bluuebunny/crossref_metadata_2025_split huggingface dataset:
Integrating environmental gradients into breeding: application of genomic reactions norms in a perennial species
Authors: Papin Victor , Bosc Alexandre , Sanchez Leopoldo , Bouffier Laurent 
Published: November 2023

AbstractGlobal warming threatens the productivity of forest plantations. We propose here the integration of environmental information into a genomic evaluation scheme using individual reaction norms, to enable the quantification of resilience in forest tree improvement and conservation strategies in the coming decades. Random regression models were used to fit wood ring series, reflecting the longitudinal phenotypic plasticity of tree growth, according to various environmental gradients. The predictive performance of the models was considered to select the most relevant environmental gradient, namely a gradient derived from an ecophysiological model and combining trunk water potential and temperature. Even if the genotype ranking was preserved over most of the environmental gradient, strong genotype x environment interactions were detected in the extreme unfavorable part of the gradient, which includes environmental conditions that are very likely to increase in the future. Combining genomic information and longitudinal data allowed to predict growth in unobserved environments: considering an equivalent phenotyping effort, the cross-validation scenarios led to predictive performances ranging from 0.25 to 0.59 highlighting the importance of phenotypic data allocation. Genomic reaction norms are useful for the characterization and prediction of the function of genetic parameters and facilitate breeding in a climate change context.
Integration of transcription regulation and functional genomic data reveals lncRNA SNHG6’s role in hematopoietic differentiation and leukemia
Authors: Hazan Joshua M. , Amador Raziel , Lahav Tamar , Assaraf Yehuda G. , Guigó Roderic , Bester Assaf C. 
Published: November 2023

AbstractBackgroundLong non-coding RNAs (lncRNAs) are pivotal players in cellular processes, and their unique cell-type specific expression patterns make them attractive biomarkers and therapeutic targets. Yet, the functional roles of most lncRNAs remain enigmatic. To address the need to identify new druggable lncRNAs, we developed a comprehensive approach integrating transcription factor binding data with other genetic features to generate a machine learning model, which we have called INFLAMeR (Identifying Novel Functional LncRNAs with Advanced Machine Learning Resources).MethodsINFLAMeR was trained on high-throughput CRISPR interference (CRISPRi) screens across seven cell lines, and the algorithm was based on 71 genetic features. To validate the predictions, we selected candidate lncRNAs in the K562 leukemia cell line and determined the effect of their knockdown on cell proliferation and chemotherapy drug resistance. We further performed transcriptomic analysis for candidate genes. Based on these findings, we assessed the lncRNA Small Nucleolar RNA Host Gene 6 (SNHG6) for its role in myeloid differentiation by incubation with Phorbol 12-myristate 13-acetate (PMA) to induce megakaryocyte differentiation, or with hemin to induce erythrocyte differentiation.ResultsThe INFLAMeR model successfully reconstituted CRISPRi screening data and predicted functional lncRNAs that were previously overlooked. Intensive cell-based and transcriptomic validation of nearly fifty genes in K562 revealed cell type-specific functionality for 85% of the predicted lncRNAs. Our cell-based and transcriptomic analyses predicted a role for SNHG6 in hematopoiesis and leukemia. Consistent with its predicted role in hematopoietic differentiation,SNHG6transcription is regulated by hematopoiesis-associated transcription factors. Knockdown of SNHG6 reduced the proliferation of leukemia cells and sensitized them to differentiation. Treatment of K562 leukemic cells with hemin and PMA, respectively, demonstrated that SNHG6 inhibits red blood cell differentiation but strongly promotes megakaryocyte differentiation. DespiteSNHG6transcripts showing strong cytoplasmic enrichment,SNHG6regulates the expression of hematopoietic genes such asPPBP(Pro-Platelet Basic Protein) andPF4(Platelet Factor 4).ConclusionsOur approach not only improved the identification and characterization of functional lncRNAs through genomic approaches in a cell type-specific manner, but also identified new lncRNAs with a role in hematopoiesis and leukemia. Such approaches cab be used to identify new targets for precision therapy.
Aging and freezing of active nematic dynamics of cancer-associated fibroblasts by fibronectin matrix remodeling
Authors: Jacques Cécile , Ackermann Joseph , Bell Samuel , Hallopeau Clément , Gonzalez Carlos Perez- , Balasubramaniam Lakshmi , Trepat Xavier , Ladoux Benoît , Maitra Ananyo , Voituriez Raphael , Vignjevic Danijela Matic 
Published: November 2023

AbstractIn the initial cancer stages, cancer-associated fibroblasts (CAFs) create a capsule around tumors. Exhibiting an elongated morphology, CAFs align with each other, closely resembling nematic ordering in liquid crystal physics. While these aligned CAFs may act as a defensive barrier hindering tumor expansion, inherent topological defects could represent weak spots, facilitating cancer cell dissemination. CAFs play a pivotal role in the genesis and remodeling of the extracellular matrix (ECM), with ECM proteins, especially fibronectin, reciprocally modulating CAF alignment and coherence. Yet, the intricate feedback loops between fibronectin deposition and CAF structuring remain largely unexplored. Here, we combined CAF live imaging, traction force microscopy, ECM microfabrication, and theoretical modeling to assess how the ECM influences the dynamics of nematically ordered CAFs. We found that CAFs dynamically orchestrate a fibronectin network that mirrors their nematic ordering. Over time, this passive nematic ordering of fibronectin, in turn, steers CAF rearrangement. Contrary to most cellular systems where defects remain dynamic at a steady state, our data highlights that the ECM/CAF interplay profoundly alters the behavior of both CAF and ECM nematics, leading to aging – massive slow down and even freezing of defect dynamics. This leads to a scenario where aligned areas and defects in CAFs layer are spatially and temporally fixed, yet active – exerting forces at the substate and transmitting forces between cells. Such a state could introduce localized vulnerabilities in the CAF layer, potentially promoting cancer cell spreading.
The recombination initiation functions DprA and RecFOR suppress microindel mutations inAcinetobacter baylyiADP1
Authors: Liljegren Mikkel M. , Gama João A. , Johnsen Pål J. , Harms Klaus 
Published: November 2023

SummaryShort-Patch Double Illegitimate Recombination (SPDIR) has been recently identified as a rare mutation mechanism. During SPDIR, ectopic DNA single-strands anneal with genomic DNA at microhomologies and get integrated in the course of DNA replication, presumably acting as Okazaki fragments. The resulting microindel mutations are highly variable in size and sequence. In the soil bacteriumAcinetobacter baylyi, SPDIR mutations are tightly controlled by genome maintenance functions including RecA. In this study, we investigate the roles of DprA, RecFOR and RecBCD, which are cytoplasmic functions that load DNA single-strands with RecA. All three functions suppress SPDIR mutations in wildtype to levels below the detection limit. While SPDIR mutations are slightly elevated in the absence of DprA alone, they are strongly increased in the absence of both DprA and RecA. This SPDIR-avoiding function of DprA is not related to its role in natural transformation. These results suggest an antimutational function for DprA and offer an explanation for the ubiquity ofdprAin the genomes of non-transformable bacteria.
Guiding diffusion models for antibody sequence and structure co-design with developability properties
Authors: Villegas-Morcillo Amelia , Weber Jana M. , Reinders Marcel J.T. 
Published: November 2023

AbstractRecent advances in deep generative methods have allowed antibody sequence and structure co-design. This study addresses the challenge of tailoring the highly variable complementarity-determining regions (CDRs) in antibodies to fulfill developability requirements. We introduce a novel approach that integrates property guidance into the antibody design process using diffusion probabilistic models. This approach allows us to simultaneously design CDRs conditioned on antigen structures while considering critical properties like solubility and folding stability. Our property-conditioned diffusion model offers versatility by accommodating diverse property constraints, presenting a promising avenue for computational antibody design in therapeutic applications. Code is available athttps://github.com/amelvim/antibody-diffusion-properties.
Freezing responses during prolonged threat memory retrieval reflect trait-like anxiety endophenotypes in female and male inbred mice
Authors: Kovlyagina Irina , Wierczeiko Anna , Todorov Hristo , Jacobi Eric , Tevosian Margaryta , von Engelhardt Jakob , Gerber Susanne , Lutz Beat 
Published: November 2023

AbstractTrait anxiety is a major risk factor for stress-induced and anxiety disorders in humans. However, animal models accounting for the inter-individual variability in stress vulnerability are largely lacking. Moreover, the pervasive bias of using mostly male animals in preclinical studies poorly reflects the increased prevalence of psychiatric disorders in women. Using the threat imminence continuum theory, we designed and validated an auditory aversive conditioning-based pipeline in both female and male mice. We operationalized trait anxiety by harnessing the naturally occurring variability of defensive freezing responses combined with a model-based clustering strategy. While sustained freezing during prolonged retrieval sessions was identified as an anxiety-endophenotype biomarker in both sexes, females were consistently associated with an increased freezing response RNA-sequencing of CeA, BLA, ACC and BNST revealed massive differences in phasic and sustained responders’ transcriptomes, correlating with transcriptomic signatures of psychiatric disorders, particularly PTSD. Moreover, we detected significant alterations in the excitation/inhibition balance of principal neurons in the lateral amygdala. These findings provide compelling evidence that trait anxiety in inbred mice can be leveraged to develop translationally relevant preclinical models to investigate mechanisms of stress susceptibility in a sex-specific manner.We like to think we have constrained an organism to the task we have set. In practice, our paradigms are constrained by the way the organisms respondMcNaughton & Corr, 2004
Integrating leaf gas exchange and chlorophyll fluorescence to reveal the long-term regulation of photosynthesisin situ
Authors: Oivukkamäki Jaakko , Aalto Juho , Pfündel Erhard E. , Tian Manqing , Zhang Chao , Grebe Steffen , Salmon Yann , Hölttä Teemu , Porcar-Castell Albert 
Published: November 2023

AbstractUnderstanding the diurnal and seasonal regulation of photosynthesis is an essential step in quantifying and modeling the impact of the environment on plant function. Although the dynamics of photosynthesis have been widely investigated in terms of CO2exchange measurements, a more comprehensive view can be obtained when combining gas exchange and chlorophyll fluorescence (ChlF) measurements. However, such integrated measurements have been so far restricted to short term analysis using portable systems that combine IRGA and PAM-ChlF techniques. Here we introduce and demonstrate a new method for integrated, long-term andin situmeasurements of leaf gas exchange and ChlF, based on an autonomous gas exchange system and a new miniature PAM- fluorometer. The method is used to simultaneously track the dynamics of the light and carbon reactions of photosynthesis at a 20-minute resolution in leaves of silver birch during summer time. The potential of the method is initially demonstrated using the ratio between electron transport and net assimilation (ETR/ANET). We successfully captured the diurnal patterns in the ETR/ANETduring summer time, including a drastic increase in ETR/ANETupon a high-temperature period. We suggest that these measurements can provide valuable data to model and quantify the regulation of leaf photosynthesisin situ.HighlightWe introduce new integrated measurements to help resolve the seasonal and diurnal dynamics of photosynthesis regulation by combining long-term simultaneous measurements of gas exchange and chlorophyll fluorescence in field conditions.
The bile acid receptor TGR5 regulates the hematopoietic support capacity of the bone marrow niche
Authors: Alonso-Calleja Alejandro , Perino Alessia , Schyrr Frédérica , Lopes Silvia Ferreira , Delitsikou Vasiliki , Jalil Antoine , Kettenberger Ulrike , Pioletti Dominique P. , Schoonjans Kristina , Naveiras Olaia 
Published: November 2023

AbstractThe gut is an emerging regulator of bone marrow (BM) hematopoiesis and several signaling molecules are involved in this communication. Among them, bile acids (BAs), originally classified as lipid solubilizers, have emerged as powerful signaling molecules that act as a relay between the digestive system, the microbiota and the rest of the body. The signaling function of BAs relies on specific receptors, including Takeda-G-protein-receptor-5 (TGR5). TGR5 has potent regulatory effects in immune cells, but its effect on the BM as a primary immune organ remains unknown. Here, we investigated the BM of young mice and observed a significant reduction in bone marrow adipose tissue (BMAT) upon loss of TGR5, accompanied by an enrichment in BM adipocyte progenitors which translated into enhanced hematopoietic recovery upon transplantation. These findings open the possibility of modulating stromal hematopoietic support by acting on TGR5 signaling.SummaryThis work shows that TGR5 loss-of-function reduces regulated bone marrow adipose tissue and accelerates recovery upon bone marrow transplantation. These data highlight TGR5 as key player of the bone marrow microenvironment.
Cargo selective vesicle tethering: the structural basis for binding of specific cargo proteins by the Golgi tether component TBC1D23
Authors: Cattin-Ortolá Jérôme , Kaufman Jonathan G. G. , Gillingham Alison K. , Wagstaff Jane L. , Peak-Chew Sew-Yeu , Stevens Tim J. , Owen David J. , Munro Sean 
Published: November 2023

AbstractFor accurate membrane traffic it is essential that vesicles and other carriers tether and fuse to only the correct compartment. The TGN-localised golgins golgin-97 and golgin-245 capture transport vesicles arriving from endosomes via the protein TBC1D23 that forms a bridge between the golgins and endosome-derived vesicles. The C-terminal domain of TBC1D23 is responsible for vesicle capture, but how it recognises a specific type of vesicle was unclear. A search for binding partners of the C-terminal domain surprisingly revealed direct binding to carboxypeptidase D (CPD) and syntaxin-16, both known cargo proteins of the captured vesicles. Binding is via a TLY-containing sequence present in both proteins. A crystal structure reveals how this “acidic TLY motif” binds to the C-terminal domain of TBC1D23. An acidic TLY motif is also present in the tails of other endosome-to-Golgi cargo, and these also bind TBC1D23. Structure-guided mutations in the C-terminal domain that disrupt motif binding in vitro also block vesicle capture in vivo. Thus, TBC1D23 attached to golgin-97 and golgin-245 captures vesicles by a previously undescribed mechanism: the recognition of a motif shared by cargo proteins carried by the vesicle.One sentence summaryA class of transport vesicle destined for the Golgi is recognized by a tether binding directly to the cargo it is carrying.
Multidimensional neural representations of social features during movie viewing
Authors: Masson Haemy Lee , Chang Lucy , Isik Leyla 
Published: November 2023

AbstractThe social world is dynamic and contextually embedded. Yet, most studies utilize simple stimuli that do not capture the complexity of everyday social episodes. To address this, we implemented a movie viewing paradigm and investigated how the everyday social episodes are processed in the brain. Participants watched one of two movies during an MRI scan. Neural patterns from brain regions involved in social perception, mentalization, action observation, and sensory processing were extracted. Representational similarity analysis results revealed that several labeled social features (including social interaction, mentalization, the actions of others, characters talking about themselves, talking about others, and talking about objects) were represented in superior temporal gyrus (STG) and middle temporal gyrus (MTG). The mentalization feature was also represented throughout the theory of mind network, and characters talking about others engaged the temporoparietal junction (TPJ), suggesting that listeners may spontaneously infer the mental state of those being talked about. In contrast, we did not observe the action representations in frontoparietal regions of the action observation network. The current findings indicate that STG and MTG serve as central hubs for social processing, and that listening to characters talk about others elicits spontaneous mental state inference in TPJ during natural movie viewing.
β-lactamase expression induces collateral sensitivity inEscherichia coli
Authors: Herencias Cristina , Álvaro-Llorente Laura , Ramiro-Martínez Paula , Muñoz-Cazalla Ada , DeLaFuente Javier , Jaraba-Soto Laura , Castillo-Polo Juan Antonio , Cantón Rafael , San Millán Álvaro , Rodríguez-Beltrán Jerónimo 
Published: November 2023

AbstractMajor antibiotic groups are losing effectiveness due to the uncontrollable spread of antimicrobial resistance (AMR) genes. Among these, β-lactam resistance genes –encoding β-lactamases– stand as the most common resistance mechanism in Enterobacterales due to their frequent association with mobile genetic elements. In this context, novel approaches that counter mobile AMR are urgently needed. Collateral sensitivity (CS) occurs when the acquisition of resistance to one antibiotic increases susceptibility to another antibiotic and can be exploited to selectively eliminate AMR. However, most CS networks described so far emerge as a consequence of chromosomal mutations and cannot be leveraged to tackle mobile AMR. Here, we dissected the CS response elicited by the acquisition of a prevalent antibiotic resistance plasmid to reveal that the expression of the β-lactamaseblaOXA-48induces CS to colistin and azithromycin. We next showed that expression of other clinically relevant mobile β-lactamases produces similar CS responses in multiple, phylogenetically unrelatedE. colistrains. Finally, by combining experiments with surveillance data comprising thousands of antibiotic susceptibility tests, we showed that β-lactamase-induced CS is pervasive within Enterobacterales. These results highlight that the physiological side-effects of β-lactamases can be leveraged therapeutically, paving the way for the rational design of specific therapies to block mobile AMR or at least counteract their effects.
ChromaFactor: deconvolution of single-molecule chromatin organization with non-negative matrix factorization
Authors: Gunsalus Laura M. , Keiser Michael J. , Pollard Katherine S. 
Published: November 2023

AbstractThe investigation of chromatin organization in single cells holds great promise for identifying causal relationships between genome structure and function. However, analysis of single-molecule data is hampered by extreme yet inherent heterogeneity, making it challenging to determine the contributions of individual chromatin fibers to bulk trends. To address this challenge, we propose ChromaFactor, a novel computational approach based on non-negative matrix factorization that deconvolves single-molecule chromatin organization datasets into their most salient primary components. ChromaFactor provides the ability to identify trends accounting for the maximum variance in the dataset while simultaneously describing the contribution of individual molecules to each component. Applying our approach to two single-molecule imaging datasets across different genomic scales, we find that these primary components demonstrate significant correlation with key functional phenotypes, including active transcription, enhancer-promoter distance, and genomic compartment. ChromaFactor offers a robust tool for understanding the complex interplay between chromatin structure and function on individual DNA molecules, pinpointing which subpopulations drive functional changes and fostering new insights into cellular heterogeneity and its implications for bulk genomic phenomena.
Efficacy of an oral lipid nanocrystal (LNC) formulation of amphotericin B (MAT2203) in the neutropenic mouse model of pulmonary mucormycosis
Authors: Gu Yiyou , Gebremariam Teclegiorgis , Alkhazraji Sondus , Youssef Eman , El-Gamal Sabrina , Matkovits Theresa , Cobb Jenel , Mannino Raphael , Ibrahim Ashraf S. 
Published: November 2023

AbstractInvasive mucormycosis (IM) is associated with high mortality and morbidity and commonly afflicts patients with weakened immune systems. MAT2203 is an orally administered lipid nanocrystal (LNC) formulation of amphotericin B, which has been shown to be safe and effective against other fungal infections. We sought to compare the efficacy of MAT2203 to liposomal amphotericin B (LAMB) treatment in a neutropenic mouse model of IM due toR. arrhizusvar.delemarorMucor circinelloides f. jensseniiDI15-131. Treatment with placebo (diluent control), oral MAT2203 administered as BID and QD or intravenous LAMB for 4 days, began 16 h post infection and continued for 7 and 4 days, respectively. Survival through Day +21 and tissue fungal burden of lung or brain in animals euthanized on Day +4 served as a primary and secondary endpoint, respectively. In both infection types, MAT2203 was as effective as LAMB in prolonging median survival time (MST) and enhancing overall survivalvs.placebo-treated mice (P<0.05 by Log-Rank). Furthermore, both MAT2203 and LAMB treatment resulted in significant ∼1.0-1.5-log reduction and ∼2.0-2.2-login R. delemarorM. circinelloideslung and brain burden,vs.placebo mice, respectively. These results support the potential efficacy of oral MAT2203 as an alternative to LAMB. Continued investigation and development of this novel oral formulation of the amphotericin B for the treatment of mucormycosis is warranted.