bluuebunny/crossref_metadata_2025 huggingface dataset:
Dynamics of aqueous suspension of short Hyaluronic acid chains near DPPC bilayer
Authors: PAUL ANIRBAN , Chakrabarti Jaydeb
Published: February 2024

The synergy between Hyaluronic acid (HA) and lipid molecules plays a crucial role in synovial fluids, cell coatings, etc. Diseased cells in cancer and arthritis, show changes in HA concentration and chain size, impacting the viscoelastic and mechanical properties of the cells. Although the solution behavior of HA is known in experiments, a molecular-level understanding of the role of HA on the dynamics at the interface of HA-water and the cellular boundary is lacking. Here we perform atomistic molecular dynamics simulation of short HA chains in explicit water solvent in presence of DPPC bilayer, relevant in pathological cases. We identify a stable interface between HA-water and the bilayer where the water molecules are in contact with the bilayer and the HA chains are located away without any direct contact. Both translation and rotation of the interfacial waters in contact with the lipid bilayer and translation of the HA chains exhibit subdiffusive behavior. The diffusive behavior sets in slightly away from the bilayer, where the diffusion coefficients of water and HA decrease monotonically with increase in HA concentration. On the contrary, the dependence on HA chain size is only marginal due to enhanced chain flexibility as their size increases.
A novel pyridoindole improves the recovery of residual hearing following cochlear implantation after a single preoperative application
Authors: Nieratschker Michael , Yildiz Erdem , Gerlitz Matthias , Bera Sujoy , Gadenstaetter Anselm J. , Kramer Anne-Margarethe , Kwiatkowska Monika , Mistrik Pavel , Landegger Lukas D. , Braun Susanne , Schlingensiepen Reimar , Honeder Clemens , Arnoldner Christoph , Rommelspacher Hans
Published: February 2024

Sensorineural hearing loss (SNHL) is the most common sensory deficit worldwide. Due to the heterogeneity of causes for SNHL, effective treatment options remain scarce, creating an unmet need for novel drugs in the field of otology. Cochlear implantation (CI) currently is the only established method to restore hearing function in profound SNHL and deaf patients. The cochlear implant bypasses the non-functioning sensory hair cells (HCs) and electrically stimulates the neurons of the cochlear nerve. CI also benefits patients with residual hearing by combined electrical and auditory stimulation. However, the insertion of an electrode array into the cochlea induces an inflammatory response, characterized by the expression of pro-inflammatory cytokines, upregulation of reactive oxygen species, and apoptosis and necrosis of HCs, putting residual hearing at risk. Here, we characterize the effects of the small molecule AC102, a pyridoindole, for its protective effects on residual hearing in CI. We show that AC102 significantly preserves hearing thresholds across the whole cochlea and confines the cochlear trauma to the directly mechanically injured area. In addition, AC102 significantly preserves auditory nerve fibers and inner HC synapses throughout the whole cochlea. AC102s effects are likely elicited during the inflammatory phase of electrode insertion trauma (EIT) and mediated by anti-apoptotic and anti-inflammatory properties, as uncovered by an in vitro assay of ethanol induced apoptosis and evaluation of mRNA expression of pro-inflammatory cytokines in an organotypic ex vivo model of EIT. The results in this study highlight AC102 as a promising compound for the attenuation of EIT during CI. Moreover, as the inflammatory response in cochlear implantation shares similarities to other etiologies of SNHL, a beneficial effect of AC102 can be inferred for other inner ear conditions as well.
Adaptive diversification through structural variation in barley
Authors: Jayakodi Murukarthick , Lu Qiongxian , Pidon Helene , Rabanus-Wallace M. Timothy , Bayer Micha , Lux Thomas , Guo Yu , Jaegle Benjamin , Badea Ana , Bekele Wubishet , Brar Gurcharn , Braune Katarzyna , Bunk Boyke , Chalmers Kenneth , Chapman Brett , Jorgensen Morten Egevang , Feng Jia-Wu , Feser Manuel , Fiebig Anne , Gundlach Heidrun , Guo Wenbin , Haberer Georg , Hansson Mats , Himmelbach Axel , Hoffie Iris , Hoffie Robert , Hu Haifei , Isobe Sachiko , Koenig Patrick , Kale Sandip , Kamal Nadia , Keeble-Gagnere Gabriel , Keller Beat , Knauft Manuela , Koppolu Ravi , Krattinger Simon , Kumlehn Jochen , Langridge Peter , Li Chengdao , Marone Marina , Maurer Andreas , Mayer Klaus , Melzer Michael , Muehlbauer Gary , Murozuka Emiko , Padmarasu Sudharsan , Perovic Dragan , Pillen Klaus , Pin Pierre , Pozniak Curtis , Ramsay Luke , Pedas Pai Rosager , Rutten Twan , Sakuma Shun , Sato Kazuhiro , Schueler Danuta , Schmutzer Thomas , Scholz Uwe , Schreiber Miriam , Shirasawa Kenta , Simpson Craig , Skadhauge Birgitte , Spannagl Manuel , Steffenson Brian , Thomsen Hanne , Tibbits Josquin , Nielsen Martin Toft Simmelsgaard , Trautewig Corinna , Vequaud Dominique , Voss Cynthia , Wang Penghao , Waugh Robbie , Westcott Sharon , Rasmussen Magnus Wohlfahrt , Zhang Runxuan , Zhang Xiao-Qi , Wicker Thomas , Dockter Christoph , Mascher Martin , Stein Nils
Published: February 2024

Pangenomes are collections of annotated genome sequences of multiple individuals of a species. The structural variants uncovered by these datasets are a major asset to genetic analysis in crop plants. Here, we report a pangenome of barley comprising long-read sequence assemblies of 76 wild and domesticated genomes and short-read sequence data of 1,315 genotypes. An expanded catalogue of sequence variation in the crop includes structurally complex loci that have become hot spots of gene copy number variation in evolutionarily recent times. To demonstrate the utility of the pangenome, we focus on four loci involved in disease resistance, plant architecture, nutrient release, and trichome development. Novel allelic variation at a powdery mildew resistance locus and population-specific copy number gains in a regulator of vegetative branching were found. Expansion of a family of starch-cleaving enzymes in elite malting barleys was linked to shifts in enzymatic activity in micro-malting trials. Deletion of an enhancer motif is likely to change the developmental trajectory of the hairy appendages on barley grains. Our findings indicate that rapid evolution at structurally complex loci may have helped crop plants adapt to new selective regimes in agricultural ecosystems.
The freeze-avoiding mountain pine beetle (Dendroctonus ponderosae) survives prolonged exposure to stressful cold by mitigating ionoregulatory collapse
Authors: Andersen Mads Kuhlmann , Roe Amanda Diane , Liu Alice (Yuehong) , Musso Antonia E , Fudlosid Serita , Haider Fouzia , Evenden Maya L , MacMillan Heath A.
Published: February 2024

Insect performance is intrinsically linked to environmental temperature, and surviving through winter represents a key challenge for temperate, alpine, and polar species. To overwinter, insects have adapted a wide range of strategies to become truly cold hardy. However, while the physiological mechanisms underlying the ability to avoid or tolerate freezing have been well-studied, little attention has been given to the challenge of maintaining ion homeostasis at frigid temperatures in these species, despite this being a central issue for insects susceptible to mild chilling. Here we investigate how prolonged exposure to temperatures just above the supercooling point affects ion balance in freeze-avoiding larvae of the mountain pine beetle (Dendroctonus ponderosae) in autumn, mid-winter, and spring, and relate it to organismal recovery times and survival outcomes. We found that hemolymph ion balance was gradually disrupted during the first day of exposure, characterized by hyperkalemia and hyponatremia, after which a plateau was reached and maintained for the rest of the seven day experiment. The degree of ionoregulatory collapse experienced by larvae correlated strongly with recovery times, which followed a similar asymptotical progression. Mortality increased slightly during the most severe cold exposures, where hemolymph K+ concentration was highest, and a logistic relationship was found between survival and hyperkalemia. Thus, the cold tolerance of the freeze-avoiding larvae of D. ponderosae appears limited by the ability to prevent ionoregulatory collapse in a manner similar to less tolerant chill-susceptible insects, albeit at much lower temperatures. Furthermore, we posit that a prerequisite for the evolution of insect freeze avoidance is a convergent or ancestral ability to maintain ion homeostasis during exposure to extreme cold stress.
Aerobic exercise promotes PDAC vascular normalization through S1PR1 signaling in tumor endothelial cells
Authors: Ballarò Riccardo , Pareek Sumedha , Lee Jonghae , Patel Hetal , Tirumala Priya , Liu Guanshu , Hayek Karma , Savage Hannah , Guerrouahen Bella , Ngo-Huang An , Parker Nathan , Katz Matthew HG , Petzel Maria , McAllister Florencia , Wright Robin , Tan Lin , Lorenzi Philip L , Schadler Keri
Published: February 2024

Pancreatic Ductal Adenocarcinoma (PDAC) is characterized by high resistance to anti-cancer therapies. This resistance is caused in part by hypo-vascularization and dysfunctional vessels which inefficiently deliver chemotherapy. Here, we define the mechanism of aerobic exercise-induced tumor vascular remodeling and improved chemotherapy delivery and efficacy. We found that aerobic exercise was able to improve tumor vascular function and increase the number of lymphatic vessels, and these effects were associated with increased gemcitabine delivery to and efficacy against PDAC in mice. Further, exercise increased sphingosine-1-phosphate (S1P) in plasma and the activation of sphingosine-1-phosphate receptor 1 (S1PR1) in tumor endothelial cells. S1PR1 endothelial cell-specific deletion blunted the exercise-induced improvements in tumor vascular function, gemcitabine efficacy and drug concentration. Preclinical findings were validated in a patient cohort in which we found that exercise remodeled PDAC vasculature and improved tumor vascular function. These findings provide direct evidence that exercise increases chemotherapy delivery and efficacy by improving vascular function, defining S1PR1 as a necessary mediator of exercise-induced vascular remodeling.
Dynamic medial parietal and hippocampal deactivations under DMT relate to sympathetic output and altered sense of time, space, and the self
Authors: Pasquini Lorenzo , Simon Alexander J. , Gallen Courtney L. , Kettner Hannes , Roseman Leor , Gazzaley Adam , Carhart-Harris Robin L. , Timmermann Christopher
Published: February 2024

N,N-Dimethyltryptamine (DMT) is a serotonergic psychedelic, known to rapidly induce short-lasting alterations in conscious experience, characterized by a profound and immersive sense of physical transcendence alongside rich and vivid auditory distortions and visual imagery. Multimodal neuroimaging data paired with dynamic analysis techniques offer a valuable approach for identifying unique signatures of brain activity – and linked autonomic physiology – naturally unfolding during the altered state of consciousness induced by DMT. We leveraged simultaneous fMRI and EKG data acquired in 14 healthy volunteers prior to, during, and after intravenous administration of DMT, and, separately, placebo. fMRI data was preprocessed to derive individual dynamic activity matrices, reflecting the similarity of brain activity in time, and community detection algorithms were applied on these matrices to identify brain activity substates; EKG data was used to derive continuous heart rate. We identified a brain substate occurring immediately after DMT injection, characterized by hippocampal and medial parietal deactivations and increased superior temporal lobe activity under DMT. Deactivations in the hippocampus and medial parietal cortex correlated with alterations in the usual sense of time, space and self-referential processes, reflecting a deconstruction of essential features of ordinary consciousness. Superior lobe activations instead correlated with audio/visual hallucinations and experience of “entities”, reflecting the emergence of altered sensory experiences under DMT. Finally, increased heart rate under DMT correlated positively with hippocampus/medial parietal deactivation and the experience of “entities”, and negatively with altered self-referential processes. These results suggest a chain of influence linking sympathetic regulation to hippocampal and medial parietal deactivations under DMT, which combined, may contribute to positive mental health outcomes related to self-referential processing following psychedelic administration.
High-resolution single-particle imaging at 100-200 keV with the Gatan Alpine direct electron detector
Authors: Chan Lieza M. , Courteau Brandon J. , Maker Allison , Wu Mengyu , Basanta Benjamin , Mehmood Hevatib , Bulkley David , Joyce David , Lee Brian C. , Mick Stephen , Gulati Sahil , Lander Gabriel C. , Verba Kliment A.
Published: February 2024

Developments in direct electron detector technology have played a pivotal role in enabling high-resolution structural studies by cryo-EM at 200 and 300 keV. Yet, theory and recent experiments indicate advantages to imaging at 100 keV, energies for which the current detectors have not been optimized. In this study, we evaluated the Gatan Alpine detector, designed for operation at 100 and 200 keV. Compared to the Gatan K3, Alpine demonstrated a significant DQE improvement at these voltages, specifically a ~4-fold improvement at Nyquist at 100 keV. In single-particle cryo-EM experiments, Alpine datasets yielded better than 2 Å resolution reconstructions of apoferritin at 120 and 200 keV on a ThermoFisher Scientific (TFS) Glacios microscope. We also achieved a ~3.2 Å resolution reconstruction for a 115 kDa asymmetric protein complex, proving its effectiveness with complex biological samples. In-depth analysis revealed that Alpine reconstructions are comparable to K3 reconstructions at 200 keV, and remarkably, reconstruction from Alpine at 120 keV on a TFS Glacios surpassed all but the 300 keV data from a TFS Titan Krios with GIF/K3. Additionally, we show Alpine’s capability for high-resolution data acquisition and screening on lower-end systems by obtaining ~3 Å resolution reconstructions of apoferritin and aldolase at 100 keV and detailed 2D averages of a 55 kDa sample using a side-entry cryo holder. Overall, we show that Gatan Alpine performs well with the standard 200 keV imaging systems and may potentially capture the benefits of lower accelerating voltages, possibly bringing smaller sized particles within the scope of cryo-EM.
regLM: Designing realistic regulatory DNA with autoregressive language models
Authors: Lal Avantika , Garfield David , Biancalani Tommaso , Eraslan Gokcen
Published: February 2024

Cis-regulatory elements (CREs), such as promoters and enhancers, are DNA sequences that regulate the expression of genes. The activity of a CRE is influenced by the order, composition and spacing of sequence motifs that bind to proteins called transcription factors (TFs). Synthetic CREs with specific properties are needed for biomanufacturing as well as for many therapeutic applications including cell and gene therapy. Here, we present regLM, a framework to design synthetic CREs with desired properties, such as high, low or cell type-specific activity, using autoregressive language models in conjunction with supervised sequence-to-function models. We used our framework to design synthetic yeast promoters and cell type-specific human enhancers. We demonstrate that the synthetic CREs generated by our approach are not only predicted to have the desired functionality but also contain biological features similar to experimentally validated CREs. regLM thus facilitates the design of realistic regulatory DNA elements while providing insights into the cis-regulatory code.
Dual Targeting of STING and PI3Kγ Eliminates Regulatory B Cells to Overcome STING Resistance for Pancreatic Cancer Immunotherapy
Authors: LI Chengyi , Mao Shuai , Zhao Hongyi , He Miao , Wang Meilin , Liu Zhongwei , Wen Hanning , Yu Zhixin , Wen Bo , Djibo Mahamadou , Tao Jinsong , Bu Yingzi , Gao Wei , Sun Duxin
Published: February 2024

The immune suppression in tumors and lymph nodes of pancreatic ductal adenocarcinoma (PDAC), regulated by suppressive myeloid cells and regulatory B (Breg) cells, hinders the effectiveness of immunotherapy. Although STING agonists activate myeloid cells to overcome immune suppression, it expands Breg cells, conferring STING resistance in PDAC. We discovered that blocking PI3Kγ during STING activation abolished IRF3 phosphorylation to eliminate Breg cells, while PI3Kγ inhibition sustained STING-induced IRF3 phosphorylation to preserve STING function in myeloid cells. Therefore, we developed a dual functional compound SH-273 and its albumin nanoformulation Nano-273, which stimulates STING to activate myeloid cells and inhibits PI3Kγ to eliminates Breg cells overcoming STING resistance. Nano-273 achieved systemic antitumor immunity through intravenous administration, which decreases Breg cells and remodels microenvironment in tumors and lymph nodes. Nano-273, combined with anti-PD-1, extended median survival to 200 days in transgenic KPC PDAC mice (KrasG12D-P53R172H-Cre), offering potential for PDAC treatment.
Leveraging Transcriptomics-Based Approaches to Enhance Genomic Prediction: Integrating SNP weights and gene-networks for Cotton Fibre Quality Improvement
Authors: Khalilisamani Nima , Li Zitong , Pettolino Filomena , Moncuquet Philippe , Reverter Antonio , MacMillan Colleen P
Published: February 2024

The cotton genome (Gossypium hirsutum) contains ~80K protein-coding genes, making precision breeding for complex traits a challenge. This study tested biology-informed approaches to improve genomic prediction (GP) accuracy for cotton fibre traits to help accelerate precision breeding of valuable traits. The foundational approach was the use of RNA-seq data from key time points during fibre development, namely fibre cells undergoing primary, transition, and secondary wall development. The test approaches included using a range of summary statistics from RNA-seq analysis such as gene Differential Expression (DE). The three test approaches included DE genes overall, target pairwise DE lists informed by gene functional annotation, and finally, gene-network-clusters created based on Partial Correlation and Information Theory (PCIT) as the prior information in Bayesian GP models. The most promising improvements in GP accuracy were at the level of ~ 5% increase by using PCIT-based gene-network clusters as the prior knowledge network neighbours of key genes, and for the traits of cotton fibre Elongation and Strength. These results indicate that there is scope to help improve precision breeding of target traits by incorporating biology-based inference into GP models, and points to specific approaches to achieve this.
ACK1 and BRK non-receptor tyrosine kinase deficiencies are associated with familial systemic lupus and involved in efferocytosis
Authors: Guillet Stephanie , Lazarov Tomi , Jordan Natasha , Boisson Bertrand , Tello Maria , Craddock Barbara , Zhou Ting , Nishi Chihiro , Bareja Rohan , Yang Hairu , Rieux-Laucat Frederic , Lorenzo Rosa Irene Fregel , Dyall Sabrina D. , Isenberg David , D’Cruz David , Lachmann Nico , Elemento Olivier , Viale Agnes , Socci Nicholas D. , Abel Laurent , Nagata Shigekazu , Huse Morgan , Todd Miller W. , Casanova Jean-Laurent , Geissmann Frederic
Published: February 2024

Systemic Lupus Erythematosus (SLE) is an autoimmune disease, the pathophysiology and genetic basis of which are incompletely understood. Using a forward genetic screen in multiplex families with systemic lupus erythematosus (SLE) we identified an association between SLE and compound heterozygous deleterious variants in the non-receptor tyrosine kinases (NRTKs) ACK1 and BRK. Experimental blockade of ACK1 or BRK increased circulating autoantibodiesin vivoin mice and exacerbated glomerular IgG deposits in an SLE mouse model. Mechanistically, non-receptor tyrosine kinases (NRTKs) regulate activation, migration, and proliferation of immune cells. We found that the patients’ ACK1 and BRK variants impair efferocytosis, the MERTK-mediated anti-inflammatory response to apoptotic cells, in human induced Pluripotent Stem Cell (hiPSC)-derived macrophages, which may contribute to SLE pathogenesis. Overall, our data suggest that ACK1 and BRK deficiencies are associated with human SLE and impair efferocytosis in macrophages.

One sentence summary

Loss of function variants of human ACK1 and BRK kinase underlie systemic lupus erythematosus in young patients from multiplex families and disrupt the anti-inflammatory response of macrophages to apoptotic cells.
Body reconstruction and size estimation of plesiosaurs
Authors: Zhao Ruizhe Jackevan
Published: February 2024

Body size is the key to understanding many biological properties. Sizes of extinct animals are usually estimated from body reconstructions since their masses can not be weighed directly. Plesiosaurs were Mesozoic marine reptiles that were diverse in both body plan and size. Attempts to estimate body masses of plesiosaurs were rare in the past two centuries, possibly due to lack of knowledge about their postcranial anatomy and body shapes in life. The burst of plesiosaur studies in the past two decades has greatly expanded our cognition of their physiology, taxonomy, potential behavior and even soft body outlines. Here I present a comprehensive review of relevant knowledge, and propose a uniform set of methodology for rigorous body reconstruction of plesiosaurs. Twenty-two plesiosaur models were constructed under these criteria, and they were subsequently used as samples to find proxies for body mass. It is revealed that multiple skeletal elements are good indicators of plesiosaur size. This study offers scaling equations for size estimation, enabling quick acquisition of body mass information from fragmented fossils. A summary of body size evolution of different plesiosaur clades is also provided.
Metformin Enhances Antibody-Mediated Recognition of HIV-Infected CD4+ T-Cells by Decreasing Viral Release
Authors: Fert Augustine , Richard Jonathan , Raymond Marchand Laurence , Planas Delphine , Routy Jean-Pierre , Chomont Nicolas , Finzi Andres , Ancuta Petronela
Published: February 2024

The mechanistic target of rapamycin (mTOR) positively regulates multiple steps of the HIV-1 replication cycle. We previously reported that a 12-weeks supplementation of antiretroviral therapy (ART) with metformin, an indirect mTOR inhibitor used in type-2 diabetes treatment, reduced mTOR activation and HIV transcription in colon-infiltrating CD4+ T-cells, together with systemic inflammation in nondiabetic people with HIV-1 (PWH). Herein, we investigated the antiviral mechanisms of metformin. In a viral outgrowth assay performed with CD4+ T-cells from ART-treated PWH, and upon infection in vitro with replication-competent and VSV-G-pseudotyped HIV-1, metformin decreased virion release, but increased the frequency of productively infected CD4lowHIV-p24+ T-cells. These observations coincided with increased BST2/Tetherin (HIV release inhibitor) and Bcl-2 (pro-survival factor) expression, and improved recognition of productively infected T-cells by HIV-1 Envelope antibodies. Thus, metformin exerts pleiotropic effects on post-transcription/translation steps of the HIV-1 replication cycle and may be used to accelerate viral reservoir decay in ART-treated PWH.
Contributions of PD1 and PD2 to the [PD1PD2]+-minus-[PD1PD2] difference spectrum in the Soret region in Photosystem II
Authors: Boussac Alain , Sugiura Miwa , Nagao Ryo , Noguchi Takumi , Rutherford A. William , Sellés Julien
Published: February 2024

Flash-induced absorption changes in the Soret region, which originate from the [PD1PD2]+ state, the chlorophyll cation radical formed upon Photosystem II (PSII) excitation, were investigated in Mn-depleted Photosystem II. In wild-type PSII from Thermosynechococcus elongatus, the [PD1PD2]+-minus-[PD1PD2] difference spectrum shows a main negative feature at 434 nm and a smaller negative feature at 446 nm [Boussac et al. Photosynth Res (2023), https://doi.org/10.1007/s11120-023-01049-3]. While the main feature at 434 nm is associated with PD1+ formation, the origin of the dip at 446 nm remains to be identified. For that, we have compared the [PD1PD2]+-minus-[PD1PD2] difference spectra from the PsbA3/H198Q PSII mutant in T. elongatus and D2/H197A PSII mutant in Synechocystis sp. PCC 6803 with their respective wild type strains. By modifying the PD1 axial ligand with the H198Q mutation in the D1 protein in T. elongatus, the contribution at 434 nm was shifted to 431 nm, while the contribution at 446 nm was hardly affected. In Synechocystis sp. PCC 6803, by modifying the PD2 axial ligand with the H197A mutation in the D2 protein, the contribution at 446 nm was downshifted by approx. 3 nm to approx. 443 nm, while the main contribution at 432 nm was only slightly shifted upwards to 433 nm. This result suggests that the bleaching seen at 446 nm involves PD2. This could reflects a change in the [PD1+PD2]/[PD1PD2+] equilibrium or a more complex mechanism.
Emotional Content and Semantic Structure of Dialogues Are Associated With Interpersonal Neural Synchrony in the Prefrontal Cortex
Authors: Carollo Alessandro , Stella Massimo , Lim Mengyu , Bizzego Andrea , Esposito Gianluca
Published: February 2024

A fundamental characteristic of social exchanges is the synchronization of individuals’ behaviors, physiological responses, and neural activity. However, the association between how individuals communicate in terms of emotional content and expressed associative knowledge and interpersonal synchrony has been scarcely investigated so far. This study addresses this research gap by bridging recent advances in cognitive neuroscience data, affective computing, and cognitive data science frameworks. Using functional near-infrared spectroscopy (fNIRS) hyperscanning, prefrontal neural data were collected during social interactions involving 84 participants (i.e., 42 dyads) aged 18-35 years. Wavelet transform coherence was used to assess interpersonal neural synchrony between participants. We used manual transcription of dialogues and automated methods to codify transcriptions as emotional levels and syntactic/semantic networks. Our quantitative findings reveal higher than random expectations levels of interpersonal neural synchrony in the superior frontal gyrus (q= .038) and the bilateral middle frontal gyri (q<.001,q<.001). Linear mixed models based on dialogues’ emotional content only significantly predicted interpersonal neural synchrony across the prefrontal cortex. Conversely, models relying on syntactic/semantic features were more effective at the local level, for predicting brain synchrony in the right middle frontal gyrusGenerally, models based on the emotional content of dialogues were not effective when limited to data from one region of interest at a time, whereas models based on syntactic/semantic features show the opposite trend, losing predictive power when incorporating data from all regions of interest. Moreover, we found an interplay between emotions and associative knowledge in predicting brain synchrony, providing quantitative support to the major role played by these linguistic components in social interactions and in prefrontal processes. Our study identifies a mind-brain duality in emotions and associative knowledge reflecting neural synchrony levels, opening new ways for investigating human interactions.
A biodegradable microgrooved and tissue mechanocompatible citrate-based scaffold improves bladder tissue regeneration
Authors: Goedegebuure Madeleine , Bury Matthew , Wang Xinlong , San Felice Pasquale , Cammarata Federico , Wang Larry , Sharma Tiffany , Rajinikanth Nachiket , Karra Vikram , Siddha Vidhika , Sharma Arun , Ameer Guillermo
Published: February 2024

Chronic bladder dysfunction due to bladder disease or trauma is detrimental to affected patients as it can lead to increased risk of upper urinary tract dysfunction. Current treatment options include surgical intervention that enlarge the bladder with autologous bowel tissue to alleviate pressure on the upper urinary tract. This highly invasive procedure, termed bladder augmentation enterocystoplasty (BAE), significantly increases risk of patient morbidity and mortality due to the incompatibility between the bowel and bladder tissue. Therefore, patients would significantly benefit from an alternative treatment strategy that can regenerate healthy tissue and restore overall bladder function. Previous research has demonstrated the potential of citrate-based scaffolds co-seeded with bone marrow-derived stem/progenitor cells as an alternative graft for bladder augmentation. Recognizing that contact guidance is known to influence tissue regeneration, we hypothesized that patterned scaffolds would modulate cell responses and improve overall quality of the regenerated bladder tissue. We fabricated microgrooved (MG) scaffolds using citrate-based biomaterial poly(1,8-octamethylene-citrate-co-octanol) (POCO) and co-seeded them with human bone marrow derived mesenchymal stem cells (MSCs) and CD34+ hematopoietic stem/progenitor cells (HSPCs). Microgrooved POCO scaffolds supported MSC and HSPC attachment, and MSC alignment within the microgrooves. All scaffolds were characterized and assessed for bladder tissue regeneration in an established nude rat bladder augmentation model. In all cases, normal physiological function was maintained post-augmentation, even without the presence of stem/progenitor cells. Urodynamic testing at 4-weeks post-augmentation for all experimental groups demonstrated that capacity increased and compliance was normal. Histological evaluation of the regenerated tissue revealed that cell-seeded scaffolds restored normal bladder smooth muscle content and resulted in increased revascularization and peripheral nerve regeneration. The presence of microgrooves on the cell-seeded scaffolds increased microvasculature formation by 20% and urothelium layer thickness by 25% in the regenerating tissue. Thus, this work demonstrates that micropatterning affects bladder regeneration to improve overall anatomical structure and re-establish bladder physiology.
Identifying Reproducible Transcription Regulator Coexpression Patterns with Single Cell Transcriptomics
Authors: Morin Alexander , Chu C. Pan , Pavlidis Paul
Published: February 2024

The proliferation of single cell transcriptomics has potentiated our ability to unveil patterns that reflect dynamic cellular processes such as the regulation of gene transcription. In this study, we leverage a broad collection of single cell RNA-seq data to identify the gene partners whose expression is most coordinated with each human and mouse transcription regulator (TR). We assembled 120 human and 103 mouse scRNA-seq datasets from the literature (>28 million cells), constructing a single cell coexpression network for each. We aimed to understand the consistency of TR coexpression profiles across a broad sampling of biological contexts, rather than examine the preservation of context-specific signals. Our workflow therefore explicitly prioritizes the patterns that are most reproducible across cell types. Towards this goal, we characterize the similarity of each TR’s coexpression within and across species. We create single cell coexpression rankings for each TR, demonstrating that this aggregated information recovers literature curated targets on par with ChIP-seq data. We then combine the coexpression and ChIP-seq information to identify candidate regulatory interactions supported across methods and species. Finally, we highlight interactions for the important neural TR ASCL1 to demonstrate how our compiled information can be adopted for community use.

Author Summary

A common way to analyze gene expression (transcriptomics) data is to correlate gene transcript levels across samples for every pair of genes (coexpression). Coordinated expression between genes may imply a shared biological function, though this warrants cautious interpretation given assumptions about cellular processes inferred from RNA abundances alone. Still, coexpression inference is often used to nominate genes whose expression may be controlled by transcription regulators (TRs). The rapid generation of diverse single cell transcriptomics data has unlocked our ability to discover coexpression patterns across individual cells — though these signals are often noisy. Reproducible patterns across studies can help distinguish meaningful biological relationships from spurious correlations. We used this study to analyze a broad collection of single cell data spanning numerous tissues in human and mouse to infer global TR coexpression patterns. We aimed to learn which interactions were generally observable, to better potentiate future examinations of reproducible coexpression in specific contexts. We evaluate the predictive performance of these global single cell coexpression rankings using independent gene regulation evidence, and highlight TR-gene pairs that are supported across data modalities as well as species. By disseminating these rankings, we hope that other researchers can extract insight for their own TRs of interest.
Mechanisms of Epigenomic and Functional Convergence Between Glucocorticoid and IL4-Driven Macrophage Programming
Authors: Deochand Dinesh K , Dacic Marija , Bale Michael J , Daman Andrew W , Josefowicz Steven Z , Oliver David , Chinenov Yurii , Rogatsky Inez
Published: February 2024

Macrophages adopt distinct phenotypes in response to environmental cues, with type-2 cytokine interleukin-4 promoting a tissue-repair homeostatic state (M2IL4). Glucocorticoids, widely used anti-inflammatory therapeutics, reportedly impart a similar phenotype (M2GC), but how such disparate pathways may functionally converge is unknown. We show using integrative functional genomics that M2IL4 and M2GC transcriptomes share a striking overlap mirrored by a shift in chromatin landscape in both common and signal-specific gene subsets. This core homeostatic program is enacted by transcriptional effectors KLF4 and the GC receptor, whose genome-wide occupancy and actions are integrated in a stimulus-specific manner by the nuclear receptor cofactor GRIP1. Indeed, many of the M2IL4:M2GC-shared transcriptomic changes were GRIP1-dependent. Consistently, GRIP1 loss attenuated phagocytic activity of both populations in vitro and macrophage tissue-repair properties in the murine colitis model in vivo. These findings provide a mechanistic framework for homeostatic macrophage programming by distinct signals, to better inform anti-inflammatory drug design.
Transpiration efficiency variations in the pearl millet reference collection PMiGAP
Authors: Gregoire Laura , Kholova Jana , Srivastava Rakesh , Hash Charles Thomas , Vigouroux Yves , Vadez Vincent
Published: February 2024

Transpiration efficiency (TE), the biomass produced per unit of water transpired, is a key trait for crop performance under limited water. As water becomes scarce, increasing TE would contribute to increase crop drought tolerance. This study is a first step to explore pearl millet genotypic variability for TE on a large and representative diversity panel. We analyzed TE on 538 pearl millet genotypes, including inbred lines, test-cross hybrids, and hybrids bred for different agroecological zones. Three lysimeter trials were conducted in 2012, 2013 and 2015, to assess TE both under well-watered and terminal-water stress conditions. We recorded grain yield to assess its relationship with TE. Up to two-fold variation for TE was observed over the accessions used. Mean TE varied between inbred and testcross hybrids, across years and was slightly higher under water stress. TE also differed among hybrids developed for three agroecological zones, being higher in hybrids bred for the wetter zone, underlining the importance of selecting germplasm according to the target area. Environmental conditions triggered large genotype-by-environment interactions, although TE showed some moderately high heritability. Transpiration efficiency was the second contributor to grain yield after harvest index, hence its relevance in pearl millet breeding programs. Future research on TE in pearl millet should focus (i) on investigating the causes of its plasticity i.e. the GxE interaction (ii) on studying its genetic basis and its association with other important physiological traits.
Limited parallelism in genetic adaptation to brackish water bodies in European sprat and Atlantic herring
Authors: Pettersson Mats E , Quintela Maria , Besnier Francois , Deng Qiaoling , Berg Florian , Kvamme Cecilie , Bekkevold Dorte , Mosbech Mai-Britt , Bunikis Ignas , Lille-Langoey Roger , Leonori Iole , Wallberg Andreas , Glover Kevin A , Andersson Leif
Published: February 2024

The European sprat is a small plankton-feeding clupeid present in the northeastern Atlantic Ocean, the Mediterranean Sea as well as in the brackish Baltic Sea and Black Sea. This species is the target of a major fishery and therefore an accurate characterization of its genetic population structure is crucial to delineate proper stock assessments that aid ensuring the fishery's sustainability. Here we present (i) a draft genome assembly, (ii) pooled whole genome sequencing of 19 population samples covering most of the species' distribution range, and (iii) the design and test of a SNP-chip resource and use this to validate the population structure inferred from pooled sequencing. These approaches revealed, using the populations sampled here, three major groups of European sprat: Oceanic, Coastal and Brackish with limited differentiation within groups even over wide geographical stretches. Genetic structure is largely driven by six large putative inversions that differentiate Oceanic and Brackish sprats, while Coastal populations display intermediate frequencies. Interestingly, populations from the Baltic and the Black Seas share similar frequencies of haplotypes at these putative inversions despite their distant geographic location. The closely related clupeids European sprat and Atlantic herring both show genetic adaptation to the brackish Baltic Sea, providing an opportunity to explore the extent of genetic parallelism. This analysis revealed limited parallelism in the form of three sharp signals of selection that overlapped between the two species and contained single genes such asPRLRA, which encodes the receptor for prolactin, a freshwater-adapting hormone in euryhaline species, andTHRB, a receptor for thyroid hormones, important both for metabolic regulation and the development of red cone photoreceptors.
Quantifying forms and functions of intestinal bile acid pools in mice
Authors: Sudo Koichi , Delmas-Eliason Amber , Soucy Shannon , Barrack Kaitlyn E. , Liu Jiabao , Balasubramanian Akshaya , Shu Chengyi Jenny , James Michael , Hegner Courtney L. , Dionne Henry D. , Rodriguez-Palacios Alexander , Krause Henry , O'Toole George A. , Karpen Saul J. , Dawson Paul A. , Schultz Daniel , Sundrud Mark S
Published: February 2024

Bile acids (BAs) are gastrointestinal metabolites that serve dual functions in lipid absorption and cell signaling. BAs circulate actively between the liver and distal small intestine (i.e., ileum), yet the dynamics through which complex BA pools are absorbed in the ileum and interact with intestinal cells in vivo remain ill-defined. Through multi-site sampling of nearly 100 BA species in individual wild type mice, as well as mice lacking the ileal BA transporter, Asbt/Slc10a2, we calculate the ileal BA pool in fasting C57BL/6J mice to be ~0.3 μmoles/g. Asbt-mediated transport accounts for ~80% of this pool and amplifies size, whereas passive absorption explains the remaining ~20%, and generates diversity. Accordingly, ileal BA pools in mice lacking Asbt are ~5-fold smaller than in wild type controls, enriched in secondary BA species normally found in the colon, and elicit unique transcriptional responses in cultured ileal explants. This work quantitatively defines ileal BA pools in mice and reveals how BA dysmetabolism can impinge on intestinal physiology.
Discovery and characterization of chromosomal inversions in the arboviral vector mosquito Aedes aegypti
Authors: Liang Jiangtao , Rose Noah H , Brusentsov Ilya I , Lukyanchikova Varvara , Karagodin Dmitriy A , Feng Yifan , Yurchenko Andrey A , Sylla Massamby , Lutomiah Joel , Badolo Athanase , Aribodor Ogechukwu B. , Ayala Diego , Acosta Cassandra Gonzalez , Alto Barry W. , Ahmad Nazni Wasi , Tu Zhijian , Gloria-Soria Andrea , Black William C. , Powell Jeffrey , Sharakhov Igor V , McBride Carolyn Sarah , Sharakhova Maria V
Published: February 2024

Chromosomal inversions play a fundamental role in evolution and have been shown to regulate epidemiologically important traits in malaria mosquitoes. However, they have never been characterized in Aedes aegypti, the major vector of arboviruses, because of the poor structure of its polytene chromosomes. In this study, we applied a Hi-C proximity ligation approach to identify chromosomal inversions in 25 strains of Ae. aegypti, acquired from its worldwide distribution, as well as in one strain of Ae. mascarensis. The study identified 21 multi-megabase inversions with uneven distributions along the three chromosomes. All chromosomal inversions, including one specific for Ae. mascarensis, were polymorphic. Nevertheless, geographic origin separated the strains into two clusters carrying African and non-African inversions suggesting their potential association with Ae. aegypti subspecies. Some of the inversions colocalized with chemoreceptor genes and quantitative trait loci associated with pathogen infection, implicating the potential role of inversions in host choice and disease transmission.
Dynamic modulation of social gaze by sex and familiarity in marmoset dyads
Authors: Xing Feng , Sheffield Alec G. , Jadi Monika P. , Chang Steve W. C. , Nandy Anirvan S.
Published: February 2024

Social communication relies on the ability to perceive and interpret the direction of others’ attention, and is commonly conveyed through head orientation and gaze direction in humans and nonhuman primates. However, traditional social gaze experiments in nonhuman primates require restraining head movements, significantly limiting their natural behavioral repertoire. Here, we developed a novel framework for accurately tracking facial features and three-dimensional head gaze orientations of multiple freely moving common marmosets (Callithrix jacchus). By combining deep learning-based computer vision tools with triangulation algorithms, we were able to track the facial features of marmoset dyads within an arena. This method effectively generates dynamic 3D geometrical facial frames while overcoming common challenges like occlusion. To detect the head gaze direction, we constructed a virtual cone, oriented perpendicular to the facial frame. Using this pipeline, we quantified different types of interactive social gaze events, including partner-directed gaze and joint gaze to a shared spatial location. We observed clear effects of sex and familiarity on both interpersonal distance and gaze dynamics in marmoset dyads. Unfamiliar pairs exhibited more stereotyped patterns of arena occupancy, more sustained levels of social gaze across social distance, and increased social gaze monitoring. On the other hand, familiar pairs exhibited higher levels of joint gazes. Moreover, males displayed significantly elevated levels of gazes toward females’ faces and the surrounding regions, irrespective of familiarity. Our study reveals the importance of two key social factors in driving the gaze behaviors of a prosocial primate species and lays the groundwork for a rigorous quantification of primate behaviors in naturalistic settings.
Pneumocystis murinaPromotes Inflammasome Formation and NETosis duringPneumocystisPneumonia
Authors: Sayson Steven G. , Ashbaugh Alan , Porollo Aleksey , Cushion Melanie T.
Published: February 2024

Pneumocystis jiroveciipneumonia (PjP) poses a serious risk to individuals with compromised immune systems, such as individuals with HIV/AIDS or undergoing immunosuppressive therapies for cancer or solid organ transplants. Severe PjP triggers excessive lung inflammation, resulting in lung function decline and consequential alveolar damage, potentially culminating in acute respiratory distress syndrome. Non-HIV patients face a 30-60%mortality rate, emphasizing the need for a deeper understanding of inflammatory responses in PjP. Prior research emphasized macrophages inPneumocystisinfections, neglecting neutrophils' role in tissue damage. Consequently, the overemphasis on macrophages led to an incomplete understanding of the role of neutrophils and inflammatory responses. In the current investigation, our RNAseq studies on a murine surrogate model of PjP revealed heightened activation of the NLRP3 inflammasome and NETosis cell death pathways in their lungs. Immunofluorescence staining confirmed Neutrophil Extracellular Trap (NET) presence in the lungs of theP. murina-infected mice, validating our findings. Moreover, isolated neutrophils exhibited NETosis when directly stimulated withP. murina. While isolated NETs did not compromiseP. murinaviability, our data highlight the potential role of neutrophils in promoting inflammation duringP. murinapneumonia through NLRP3 inflammasome assembly and NETosis. These pathways, essential for inflammation and pathogen elimination, bear the risk of uncontrolled activation leading to excessive tissue damage and persistent inflammation. This pioneering study is the first to identify the formation of NETs and inflammasomes duringPneumocystisinfection, paving the way for comprehensive investigations into treatments aimed at mitigating lung damage and augmenting survival rates for individuals with PjP.
WITHDRAWN: Gammaherpesvirus infection alters transfer RNA splicing and triggers tRNA cleavage
Authors: Manning Aidan C. , Bashir Mahmoud M. , Jimenez Ariana R. , Upton Heather E. , Collins Kathleen , Lowe Todd M. , Tucker Jessica M.
Published: February 2024

Withdrawal statement

The authors have withdrawn this manuscript due to a duplicate posting of manuscript number BIORXIV/2024/592122. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author. The correct preprint can be found at doi:https://doi.org/10.1101/2024.05.01.592122.