bluuebunny/crossref_metadata_2025_split huggingface dataset:
The impact of burn trauma on glycocalyx derangement
Authors: Kühtreiber Hannes , Bormann Daniel , Salek Melanie , Haider Thomas , Mildner Caterina Selina , Lingitz Marie-Therese , Aigner Clemens , Radtke Christine , Ankersmit Hendrik Jan , Mildner Michael 
Published: September 2024

AbstractBurn injuries often lead to severe complications, including acute respiratory distress syndrome (ARDS), driven in part by systemic inflammation and glycocalyx disruption. In this study, we analyzed the sera of 28 patients after burn trauma and utilized transcriptomic analyses to decipher the impact of burn injury on glycocalyx derangement. We observed significant upregulation of immune cell-derived degrading enzymes, particularly matrix metalloproteinase-8 (MMP8), which correlated with increased immune cell infiltration and glycocalyx derangement. Serum analysis of burn patients revealed significantly elevated levels of shed glycocalyx components and MMP8, both correlating with the presence of inhalation injury. Consequently, treatment of human in vitro lung tissue models with MMP8 induced significant glycocalyx shedding in both, the endothelium and epithelium. Together our data suggest MMP8 as a contributor of glycocalyx disruption and lung injury post-burn.
Causal effects of breast cancer risk factors across hormone receptor breast cancer subtypes: A two-sample Mendelian randomization study
Authors: Verdiesen Renée MG , Shokouhi Mehrnoosh , Burgess Stephen , Canisius Sander , Chang-Claude Jenny , Bojesen Stig E , Schmidt Marjanka K 
Published: September 2024

AbstractBackgroundIt is unclear if established breast cancer risk factors exert similar causal effects across hormone receptor breast cancer subtypes. We estimated and compared causal estimates of height, body mass index (BMI), type 2 diabetes, age at menarche, age at menopause, breast density, alcohol consumption, regular smoking, and physical activity across these subtypes.MethodsWe used a two-sample Mendelian randomization approach and selected genetic instrumental variables from large-scale risk factor GWAS. Publicly available summary-level data for the following subtypes were included: luminal A-like; luminal B/HER2-negative-like; luminal B-like; HER2-enriched-like; triple negative. We employed multiple methods to evaluate the strength of causal evidence for each risk factor-subtype association.ResultsCollectively, our analyses indicated that increased height and decreased BMI are probable causal risk factors for all five subtypes. For the other risk factors, the strength of evidence for causal effects differed across subtypes. Heterogeneity in the magnitude of causal effect estimates for age at menopause and breast density was explained by null findings for triple negative tumours. Regular smoking was the sole risk factor for which there was no evidence for a causal effect on any subtype.ConclusionsThis study suggests that established breast cancer risk factors differ across hormone receptor subtypes.
Hyperbaric Oxygen Therapy for Long COVID: 3-Month Follow up Results from a Prospective Registry of 232 patients
Authors: van Berkel J. , Lalieu R.C , Joseph D. , Hellemons M. , Lansdorp C.A. 
Published: September 2024

ABSTRACTA potential beneficial effect of hyperbaric oxygen therapy (HBOT) on complaints of long COVID was found, leading to increased demand for this treatment despite many remaining clinical questions and lack of formal guideline recommendations and reimbursement. A registry was set up in order to gain more insight into patient characteristics and (long-term) outcomes of long COVID patients undergoing HBOT. Patient-reported outcome measures were collected at baseline, after treatment and at 3-month follow up. The primary outcome measures were the mental and physical component score (MCS/PCS) of the SF-36 questionnaire 3 months after HBOT. A clinically relevant positive or negative response was defined as an increase or decrease of ≥10% in MCS and/or PCS after 3 months. Secondary outcomes included the EQ-5D, severity of complaints and ability to work. In this prospective registry of 232 long COVID patients, 65% of long term-ill patients had a clinically relevant increase in quality of life. However, 15% of the patients experienced deterioration in quality of life. Symptoms that showed most improvement were predominantly in the cognitive domain. This indicates that HBOT may have a positive effect on complaints of long COVID, but alertness for worsening of the condition should be exercised.
Pulmonary inflammation in severe pneumonia is characterised by compartmentalised and mechanistically distinct sub-phenotypes
Authors: Jeffrey M , Bartholdson Scott J , White RJ , Higginson E , Maes M , Forrest S , Pereira-Dias J , Parmar S , Heasman-Hunt E , Curran MD , Polgarova P , Herre J , Davenport EE , Baker S , Dougan G , Navapurkar V , Conway Morris A 
Published: September 2024

AbstractPneumonia is the leading infectious disease killer worldwide and commonly requires admission to critical care. Despite its prevalence, the underpinning biology of severe pneumonia remains incompletely understood. We performed multifaceted assessments of bronchoalveolar transcriptome, cytokines, microbiology, and clinical features to biologically dissect a cohort of patients with suspected severe pneumonia. Our data revealed three lung-restricted transcriptionally defined severe pneumonia endotypes (termed ‘Pneumotypes’ (Pn)). All three Pneumotypes had comparable clinical presentations and severity of respiratory failure but critically had divergent outcomes. Pn1, the most common, was characterised by low alveolar cytokines, expanded tolerogenic macrophages and epithelial damage. Pn3 was characterised by neutrophil-monocyte infiltration, IL-6-STAT3 activation and longer duration of mechanical ventilation. Pn2 displayed the fastest resolution, exhibiting a balanced immune response and epithelial-endothelial repair signatures. Our work has identified mechanistically distinct phenotypes in the lungs of patients with suspected pneumonia and acute lung injury, providing new targets for personalised therapy.
Mature leaves produce a multi-layered wound periderm by integrating phytohormone signaling with ATML1-mediated epidermal specification
Authors: Lee Jung-Min , Jeon Woo-Taek , Han Minsoo , Kwon Myung , Kim Kyungyoon , Je Sujeong , Jung Hoon , Heo Geon , Yamaoka Yasuyo , Lee Yuree 
Published: September 2024

SummaryThe epidermis of plants forms a protective barrier against various stress, but how breaches in the epidermis are repaired is not well understood. Here, we investigated wound healing in the mature leaves ofArabidopsis. We discover a novel type of wound periderm comprising a multi-layered ligno-suberized barrier covered with cuticular wax, which is formed by mesophyll cells that adopt an epidermal fate. Mesophyll cells of protective layer 1 (P1), just beneath the wound, transition into epidermal cells, which seal the wound by depositing cuticle. As P1 undergoes cell death, protective layer 2 (P2), which underlies P1, takes the place of P1 and undergoes ligno-suberization. This multi-layered periderm involves integration of ethylene and jasmonic acid signaling with ATML1, a key transcription factor in epidermal specification, to coordinate cell layer-specific functions. This novel wound periderm also occurs in the leaves of tobacco andCapsella, suggesting it is a widespread phenomenon.
Lower-Limb Muscle Synergies in Musician’s Dystonia: A Case Study of a Drummer
Authors: Sata Shizuka , Honda Kazuaki , Yamaguchi Satoshi , Komine Mizuki , Kim SungHyek , Kashino Makio , Hagio Shota , Fujii Shinya 
Published: September 2024

AbstractMusician’s dystonia (MD) is a movement disorder characterized by involuntary muscle contractions specifically triggered by playing an instrument. This condition often leads to a loss of fine motor control, threatening the careers of affected musicians. While MD is commonly associated with the hands, it can also affect the lower limbs, particularly in drummers. Understanding the muscle coordination involved in MD is crucial for comprehending its neurological mechanisms, yet the muscle coordination of lower-limb dystonia has not been thoroughly explored. This study aimed to investigate the differences in lower-limb muscle synergies in a drummer with MD, utilizing Non-negative Matrix Factorization (NMF) to analyze coordinated muscle activity patterns during drumming tasks. A 36-year-old male professional drummer with lower-limb MD was instructed to play a drum set in time with a metronome set at 80 beats per minute. The task involved striking the bass drum pedal in time with the downbeat. Electromyographic (EMG) data were collected from ten muscles in the right lower limb. The data were analyzed using NMF to extract muscle synergies and compare the number of synergies, spatial modules, and temporal modules between the data with and without dystonia symptoms. The number of muscle synergies did not differ significantly between the data with and without symptoms. Notably, changes were observed in both the spatial and temporal modules of muscle synergies. Spatial modules revealed the appearance of dystonia-specific muscle synergy, which is considered related to compensatory movement. Temporal modules showed significant earlier overactivation in timing, which is considered the direct manifestation of dystonia symptoms. These findings indicate that lower-limb dystonia in drummers affects the spatial and temporal profiles of muscle synergies. This study underscores the importance of considering both spatial and temporal modules of muscle synergy in understanding and treating lower-limb dystonia in drummers. Further research is needed to validate these findings and apply muscle synergy analysis for the clinical assessment of lower-limb dystonia in drummers.
Contractile forces direct the chiral swirling of minimal cell collectives
Authors: Badih Ghina , Schaeffer Alexandre , Vianay Benoît , Smilovici Pauline , Blanchoin Laurent , Thery Manuel , Kurzawa Laëtitia 
Published: September 2024

AbstractChirality is a conserved biological feature with critical implications in tissue morphogenesis and embryonic development. In culture, large multicellular groups exhibit spontaneous chiral symmetry break when moving collectively on micropatterned surfaces. Although several studies have shown that actin network integrity and acto-myosin network contractility participate to the establishment of the chirality of the movement, the exact contribution of contractile forces to the directionality of the chiral bias in collectives remains to be elucidated. Here we studied the contractile forces produced by a minimal collective constituted of a pair of endothelial cells. We first show that cell doublets confined on disk-shaped micropatterns undergo spontaneous and persistent chiral swirling, displaying a mild but robust clockwise (CW) bias, as the one observed in bigger collectives. This bias could be amplified or reversed by modulating contractile forces. Traction force measurements revealed that large forces tend to drive counter-clockwise (CCW) rotation whereas low forces rather favor a CW rotation. Furthermore, the study of heterotypic doublets indicates that the speed and direction of the rotation is determined by the more contractile cells within the doublets. These results thus revealed that contractile leader cells could drive the chiral motion of minimal collectives.Significance StatementChirality, which represents a fundamental property of living systems, manifests in cell collectives by their persistent biased directional swirling. Despite the clear identification of the implication of actomyosin cytoskeleton in driving the internal chiral symmetry break occurring in cells, little is known about the actual role of cellular forces produced by this network in the development of handedness in collectives. Our findings establish that the level of mechanical energy developed by pairs of confined endothelial cells regulates the strength and direction of their rotation. Our results also identify the more contractile cell of the doublet as the cell driving the direction and speed of rotation of the pair. This study thus sheds new light on the importance of the generation and integration of mechanical forces within a small collective in the determination of its chiral rotation.
Pangenomics to understand prophage dynamics in thePectobacteriumgenus and the radiating lineages ofP. Brasiliense
Authors: Pardeshi Lakhansing A. , van Duivenbode Inge , Pel Michiel J. C. , Jonkheer Eef M. , Kupczok Anne , de Ridder Dick , Smit Sandra , van der Lee Theo A. J. 
Published: September 2024

AbstractBacterial pathogens of the genusPectobacteriumare responsible for soft rot and blackleg disease in a wide range of crops and have a global impact on food production. The emergence of new lineages and their competitive succession is frequently observed inPectobacteriumspecies, in particular inP. brasiliense. With a focus on one such recently emergedP. brasilienselineage in the Netherlands that causes blackleg in potatoes, we studied genome evolution in this genus using a reference-free graph-based pangenome approach. We clustered 1,977,865 proteins from 454Pectobacteriumspp. genomes into 30,156 homology groups. ThePectobacteriumgenus pangenome is open and its growth is mainly contributed by the accessory genome. Bacteriophage genes were enriched in the accessory genome and contributed 16% of the pangenome. Blackleg-causingP. brasilienseisolates had increased genome size with high levels of prophage integration. To study the diversity and dynamics of these prophages across the pangenome, we developed an approach to trace prophages across genomes using pangenome homology group signatures. We identified lineage-specific as well as generalist bacteriophages infectingPectobacteriumspecies. Our results capture the ongoing dynamics of mobile genetic elements, even in the clonal lineages. The observed lineage-specific prophage dynamics provide mechanistic insights intoPectobacteriumpangenome growth and contribution to the radiating lineages ofP. brasiliense.
Deep contrastive learning enables genome-wide virtual screening
Authors: Jia Yinjun , Gao Bowen , Tan Jiaxin , Hong Xin , Zhu Wenyu , Tan Haichuan , Xiao Yuan , Huang Yanwen , Jin Yue , Yuan Yafei , Tian Jiekang , Ma Weiying , Zhang Yaqin , Yan Chuangye , Zhang Wei , Lan Yanyan 
Published: September 2024

AbstractNumerous protein-coding genes are associated with human diseases, yet approximately 90% of them lack targeted therapeutic intervention. While conventional computational methods such as molecular docking have facilitated the discovery of potential hit compounds, the development of genome-wide virtual screening against the expansive chemical space remains a formidable challenge. Here we introduce DrugCLIP, a novel framework that combines contrastive learning and dense retrieval to achieve rapid and accurate virtual screening. Compared to traditional docking methods, DrugCLIP improves the speed of virtual screening by several orders of magnitude. In terms of performance, DrugCLIP not only surpasses docking and other deep learning-based methods across two standard benchmark datasets but also demonstrates high efficacy in wet-lab experiments. Specifically, DrugCLIP successfully identified agonists with < 100 nM affinities for 5HT2AR, a key target in psychiatric diseases. For another target NET, whose structure is newly solved and not included in the training set, our method achieved a hit rate of 15%, with 12 diverse molecules exhibiting affinities better than Bupropion. Additionally, two chemically novel inhibitors were validated by structure determination with Cryo-EM. Building on this foundation, we present the results of a pioneering trillion-scale genome-wide virtual screening, encompassing approximately 10,000 AlphaFold2 predicted proteins within the human genome and 500 million molecules from the ZINC and Enamine REAL database. This work provides an innovative perspective on drug discovery in the post-AlphaFold era, where comprehensive targeting of all disease-related proteins is within reach.
Continuous self-repair protects vimentin intermediate filaments from fragmentation
Authors: Tran Quang D. , Lenz Martin , Wioland Hugo , Jegou Antoine , Romet-Lemonne Guillaume , Leduc Cécile 
Published: September 2024

AbstractIntermediate filaments are key regulators of cell mechanics. Vimentin, a type of intermediate filament expressed in mesenchymal cells and involved in migration, forms a dense network in the cytoplasm that is constantly remodeled through filament transport, elongation/shortening, and subunit exchange. While it is known that filament elongation involves end-to-end annealing, it is unclear how the reverse process of filament shortening by fragmentation occurs. Here, we use a combination ofin vitroreconstitution probed by fluorescence imaging and theoretical modeling to uncover the molecular mechanism involved in filament breakage. We first show that vimentin filaments are composed of two layers of subunits, half of which are exchangeable and half of which are immobile. We also show that the exchangeable subunits are tetramers. We further reveal a mechanism of continuous filament self-repair in which a soluble pool of vimentin tetramers in equilibrium with the filaments is essential to maintain filament integrity. Filaments break as a consequence of local fluctuations in the number of subunits per cross-section induced by the constant subunit exchange of tetramers. We determine that a filament tends to break if about four tetramers are removed from the same filament cross-section. Finally, we analyze the dynamics of association/dissociation and fragmentation to estimate the binding energy of a tetramer to a complete versus a partially disassembled filament. Our results provide a comprehensive description of vimentin turnover and reveal the link between subunit exchange and fragmentation.SIGNIFICANCE STATEMENTIntermediate filaments, including vimentin, are a key component of the cytoskeleton, which is essential for cell mechanics. Inside the cell, vimentin forms a dense network that is constantly remodeled to fulfill its functions. In particular, the filaments elongate and fragment, but the molecular mechanism involved in this breakage was unknown. Here we show that fragmentation is a consequence of the constant exchange of subunits along the filament length, which could locally weaken the filament. Our results provide a physical understanding of the mechanisms involved in regulating filament length, a feature that is essential for determining the dynamic organization of the network in both healthy and diseased cells in which intermediate filament assembly is disrupted.
Apusomonad photophobic behavior highlights cytoskeletal responses to blue light in early eukaryotes
Authors: Shibata Aika , Yamamoto Chiaki , Yanase Ryuji , Shiba Kogiku , Sato Yu , Yabuki Akinori , Inaba Kazuo 
Published: September 2024

AbstractLight response is a fundamental characteristic of eukaryotic organisms, both unicellular and multicellular. However, no photoresponse has previously been reported in Apusomonadida, a group of small, free-living biflagellates phylogenetically positioned as a sister group to Opisthokonta (animals, fungi, and their unicellular relatives). Apusomonads are thus crucial for understanding the evolution of opisthokonts. Here, we report for the first time an avoidance response to blue light in the apusomonadPodomonas kaiyoae. This avoidance response is accompanied by an increase in gliding velocity, transient changes in flagellar waveforms, and alterations in cell shape. Dynamic cell contraction is induced by an increase in intracellular free Ca2+ and is inhibited by either a dynein inhibitor or an actin-disrupting drug. These findings suggest that the photophobic behavior ofPodomonas kaiyoaerelies on cytoskeletal responses mediated by both the dynein/tubulin and myosin/actin systems, which were acquired early in eukaryotic evolution. The dominance of the posterior flagellum in cilia-driven directional changes further supports the phylogenetic placement of apusomonads as a sister group to opisthokonts rather than other eukaryotic lineages.
Bumblebees locate goals in 3D with absolute height estimation from ventral optic flow
Authors: Sonntag Annkathrin , Egelhaaf Martin , Bertrand Olivier J. N. , Lihoreau Mathieu 
Published: September 2024

ABSTRACTIntroductionWhen foraging, flying animals like bees are often required to change their flight altitude from close to the ground to above the height of the vegetation to reach their nest or a food source. While the mechanisms of navigating towards a goal in two dimensions are well understood, the explicit use of height as a source for navigation in three dimensions remains mostly unknown. Our study aims to unravel which strategies bumblebees use for height estimation and whether they rely on global or local cues.MethodsWe expanded a 2D goal localization paradigm, where a goal location is indicated by cylindrical landmarks, to the third dimension by using spherical landmarks to indicate a feeder’s position in 3D and examined the search pattern of bumblebees. Additionally, we assessed the ability of bees to estimate the height of a feeder based on local landmarks and global references such as the ground floor.ResultsThe search distribution for a feeder’s position in 3D was less spatially concentrated compared to in 2D. Assessing the bees’ height estimation ability, we found that bees could estimate a feeder’s height using the ground floor as a reference. However, the feeder needed to be sufficiently close to the ground floor for the bees to choose correctly.DiscussionWhen bumblebees are faced with the challenge of foraging in a 3D environment where the height of a food source and landmark cues are important, they demonstrate the ability to learn and return to a specific flower height. This suggests they rely on ventral optic flow for goal height estimation in bumblebees.