bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lineage-tracing reveals an expanded population of NPY neurons in the inferior colliculus
Authors: Silveira Marina A. , Herrera Yoani N. , Beebe Nichole L. , Schofield Brett R. , Roberts Michael T. 
Published: March 2024

AbstractGrowing evidence suggests that neuropeptide signaling shapes auditory computations. We previously showed that neuropeptide Y (NPY) is expressed in the inferior colliculus (IC) by a population of GABAergic stellate neurons and that NPY regulates the strength of local excitatory circuits in the IC. NPY neurons were initially characterized using the NPY-hrGFP reporter mouse, in which hrGFP expression indicates NPY expression at the time of assay, i.e., an expression-tracking approach. However, studies in other brain regions have shown that NPY expression can vary based on a range of factors, suggesting that the NPY-hrGFP mouse might miss NPY neurons not expressing NPY proximal to the experiment date. Here, we hypothesized that neurons with the ability to express NPY represent a larger population of IC GABAergic neurons than previously reported. To test this hypothesis, we used a lineage-tracing approach to irreversibly tag neurons that expressed NPY at any point prior to the experiment date. We then compared the physiological and anatomical features of neurons labeled with this lineage-tracing approach to our prior data set, revealing a larger population of NPY neurons than previously found. In addition, we used optogenetics to test the local connectivity of NPY neurons and found that NPY neurons routinely provide inhibitory synaptic input to other neurons in the ipsilateral IC. Together, our data expand the definition of NPY neurons in the IC, suggest that NPY expression might be dynamically regulated in the IC, and provide functional evidence that NPY neurons form local inhibitory circuits in the IC.
The importance of visual and chemical cues in infection detection and avoidance in a freshwater fish
Authors: Côté Ariane , Binning Sandra A. 
Published: March 2024

AbstractThe characteristics of infected animals, including their smell, appearance, behaviour or sound, can greatly differ from those of uninfected conspecifics. These differences can serve as cues to recognize and avoid infected individuals to minimize the risk of infection. Avoidance of infected conspecifics is a risk-sensitive behaviour that can be influenced by various factors such as sensory cues and environmental parasite load, which both remain poorly understood in fish. We investigated the ability of two populations of wild caught pumpkinseed sunfish (Lepomis gibbosus) to distinguish between conspecifics infected with parasitic worms versus uninfected individuals in two-choice experiments using visual and chemical cues separately. One population was from a lake without parasites (parasite naive) whereas the other population originated from a lake with a high prevalence of trematode and cestode worms (parasite experienced). Both populations preferred to be with conspecifics, regardless of their infection level, over being alone when given visual cues but avoided conspecifics and remained alone when given chemical cues, suggesting that visual and chemical cues are not redundant. Neither population showed any preference between infected and uninfected conspecifics when given visual cues. However, in the presence of chemical cues, there was a great interindividual variation: some fish preferred uninfected conspecifics while others preferred infected ones. On average, naive fish avoided infected conspecifics whereas experienced fish did not show any preferences, suggesting that fish from lakes with high prevalence of infection habituate to infection cues. We suggest that pumpkinseeds use chemical rather than visual cues to discriminate between infected and uninfected conspecifics and make a shoaling decision. Our study highlights the importance of considering different sensory cues as well as parasite load when studying avoidance and shoaling behaviours, especially in a time of modifying sensory landscape and parasites abundance of freshwater ecosystems through global changes.
Evaluation of Plant- and Microbial-Derived Protein Hydrolysates as Substitutes for Fetal Bovine Serum in Cultivated Seafood Cell Culture Media
Authors: Amirvaresi Arian , Ovissipour Reza 
Published: March 2024

AbstractThis study seeks to explore alternatives by substituting or reducing the conventional 10% serum concentration in Zebrafish embryonic stem cell (ESC) growth media with protein hydrolysates sourced from peas, mushrooms, yeast, and algae. Notably, algae exhibited the highest protein content, optimal amino acid balance, and favorable functional properties. When applied at concentrations ranging from 1 to 10 mg/mL, all protein hydrolysates demonstrated pro-apoptotic effects and inhibited cell growth, particularly when used in conjunction with 10% serum. However, concentrations ranging from 0.001 to 0.1 mg/mL displayed anti-apoptotic properties and promoted cell proliferation. The study found that media containing 1% or 2.5% serum, along with 0.01 mg/mL of protein hydrolysates, supported cell growth effectively. Lactate Dehydrogenase (LDH) Activity served as an indicator of cell health and integrity under the specified conditions of protein hydrolysate supplementation. Cells cultured in serum-free media exhibited significantly decreased cell membrane integrity (P < 0.05) compared to those in regular media or media containing low serum (1% and 2.5%) along with low concentrations (0.01 mg/mL) of protein hydrolysates. Furthermore, analysis of Greenhouse Gas emissions (GHG) suggested that media formulations containing 1% serum combined with low concentrations of protein hydrolysates present a sustainable approach for cell-based seafood production.
Uncertainty in Thermosensory Expectations Enhances an Illusion of Pain
Authors: Ehmsen Jesper Fischer , Nikolova Niia , Christensen Daniel Elmstrøm , Banellis Leah , Brændholt Malthe , Courtin Arthur S. , Kraenge Camilla E. , Mitchell Alexandra G. , Deolindo Camila Sardeto , Steenkjær Christian , Vejlø Melina , Mathys Christoph , Allen Micah G. , Fardo Francesca 
Published: March 2024

AbstractThe human brain has a remarkable ability to learn and update its beliefs about the world. Here, we investigate how thermosensory learning shapes our subjective experience of temperature and the misperception of pain in response to harmless thermal stimuli. Through computational modeling, we demonstrate that the brain uses a probabilistic predictive coding scheme to update beliefs about temperature changes based on their uncertainty. We find that these expectations directly modulate the perception of pain in the thermal grill illusion. Quantitative microstructural brain imaging revealed that the myeloarchitecture and iron content of the somatosensory cortex, the posterior insula and the amygdala reflect inter-individual variability in computational parameters related to learning and the degree to which uncertainty modulates illusory pain perception. Our findings offer a new framework to explain how the brain infers pain from innocuous thermal inputs. Our model has important implications for understanding the etiology of thermosensory symptoms in chronic pain conditions.
Glycoengineered recombinant alpha1-antitrypsin results in comparablein vitroandin vivoactivities to human plasma-derived protein
Authors: Rocamora Frances , Schoffelen Sanne , Arnsdorf Johnny , Toth Eric A. , Abdul Yunus , Cleveland Thomas E. , Bjørn Sara Petersen , Min Wu Mina Ying , McElvaney Noel G. , Voldborg Bjørn Gunnar Rude , Fuerst Thomas R. , Lewis Nathan E. 
Published: March 2024

AbstractAlpha-1-antitrypsin (A1AT) is a multifunctional, clinically important, high value therapeutic glycoprotein that can be used for the treatment of many diseases such as alpha-1-antitrypsin deficiency, diabetes, graft-versus-host-disease, cystic fibrosis and various viral infections. Currently, the only FDA-approved treatment for A1AT disorders is intravenous augmentation therapy with human plasma-derived A1AT. In addition to its limited supply, this approach poses a risk of infection transmission, since it uses therapeutic A1AT harvested from donors. To address these issues, we sought to generate recombinant human A1AT (rhA1AT) that is chemically and biologically indistinguishable from its plasma-derived counterpart using glycoengineered Chinese Hamster Ovary (geCHO-L) cells. By deleting nine key genes that are part of the CHO glycosylation machinery and expressing the human ST6GAL1 and A1AT genes, we obtained stable, high producing geCHO-L lines that produced rhA1AT having an identical glycoprofile to plasma-derived A1AT (pdA1AT). Additionally, the rhA1AT demonstratedin vitroactivity andin vivohalf-life comparable to commercial pdA1AT. Thus, we anticipate that this platform will help produce human-like recombinant plasma proteins, thereby providing a more sustainable and reliable source of therapeutics that are cost-effective and better-controlled with regard to purity, clinical safety and quality.
On the recovery of malformed horseshoe crabs across multiple moulting stages
Authors: Bicknell Russell D. C. , Cuomo Carmela 
Published: March 2024

AbstractMalformed horseshoe crabs have been documented for over a century. However, most of these records are anecdotal observations of often striking morphologies recorded in isolation. There is therefore little understanding of how malformations are manifested and how they can develop in the group. Here we consider the moult sequences of three extantLimulus polyphemusindividuals to explore different patterns of malformation development. One specimen with an injured telson demonstrates a gradual recovery of the telson section over three moulting events. The second individual demonstrates a fused thoracetron-telson articulation with a hole for the telson. This individual shows consistent growth of a reduced telson across moults. The third individual shows a thoracetronic injury incurred during at least moult-stage 7 that shows no evidence of recovery over five moulting stages. These records illustrate that horseshoe crab malformation recovery is far more complicated than previously thought. This also suggests that unless an exoskeletal section has functional morphological importance (i.e., the telson), the region is unlikely to recover from an older malformation. From a conservation standpoint, the ability or inability to fully recover from injury affects a horseshoe crab’s ability to survive and/or reproduce in the wild particularly if the injury affects the telson. Given the global decline in horseshoe crab populations and conservation efforts underway, the extent of injuries in extant populations of horseshoe crabs may affect population recovery and should be considered.
CXCR2-mediated recruitment of adaptive NK cells with NKG2C/HLA-E dependent antigen-specific memory enhances tumor killing in ovarian cancer
Authors: Sun Yizhe , Rodgers-Furones Andrea , Gultekin Okan , Khare Shruti , Neo Shi Yong , Shi Wenyang , Galceran Lidia Moyano , Lam Kong-Peng , Dasgupta Ramanuj , Fuxe Jonas , Salehi Sahar , Lehti Kaisa , Sarhan Dhifaf 
Published: March 2024

AbstractNatural killer (NK) cells have emerged as promising effectors in cancer immunotherapy due to their ability to recognize and eliminate tumor cells. To investigate the immunological memory and tumor reactivity of adaptive (a)NK cells in the context of desmoplastic tumors, we used human ovarian cancer as a model. Throughin vitroculture systems resembling dendritic cell (DC)-mediated T cell activation, we demonstrated that aNK cells exhibit antigen-specific cytotoxic responses and memory generation towards ovarian tumor antigens. Furthermore, mature DCs presenting tumor-associated antigens induced the expansion of aNK cells, suggesting antigen-specific proliferation. Single-cell transcriptomics revealed a distinct genetic signature of aNK cells in tumor samples, characterized by a cytotoxic phenotype and interactions with myeloid cells, particularly DCs. The spatial analysis confirmed the intratumoral presence of aNK cells, with higher abundance in the tumor nest compared to conventional (c)NK cells. Functional assays demonstrated the cytotoxicity of expanded aNK cells against autologous ovarian tumors, accompanied by an activated receptor profile. Importantly, aNK cells displayed antigen-specific memory responses towards primary tumors, maintaining specificity over time. Blockade of NKG2C and HLA-E influenced aNK cell recall responses, indicating their roles in the adaptive NK cell immune memory. Additionally, CXCR2 was essential for efficient aNK cell migration toward tumors. These findings shed light on the therapeutic potential of aNK cells in ovarian cancer immunotherapy, highlighting their ability to develop immunological memory and effectively eradicate tumor cells.
Learning and actioning general principles of cancer cell drug sensitivity
Authors: Carli Francesco , Di Chiaro Pierluigi , Morelli Mariangela , Arora Chakit , Bisceglia Luisa , De Oliveira Rosa Natalia , Cortesi Alice , Franceschi Sara , Lessi Francesca , Di Stefano Anna Luisa , Santonocito Orazio , Pasqualetti Francesco , Aretini Paolo , Miglionico Pasquale , Diaferia Giuseppe R. , Giannotti Fosca , Liò Pietro , Duran-Frigola Miquel , Mazzanti Chiara Maria , Natoli Gioacchino , Raimondi Francesco 
Published: March 2024

AbstractHigh-throughput screening platforms for the profiling of drug sensitivity of hundreds of cancer cell lines (CCLs) have generated large datasets that hold the potential to unlock targeted, anti-tumor therapies.In this study, we leveraged these datasets to create predictive models of cancer cells drug sensitivity. To this aim we trained explainable machine learning algorithms by employing cell line transcriptomics to predict the growth inhibitory potential of drugs. We used large language models (LLMs) to expand descriptions of the mechanisms of action (MOA) for each drug starting from available annotations, which were matched to the semantically closest pathways from reference knowledge bases. By leveraging this AI-curated resource, and the interpretability of our model, we demonstrated that pathways enriched for genes crucial for prediction often matched known drug-MOAs and essential genes, suggesting that our models learned the molecular determinants of drug response. Furthermore, we demonstrated that by incorporating only LLM-curated genes associated with MOAs, we enhanced the predictive accuracy of our drug models.To enhance translatability to a clinical setting, we employed a pipeline to align bulk RNAseq from CCLs, used for training the models, to those from patient samples, used for inference. We proved the effectiveness of our approach on TCGA samples, where patients’ best scoring drugs matched those prescribed for their cancer type. We further showed its usefulness by predicting and experimentally validating effective drugs for the patients of two highly lethal solid tumors, i.e. pancreatic cancer and glioblastoma.In summary, our method facilitates the inference and interpretation of cancer cell line drug sensitivity and holds potential to effectively translate them into new cancer therapeutics.Highlights-Interpretable drug-response prediction models were trained on large scale pharmacogenomics data sets (i.e. GDSC and PRISM).-Large language models were used to enhance the curation of biological pathways associated to drugs MOA-Unbiased interpretation of the models demonstrated learning of drug MOAsandgene essentiality-Inference of TCGA cohort samples recovered mono- and combination cancer drug prescriptions and indicate potential repurposing candidates.-Drug candidates predicted from bulk RNAseq samples of pancreatic cancer and glioblastoma were experimentally validated.
SKP2-mediated FBXO2 proteasomal degradation drives hepatocellular carcinoma progression via stabilizing Hsp47
Authors: Xue Cailin , Yang Fei , Bao Guojian , Yan Jiawu , Fu Rao , Zhang Minglu , Ding Jialu , Feng Jiale , Han Jianbo , Qin Xihu , Su Hua , Sun Beicheng 
Published: March 2024

AbstractAccumulating studies highlight that dysregulated E3 ubiquitin ligases are associated with the onset and advancement of cancers. Nevertheless, the impact and mechanism of most E3 ubiquitin ligases on tumorigenesis and tumor metastasis remain poorly understood. Here, we show that loss of FBXO2, an E3 ubiquitin ligase, accelerates hepatocellular carcinoma (HCC) tumor growth and metastasis to the lung through stabilizing heat shock protein 47 (Hsp47). Downregulation of FBXO2, caused by DNA-PKcs-medicated phosphorylation at serine 17 and E3 ligase SKP2-mediated ubiquitination at lysine 79 and subsequent proteasomal degradation, is observed in tumor tissues compared to their parallel non-tumor tissues resected from patients with HCC. Patients whose tumors are enriched for SKP2 or Hsp47 or express low levels of FBXO2 have poor median survival compared to those whose tumors have reversed levels of SKP2, FBXO2 and Hsp47. Together, FBXO2 acts as a tumor suppressor in HCC development. The components of the SKP2-FBXO2-Hsp47 axis provide newly prognostic and therapeutic factors for anti-HCC.
APP and β-amyloid modulate protein aggregation and dissociation from recycling endosomal and exosomal membranes
Authors: Singh Preman J. , Verma Bhavna , Wells Adam , Mendes Cláudia C. , Dunn Dali , Chen Ying-Ni , Oh Jade , Blincowe Lewis , Wainwright S. Mark , Fischer Roman , Fan Shih-Jung , Harris Adrian L. , Goberdhan Deborah C. I. , Wilson Clive 
Published: March 2024

SummarySecretory proteins frequently aggregate into non-soluble dense-core granules (DCGs) in recycling endosome-like compartments prior to release. By contrast, aberrantly processed Aβ-peptides derived from Amyloid Precursor Protein (APP) form pathological amyloidogenic aggregations in late-stage Alzheimer’s Disease (AD) after secretion. By examining livingDrosophilaprostate-like secondary cells, we show both APP and Aβ-peptides affect normal DCG biogenesis. These cells generate DCGs and secreted nanovesicles called Rab11-exosomes within enlarged recycling endosomes. The fly APP homologue, APP-like (APPL), associates with Rab11-exosomes and the compartmental limiting membrane, from where its extracellular domain controls protein aggregation. Proteolytic release of this membrane-associated domain permits aggregates to coalesce into a large central DCG. Mutant Aβ-peptide expression, likeApplloss-of-function, disrupts this assembly step and compartment motility, and increases lysosomal targeting, mirroring pathological events reported in early-stage AD. Our data therefore reveal a physiological role for APP in membrane-dependent protein aggregation, which when disrupted, rapidly triggers AD-relevant intracellular pathologies.
Structural basis of eukaryotic transcription termination by the Rat1 exonuclease complex
Authors: Yanagisawa Tatsuo , Murayama Yuko , Ehara Haruhiko , Goto Mie , Aoki Mari , Sekine Shun-ichi 
Published: March 2024

AbstractThe 5’-3’ exoribonuclease Rat1 (or Xrn2) plays a pivotal role in termination of mRNA transcription by eukaryotic RNA polymerase II (RNAPII). Rat1 forms a complex with its partner proteins, Rai1 and Rtt103, and acts as a “torpedo” to bind transcribing RNAPII and dissociate DNA/RNA from it. Here we report the cryo-electron microscopy structures of a Rat1-Rai1-Rtt103 complex and three Rat1-Rai1-associated RNAPII complexes (type-1, type-1b, and type-2) from the yeastKomagataella phaffii. The Rat1-Rai1-Rtt103 complex structure revealed that Rat1 and Rai1 form a heterotetramer, with a single Rtt103 bound between two Rai1 molecules. In the type-1 complex, Rat1-Rai1 forms a heterodimer and directly binds to the RNA exit site of transcribing RNAPII to extract RNA into the Rat1 nuclease active site. This interaction changes the RNA path in favor of termination (the “pre-termination” state). The type-1b and type-2 complexes have no bound DNA/RNA, likely representing the “post-termination” states. These structures shed light on the mechanism of eukaryotic mRNA transcription termination.
ORCA: Predicting replication origins in circular prokaryotic chromosomes
Authors: van Meel Zoya , Baaijens Jasmijn A. 
Published: March 2024

AbstractThe proximity of genes to the origin of replication plays a key role in replication and transcription-related processes in bacteria. Computational prediction of potential origin locations has an important role in origin discovery, critically reducing experimental costs. We present ORCA (Origin of RepliCation Assessment) as a fast and lightweight tool for the visualisation of nucleotide disparities and the prediction of the location of replication origins. ORCA uses the analysis of nucleotide disparities,dnaA-box regions, and target gene positions to find potential origin sites, and has a random forest classifier to predict which of these sites are likely origins. ORCA’s prediction and visualization capabilities make it a valuablein silicomethod to assist in experimental determination of replication origins. ORCA is written in Python-3.11, works on any operating system with minimal effort, and can process large databases. Full implementation details are provided in the supplementary material and the source code is freely available on GitHub:https://github.com/ZoyavanMeel/ORCA.
Force Reserve Predicts Compensation in Reaching Movement with Induced Shoulder Strength Deficit
Authors: Faity Germain , Barradas Victor R. , Schweighofer Nicolas , Mottet Denis 
Published: March 2024

ABSTRACTFollowing events such as fatigue or stroke, individuals often move their trunks forward during reaching, leveraging a broader muscle group even when only arm movement would suffice. In previous work, we showed the existence of a ‘force reserve’ — a phenomenon where individuals, when challenged with a heavy weight, adjusted their motor coordination to preserve approximately 40% of their shoulder’s force. Here, we investigated if such reserve can predict hip, shoulder, and elbow movements and torques resulting from an induced shoulder strength deficit. We engaged 20 healthy participants in a reaching task with incrementally heavier dumbbells, analyzing arm and trunk movements via motion capture and joint torques through inverse dynamics. We simulated these movements using an optimal control model of a 3-degree-of-freedom upper body, contrasting three cost functions: traditional sum of squared torques, a force reserve function incorporating a nonlinear penalty, and a normalized torque function. Our results demonstrate a clear increase in trunk movement correlated with heavier dumbbell weights, with participants employing compensatory movements to maintain a shoulder force reserve of approximately 40% of maximum torque. Simulations showed that while traditional and reserve functions accurately predicted trunk compensation, only the reserve function effectively predicted joint torques under heavier weights. These findings suggest that compensatory movements are strategically employed to minimize shoulder effort and distribute load across multiple joints in response to weakness. We discuss the implications of the force reserve cost function in the context of optimal control of human movements and its relevance for understanding of compensatory movements post-stroke.NEW & NOTEWORTHYOur study reveals key findings on compensatory movements during upper limb reaching tasks under shoulder strength deficits, as observed post-stroke. Using heavy dumbbells with healthy volunteers, we demonstrate how forward trunk displacement conserves around 40% of shoulder strength reserve during reaching. We show that an optimal controller employing a cost function combining squared motor torque and a nonlinear penalty for excessive muscle activation outperforms traditional controllers in predicting torques and compensatory movements in these scenarios.