in-house liver cancer series, SpliceAI uncovers many cryptic splice mutations, located outside essential splice sites, that validate at a high rate in matched RNA-seq data. We then extend the analysis to a large pan-cancer cohort of 18,115 tumors, revealing >100,000 cryptic splice mutations. Taking into account these mutations increases the power of driver gene discovery, revealing >100 new candidate driver genes. It also reveals new driver mutations in known cancer genes, doubling the frequency of splice alterations in tumor suppressor genes. Mutational signature analysis reveals the mutational processes that give rise to splice mutations in each cancer type, with an enrichment of signatures related to clock-like processes and DNA repair deficiency. Altogether, this work sheds light on the causes and impact of cryptic splice mutations in cancer, and highlights the power of deep learning approaches to better annotate the functional consequences of mutations in oncology.
Barrier properties of Nup98 FG phases ruled by FG motif identity and inter-FG spacer length
Authors: Ng Sheung Chun , Biswas Abin , Huyton Trevor , Schünemann Jürgen , Reber Simone , Görlich Dirk 
Published: October 2022

AbstractNup98 FG repeat domains comprise hydrophobic FG motifs linked through uncharged spacers. FG motifs capture nuclear transport receptors (NTRs) during nuclear pore complex (NPC) passage, confer inter-repeat cohesion, and condense the domains into a selective phase with NPC-typical barrier properties. We found that shortening inter-FG spacers enhances cohesion, increases phase density, and tightens such barrier, all consistent with a sieve-like phase. Phase separation tolerated mutating the Nup98-typical GLFG motifs, provided domain-hydrophobicity remained preserved. NTR-entry, however, was sensitive to (certain) deviations from canonical FG motifs, suggesting co-evolutionary adaptation. Unexpectedly, we found arginines to promote FG-phase-entry apparently also by hydrophobic interactions/ H-bonding and not just through cation-π interactions. Although incompatible with NTR·cargo complexes, a YG phase displayed remarkable transport selectivity, particularly for engineered GFPNTR-variants. GLFG to FSFG mutations made the FG phase hypercohesive, precluding NTR-entry. Extending spacers relaxed this hypercohesion. Thus, antagonism between cohesion and NTR·FG interactions is key to transport selectivity.
Machine-guided cell-fate engineering
Authors: Appleton Evan , Tao Jenhan , Fonseca Greg , Liu Songlei , Glass Christopher , Church George 
Published: October 2022

AbstractThe creation of induced pluripotent stem cells (iPSCs) has enabled scientists to explore the derivation of many types of cells. While there are diverse general approaches for cell-fate engineering, one of the fastest and most efficient approaches is transcription factor (TF) over-expression. However, finding the right combination of TFs to over-express to differentiate iPSCs directly into other cell-types is a difficult task. Here were describe a machine-learning (ML) pipeline, calledCellCartographer, for using chromatin accessibility data to design multiplex TF pooled-screens for cell type conversions. We validate this method by differentiating iPSCs into twelve diverse cell types at low efficiency in preliminary screens and then iteratively refining our TF combinations to achieve high efficiency differentiation for six of these cell types in < 6 days. Finally, we functionally characterized engineered iPSC-derived cytotoxic T-cells (iCytoT), regulatory T-cells (iTReg), type II astrocytes (iAstII), and hepatocytes (iHep) to validate functionally accurate differentiation.
Investigating the unique ability ofTrichodesmiumto fix carbon and nitrogen simultaneously using MiMoSA
Authors: Gardner Joseph J. , Hodge Bri-Mathias S. , Boyle Nanette R. 
Published: October 2022

ABSTRACTThe open ocean is an extremely competitive environment, partially due to the dearth of nutrients.Trichodesmium erythraeum, a marine diazotrophic cyanobacterium, is a keystone species in the ocean due to its ability to fix nitrogen and leak 30-50% into the surrounding environment, providing a valuable source of a necessary macronutrient to other species. While there are other diazotrophic cyanobacteria that play an important role in the marine nitrogen cycle,Trichodesmiumis unique in its ability to fix both carbon and nitrogen simultaneously during the day without the use of specialized cells called heterocysts to protect nitrogenase from oxygen. Here, we use the advanced modeling framework calledMultiscaleMultiobjectiveSystemsAnalysis (MiMoSA) to investigate howTrichodesmium erythraeumcan reduce dimolecular nitrogen to ammonium in the presence of oxygen. Our simulations indicate that nitrogenase inhibition is best modeled as Michealis Menten competitive inhibition and that cells along the filament maintain microaerobia using high flux through Mehler’s reactions in order to protect nitrogenase from oxygen. We also examined the effect of location on metabolic flux and found that cells at the end of filaments operate in distinctly different metabolic modes than internal cells despite both operating in a photoautotrophic mode. These results give us important insight into how this species is able to operate photosynthesis and nitrogen fixation simultaneously, giving it a distinct advantage over other diazotrophic cyanobacteria because they can harvest light directly to fuel the energy demand of nitrogen fixation.IMPORTANCETrichodesmium erythraeumis a marine cyanobacterium responsible for approximately half of all biologically fixed nitrogen, making it an integral part of the global nitrogen cycle. Interestingly, unlike other nitrogen fixing cyanobacteria,Trichodesmiumdoes not use temporal or spatial separation to protect nitrogenase from oxygen poisoning; instead, it operates photosynthesis and nitrogen fixation reactions simultaneously during the day. Unfortunately, the exact mechanism the cells utilize to operate carbon and nitrogen fixation simultaneously is unknown. Here, we use an advanced metabolic modeling framework to investigate and identify the most likely mechanismsTrichodesmiumuses to protect nitrogenase from oxygen. The model predicts that cells operate in a microaerobic mode, using both respiratory and Mehler reactions to dramatically reduce intracellular oxygen concentrations.
Incorporating knowledge of plates in batch normalization improves generalization of deep learning for microscopy images
Authors: Lin Alexander , Lu Alex X. 
Published: October 2022

AbstractData collected by high-throughput microscopy experiments are affected by batch effects, stemming from slight technical differences between experimental batches. Batch effects significantly impede machine learning efforts, as models learn spurious technical variation that do not generalize. We introducebatch effects normalization(BEN), a simple method for correcting batch effects that can be applied to any neural network with batch normalization (BN) layers. BEN aligns the concept of a “batch” in biological experiments with that of a “batch” in deep learning. During each training step, data points forming the deep learning batch are always sampled from the same experimental batch. This small tweak turns the batch normalization layers into an estimate of the shared batch effects between images, allowing for these technical effects to be standardized out during training and inference. We demonstrate that BEN results in dramatic performance boosts in both supervised and unsupervised learning, leading to state-of-the-art performance on the RxRx1-Wilds benchmark.1
Single-gene resolution of diversity-driven community overyielding
Authors: Wuest Samuel E. , Schulz Lukas , Rana Surbhi , Frommelt Julia , Ehmig Merten , Pires Nuno D. , Grossniklaus Ueli , Hardtke Christian S. , Hammes Ulrich , Schmid Bernhard , Niklaus Pascal A. 
Published: October 2022

SummaryIn plant communities, diversity often increases community productivity and functioning, but the specific underlying drivers are difficult to identify. Most ecological theories attribute the positive diversity effects to complementary niches occupied by different species or genotypes. However, the type of niche complementarity often remains unclear, including how complementarity is expressed in terms of trait differences between plants. Here, we use a gene-centred approach to identify differences associated with positive diversity effects in mixtures of naturalArabidopsis thalianagenotypes. Using two orthogonal genetic mapping approaches, we found that between-plant allelic differences at theAtSUC8locus contribute strongly to mixture overyielding. The corresponding gene encodes a proton-sucrose symporter and is expressed in root tissues. Genetic variation inAtSUC8affected the biochemical activities of protein variants and resulted in different sensitivities of root growth to changes in substrate pH. We thus speculate that - in the particular case studied here - evolutionary divergence along an edaphic gradient resulted in the niche complementarity between genotypes that now drives overyielding in mixtures. Identifying such genes important for ecosystem functioning may ultimately allow the linking of ecological processes to evolutionary drivers, help to identify the traits underlying positive diversity effects, and facilitate the development of high-performing crop variety mixtures in agriculture.