bluuebunny/crossref_metadata_2025 huggingface dataset:
Quantifying similarities between MediaPipe and a known standard for tracking 2D hand trajectories
Authors: Wagh Vaidehi P. , Scott Matthew W. , Kraeutner Sarah N.
Published: November 2023

Marker-less motion tracking methods have promise for use in a range of domains, including clinical settings where traditional marker-based systems for human pose estimation is not feasible. MediaPipe is an artificial intelligence-based system that offers a markerless, lightweight approach to motion capture, and encompasses MediaPipe Hands, for recognition of hand landmarks. However, the accuracy of MediaPipe for tracking fine upper limb movements involving the hand has not been explored. Here we aimed to evaluate 2-dimensional accuracy of MediaPipe against a known standard. Participants (N = 10) performed trials in blocks of a touchscreen-based shape-tracing task. Each trial was simultaneously captured by a video camera. Trajectories for each trial were extracted from the touchscreen and compared to those predicted by MediaPipe. Specifically, following re-sampling, normalization, and Procrustes transformations, root mean squared error (RMSE; primary outcome measure) was calculated for coordinates generated by MediaPipe vs. the touchscreen computer. Resultant mean RMSE was 0.28 +/-0.064 normalized px. Equivalence testing revealed that accuracy differed between MediaPipe and the touchscreen, but that the true difference was between 0-0.30 normalized px (t(114) = -3.02,p= 0.002). Overall, we quantify similarities between MediaPipe and a known standard for tracking fine upper limb movements, informing applications of MediaPipe in a domains such as clinical and research settings. Future work should address accuracy in 3-dimensions to further validate the use of MediaPipe in such domains.
Chemical cues from beetle larvae trigger proliferation and putative virulence gene expression of a plant pathogen
Authors: Cambon Marine C. , Thomas Gareth , Caulfield John , Crampton Michael , Reed Katy , Doonan James M. , Hussain Usman , Denman Sandra , Vuts Jozsef , McDonald James E.
Published: November 2023

Agricultural crop productivity and global forest biomes are coming under increasing threat from insect pests and microbial pathogens. This impact is worsened by inter- kingdom insect-microbe interactions that can increase transmission and disease severity in affected plants. Whilst bacterial chemical cues have been shown to directly influence insect behaviour, the impact of insect-derived compounds on phytopathogens is poorly understood. Here, we investigated the chemical basis for interactions between beetle larvae and bacteria in acute oak decline (AOD), a disease characterised by inner bark necrosis and involving a polymicrobial consortium includingBrenneria goodwiniiand larval galleries ofAgrilus biguttatus. We found thatA. biguttatuslarval extracts contain chemical elicitors that increase bacterial growth rate and final cell density duringin vitroculture, and stimulate the differential expression of ∼600 genes, including the Type III Secretion System and its effectors, which are major virulence factors in plant pathogens. Chemical compounds from closely related insect species did not have this effect. These findings highlight the importance of inter-kingdom interactions in plant disease and suggests a novel mode-of-action for insect-derived chemical elicitors in facilitating the virulence of phytopathogens.
Constraining activity and growth substrate of fungal decomposers via assimilation patterns of inorganic carbon and water into lipid biomarkers
Authors: Jabinski Stanislav , Rangel Wesley d.M. , Kopáček Marek , Jílková Veronika , Jansa Jan , Meador Travis B.
Published: November 2023

Fungi are among the few organisms on the planet that can metabolize recalcitrant C but are also known to access recently produced plant photosynthate. Therefore, improved quantification of growth and substrate utilization by different fungal ecotypes will help to define the rates and controls of fungal production, the cycling of soil organic matter, and thus the C storage and CO2buffering capacity soil ecosystems. This study combined a dual stable isotope probing approach together with rapid analysis by tandem pyrolysis gas chromatography isotope ratio mass spectrometry (Pyr-GC-IRMS) to determine the patterns of water-derived hydrogen (H) and inorganic C assimilated into lipid biomarkers of heterotrophic fungi as a function of C substrate. The water H assimilation factor (αw) and the inorganic C assimilation for C18:2fatty acid isolated from five fungal species growing on glucose was lower (0.62±0.01 and 4.7±1.6%, respectively) than for species grown on glutamic acid (0.90±0.02 and 7.4±3.7%, respectively). Furthermore, the assimilation ratio (RIC/αW) for growth on glucose and glutamic acid can distinguish between these two metabolic modes. This dual SIP assay thus delivers estimates of fungal activity and may help to delineate the predominant substrates that are respired among a matrix of compounds found in natural environments. (200 Words)

Importance

Fungi decomposers play important roles in food webs and nutrient cycling because they can feed on both labile and stable forms of carbon. This study developed and applied a dual stable isotope assay to improve the investigation of fungal activity in the environment. By determining the incorporation patterns of hydrogen and carbon into fungal lipids, this assay delivers estimates of fungal activity and the different metabolic pathways that they employ in ecological and environmental systems. (75 Words)
Outer membrane vesicles from commensal and pathogenic anaerobic bacteria: a systematic review of literature reviews
Authors: Castro-Vargas Priscilla , Barloy-Hubler Frédérique , Acuña-Amador Luis
Published: November 2023

Outer membrane vesicles (OMVs) are constitutively produced by Gram-negative bacteria (GNB), those from pathogenic bacteria play key roles in pathogen-host interactions, modulating host’s immune response and promoting virulence. OMVs of commensal bacteria are fundamental in the maturation of the host immune system and to maintain intestinal homeostasis.

The objective of this systematic review was to synthesize the knowledge available on literature reviews on OMVs from anaerobic GNB. The information was classified into categories: induction and biogenesis, OMVs liberation, internalization by host cells, and their interaction. The most studied OMVs are fromPorphyromonas gingivalisandBacteroidesspp.
THER: Integrative Web Tool for Tumor Hypoxia Exploration and Research
Authors: Zhang Yasi , Lin Anqi , Yang Hong , Liu Zaoqu , Cheng Quan , Zhang Jian , Luo Peng
Published: November 2023

Hypoxia is an important factor in the adaptation of tumor cells to their environment, contributes to their malignant progression, and affects tumor prognosis and drug sensitivity. Although there is a wealth of transcriptomic data stored in public databases, there is a lack of web-based tools for analyzing these data to explore the link between hypoxia and the mechanisms of tumorigenesis and progression. To this end, we have developed an interactive web-based tool called THER, which is designed to help users easily identify potential targets, mechanisms of action and effective drugs for treating hypoxic tumors. THER integrates 63 transcriptomic tumor hypoxia datasets from the Gene Expression Omnibus (GEO) database, covering 3 species, 18 tumor types and 42 cell line types. This web tool provides five modules that allow users to perform differential expression analysis, expression profiling analysis, correlation analysis, enrichment analysis and drug sensitivity analysis on different datasets based on different oxygen statuses. We expect that users will be able to use the tool to identify valuable biomarkers, further reveal the molecular mechanisms of tumor hypoxia, and identify effective drugs, thus providing a scientific basis for tumor diagnosis and treatment. THER is open to all users and can be accessed without login athttps://smuonco.shinyapps.io/THER/.
Baseline malaria infection status and RTS,S/AS01E malaria vaccine efficacy
Authors: Juraska Michal , Early Angela M. , Li Li , Schaffner Stephen F. , Lievens Marc , Khorgade Akanksha , Simpkins Brian , Hejazi Nima S. , Benkeser David A. , Wang Qi , Mercer Laina D. , Adjei Samuel , Agbenyega Tsiri , Anderson Scott , Ansong Daniel , Bii Dennis K. , Buabeng Patrick B.Y. , English Sean , Fitzgerald Nicholas , Grimsby Jonna , Kariuki Simon K. , Otieno Kephas , Roman François , Samuels Aaron M. , Westercamp Nelli , Ockenhouse Christian F. , Ofori-Anyinam Opokua , Lee Cynthia K. , MacInnis Bronwyn L. , Wirth Dyann F. , Gilbert Peter B. , Neafsey Daniel E.
Published: November 2023

Background

The only licensed malaria vaccine, RTS,S/AS01E, confers moderate protection against symptomatic disease. Because many malaria infections are asymptomatic, we conducted a large-scale longitudinal parasite genotyping study of samples from a clinical trial exploring how vaccine dosing regimen affects vaccine efficacy (VE).

Methods

1,500 children aged 5–17 months were randomized to receive four different RTS,S/AS01Eregimens or a rabies control vaccine in a phase 2b clinical trial in Ghana and Kenya. We evaluated the time to the first new genotypically detected infection and the total number of new infections during two follow-up periods in over 36K participant specimens. We performed a post hoc analysis of VE based on malaria infection status at first vaccination and force of infection.

Results

We observed significant and comparable VE (25–43%, 95% CI union 9–53%) against first new infection for all four RTS,S/AS01Eregimens across both follow-up periods (12 and 20 months). Each RTS,S/AS01Eregimen significantly reduced the number of new infections in the 20-month follow-up period (control mean 4.1 vs. RTS,S/AS01Emean 2.6–3.0). VE against first new infection was significantly higher in participants who were malaria-infected (68%; 95% CI, 50 to 80%) versus uninfected (37%; 95% CI, 23 to 48%) at the first vaccination (P=0.0053) and in participants experiencing greater force of infection between dose 1 and 3 (P=0.059).

Conclusions

All tested dosing regimens blocked some infections to a similar degree. Improved VE in participants infected during vaccination could suggest new strategies for highly efficacious malaria vaccine development and implementation. (ClinicalTrials.govnumber,NCT03276962)
INFLUENCE OF BACILLUS SUBTILIS ON THE BIOTOXICITY OF SOILS CONTAMINATED WITH COPPER
Authors: Galaktionova L.V.
Published: November 2023

An urgent environmental problem is pollution of the environment with heavy metals, which have a negative impact on the components of ecosystems. Therefore, the search for new approaches to reduce their toxicity/availability in soil is a task of applied research. This work studied the effect of inoculation with bacteriaBacillus subtilis534 of contaminated soils with copper acetates on their toxicity to higher plants, earthworms, and bacteria of the genusAzotobacter.
Synaptic strength dynamics at cortical pathways is encoded by vigilance states duration
Authors: Marchal Paul , Salin Paul , Missaire Megane , Rampon Manon , Carponcy Julien , Parmentier Regis , Poe Gina , Malleret Gael , Comte Jean-Christophe
Published: November 2023

Interactions among brain areas are essential to most cognitive functions. Neuronal interactions between these areas depend on the modulation of synaptic strength. However, this modulation remains poorly understood. We recorded evoked synaptic responses at four hippocampal pathways in freely moving male rats across 24 hours: the Perforant Path to Dentate Gyrus (PP-DG), Fornix to Prefrontal Cortex (Fx-PFC), Fornix to Nucleus Accumbens (Fx-NAc), and the Schaffer Collaterals to CA1 (SC-CA1). We preserved the temporal dynamics of vigilance states and synaptic responses and show for the first time that synaptic strength at these four hippocampal pathways oscillates, with a very slow periodicity. We demonstrate that synaptic strength at the PP-DG, Fx-PFC, Fx-NAc pathways show a positive correlation with the duration of active wakefulness (aWK) and a negative one with the duration of most sleep states (slow wave sleep (SWS) and rapid eye movement sleep (REM)), with a positive peak correlation time-lag of 1 to 10 minutes for aWK and SWS at these 3 pathways. In contrast, no significant correlation peak is found at the SC-CA1 pathway. Finally, a model based on hypnogram data and synaptic strength at the PP-DG pathway was able to predict the evolution of synaptic strength at the PP-DG, Fx-PFC and Fx-NAc pathways, but not at the SC-CA1 pathway. These results reveal that the temporal succession of vigilance states, particularly aWK and SWS, may contribute to memory processes through rapid modulation of synaptic strength at several pathways during the sleep-wakefulness cycle, suggesting that memory processes are not only dependent on sleep amount but also on sleep architecture.
Transwell-based microphysiological platform for high-resolution imaging of airway tissues
Authors: Kurmashev Amanzhol , Boos Julia A. , Laventie Benoît-Joseph , Swart A. Leoni , Sütterlin Rosmarie , Junne Tina , Jenal Urs , Hierlemann Andreas
Published: November 2023

Transwell-based airway models have become increasingly important to study the effects of respiratory diseases and drug treatment at the air-liquid interface of the lung epithelial barrier. However, the underlying mechanisms at tissue and cell level often remain unclear, as transwell inserts feature limited live-cell imaging compatibility. Here, we report on a novel microphysiological platform for the cultivation of transwell-based lung tissues providing the possibility to alternate between air-liquid and liquid-liquid interfaces. While the air-liquid interface recapitulates physiological conditions for the lung model, the liquid-liquid interface enables live-imaging of the tissue at high spatiotemporal resolution. The plastics-based microfluidic platform enables insertion and recuperation of the transwell inserts, which allows for tissue cultivation and analysis under standardized well plate conditions. We used the device to monitor infections ofPseudomonas aeruginosain human stem-cell-derived bronchial epithelial tissue. We continuously imaged the progression of aP. aeruginosainfection in real time at high resolution, which provided insights into bacterial spreading and invasion on the apical tissue surface, as well as insights into tissue breaching and destruction over time. The airway tissue culture system is a powerful tool to visualize and elucidate key processes of developing respiratory diseases and to facilitate drug testing and development.
Durable immunity to SARS-CoV-2 in both lower and upper airways achieved with a gorilla adenovirus (GRAd) S-2P vaccine in non-human primates
Authors: Moliva Juan I. , Andrew Shayne F. , Flynn Barbara J. , Wagner Danielle A. , Foulds Kathryn E. , Gagne Matthew , Flebbe Dillon R. , Lamb Evan , Provost Samantha , Marquez Josue , Mychalowych Anna , Lorag Cynthia G. , Honeycutt Christopher Cole , Burnett Matthew R. , McCormick Lauren , Henry Amy R. , Godbole Sucheta , Davis-Gardner Meredith E. , Minai Mahnaz , Bock Kevin W. , Nagata Bianca M. , Todd John-Paul M. , McCarthy Elizabeth , Dodson Alan , Kouneski Katelyn , Cook Anthony , Pessaint Laurent , Van Ry Alex , Valentin Daniel , Young Steve , Littman Yoav , Boon Adrianus C. M. , Suthar Mehul S. , Lewis Mark G. , Andersen Hanne , Alves Derron A. , Woodward Ruth , Leuzzi Adriano , Vitelli Alessandra , Colloca Stefano , Folgori Antonella , Raggiolli Angelo , Capone Stefania , Nason Martha C. , Douek Daniel C. , Roederer Mario , Seder Robert A. , Sullivan Nancy J.
Published: November 2023

SARS-CoV-2 continues to pose a global threat, and current vaccines, while effective against severe illness, fall short in preventing transmission. To address this challenge, there’s a need for vaccines that induce mucosal immunity and can rapidly control the virus. In this study, we demonstrate that a single immunization with a novel gorilla adenovirus-based vaccine (GRAd) carrying the pre-fusion stabilized Spike protein (S-2P) in non-human primates provided protective immunity for over one year against the BA.5 variant of SARS-CoV-2. A prime-boost regimen using GRAd followed by adjuvanted S-2P (GRAd+S-2P) accelerated viral clearance in both the lower and upper airways. GRAd delivered via aerosol (GRAd(AE)+S-2P) modestly improved protection compared to its matched intramuscular regimen, but showed dramatically superior boosting by mRNA and, importantly, total virus clearance in the upper airway by day 4 post infection. GrAd vaccination regimens elicited robust and durable systemic and mucosal antibody responses to multiple SARS-CoV-2 variants, but only GRAd(AE)+S-2P generated long-lasting T cell responses in the lung. This research underscores the flexibility of the GRAd vaccine platform to provide durable immunity against SARS-CoV-2 in both the lower and upper airways.
Printing, Characterising, and Assessing Transparent 3D Printed Lenses for Optical Imaging
Authors: Rooney Liam M. , Christopher Jay , Watson Ben , Kumar Yash Susir , Copeland Laura , Walker Lewis D. , Foylan Shannan , Amos William B. , Bauer Ralf , McConnell Gail
Published: November 2023

High-quality lens production has involved subtractive manufacturing methods for centuries. These methods demand specialist equipment and expertise that often render custom high-grade glass optics inaccessible. We aimed to develop a low-cost, accessible, and reproducible method to manufacture high-quality three-dimensional (3D) printed lenses using consumer-grade technology. Various planoconvex lenses were produced using a consumer-grade 3D printer and low-cost spin coating setup, and printed lenses were compared to commercial glass counterparts. A range of mechanical and optical methods are introduced to determine the surface quality and curvature of 3D printed lenses. Amongst others, high-resolution interference reflection microscopy methods were used to reconstruct the convex surface of printed lenses and quantify their radius of curvature. The optical throughput and performance of 3D printed lenses were assessed using optical transmissivity measurements and classical beam characterisation methods. We determined that 3D printed lenses had comparable curvature and performance to commercial glass lenses. Finally, we demonstrated the application of 3D printed lenses for brightfield transmission microscopy, resolving sub-cellular structures over a 2.3 mm field-of-view. The high reproducibility and comparable performance of 3D printed lenses present great opportunities for additive manufacturing of bespoke optics for low-cost rapid prototyping and improved accessibility to high-quality optics in low-resource settings.
Glutathione overproduction mediates lymphoma initiating cells survival and has a sex-dependent effect on lymphomagenesis
Authors: Alberto H.-Alcántara , Kourani Omar , Marcos-Jiménez Ana , Martínez-Núñez Patricia , Herranz-Martín Estela , Fuentes Patricia , Toribio María Luisa , Muñoz-Calleja Cecilia , Iglesias Teresa , Campanero Miguel R.
Published: November 2023

Lymphoid tumor patients often exhibit resistance to standard therapies or experience rapid relapse post-remission. Tumor-initiating cells (TICs), a small fraction of the tumor cell population known for their self-renewal capacity and resistance to cancer therapies, likely drive tumor relapse. Tumorigenicity strongly correlates with growth in soft gels and TICs are the only cancer cells capable of growing in soft gels. Targeting pathways critical for TIC survival or growth holds promise for improving cancer treatment outcomes but TIC biology remains poorly understood. Here, we show that culturing lymphoid cells in soft hydrogels triggers reactive oxygen species (ROS) production, leading to non-tumor lymphoid cell death while enabling the survival and proliferation of a subset of lymphoma/leukemia cells, TICs or TIC-like cells. Treatment with the antioxidant N-acetylcysteine inhibits this lethality and even promotes the growth of primary non-tumor lymphoid cells in soft gels. Some lymphoma cells escape ROS-induced lethality by boosting antioxidant glutathione production, a response not seen in non-tumor cells. Reducing glutathione production in lymphoma cells, either through pharmacological inhibition of glutamate cysteine ligase (GCL), the enzyme catalyzing the rate-limiting step in glutathione biosynthesis, or via knockdown ofGCLC, the GCL catalytic subunit, sharply decreased cell viability and proliferation in soft gels and tumor growth in immunodeficient mice. Tumor cells from B-cell lymphoma/leukemia patients and λ-MYC mice, a B-cell lymphoma mouse model, overproduce glutathione. Importantly, pharmacological GCL inhibition hindered lymphoma growth in female λ-MYC mice, suggesting that this treatment holds promise as a therapeutic strategy for female lymphoma/leukemia patients.
Adolescent Thalamocortical Inhibition Alters Prefrontal Excitation-Inhibition Balance
Authors: Petersen David , Raudales Ricardo , Silva Ariadna Kim , Kellendonk Christoph , Canetta Sarah
Published: November 2023

Adolescent inhibition of thalamo-cortical projections from postnatal day P20-50 leads to long lasting deficits in prefrontal cortex function and cognition in the adult mouse. While this suggests a role of thalamic activity in prefrontal cortex maturation, it is unclear how inhibition of these projections affects prefrontal circuit connectivity during adolescence. Here, we used chemogenetic tools to inhibit thalamo-prefrontal projections in the mouse from P20-35 and measured synaptic inputs to prefrontal pyramidal neurons by layer (either II/III or V/VI) and projection target twenty-four hours later using slice physiology. We found a decrease in the frequency of excitatory and inhibitory currents in layer II/III nucleus accumbens (NAc) and layer V/VI medio-dorsal thalamus projecting neurons while layer V/VI NAc-projecting neurons showed an increase in the amplitude of excitatory and inhibitory currents. Regarding cortical projections, the frequency of inhibitory but not excitatory currents was enhanced in contralateral mPFC-projecting neurons. Notably, despite these complex changes in individual levels of excitation and inhibition, the overall balance between excitation and inhibition in each cell was only changed in the contralateral mPFC projections. This finding suggests homeostatic regulation occurs within subcortically but not intracortical callosally-projecting neurons. Increased inhibition of intra-prefrontal connectivity may therefore be particularly important for prefrontal cortex circuit maturation. Finally, we observed cognitive deficits in the adult mouse using this narrowed window of thalamocortical inhibition (P20-P35).

Significance Statement

Connectivity between two brain regions, the thalamus and the prefrontal cortex, has been found to be reduced in patients with schizophrenia. Neuronal activity in thalamo-cortical projections is important for the proper development of sensory cortices. How thalamo-cortical activity regulates prefrontal cortex development is less well understood. Here, we show that decreasing activity in thalamo-prefrontal projections in mice during early adolescence alters synaptic connectivity to distinct neuronal projections within the prefrontal cortex that are already evident in adolescence. While some of these changes can be explained by reduced thalamo-cortical projections, other adaptations are intrinsic to the prefrontal cortex. These findings implicate adolescence as a critical period of cortical development and demonstrate this period as a potential target for therapeutic intervention.
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

Global 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

Background

Long 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).

Methods

INFLAMeR 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.

Results

The 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).

Conclusions

Our 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

In 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

Short-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

Recent 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

Trait 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 respond

McNaughton & 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

Understanding 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.

Highlight

We 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

The 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.

This 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

For 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 summary

A 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

The 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

Major 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

The 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

Invasive 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.
GDF15 mediates inflammation-associated bone loss through a brain-bone axis
Authors: Van der Cruyssen Renée , Devan Jan , Heggli Irina , Burri Dominik , Gaublomme Djoere , Josipovic Ivan , Dumas Emilie , Vlieghe Carolien , Raimondo Maria Gabriella , Zakharov Pavel , Jacques Peggy , Mits Sophie De , Lukasik Zuzanna , Vuylsteke Marnik , Renson Thomas , Schots Lisa , Planckaert Guillaume , Stappers Flore , Decruy Tine , Coudenys Julie , Manuello Teddy , Vereecke Lars , Dmitriev Ruslan I. , Lambrecht Stijn , Hoorebeke Luc Van , Lambert Jo , Ravichandran Kodi , Ramming Andreas , Dudli Stefan , Schett Georg , Gracey Eric , Elewaut Dirk
Published: November 2023

Metabolic mediators play an important role in regulating chronic inflammation in the body. Here we report an unexpected role for GDF15 (Growth Differentiation Factor 15), a central mediator of food intake, in inflammation-associated bone loss. GDF15 serum levels were found to be elevated in arthritis patients and inversely correlated with bone density. Despite being associated with inflammation, we found that GDF15 itself does not cause, nor contribute to, clinical or histopathological arthritis. Rather, under inflammatory conditions, GDF15 mediates trabecular bone loss through its receptor GFRAL, which is exclusively expressed in the hindbrain. GDF15-GFRAL binding results in β-adrenergic activation of MALPs (Marrow Adipocytic Lineage Precursors) in the bone marrow, which stimulate osteoclasts and trigger bone loss. These data suggest a metabolic mediator-controlled brain-bone axis in inflammation, through which bone loss is induced in a contextual rather than general manner. These findings may lead to more specific therapeutic interventions to protect bone.