bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Novel, Robust, and Portable Platform for Magnetoencephalography using Optically Pumped Magnetometers
Authors: Schofield Holly , Hill Ryan M. , Feys Odile , Holmes Niall , Osborne James , Doyle Cody , Bobela David , Corvilian Pierre , Wens Vincent , Rier Lukas , Bowtell Richard , Ferez Maxime , Mullinger Karen J. , Coleman Sebastian , Rhodes Natalie , Rea Molly , Tanner Zoe , Boto Elena , de Tiège Xavier , Shah Vishal , Brookes Matthew J. 
Published: March 2024

ABSTRACTMagnetoencephalography (MEG) measures brain function via assessment of magnetic fields generated by neural currents. Conventional MEG uses superconducting sensors, which place significant limitations on performance, practicality, and deployment; however, the field has been revolutionised in recent years by the introduction of optically-pumped-magnetometers (OPMs). OPMs enable measurement of the MEG signal without cryogenics, and consequently the conception of ‘OPM-MEG’ systems which ostensibly allow increased sensitivity and resolution, lifespan compliance, free subject movement, and lower cost. However, OPM-MEG remains in its infancy with limitations on both sensor and system design. Here, we report a new OPM-MEG design with miniaturised and integrated electronic control, a high level of portability, and improved sensor dynamic range (arguably the biggest limitation of existing instrumentation). We show that this system produces equivalent measures when compared to an established instrument; specifically, when measuring task-induced beta-band, gamma-band and evoked neuro-electrical responses, source localisations from the two systems were highly comparable and temporal correlation was >0.7 at the individual level and >0.9 for groups. Using an electromagnetic phantom, we demonstrate improved dynamic range by running the system in background fields up to 8 nT. We show that the system is effective in gathering data during free movement (including a sitting-to-standing paradigm) and that it is compatible with simultaneous electroencephalography (EEG – the clinical standard). Finally, we demonstrate portability by moving the system between two laboratories. Overall, our new system is shown to be a significant step forward for OPM-MEG technology and offers an attractive platform for next generation functional medical imaging.
Principles of chromosome organization for meiotic recombination
Authors: Biot Mathilde , Toth Attila , Brun Christine , Guichard Leon , Massy Bernard de , Grey Corinne 
Published: March 2024

SUMMARYIn meiotic cells, chromosomes are organized as chromatin loop arrays anchored to a protein axis. This organization is essential to regulate meiotic recombination, from DNA double-strand break (DSB) formation to their repair1. In mammals, it is unknown how chromatin loops are organized along the genome and how proteins participating in DSB formation are tethered to the chromosome axes. Here, we identified three categories of axis-associated genomic sites: PRDM9 binding sites, where DSBs form2, binding sites of the insulator protein CTCF, and H3K4me3-enriched sites. We demonstrated that PRDM9 promotes the recruitment of MEI4 and IHO1, two proteins essential for DSB formation3,4. In turn, IHO1 anchors DSB sites to the axis components HORMAD1 and SYCP3. We discovered that IHO1, HORMAD1 and SYCP3 are associated at the DSB ends during DSB repair. Our results highlight how interactions of proteins with specific genomic elements shape the meiotic chromosome organization for recombination.
Interleaved intersectional strategy enables genetic lineage tracing with enhanced specificity
Authors: Han Maoying , Liu Zhicong , Huang Xiuzhen , Liu Lei , Zhou Bo , Lui Kathy O. , Shu Qiang , Zhou Bin 
Published: March 2024

ABSTRACTBACKGROUNDDual recombinases have been increasingly employed for enhanced precision in genetic targeting. A recent study utilizing an intersectional genetic approach through dual recombinases (Dre + CreER) has revealed that endocardium-derived fibroblasts (EndoFbs) play a pivotal role in cardiac fibrosis after pressure overload. However, this intersectional strategy has limitations, primarily due to ectopic genetic labeling of non-target cells within the adult heart by the constitutively active Dre recombinase.METHODSTo address this issue, we have developed an advanced, interleaved and intersectional reporter (IIR) strategy in this study. This IIR strategy leverages an inducible CreER to prevent inadvertent Dre-rox recombination during development or disease progression by designing an interleaved reporter to allow for more specific tracing of EndoFbs. Moreover, our IIR system also incorporates Diphtheria Toxin Receptor (DTR) in targeted cells, enabling functional characterization of these cells after genetic ablation.RESULTSEndoFbs were regionally distributed in the heart during homeostasis and proliferated preferentially in response to pressure overload, leading to cardiac fibrosis in defined regions. The IIR strategy enables the tracing of EndoFbs with a more prominent regional pattern and facilitates genetic ablation of EndoFbs through DT injection. In addition, we have applied this IIR strategy to specifically target fibroblasts derived from the epicardium (EpiFbs). Genetic lineage tracing of EpiFb reveals that their distribution pattern is complementary to that of EndoFbs in the adult heart. When a substantial number of EpiFbs were genetically ablated, EndoFbs could replace the loss of EpiFbs in some specific regions of hearts.CONCLUSIONSThe IIR strategy refines the precision of genetic lineage tracing while still employing the constitutively active Dre recombinase in tandem with inducible Cre. EndoFbs and EpiFbs are complementary in their distribution pattern in the heart, where EndoFbs have the potential to replace the loss of EpiFbs in some regions.
Deletion of RFX6, a Diabetes-Associated Gene, Impairs iPSC-Derived Islet Organoid Development and Survival, With No Impact on the Generation of PDX1+/NKX6.1+ Progenitors
Authors: Aldous Noura , Elsayed Ahmed K. , Memon Bushra , Ijaz Sadaf , Hayat Sikander , Abdelalim Essam M. 
Published: March 2024

AbstractRFX6 is essential for pancreatic development and insulin secretion, while its role in diabetes pathogenesis is unclear. Here, RFX6 expression was detected in PDX1+ cells in the hESC-derived posterior foregut (PF). However, in the pancreatic progenitors (PPs), RFX6 did not co-localize with PDX1 and NKX6.1, but instead with NEUROG3, NKX2.2, and islet hormones in the endocrine progenitor (EPs) and islets. Single-cell analysis revealed high RFX6 expression in endocrine clusters across various hESC-derived pancreatic differentiation stages. Upon differentiating iPSCs lacking RFX6 into pancreatic islets, a significant decrease in PDX1 expression at the PF stage was observed, although it did not affect PPs co-expressing PDX1 and NKX6.1. RNA sequencing showed the downregulation of essential genes involved in pancreatic endocrine differentiation, insulin secretion, and ion transport due to RFX6 deficiency. Furthermore, RFX6 deficiency resulted in the formation of smaller islet organoids due to increased cellular apoptosis, linked to reduced Catalase (CAT) expression, implying a protective role for RFX6. Overexpression of RFX6 reversed defective phenotypes in PPs and EPs. These findings suggest that pancreatic hypoplasia and reduced islet cell formation associated with RFX6 mutations are not due to alterations in PDX1+/NKX6.1+ PPs but instead result from cellular apoptosis and downregulation of pancreatic endocrine genes.
Mechanisms underlying the loss of migratory behaviour in a long-lived bird
Authors: Andrade Pedro , Franco Aldina M. A. , Acácio Marta , Afonso Sandra , Marques Cristiana I. , Moreira Francisco , Carneiro Miguel , Catry Inês 
Published: March 2024

ABSTRACTHuman-induced environmental changes are shifting the migration patterns of birds worldwide. Species are adjusting migration timings, shortening and diversifying migratory routes, or even completely disrupting migration and transitioning towards residency. Whilst the ultimate causes driving changes in migratory patterns are well established, the underlying mechanisms by which migratory species adapt to environmental change remain unclear.Here, we studied the mechanisms driving the recent and rapid loss of migratory behaviour in Iberian white storksCiconia ciconia, a long-lived and previously fully migratory species through the African-Eurasian flyway. We combined 25 years of census data, GPS-tracking data from 213 individuals (80 adults and 133 first-year juveniles) followed for multiple years, and whole-genome sequencing, to disentangle whether within- (phenotypic flexibility) or between- (developmental plasticity or microevolution, through selection) individual shifts in migratory behaviour over time can explain the observed population-level changes towards residency.Between 1995 and 2020, the proportion of individuals no longer migrating and remaining in Southern Europe year-round increased dramatically, from 18% to 68-83%. We demonstrate that this behavioural shift is likely explained by developmental plasticity. Within first-year birds, 98% crossed the Strait of Gibraltar towards their African wintering grounds, in Morocco or Sub-Saharan Africa. However, the majority shifted towards a non-migratory strategy as they aged - the proportion of migrants decreased to 67% and 33%, on their second and third year of life, respectively - suggesting that migratory behaviour is determined during ontogeny. Supporting these findings, only 19% of GPS-tracked adults migrated. Moreover, we did not find evidence of phenotypic flexibility, as adults were highly consistent in migratory behaviour over multiple years (only 3 individuals changed strategy between years, out of 113 yearly transitions), nor of selection acting on genetic variation, since genomes of migrants and residents are essentially undifferentiated.Our results suggest that through developmental plasticity, traits that are plastic during specific windows of development, become fixed during adulthood. Thus, inter-generational shifts in the frequency of migratory and non-migratory young individuals could drive population changes in migratory behaviour. This can provide a fast mechanism for long-lived migratory birds to respond to rapid human-driven environmental changes.
Prediction of Aggregation Prone Regions in Proteins Using Deep Neural Networks and Their Suppression by Computational Design
Authors: Cima Vojtech , Kunka Antonin , Grakova Ekaterina , Planas-Iglesias Joan , Havlasek Martin , Subramanian Madhumalar , Beloch Michal , Marek Martin , Slaninova Katerina , Damborsky Jiri , Prokop Zbynek , Bednar David , Martinovic Jan 
Published: March 2024

AbstractProtein aggregation is a hallmark of multiple neurodegenerative diseases and a great hindrance in recombinant protein production, handling, and storage. Identification of aggregation prone residues or regions (APRs) in proteins and their suppression by mutations is a powerful and straightforward strategy for improving protein solubility and yield, which significantly increases their application potential. Towards this, we developed a deep neural network based predictor that generates residue level aggregation profile for one or several input protein sequences. The model was trained on a set of hexapeptides with experimentally characterised aggregation propensities and validated on two independent sets of data including hexapeptides and full-length proteins with annotated APRs. In both cases, the model matched, or outperformed the state-of-the-art algorithms. Its performance was further verified using a set of 34 hexapeptides identified in model haloalkane dehalogenase LinB and seven proteins from AmyPro database. The experimental data from Thioflavin T fluorescence and transmission electron microscopy matched the predictions in 79% of the cases, and revealed inaccuracies in the database annotations. Finally, the utility of the algorithm was demonstrated by identifying APRs in a model enzyme (LinB) and designing aggregation-suppressing mutations in the exposed regions. The designed variants showed reduced aggregation propensity, increased solubility and improved yield, with up to a 100% enhancement compared to the wild type for the best one.
Buzz-world: Global patterns and drivers of buzzing bees and poricidal plants
Authors: Russell Avery L. , Buchmann Stephen L. , Ascher John S. , Wang Zhiheng , Kriebel Ricardo , Jolles Diana D. , Orr Michael C. , Hughes Alice C. 
Published: March 2024

SUMMARYForaging behavior frequently plays a major role in driving the geographic distribution of animals. Buzzing to extract protein-rich pollen from flowers is a key foraging behavior used by bee species across at least 83 genera (these genera comprise ∼58% of all bee species). Although buzzing is widely recognized to affect the ecology and evolution of bees and flowering plants (e.g., buzz-pollinated flowers), global patterns and drivers of buzzing bee biogeography remain unexplored. Here, we investigate the global species distribution patterns within each bee family and how patterns and drivers differ with respect to buzzing bee species. We found that both distributional patterns and drivers of richness typically differed for buzzing species compared to hotspots for all bee species and when grouped by family. A major predictor of the distribution, but not species richness overall for buzzing members of four of the five major bee families included in analyses (Andrenidae, Halictidae, Colletidae and to a lesser extent, Apidae) was the richness of poricidal flowering plant species, which depend on buzzing bees for pollination. As poricidal plant richness was highest in areas with low wind and high aridity, we discuss how global hotspots of buzzing bee biodiversity are likely driven by both biogeographic factors and plant host availability. Whilst we explored global patterns with State-level data, higher resolution work is needed to explore local level drivers of patterns, but from a global perspective, buzz-pollinated plants clearly play a greater role in the ecology and evolution of buzzing bees than previously predicted.
Pharmacological inhibition of macrophage triglyceride biosynthesis pathways does not improveMycobacterium tuberculosiscontrol in infected mice
Authors: Castillo Jennie Ruelas , Guerrini Valentina , Quijada Darla , Karanika Styliani , Neupane Pranita , Harris Harley , Garcia Andrew , Shenkoya Babajide , Yilma Addis , Bailey Hannah , Khan Rehan , Gopalakrishnan Mathangi , Gennaro Maria L. , Karakousis Petros C. 
Published: March 2024

AbstractTriglyceride rich macrophages (foam cells) are a hallmark of necrotic granulomas in tuberculosis, and multiple antimicrobial functions are down-regulated in these cells. In this study, we assessed the ability of two different compounds to reduce triglyceride content and intracellular burden inMycobacterium tuberculosis(Mtb)-infected macrophages: A-922500 (DGATi), an inhibitor of diacylglycerol acyltransferase 1, an enzyme involved in triglyceride synthesis; and LY2584702 (p70S6Ki), an inhibitor of p70 S6 kinase, a serine/threonine kinase involved in mTORC-1dependent lipid biogenesis. Additionally, we evaluated the adjunctive activity of these inhibitors as host-directed therapies against chronic Mtb infection in C3HeB/FeJ mice. DGATi and p70S6Ki significantly reduced the lipid content and bacillary burden in Mtb-infected human monocyte-derived macrophages. In Mtb-infected mice, each inhibitor reduced the triglyceride content (P≤ 0.0001) in cells from bronchoalveolar lavage samples. Adjunctive treatment of DGATi with isoniazid and p70S6Ki monotherapy reduced the lipid droplet content (P≤ 0.05) within lung macrophages of Mtb-infected mice. However, neither inhibitor reduced the lung bacterial burden in Mtb-infected mice alone or in combination with isoniazid, and they did not alter lung inflammation. These findings provide further insights into the role of foam cells in tuberculosis pathogenesis and the utility of interventions targeting these cell populations as adjunctive host-directed therapies.
MegaLMM improves genomic predictions in new environments using environmental covariates
Authors: Hu Haixiao , Rincent Renaud , Runcie Daniel E. 
Published: March 2024

ABSTRACTMulti-environment trials (METs) are crucial for identifying varieties that perform well across a target population of environments (TPE). However, METs are typically too small to sufficiently represent all relevant environment-types, and face challenges from changing environment-types due to climate change. Statistical methods that enable prediction of variety performance for new environments beyond the METs are needed. We recently developed MegaLMM, a statistical model that can leverage hundreds of trials to significantly improve genetic value prediction accuracy within METs. Here, we extend MegaLMM to enable genomic prediction in new environments by learning regressions of latent factor loadings on Environmental Covariates (ECs) across trials. We evaluated the extended MegaLMM using the maize Genome-To-Fields dataset, consisting of 4402 varieties cultivated in 195 trials with 87.1% of phenotypic values missing, and demonstrated its high accuracy in genomic prediction under various breeding scenarios. Furthermore, we showcased MegaLMM’s superiority over univariate GBLUP in predicting trait performance of experimental genotypes in new environments. Finally, we explored the use of higher-dimensional quantitative ECs and discussed when and how detailed environmental data can be leveraged for genomic prediction from METs. We propose that MegaLMM can be applied to plant breeding of diverse crops and different fields of genetics where large-scale linear mixed models are utilized.
Reactive microglia fail to respond to environmental damage signals in a viral-induced mouse model of temporal lobe epilepsy
Authors: Wallis Glenna J. , Bell Laura A. , Wagner John N. , Buxton Lauren , Balachandar Lakshmini , Wilcox Karen S. 
Published: March 2024

AbstractMicroglia are highly adaptable innate immune cells that rapidly respond to damage signals in the brain through adoption of a reactive phenotype and production of defensive inflammatory cytokines. Microglia express a distinct transcriptome, encoding receptors that allow them to dynamically respond to pathogens, damage signals, and cellular debris. Expression of one such receptor, the microglia-specific purinergic receptorP2ry12, is known to be downregulated in reactive microglia. Here, we explore the microglial response to purinergic damage signals in reactive microglia in the TMEV mouse model of viral brain infection and temporal lobe epilepsy. Using two-photon calcium imaging in acute hippocampal brain slices, we found that the ability of microglia to detect damage signals, engage calcium signaling pathways, and chemoattract towards laser-induced tissue damage was dramatically reduced during the peak period of seizures, cytokine production, and infection. Using combined RNAscopein situhybridization and immunohistochemistry, we found that during this same stage of heightened infection and seizures, microglialP2ry12expression was reduced, while the pro-inflammatory cytokineTNF-aexpression was upregulated in microglia, suggesting that the depressed ability of microglia to respond to new damage signals viaP2ry12occurs during the time when local elevated cytokine production contributes to seizure generation following infection. Therefore, changes in microglial purinergic receptors during infection likely limit the ability of reactive microglia to respond to new threats in the CNS and locally contain the scale of the innate immune response in the brain.
Cell-cycle and Age-Related Modulations of Mouse Chromosome Stiffness
Authors: Liu Ning , Qiang Wenan , Jordan Philip , Marko John F , Qiao Huanyu 
Published: March 2024

AbstractChromosome structure is complex, and many aspects of its organization remain poorly understood. Measuring chromosome stiffness offers valuable insight into their structural properties. In this study, we analyzed the stiffness of chromosomes from metaphase I (MI) and metaphase II (MII) oocytes. Our results revealed a ten-fold increase in stiffness (Young’s modulus) of MI chromosomes compared to somatic chromosomes. Furthermore, the stiffness of MII chromosomes was lower than that of MI chromosomes. We examined the role of meiosis-specific cohesin complexes in regulating chromosome stiffness. Surprisingly, chromosomes from three meiosis-specific cohesin mutants exhibited stiffness comparable to that of wild-type chromosomes, indicating that these cohesins are not the primary determinants of chromosome stiffness. Additionally, our findings revealed an age-related increase in chromosome stiffness in MI oocytes. Since aging is associated with elevated levels of DNA damage, we investigated the impact of etoposide-induced DNA damage on oocyte chromosome stiffness and found that it led to a reduction in MI chromosome stiffness. Overall, our study underscores the dynamic and cyclical nature of chromosome stiffness, modulated by both the cell cycle and age-related factors.
Constitutive immune surveillance of nasal mucosa by three neutrophil subsets with distinct origin, phenotype, and function
Authors: Gonzalez Rodrigo J. , Hanč Pavel , Alvarez David , Kazer Samuel W. , Messou Marie-Angele , Mazo Irina B. , Matysiak Match Colette , Garg Rohit , Helble Jennifer D. , Pallis Paris , Ende Rachel , Basset Alan , Malley Rick , Derre Isabelle , Starnbach Michael N. , von Andrian Ulrich H. 
Published: March 2024

ABSTRACTThe nasal mucosa (NM) has several critical functions, including as a chemosensory organ, as a filter and conditioning surface of inhaled air for the lower airways, and as a first line of defense against airborne infections. Owing to its constant exposure to ever-changing environments, the NM is arguably the most frequently infected tissue in mammals. Consequently, vertebrates harbor an intricate network of subepithelial immune cells that are dispersed throughout the NM. However, the origin, composition, and function of nasal immune cells and their pathophysiological role are poorly understood. Here, we show that murine steady-state NM harbors a prominent population of extravascular neutrophils (EVN) that are abundant in both conventional and germ-free mice, suggesting that their presence is not driven by microbial stimuli. Nasal EVN can be subdivided into three phenotypically distinct subsets: one population that we have termed nN1 is CD11bintLy6Gint, while the other two subsets are both CD11bhiLy6Ghiand distinguishable by the absence (nN2) or presence (nN3) of CD11c and SiglecF. nN1 EVN originate in bone marrow (BM) within osseous structures in the skull. These locally produced neutrophils appear to access the adjacent NM via conduits that connect BM cavities to the submucosal lamina propria. nN2 cells reach the NM via the blood and readily engulf infectious microbes. In the absence of infection, nN2 cells differentiate into the nN3 subset, which does not capture microbes but assumes phenotypic and functional features of antigen-presenting cells, including the capacity to cross-present exogenous antigens to CD8 T cells. These findings indicate that steady-state mammalian NM harbors a unique innate cellular immune environment that is unlike any other barrier tissue.