bluuebunny/crossref_metadata_2025_split huggingface dataset:
Turgor and the conformational pathway for MscS recovery
Authors: Anishkin Andriy , Sukharev Sergei 
Published: February 2024

AbstractThe bacterial mechanosensitive channel MscS is an adaptive osmolyte release valve that cycles between closed, open, and inactivated states. Since some of these conformations are stable only in the lipid environment under specific conditions, the structures that are currently available cannot explain the entire functional cycle. Previous patch-clamp characterization has provided insights into the missing functional state by estimating protein expansion areas associated with the closed-to-open and closed-to-inactivated transitions and indicating that the closed state must be the most compact. In this paper, we model the conformational transition of MscS from the splayed conformation with the uncoupled gate to the putative compact closed state. The compaction pathway revealed in preliminary extrapolated motion simulations (ExMoS) involved an upward sliding motion of the internal TM3 barrel inside the outer sheath formed by TM1-TM2 helical pairs. This move leads to several structural changes: (1) the relocation of the characteristic kink at G113 to a new position at G121, (2) the establishment of the hydrophobic TM2-TM3 contact, (3) a new pattern of interactions with membrane lipids, and (4) the formation of stabilizing salt bridges between TM1-TM2 loops and the cytoplasmic cage domain. In the intact bacterial cell, the driving force for this upward motion is likely to be turgor pressure normal to the plane of the membrane acting on the upper hemisphere of the cage domain from the inside. Under continuing lipid synthesis in the inner leaflet of the plasma membrane, turgor pressure is also predicted to maximize the lateral pressure of lipids in the membrane, thus driving MscS compaction. Steered simulations were performed on the splayed state to mimic these effects by applying normal forces to the upper part of the cage domain and by applying lateral compression to the TM1-TM2 pairs, emulating the pressure of lipids. The structure arrived at the predicted compact state of the channel. This state was critically stabilized by displacing non-bilayer lipids from the TM2-TM3 crevices into the bilayer. We propose that the energized metabolic state of the cell generating high turgor and promoting lipid synthesis should strongly favor the compact closed state of MscS. The normal forces pressing the dome of the cage domain against the membrane may provide a common recovery mechanism for the entire family of MscS-like channels found exclusively in organisms with walled cells, which evolved to function under turgor pressure. A conversion of turgor into membrane tension under hypoosmotic cytoplasm swelling and peptidoglycan expansion will drive opposite processes of opening followed by adaptive MscS closure and inactivation.
Identifying regulators of associative learning using a protein-labelling approach inC. elegans
Authors: Rahmani Aelon , McMillen Anna , Allen Ericka , Ansaar Radwan , Poljak Anne , Chew Yee Lian 
Published: February 2024

AbstractThe ability to learn and form memories is critical for animals to make choices that promote their survival. The biological processes underlying learning and memory are mediated by a variety of genes in the nervous system, acting at specific times during memory encoding, consolidation, and retrieval. Many studies have utilised candidate gene approaches or random mutagenesis screens in model animals to explore the key molecular drivers for learning and memory. We propose a complementary approach to identify this network of learning regulators: the proximity-labelling tool TurboID, which promiscuously biotinylates neighbouring proteins, to snapshot the proteomic profile of neurons during learning. To do this, we expressed the TurboID enzyme in the entire nervous system ofC. elegansand exposed animals to biotin only during the training step of a gustatory associative learning paradigm. Our approach revealed hundreds of proteins specific to ‘trained’ worms, including components of molecular pathways previously implicated in learning and memory formation in multiple species. We validated several novel regulators of learning involved in neurotransmission, including cholinergic receptors (ACC-1, ACC-3, GAR-1, LGC-46) and the putative glutaminase GLNA-3. These previously uncharacterised learning regulators show a clear impact on appetitive gustatory memory, but do not appear to have a generalised role in learning. In summary, we have shown that our approach to use proximity labelling to profile the brain of a small animal during training is a feasible and effective method to advance our knowledge on the biology of learning.
Playing with the ploidy level enables to switch on and off the strict recombination control even in the vicinity ofBrassicacentromeres
Authors: Boideau Franz , Huteau Virginie , Brunet Anael , Maillet Loeiz , Coriton Olivier , Trotoux Gwenn , Lodé-Taburel Maryse , Deniot Gwenaelle , Eber Frédérique , Gilet Marie , Boutte Julien , Morice Jérôme , Falentin Cyril , Martin Olivier , Falque Matthieu , Chèvre Anne-Marie , Rousseau-Gueutin Mathieu 
Published: February 2024

AbstractMeiotic recombination is a key biological process in plant evolution and breeding, as it generates novel genetic diversity at each generation. However, due to its importance in chromosome segregation and genomic stability, crossovers are highly regulated in both frequency and distribution. We previously demonstrated that this strict regulation is not a fatality and that it can be naturally modified (3.6-fold increased frequency and altered distribution) in an allotriploidBrassicahybrid (2n=3x=29; AAC), resulting from a cross betweenB. napus(2n=4x=38; AACC) andB. rapa(2n=2x=20; AA). Taking advantage of the recently updatedBrassica napusgenome assembly, which now includes the pericentromeric regions, we unambiguously demonstrated that crossovers occur in these normally cold regions in allotriploids, with the presence of crossovers as close as 375 kb from the centromere. We deciphered that this modified recombination landscape (both frequency and distribution) can be maintained in successive generations of allotriploidy, with even a slight increase of crossover frequency. We also showed that this deregulated meiotic behavior may revert back to a strictly regulated one when recovering an allotetraploid progeny in the second generation. Overall, we provide here for the first time a practical and natural way to switch on and off the tight recombination control in a polyploid crop. We also discuss the potential role of this modified regulation of recombination in polyploid speciation success.
Eco-evolutionary dynamics for finite populations and the noise-induced reversal of selection
Authors: Bhat Ananda Shikhara , Guttal Vishwesha 
Published: February 2024

AbstractTheoretical studies from diverse areas of population biology have shown that demographic stochasticity can substantially impact evolutionary dynamics in finite populations, including scenarios where traits that are disfavored by natural selection can nevertheless increase in frequency through the course of evolution. Here, we analytically describe the eco-evolutionary dynamics of finite populations from demographic first principles to investigate how noise-induced effects can alter the evolutionary fate of populations in which total population size may vary stochastically over time. Starting from a generic birth-death process describing a finite population of individuals with discrete traits, we derive a set of stochastic differential equations (SDEs) that recover well-known descriptions of evolutionary dynamics such as the replicator-mutator equation, the Price equation, and Fisher’s fundamental theorem in the infinite population limit. For finite populations, our SDEs reveal how stochasticity can predictably bias evolutionary trajectories to favour certain traits, a phenomenon we call ‘noise-induced biasing’. We show that noise-induced biasing acts through two distinct mechanisms that we call the ‘direct’ and ‘indirect’ mechanisms. While the direct mechanism can be identified with classic bet-hedging theory, the indirect mechanism is a more subtle consequence of frequency and density-dependent demographic stochasticity. Our equations reveal that noise-induced biasing may lead to evolution proceeding in a direction opposite to that predicted by natural selection in the infinite population limit. By extending and generalizing some standard equations of population genetics, we thus describe how demographic stochasticity appears alongside and interacts with the more well-understood forces of natural selection and neutral drift to determine the eco-evolutionary dynamics of finite populations of non-constant size.
SCRAPPY - a single cell rapid assay of proteome perturbation in yeast uncovers a joint role of aromatic amino acids and oxidative stress in the toxicity of lipophilic nucleoside analogs
Authors: Ghazy Eslam , Bidiuk Victoria A. , Ryabov Fedor , Mitkevich Olga V. , Riabova Olga B. , Stanishevskiy Yaroslav M. , Levshin Igor B. , Alexandrova Liudmila A. , Jasko Maxim V. , Makarov Dmitriy A. , Zhgun Alexander A. , Avdanina Darya A. , Ermolyuk Anna A. , Kushnirov Vitaly V. , Egorova Anna P. , Agaphonov Michael O. , Alexandrov Alexander I. 
Published: February 2024

ABSTRACTAssaying cellular responses to antimicrobial molecules is a path to understanding modes of action of potential drugs. This is often achieved via transcriptomics and proteomics, but simple and inexpensive methods for rapid characterization are lacking. To bridge this gap, we assayed changes in the abundance of a panel of 64 “sentinel” proteins fused to GFP in the yeastSaccharomyces cerevisiaeusing flow cytometry. This method produced expected patterns for classical antifungals and allowed inference of common mechanisms between known and novel compounds. Single-cell data also revealed diverging responses in mitochondrial protein abundance in response to thiazolidine antifungals, and perturbations of the cell cycle caused by various compounds. Finally, the method provided insight into the unknown mode of action of alkylated nucleosides, which can be used against fungi residing on works of art. These substances elevate levels of proteins involved in the biosynthesis of aromatic amino acids (AAA), as well as in oxidative stress. Furthermore, deficiencies of Trp and Tyr biosynthesis increased the efficacy of these compounds, while antioxidants reduced it. Most surprisingly, antioxidant effectiveness relied on AAA biosynthesis. Thus, our approach and its possible modifications for other microbes provides an easy and reliable platform for revealing modes of action of novel compounds.
Lineage-tracing ofActa2+ cells in aged mice during lung fibrosis formation and resolution supports the lipofibroblast to myofibroblast reversible switch
Authors: Lingampally Arun , Truchi Marin , Mauduit Olivier , Delcroix Vanessa , Hadzic Stefan , Koepke Janine , Vazquez-Armendariz Ana Ivonne , Herold Susanne , Samakovlis Christos , Makarenkova Helen P , Agha Elie El , Chen Chengshui , Mari Bernard , Bellusci Saverio 
Published: February 2024

AbstractIdiopathic pulmonary fibrosis (IPF) develops mostly in old man and is characterized by the irreversible accumulation of excessive extracellular matrix components by activated myofibroblasts (aMYFs) leading to lung failure. Following bleomycin administration in young mice, fibrosis formation associated with efficient resolution takes place, the later limiting the clinical relevance of this model for IPF. In young mice, we previously reported that aMYFs captured during fibrosis formation differentiate towards a lipofibroblast (LIF)-like phenotype during resolution.In this study, we used aged mice in combination with bleomycin administration to trigger enhanced fibrosis formation and delayed resolution, as a more relevant model for IPF and examined the heterogeneity and fate of aMYFs at different time points. Alveolosphere assay were carried out to compare the alveolar resident mesenchymal niche activity for AT2 stem cells in young versus old mice. Lineage tracing of the Acta2+ aMYFs in old mice exposed to bleomycin followed by scRNAseq of the lineage-traced cells isolated during fibrosis formation and resolution was performed to delineate the heterogeneity of aMYFs during fibrosis formation and their fate during resolution. Data mining of human mesenchymal cells from IPF and control datasets were also performed to decipher the heterogeneity of aMYFs and investigate differentiation trajectories during fibrosis formation.Our results show that alveolar resident mesenchymal cells from old mice display decreased supporting activity for AT2 stem cells. We report that aMYFs consist of four subclusters displaying unique pro-alveologenic versus pro-fibrotic profiles. Alveolar fibroblasts displaying a high LIF-like signature largely constitute both the origin and fate of aMYFs during fibrosis formation and resolution, respectively. The heterogeneity of aMYFs is conserved in humans and a significant proportion of human aMYFs displays a high LIF signature.In conclusion, our data indicate that the cellular and molecular bases of aMYFs formation and differentiation towards the LIF phenotype are conserved between young and old mice. Importantly, our work identifies a subcluster of aMYFs that is potentially relevant for future management of IPF.
Pathologic α-Synuclein-NOD2 Interaction and RIPK2 Activation Drives Microglia-Induced Neuroinflammation in Parkinson’s Disease
Authors: Seo Bo Am , Kwon Seung-Hwan , Kim Donghoon , Kim Han-Byeol , Ma Shi-Xun , Gadhave Kundlik , Burgess Noelle , Mao Xiaobo , Rosenthal Liana S. , Redding-Ochoa Javier , Troncoso Juan C , Lee Seulki , Dawson Valina L. , Dawson Ted M. , Ko Han Seok 
Published: February 2024

SummaryPathological aggregation of α-Synuclein (α-Syn) and neuroinflammation are closely linked to Parkinson’s disease (PD). However, the specific regulators of the neuroinflammation caused by pathological α-syn remain obscure. In this study, we show that NOD2/RIPK2 signaling is a crucial regulator of neuroinflammation in PD. Pathological α-syn binds to NOD2, causing self-oligomerization and complex formation with RIPK2, leading to RIPK2 ubiquitination and activation of MAPK and NF-kB. Notably, this NOD2/RIPK2 signaling is particularly active in microglia of human PD brains and the α-Syn preformed fibril (α-Syn PFF) mouse model. Depleting NOD2 or RIPK2 reduces neuroinflammation and protects against dopamine neuron degeneration in a pathologic α-Syn mouse model by blocking the formation of neurotoxic reactive astrocytes caused by microglia activation. The discovery of NOD2/RIPK2 signaling as a key regulator of neuroinflammation in PD provides a new understanding of α-Syn-driven neuroinflammation and neurodegeneration in PD and a potential new therapeutic strategy.Graphical AbstractIn briefPathological α-Synuclein (α-Syn) binds to the microglial NOD2 protein, which in turn triggers NOD2/RIPK2 complex and RIPK2 phosphorylation/ubiquitination. This process activates the NF-kB/MAPK pathways, ultimately leading to neurotoxic reactive astrocyte-induced dopaminergic neurodegeneration. Depletion of RIPK2 (RIPK2 KO) or NOD2 (NOD2) protects dopamine neurons in a mouse model of Parkinson’s disease (PD). These findings provide insights into α-Syn-driven neuroinflammation and offer potential therapeutic strategies for PD.HighlightsNOD2/RIPK2 signaling is identified as a crucial regulator of neuroinflammation in PD.NOD2/RIPK2 signaling is highly active in microglia in human PD brains and α-Syn PFF mouse models.Pathological α-Syn binds to NOD2, triggering self-oligomerization and RIPK2 complex formation, leading to MAPK and NF-kB activationGenetic depletion of NOD2 or RIPK2 reduces neuroinflammation and protects dopamine neurons by blocking the formation of neurotoxic reactive astrocytes.
The effects of clay minerals on bacterial community composition during arthropod decay
Authors: Corthésy Nora , Saleh Farid , Thomas Camille , Antcliffe Jonathan B. , Daley Allison C. 
Published: February 2024

ABSTRACTFossilization, or the transition of an organism from the biosphere to the geosphere, is a complex mechanism involving numerous biological and geological variables. Bacteria are one of the most significant biotic players to decompose organic matter in natural environments, early on during fossilization. However, bacterial processes are difficult to characterize as many different abiotic conditions can influence bacterial efficiency in degrading tissues. One potentially important variable is the composition and nature of the sediment on which a carcass is deposited after death. We experimentally examined this by decaying the marine shrimpPalaemon variansunderwater on three different clay sediments. Samples were then analyzed using 16S ribosomal RNA sequencing to identify the bacterial communities associated with each clay system. Results show that samples decaying on the surface of kaolinite have a lower bacterial diversity than those decaying on the surface of bentonite and montmorillonite, which could explain the limited decay of carcasses deposited on this clay. However, this is not the only role played by kaolinite, as a greater proportion of gram-negative over gram-positive bacteria is observed in this system. Gram-positive bacteria are generally thought to be more efficient at recycling complex polysaccharides such as those forming the body walls of arthropods. This is the first experimental evidence of sediments shaping an entire bacterial community. Such interaction between sediments and bacteria might have contributed to arthropods’ exquisite preservation and prevalence in kaolinite-rich Lagerstätten of the Cambrian Explosion.
A difficult coexistence: resolving the iron-induced nitrification delay in groundwater filters
Authors: Corbera-Rubio Francesc , Kruisdijk Emiel , Malheiro Sofia , Leblond Manon , Verschoor Liselotte , van Loosdrecht Mark C.M. , Laureni Michele , van Halem Doris 
Published: February 2024

AbstractRapid sand filters (RSF) are an established and widely applied technology for the removal of dissolved iron (Fe2+) and ammonium (NH+) in groundwater treatment. Most often, biological NH+oxidation is delayed and starts only upon complete Fe2+depletion. However, the mechanism(s) responsible for the inhibition of NH+oxidation by Fe2+or its oxidation (by)products remains elusive, hindering further process control and optimization. We used batch assays, lab-scale columns, and full-scale filter characterizations to resolve the individual impact of the main Fe2+oxidizing mechanisms and the resulting products on biological NH+oxidation. Modelling of the obtained datasets allowed to quantitatively assess the hydraulic implications of Fe2+oxidation. Dissolved Fe2+and the reactive oxygen species formed as byproducts during Fe2+oxidation had no direct effect on nitrification. The Fe3+oxides on the sand grain coating, commonly assumed to be the main cause for inhibited nitrification, seemed instead to enhance nitrification by providing additional surface area for biofilm growth. Modelling allowed to exclude mass transfer limitations induced by accumulation of iron flocs and consequent filter clogging as the cause for delayed nitrification. We unequivocally identify the inhibition of NH+oxidizing organisms by the Fe3+flocs generated during Fe2+oxidation as the main cause for the commonly observed nitrification delay. The addition of Fe3+flocs inhibited NH+oxidation both in batch and column tests, and the removal of Fe3+flocs by backwashing completely re-established the NH+removal capacity, suggesting that the inhibition is reversible. In conclusion, our findings not only identify the iron form that causes the inhibition, albeit the biological mechanism remains to be identified, but also highlight the ecological importance of iron cycling in nitrifying environments.Graphical abstractHighlightDissolved Fe2+and reactive oxygen species do not affect NH+oxidationFe oxide coating aids sand grain colonization by NH+-oxidizing bacteriaFe3+flocs inhibit NH+oxidation by reducing the nitrifying capacity of AOBChanges in transport patterns due to clogging do not play a major role in NH+oxidationThe inhibition of NH4+oxidation is reversible and reduced by backwashing
Adaptive predictor-set linear model: an imputation-free method for linear regression prediction on datasets with missing values
Authors: Jiménez Benjamin Planterose , Kayser Manfred , Vidaki Athina , Caliebe Amke 
Published: February 2024

SummaryLinear regression (LR) is vastly used in data analysis for continuous outcomes in biomedicine and epidemiology. Despite its popularity, LR is incompatible with missing data, which frequently occur in health sciences. For parameter estimation, this short-coming is usually resolved by complete-case analysis or imputation. Both workarounds, however, are inadequate for prediction, since they either fail to predict on incomplete records or ignore missingness-induced reduction in prediction accuracy and rely on (unrealistic) assumptions about the missing mechanism. Here, we derive adaptive predictor-set linear model (aps-lm), capable of making predictions for incomplete data without the need for imputation. It is derived by using a predictor-selection operation, the Moore-Penrose pseudoinverse and the reduced QR-decomposition. aps-lm is an LR generalization that inherently handles missing values. It is applied on a reference dataset, where complete predictors and outcome are available, and yields a set of privacy-preserving parameters. In a second stage, these are shared for making predictions of the outcome on external datasets with missing entries for predictors without imputation. Moreover, aps-lm computes prediction errors that account for the pattern of missing values even under extreme missingness. We benchmark aps-lm in a simulation study. aps-lm showed greater prediction accuracy and reduced bias compared to popular imputation strategies under a wide range of scenarios including variation of sample size, goodness-of-fit, missing value type and covariance structure. Finally, as a proof-of-principle, we apply aps-lm in the context of epigenetic aging clocks, linear models that predict a person’s biological age from epigenetic data with promising clinical applications.