bluuebunny/crossref_metadata_2025_split huggingface dataset:
Patient Centric Summarization of Radiology Findings using Large Language Models
Authors: Tariq Amara , Fathizadeh Sam , Ramaswamy Gokul , Trivedi Shubham , Urooj Aisha , Tan Nelly , Stib Matthew T. , Patel Bhavik N. , Banerjee Imon 
Published: February 2024

ABSTRACTObjectiveDevelop automated AI models for patient-sensitive summarization of radiology reports. Level of medical education or socio-economic background of a patient may dictate their level of understanding of medical jargon. Inability to understand primary findings from a radiology report may lead to unnecessary anxiety among patients or result in missed follow up.Materials and MethodsComputed tomography exams of chest were selected as a use-case for this study. Approximately 7K chest CT reports were collected from Mayo Clinic Enterprise. Summarization model was built on the T5 large language model (LLM) as its text-to-text transfer architecture is intuitively suited for abstractive text summarization, resulting in a model size of ~0.77B. Noisy groundtruth for model training was collected by prompting LLaMA 13B model.ResultsWe recruited both experts (board-certified radiologists) and laymen to manually evaluate summaries generated by model. Model-generated summaries rarely missed information as marked by majority opinion of radiologists. Laymen indicated 63% improvement in their understanding by reading layman summaries generated by the model. Comparative study with zero-shot performance of LLaMA indicated that LLaMA hallucinated and missed information 3 and 4 times more often, respectively, than the proposed model.DiscussionThe proposed patient-sensitive summarization model can generate summaries for radiology reports understandable by patients with vastly different levels of medical knowledge. In addition, task-specific training allows for more reliable performance compared to much larger off-the-shelf models.ConclusionsThe proposed model could improve adherence to follow up treatment suggested by radiology reports by increasing patients’ level of understanding of these reports.
SYNERGISTIC ANTITUMOR EFFECT OF NAPROXEN AND SORAFENIB IN HEPATOCELLULAR CARCINOMA
Authors: Akar Etkin , Beyge Seyma Unsal , Kahraman Deniz Cansen 
Published: February 2024

ABSTRACTHepatocellular carcinoma (HCC) is one of the most prevalent and deadliest cancer types in the world. Due to the inevitable development of resistance to classical chemotherapy and current targeted therapies, combination therapy became an important strategy. Recently drug repurposing studies have emphasized the potential of non-steroidal anti-inflammatory drugs (NSAIDs) in exhibiting anti-tumor activities in different cancer types, including HCC. In this study we explored the synergistic bioactivity of naproxen in combination with sorafenib in HCC cell lines. Network reconstruction analysis, performed to identify key factors mediating the synergistic therapeutic effects of sorafenib and naproxen revealed apoptosis pathways enriched in both sorafenib and naproxen networks. CAPN2 emerged as the common gene shared between the two networks.In vitrostudies on Huh7 and Mahlavu cells revealed that induction of apoptosis was associated mainly with the PI3K/AKT pathway inhibition. Furthermore, combined treatment of naproxen and sorafenib led to the downregulation of CAPN2 expression, suggesting a potential link to apoptosis and PI3K/AKT pathway regulation, which needs further investigation. In conclusion, combining sorafenib with naproxen presents a promising strategy with potential synergistic therapeutic benefits in HCC.
Limb, not touch location, is coded in 3D space
Authors: Heed Tobias , Burbach Julia , Rödenbeck Nele , Habets Boukje , Fuchs Xaver 
Published: February 2024

AbstractSkin location of touch is said to be recoded, by default, into a 3D-spatial location. Here, human participants received tactile stimulus pairs on a common or on two different limbs and judged either whether stimuli had occurred on the same limb, or on a common side of space. Misaligning skin and 3D-spatial codes through limb crossing had a stronger effect on spatial than on limb judgments, contradicting the notion that the 3D location of touch is readily available. Additionally, crossing effects were significantly reduced when stimulus pairs lay in a common dermatome, suggesting that limb choice was based on anatomical, not 3D-spatial, stimulus information. These results suggest that it is limbs, not touch, which are coded in 3D space. Commonly observed errors in reporting where touch occurred on the body depend on confusion due to where the touched limb usually resides with the spatial layout of the currently action-relevant limbs.
Substrate Stiffness Reshapes Layer Architecture and Biophysical Features of Human Induced Pluripotent Stem Cells to Modulate their Differentiation Potential
Authors: Llewellyn Jack , Charrier Anne , Helfer Emmanuèle , Dono Rosanna 
Published: February 2024

AbstractLineage-specific differentiation of human induced pluripotent stem cells (hiPSCs) relies on complex interactions between biochemical and physical cues. Here we investigated the ability of hiPSCs to undergo lineage commitment in response to inductive signals and assessed how this competence is modulated by substrate stiffness. We showed that Activin A-induced hiPSC differentiation into mesendoderm and its derivative, definitive endoderm is enhanced on gel-based substrates softer than glass. This correlated with changes in tight junction formation and extensive cytoskeletal remodeling. Further, live imaging andin silicostudies suggested changes in cell motility, shape, forces and pressures, underlie hiPSC layer reshaping on soft substrates. Finally, we repurposed an ultra-soft silicone gel, which may provide a suitable substrate for culturing hiPSCs at physiological stiffnesses. Our results provide mechanistic insight into how epithelial mechanics dictate the hiPSC response to chemical signals, and provide a tool for their efficient differentiation in emerging stem cell therapies.
OPA1and disease-causing mutants perturb mitochondrial nucleoid distribution
Authors: Macuada J. , Molina-Riquelme I. , Vidal G. , Pérez-Bravo N. , Vásquez-Trincado C. , Aedo G. , Lagos D. , Horvath R. , Rudge T.J. , Cartes-Saavedra B. , Eisner V. 
Published: February 2024

ABSTRACTOptic atrophy protein 1 (OPA1) mediates inner mitochondrial membrane (IMM) fusion and cristae organization. Mutations in OPA1 cause autosomal dominant optic atrophy (ADOA), a leading cause of blindness. Cells from ADOA patients show impaired mitochondrial fusion, cristae structure, bioenergetic function, and mitochondrial DNA (mtDNA) integrity. The mtDNA encodes electron transport chain subunits and is packaged into nucleoids spread within the mitochondrial population. Nucleoids interact with the IMM, and their distribution is tightly linked to mitochondrial fusion and cristae shaping. Yet, little is known about the physio-pathological relevance of nucleoid distribution. We studied the effect of OPA1 and ADOA-associated mutants on nucleoid distribution using high-resolution confocal microscopy. We applied a novel model incorporating the mitochondrial context, separating nucleoid distribution into the array in the mitochondrial population and intramitochondrial longitudinal distribution. Opa1-null cells showed decreased mtDNA levels and nucleoid abundance. Also, loss of Opa1 lead to an altered distribution of nucleoids in the mitochondrial population, loss of cristae periodicity, and altered nucleoids to cristae proximity partly rescued by OPA1 isoform 1. Overexpression of WT OPA1 or ADOA-causing mutants c.870+5G>A or c.2713C>T in WT cells, showed perturbed nucleoid array in the mitochondria population associated with cristae disorganization. Opa1-null and cells overexpressing ADOA mutants accumulated mitochondria without nucleoids. Interestingly, intramitochondrial nucleoid distribution was only altered in Opa1-null cells. Altogether, our results highlight the relevance of OPA1 in nucleoid distribution in the mitochondrial landscape and at a single-organelle level and shed light on new components of ADOA etiology.
Hypoxia and TNF-alpha modulate extracellular vesicle release from human induced pluripotent stem cell-derived cardiomyocytes
Authors: Viola Margarida , Bebelman Maarten P. , Maas Renee G. C. , Verweij Frederik J. , Seinen Cor S. , de Jager Saskia C. A. , Vader Pieter , Pegtel D. Michiel , Sluijter Joost P. G. 
Published: February 2024

AbstractExtracellular vesicles (EVs) have emerged as important mediators of intercellular communication in the heart under homeostatic and pathological conditions, such as myocardial infarction (MI). However, the basic mechanisms driving cardiomyocyte-derived EV (CM-EV) production following stress are poorly understood. In this study, we generated human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) that express NanoLuc-tetraspanin reporters. These modified hiPSC-CMs allow for robust quantification of CM-EV secretion from small numbers of cells without the need for time-consuming EV isolation techniques. We subjected these cells to a panel of small molecules to study their effect on CM-EV biogenesis and secretion under basal and stress-associated conditions. We observed that EV biogenesis is context-dependent in hiPSC-CMs. Nutrient starvation decreases CM-EV secretion while hypoxia increases the production of CM-EVs in a nSmase2-dependent manner. Moreover, the inflammatory cytokine TNF-α increased CM-EV secretion through a process involving NLRP3 inflammasome activation and mTOR signaling. Here, we detailed for the first time the regulatory mechanisms of EV biogenesis in hiPSC-CMs upon MI-associated stressors.
Multiplex Single-Cell Bioprinting for Engineering of Heterogeneous Tissue Constructs with Subcellular Spatial Resolution
Authors: Helms Haylie R. , Oyama Kody A. , Ware Jason P. , Ibsen Stuart D. , Bertassoni Luiz E. 
Published: February 2024

AbstractTissue development, function, and disease are largely driven by the spatial organization of individual cells and their cell-cell interactions. Precision engineered tissues with single-cell spatial resolution, therefore, have tremendous potential for next generation disease models, drug discovery, and regenerative therapeutics. Despite significant advancements in biofabrication approaches to improve feature resolution, strategies to fabricate tissues with the exact same organization of individual cells in their native cellular microenvironment have remained virtually non-existent to date. Here we report a method to spatially pattern single cells with up to eight cell phenotypes and subcellular spatial precision. As proof-of-concept we first demonstrate the ability to systematically assess the influence of cellular microenvironments on cell behavior by controllably altering the spatial arrangement of cell types in bioprinted precision cell-cell interaction arrays. We then demonstrate, for the first time, the ability to produce high-fidelity replicas of a patient’s annotated cancer biopsy with subcellular resolution. The ability to replicate native cellular microenvironments marks a significant advancement for precision biofabricated in-vitro models, where heterogenous tissues can be engineered with single-cell spatial precision to advance our understanding of complex biological systems in a controlled and systematic manner.
Quantifying Fit-for-Purpose in Real World Data: Data Grading and FitQ Scores
Authors: Jackson Michael L. , Manickam Raj , Derieg Dan , Gombar Saurabh , Low Yen S 
Published: February 2024

AbstractReal-world evidence (RWE), derived from analysis of RWD, is increasingly used to guide decisions in drug development, regulatory oversight, and clinical decision-making. Evaluating the fitness-for-purpose of RWD sources is one key component to generating transparent RWE. Here, we demonstrate tools that fill two gaps in the data grading literature. These are the need for quantitative data grading scores, and the need for scoring mechanisms that can be run in automated fashion and at scale. The Real World Data Score (RWDS) rates the overall quality and completeness of a RWD source across a range of customizable metrics. The Fitness Quotient (FitQ) grades how well a specific data source fits a specific RWE query. In concert, these tools give producers and consumers of RWE evidence to assess the quality of the underlying RWD.
Investigation of the Relationship Between Calpain and HMGB1/TLR4/NF-KB Signalling Pathway in Multiple Sclerosis and Other Demyelinating Diseases
Authors: Uluc Firdevs , Turkoglu Sule Aydin , Celik Bihter Gokce , Karabork Seyda , Kayis Seyit Ali 
Published: February 2024

ABSTRACTBackgroundTo develop more effective treatments for demyelinating diseases, it is essential to identify the associated signaling pathways and factors. The objective of this study was to investigate the possible correlation between Calpain-1 (CAPN1) and Calpain-2 (CAPN2) with the HMGB1/TLR4/NF-κB signaling pathway and to evaluate the influence of these proteins on Interleukin 17A (IL-17A) and Interleukin 37 (IL-37) cytokines in individuals with newly diagnosed and untreated Multiple Sclerosis (MS) and Neuromyelitis Optica Spectrum Disorder (NMOSD).MethodsIn this pilot study, a total of 73 newly diagnosed patients were recruited, including 36 with MS, 9 with NMOSD, and an unhealthy control group composed of 28 individuals with Pseudotumour cerebri (PTC). To ensure accuracy and transparency, all groups’ demographic and clinical characteristics were meticulously described. ELISA technique was utilized to compare levels of CAPN1, CAPN2, HMGB1, TLR4, and NF-KB, as well as IL-17A and IL-37 cytokines, between the case and the unhealthy control groups. The expectation from these findings is to provide valuable insights into the pathophysiological mechanisms of these neurological disorders, possibly opening the door to novel therapeutic perspectives.ResultsIn patients with MS, the levels of CAPN1 were found to be higher than those in patients with NMOSD and PTC. Similarly, the level of CAPN2 was significantly higher in patients with MS than in patients with NMOSD and higher in patients with PTC than in patients with NMOSD. There were no differences in the levels of HMGB1, TLR4, NF-κB, IL-17A, and IL-37 between the groups. Age and gender did not affect any of the parameters. In the MS group, both CAPN1 and CAPN2 showed positive correlation with HMGB1, TLR4, and NF-κB levels.ConclusionsIt may be suggested that CAPN1 may exhibit greater efficacy than CAPN2 during the initial stages of neuroinflammation. To obtain deeper and more guiding results of the varying levels of CAPN1 and CAPN2, and their relationship with the HMGB1/TLR4/NF-κB signaling pathway, it is advisable to conductin-vivoandin-vitroprospective studies featuring CAPN1-specific inhibitors with larger study groups.
Tumor-derived hypoxic small extracellular vesicles promote endothelial cell migration and tube formation via ALS2/Rab5/β-catenin signaling
Authors: Silva Patricio , Hernández Nadia , Tapia Héctor , Gaete-Ramírez Belén , Flores Tania , Herrera Daniela , Cáceres-Verschae Albano , Varas-Godoy Manuel , Torres Vicente A. 
Published: February 2024

AbstractTumor hypoxia has been associated with cancer progression, angiogenesis, and metastasis via modifications in the release and cargo composition of extracellular vesicles secreted by tumor cells. Indeed, hypoxic extracellular vesicles are known to trigger a variety of angiogenic responses via different mechanisms. We recently showed that hypoxia promotes endosomal signaling in tumor cells via HIF-1α-dependent induction of the guanine exchange factor ALS2, which activates Rab5, leading to downstream events involved in cell migration and invasion. Since Rab5-dependent signaling is required for endothelial cell migration and angiogenesis, we explored the possibility that hypoxia promotes the release of small extracellular vesicles containing ALS2, which in turn activate Rab5 in recipient endothelial cells leading to pro-angiogenic properties. In doing so, we found that hypoxia promoted ALS2 expression and incorporation as cargo within small extracellular vesicles, leading to subsequent transfer to recipient endothelial cells, promoting cell migration, tube formation and downstream Rab5 activation. Consequently, ALS2-containing small extracellular vesicles increased early endosome size and number in recipient endothelial cells, which was followed by subsequent sequestration of components of the β-catenin destruction complex within endosomal compartments, leading to stabilization and nuclear localization of β-catenin. These events converged in the expression of β-catenin target genes involved in angiogenesis. Knockdown of ALS2 in donor-tumor cells, which precluded its incorporation into small extracellular vesicles, prevented Rab5-downstream events and endothelial cell responses, which depended on Rab5 activity and guanine exchange factor activity of ALS2. These findings indicate that vesicular ALS2, secreted in hypoxia, promotes endothelial cell events leading to angiogenesis. Finally, these events might explain how tumor angiogenesis proceeds in hypoxic conditions.
High Shear Stress Reduces ERG Causing Endothelial-Mesenchymal Transition and Pulmonary Arterial Hypertension
Authors: Shinohara Tsutomu , Moonen Jan-Renier , Chun Yoon Hong , Lee-Yow Yannick C. , Okamura Kenichi , Szafron Jason M. , Kaplan Jordan , Cao Aiqin , Wang Lingli , Taylor Shalina , Isobe Sarasa , Dong Melody , Yang Weiguang , Guo Katherine , Franco Benjamin D , Pacharinsak Cholawat , Pisani Laura J. , Saitoh Shinji , Mitani Yoshihide , Marsden Alison L. , Engreitz Jesse M. , Körbelin Jakob , Rabinovitch Marlene 
Published: February 2024

ABSTRACTPathological high shear stress (HSS, 100 dyn/cm2) is generated in distal pulmonary arteries (PA) (100-500 μm) in congenital heart defects and in progressive PA hypertension (PAH) with inward remodeling and luminal narrowing. Human PA endothelial cells (PAEC) were subjected to HSS versus physiologic laminar shear stress (LSS, 15 dyn/cm2). Endothelial-mesenchymal transition (EndMT), a feature of PAH not previously attributed to HSS, was observed. H3K27ac peaks containing motifs for an ETS-family transcription factor (ERG) were reduced, as was ERG-Krüppel-like factors (KLF)2/4 interaction and ERG expression. Reducing ERG by siRNA in PAEC during LSS caused EndMT; transfection of ERG in PAEC under HSS prevented EndMT. An aorto-caval shunt was preformed in mice to induce HSS and progressive PAH. Elevated PA pressure, EndMT and vascular remodeling were reduced by an adeno-associated vector that selectively replenished ERG in PAEC. Agents maintaining ERG in PAEC should overcome the adverse effect of HSS on progressive PAH.
Derivation and simulation of a computational model of active cell populations: How overlap avoidance, deformability, cell-cell junctions and cytoskeletal forces affect alignment
Authors: Leech Vivienne , Kenny Fiona N , Marcotti Stefania , Shaw Tanya J , Stramer Brian M , Manhart Angelika 
Published: February 2024

AbstractCollective alignment of cell populations is a commonly observed phenomena in biology. An important example are aligning fibroblasts in healthy or scar tissue. In this work we derive and simulate a mechanistic agent-based model of the collective behaviour of actively moving and interacting cells, with a focus on understanding collective alignment. The derivation strategy is based on energy minimisation. The model ingredients are motivated by data on the behaviour of different populations of aligning fibroblasts and include: Self-propulsion, overlap avoidance, deformability, cell-cell junctions and cytoskeletal forces. We find that there is an optimal ratio of self-propulsion speed and overlap avoidance that maximises collective alignment. Further we find that deformability aids alignment, and that cell-cell junctions by themselves hinder alignment. However, if cytoskeletal forces are transmitted via cell-cell junctions we observe strong collective alignment over large spatial scales.
The Recurrent Temporal Restricted Boltzmann Machine Captures Neural Assembly Dynamics in Whole-Brain Activity
Authors: Quiroz Monnens Sebastian , Peters Casper , Hesselink Luuk Willem , Smeets Kasper , Englitz Bernhard 
Published: February 2024

AbstractAnimal behaviour alternates between stochastic exploration and goal-directed actions, which are generated by the underlying neural dynamics. Previously, we demonstrated that the compositional Restricted Boltzmann Machine (cRBM) can decompose whole-brain activity of larval zebrafish data at the neural level into a small number (∼100-200) of assemblies that can account for the stochasticity of the neural activity (van der Plas et al., eLife, 2023). Here we advance this representation by extending to a combined stochastic-dynamical representation to account for both aspects using the Recurrent Temporal RBM (RTRBM) and transfer-learning based on the cRBM estimate. We demonstrate that the functional advantage of the RTRBM is captured in the temporal weights on the hidden units, representing neural assemblies, for both simulated and experimental data. Our results show that the temporal expansion outperforms the stochastic-only cRBM in terms of generalisation error and achieves a more accurate representation of the moments in time. Lastly, we demonstrate that we can identify the original time-scale of assembly dynamics by estimating multiple RTRBMs at different temporal resolutions. Together, we propose that RTRBMs are a valuable tool for capturing the combined stochastic and time-predictive dynamics of large-scale data sets.
Prefrontal cortex temporally multiplexes slow and fast dynamics in value learning and memory
Authors: Hashemirad Seyed Reza , Abbaszadeh Mojtaba , Ghazizadeh Ali 
Published: February 2024

AbstractPrevious studies have revealed segregated circuitries in basal ganglia for fast learning that enables value adaptability and slow forgetting which underlies stable value memories. However, the mechanisms mediating the conflict between value adaptability vs stability remain unknown. Using a reinforcement learning paradigm involving a brief value reversal for objects with previously stable values, we predicted and confirmed a novel behavioral manifestation of the conflict between adaptability vs stability namely the spontaneous recovery of old values in macaque monkeys. Furthermore, we found that individual neurons in ventrolateral prefrontal cortex (vlPFC) temporally multiplexed slow and fast processes in their early and late responses to objects. The local field potential in vlPFC also reflected the two-rate system. These findings implicate vlPFC as a plexus for the interactions between adaptability vs stability in reinforcement learning and suggest spontaneous recovery of past values caused by a two-rate system to mediate relapse to old habits.