bluuebunny/crossref_metadata_2025_split huggingface dataset:
Modeling CAR Response at the Single-Cell Level Using Conditional Optimal Transport
Authors: Driessen Alice , Born Jannis , Castellanos Rueda Rocio , Reddy Sai T. , Rapsomaniki Marianna 
Published: November 2024

AbstractChimeric Antigen Receptor (CAR) T cell therapy is a promising area of cancer immunotherapy. However, many challenges such as loss of persistence, T cell exhaustion, and therapy associated toxicities hamper further advancement of CAR T cell therapy. Therefore, recent efforts have focused on designing improved CARs that show better therapeutic characteristics. However, it is unfeasible to test all CAR variants in lab-based assays as CARs consist of multiple intracellular signalling domains. This results in over 100’000 possible variants. We leverage computational modeling to navigate this vast combinatorial space by learning the relationship between CAR design and T cell functionality, thereby proposing promising CAR T cell designs. CAR T cells expressing different variants can be viewed as cells that underwent different perturbations. Neural Optimal Transport is an upcoming field that can model single cell perturbations and predict unseen cells and conditions. In this work we leverage the conditional Monge Gap to model the response to CAR expression at a single-cell level and generate gene expression of cells that express an unseen CAR design. We show that CAR OT (CAROT) significantly outperforms the baseline for gene expression prediction for in-distribution CAR variants, with distinct gene expression patterns per CAR that capture biological characteristics. When predicting unseen CAR variants, we demonstrate promising results in terms of gene expression prediction and show the model learns gene expression patterns linked to domains in the training set. This work demonstrates that optimal transport may support discovery and development of new CAR T cell designs.
DIA-BERT: pre-trained end-to-end transformer models for enhanced DIA proteomics data analysis
Authors: Liu Zhiwei , Liu Pu , Sun Yingying , Nie Zongxiang , Zhang Xiaofan , Zhang Yuqi , Chen Yi , Guo Tiannan 
Published: November 2024

AbstractData-independent acquisition mass spectrometry (DIA-MS) plays an increasingly important role in quantitative proteomics. Here, we introduce DIA-BERT, a software tool that leverages a transformer-based pre-trained artificial intelligence (AI) model for the analysis of DIA proteomics data. Over 276 million of high-quality peptide precursors extracted from existing DIA-MS files were used for training the identification model, while 34 million peptide precursors from synthetic DIA-MS files were used for training the quantification model. Compared to DIA-NN, DIA-BERT led to on average 54% more protein identifications and 37% more peptide precursors in five different human cancer (cervical cancer, pancreatic adenocarcinoma, myosarcoma, gallbladder cancer, and gastric carcinoma) sample sets with a high degree of quantitative accuracy. This study highlights the potential of utilizing pre-trained models and synthetic datasets to advance DIA proteomics analysis.
Spectrum of γ-Secretase dysfunction as a unifying predictor of ADAD age at onset acrossPSEN1,PSEN2andAPPcausal genes
Authors: Gutiérrez Fernández Sara , Gan Oria Cristina , Annaert Wim , Ringman John M. , Fox Nick C. , Ryan Natalie S. , Chávez-Gutiérrez Lucía 
Published: November 2024

AbstractAutosomal Dominant Alzheimer’s Disease (ADAD), caused by mutations in Presenilins (PSEN1/2) and Amyloid Precursor Protein (APP) genes, typically manifests before age 65. Age at symptom onset (AAO) is relatively consistent among carriers of the samePSEN1mutation, but more variable forPSEN2andAPPvariants, with these mutations associated with later AAOs thanPSEN1. Understanding this clinical variability is crucial for developing predictive models and tailored interventions in ADAD.Biochemicalin vitroassessment of γ-secretase function is valuable in evaluatingPSEN1variant pathogenicity, disease onset and progression. Here, we examined Aβ profiles’ relationships to AAO across causal genes. Our analysis showed linear correlations between mutation-induced shifts in Aβ profiles and AAO forPSEN2andAPPmutations. Integration withPSEN1data revealed parallel but shifted correlations, indicating a common pathogenic mechanism with gene-specific onset timing shifts.Our data support a unified model of ADAD pathogenesis wherein γ-secretase dysfunction and shifts in Aβ profiles define disease onset. This biochemical analysis of ADAD causality and established quantitative relationships deepen our understanding of ADAD pathogenesis, offering potential for predictive AAO modelling with implications for clinical practice, genetic research and development of therapeutic strategies modulating γ-secretase across ADAD forms and potentially more broadly in AD.SummaryWe examined the relationships between (full) Aβ peptide profiles and age at symptom onset (AAO) across all Alzheimer’s disease causal genes. Our findings establish a quantitative framework for mutation’s pathogenicity assessment and AAO prediction; with implications for clinical practice, genetic counselling, fundamental and translational research.
Conformational changes, excess area, and elasticity of the Piezo protein-membrane nanodome from coarse-grained and atomistic simulations
Authors: Dixit Sneha , Noé Frank , Weikl Thomas R. 
Published: November 2024

AbstractThe mechanosensitive ion channels Piezo 1 and 2 induce a curved protein-membrane nanodome that flattens with increasing membrane tension γ. The tension-induced flattening of the nanodome is associated with Piezo activation and driven by the energy γΔAwhere ΔAis the excess area of the curved nanodome relative to its planar projected area. Based on extensive coarse-grained and atomistic simulations of membrane-embedded Piezo 1 and 2 proteins, we report here an an excess area ΔAfor the Piezo protein-membrane nanodome of about 40 nm2in tensionless membranes, and a half-maximal reduction of ΔAat tension values of about 3 to 4 mN/m, which is within the range of experimentally determined values for the half-maximal activation of Piezo 1. In line with recent experimental investigations of Piezo proteins in cell membranes and membrane vesicles, the membrane-embedded Piezo proteins adopt conformations in our simulations that are significantly less curved than the protein conformation in the detergent micelles of cryo-EM structures. An elasticity analysis of the nanodome shapes and protein conformations obtained from our simulations leads to an elastic model for Piezo activation that distinguishes the different energy components of the protein and the membrane in the tension-induced flattening of the nanodome.
Aurora kinase A promotes trained immunity via regulation of endogenous S-adenosylmethionine metabolism
Authors: Li Mengyun , Jin Huan , Liu Yongxiang , Wang Zining , Li Lin , Wang Tiantian , Wang Xiaojuan , Zhang Hongxia , Huo Bitao , Yu Tiantian , Wang Shoujie , Zhao Wei , Liu Jinyun , Huang Peng , Cui Jun , Xia Xiaojun 
Published: November 2024

AbstractInnate immune cells can acquire a memory phenotype, termed trained immunity, but the mechanism underlying the regulation of trained immunity remains largely elusive. Here, we demonstrate that inhibition of Aurora kinase A (AurA) dampens trained immunity induced by β-glucan. ATAC-seq and RNA-seq analysis reveals that AurA inhibition restricts chromatin accessibility of genes associated with inflammatory pathways such as JAK-STAT, TNF and NF-κB pathways. Specifically, AurA inhibition promotes nuclear localization of FOXO3 and the expression of glycine N-methyltransferase (GNMT), a key enzyme responsible for adenosylmethionine (SAM) consumption. Metabolomic analysis confirms a reduction in SAM level upon AurA inhibition. As a result of SAM deficiency, trained mouse macrophages exhibit decreased H3K4me3 and H3K36me3 enrichment on gene regions ofIl6 and Tnfα. Additionally, the tumor inhibition effect of β-glucan is notably abolished by AurA inhibition. Together, our findings identify an essential role of AurA in regulating trained immunity via a methylation-dependent manner by maintaining endogenous SAM level through mTOR-FOXO3-GNMT axis.
Hunger modulates exploration through suppression of dopamine signaling in the tail of striatum
Authors: Kamath Tarun , Lodder Bart , Bilsel Eliana , Green Isobel , Dalangin Rochelin , Capelli Paolo , Raghubardayal Michelle , Legister Jessie , Hulshof Lauren , Wallace Janet Berrios , Tian Lin , Uchida Naoshige , Watabe-Uchida Mitsuko , Sabatini Bernardo L. 
Published: November 2024

SummaryCaloric depletion leads to behavioral changes that help an animal find food and restore its homeostatic balance. Hunger increases exploration and risk-taking behavior, allowing an animal to forage for food despite risks; however, the neural circuitry underlying this change is unknown. Here, we characterize how hunger restructures an animal’s spontaneous behavior as well as its directed exploration of a novel object. We show that hunger-induced changes in exploration are accompanied by and result from modulation of dopamine signaling in the tail of the striatum (TOS). Dopamine signaling in the TOS is modulated by internal hunger state through the activity of agouti-related peptide (AgRP) neurons, putative “hunger neurons” in the arcuate nucleus of the hypothalamus. These AgRP neurons are poly-synaptically connected to TOS-projecting dopaminergic neurons through the lateral hypothalamus, the central amygdala, and the periaqueductal grey. We thus delineate a hypothalamic-midbrain circuit that coordinates changes in exploration behavior in the hungry state.
“Generation of morphologically distinct astrocyte subtypes from human iPSCs reveals a link between glial shape, function and reactivity”
Authors: O’Toole Kelly , Guetta Ludovica , Urbanaviciute Paulina , Suklai Pacharaporn , Wright Chandler , Fisher Theodore , Liddelow Shane , Luisier Raphaelle , Marzi Sarah J , Serio Andrea 
Published: November 2024

AbstractAstrocyte morphologyin vivois heterogeneous across different subtypes and dynamically changes in response to various stimuli. However, several questions on the mechanistic links between shape and function remain unanswered. Here, we developed an efficient protocol to generate pure populations of morphologically distinct human astrocytesin vitro, which we used for a systematic analysis of shape-function relationships. We performed a structural, molecular, and functional characterization of these populations and highlighted how their distinct morphologies mirror distinct functional and transcriptional patterns at the population level. We were also able to both correlate gene expression profiles of these morphologically distinct astrocyte subtypes within vivoastrocytes in the human brain, and to validate our findings with primary isolated murine astrocytes in vitro. Moreover, we show that the observed morphological differences are correlated with changes in key cytoskeletal proteins, which offers a potential link to the observed functional differences. Finally, we demonstrated that different morphological subtypes of astrocytes have distinct reactivity responses to a common stimulus. This study offers a glimpse into the shape-function dynamics of human astrocytes, highlighting potential mechanistic links between cytoskeletal usage and astrocyte function, while also providing tools and datasets that will be useful for further studies into human glial biology in health and disease.
Ethanolamine-induced assembly of microcompartments is required forFusobacterium nucleatumvirulence
Authors: Franklin Dana S. , Chen Yi-Wei , Chen Yimin , Wittchen Manuel , Agnew Angela , Luu Alexis , Whitelegge Julian P , Zhou Z Hong , Tauch Andreas , Das Asis , Ton-That Hung 
Published: November 2024

ABSTRACTMany bacteria metabolize ethanolamine as a nutrient source through cytoplasmic organelles named bacterial microcompartments (BMCs). Here we investigated the molecular assembly, regulation, and function of BMCs inFusobacterium nucleatum– a Gram-negative oral pathobiont that is associated with adverse pregnancy outcomes. TheF. nucleatumgenome harbors a conserved ethanolamine utilization (eut) locus with 21 genes that encode several putative BMC shell proteins and a two-component signal transduction system (TCS), in addition to the enzymes for ethanolamine transport and catabolism. We show that the expression of most of these genes as well as BMC formation is highly increased in wild type fusobacteria when cultured in the presence of ethanolamine as a nutrient source. Deletion of the response regulator EutV eliminated this induction ofeutmRNAs and BMCs, thus demonstrating that BMC formation is transcriptionally regulated by the TCS EutV-EutW in response to ethanolamine. Mass spectrometry of isolated BMCs unveiled the identity of the constituent proteins EutL, EutM1, EutM2, and EutN. Consistent with the role of these proteins in BMC assembly and metabolism, deletion ofeutN,eutL/eutM1/eutM2, oreutL/eutM1/eutM2/eutNnot only affected BMC formation, but also ethanolamine utilization, causing cell growth defects with ethanolamine as nutrient. BMCs also assembled in fusobacteria cultured with placental cells or the culture media, a process that is dependent on the BMC shell proteins. Significantly, we show that theeutNmutant is defective in inducing preterm birth in a mouse model. Together, these results establish that BMC-mediated metabolism of ethanolamine is critical for fusobacterial virulence.IMPORTANCEThe oral anaerobeFusobacterium nucleatumcan spread to distal internal organs, such as the colon and placenta, and thereby promote the development of colorectal cancer and induce preterm birth, respectively. Yet, how this opportunistic pathogen adapts to the various metabolically distinct host cellular niches remains poorly understood. We demonstrated here that this microbe assembles specialized metabolic organelles, termed bacterial microcompartments (BMCs), to utilize environmental ethanolamine (EA) as a key environmental nutrient source. The formation ofF. nucleatumBMCs, containing BMC shell proteins EutLM1M2N, is controlled by a two-component system, EutV-EutW, responsive to EA. Significantly, this ability ofF. nucleatumto form BMCs in response to EA is crucial for its pathogenicity evidenced by the fact that the genetic disruption of BMC formation reduces fusobacterial virulence in a mouse model of preterm birth.
The Transcriptional Gradient in Negative-Strand RNA Viruses Suggests a Common RNA Transcription Mechanism
Authors: King Connor R. , Berezin Casey-Tyler , Munsky Brian , Peccoud Jean 
Published: November 2024

AbstractWe introduce a novel model of nonsegmented negative-strand RNA virus (NNSV) transcription. Previous models have relied on polymerase behavioral differences in the highly conserved intergenic sequences. Our model hypothesizes the transcriptional gradient in NNSVs is explained through a simple model with two parameters associated with the viral polymerase. Most differences in expression can be attributed to the processivity of the polymerase while additional attenuation occurs in the presence of overlapping genes. This model reveals a correlation between polymerase processivity and genome length, which is consistent with the universal entry of polymerases through the 3’ end of the genome. Using this model, it is now possible to predict the transcriptional behavior of NNSVs from genotype alone, revolutionizing the design of novel NNSV variants for biomedical applications.
Somatic gonad morphogenesis inC. elegansrequires the heterochronic pathway acting through HBL-1
Authors: Minutillo Madeleine , Kemper Kevin , Ivanova Maria , Pianin Erika , Moss Eric G. 
Published: November 2024

AbstractCharacteristically, the heterochronic genes control the stage-specific timing of developmental events throughout the developingCaenorhaditis eleganslarva while gonad development occurs mostly normally. In a few cases, some timing regulators lead to detectable variations in gonad development with little to no effect on fertility. We found that a double mutant of alin-28null allele andhbl-1hypomorphic allele results in a catastrophic failure of gonad morphogenesis resulting in sterility. This defect includes a high-penetrance disruption of normal gonad arm migration as well as frequent absence of one or both spermathecae. We demonstrate that the abnormal gonad morphology and novel sterility phenotype is ultimately due to loss ofhbl-1activity in larval development. The mechanism of howlin-28positively influenceshbl-1activity is unresolved. We demonstrate a direct interaction between the RNA-binding protein LIN- 28 and the 5’UTR oflin-46, and in turn, a direct interaction between LIN-46 and two zinc fingers of HBL-1. Nevertheless, our genetic analysis indicates thatlin-46accounts for only part oflin-28’s regulation ofhbl-1and that some portion oflin-28’s effect is independent oflin-46.
Corporate governance and SME performance: Is technological capability a missing link?
Authors: Muhammad Hussain , Migliori Stefania , Consorti Augusta 
Published: November 2024

Purpose
This paper aims to examine the role of technological capability in the relationship between corporate governance and small and medium-sized enterprise (SME) performance.

Design/methodology/approach
Using panel data comprising 1,357 European SMEs from 2014 to 2020, this paper examines how technological capability acts as a mediator and moderator within the governance-performance nexus.

Findings
The results show a positive and significant link between corporate governance mechanisms and SME performance, as well as between technological capability and SME performance. In addition, this paper show that technological capability plays a crucial role in moderating and mediating the governance-performance relationship. Specifically, technological capability accentuates the positive effects of board size, the presence of outside directors and concentrated ownership on SME performance. Conversely, it attenuates the positive impacts of CEO duality and board gender diversity on SME performance. These results highlight corporate governance mechanisms and technological capability’s crucial role in significantly influencing SME performance.

Practical implications
The results suggest that SMEs should prioritize not only the implementation of effective corporate governance mechanisms but also the strategic utilization of technological innovations to boost performance. European policymakers are encouraged to enact supportive policies on technological innovation to strengthen the governance-performance dynamic.

Originality/value
This study contributes to the governance-performance literature by offering new insights into the critical role of technological capability, which has been previously explored in partial and fragmented ways.
A straightforward method for estimating evolutionary power spectral density of non-stationary typhoon wind speed
Authors: Ma Xingliang , Liu Zhen 
Published: November 2024

PurposeA precise estimation of the evolutionary power spectral density (EPSD) of typhoon wind speed is a difficult and significant undertaking in the analysis of turbulence effects on large-expansive structures. A majority of the prevailing EPSD estimation techniques rely on complex signal processing methodologies, such as wavelet decomposition, Hilbert–Huang transformation and time-varying autoregressive moving average (ARMA) model. However, these approaches often pose challenges in terms of comprehensibility and practical implementation for engineers. In light of this issue, the present study introduces a straightforward and effective EPSD estimation method tailored specifically for typhoon wind speed, aiming to facilitate its understanding and application in engineering contexts.Design/methodology/approachFirstly, the mathematical model of a uniformly modulated non-stationary process is employed to represent the typhoon wind speed. Secondly, the reverse arrangement test serves as an auxiliary tool in conjunction with wavelet transform or empirical mode decomposition, aiding in the determination of the optimal slowly varying mean wind speed. Thirdly, Kernel regression technique is utilized to discern the time-dependent standard deviation of wind speed fluctuations. Finally, the power spectral density (PSD) of wind speed residuals is computed to facilitate the estimation of the EPSD.FindingsFirstly, the reverse arrangement test-assisted approach enables the determination of an optimal time-dependent mean from the candidate results obtained through discrete wavelet transform (DWT) and empirical mode decomposition (EMD). Secondly, the application of the Kernel regression technique facilitates accurate identification of the time-dependent variance from the fluctuating wind speed data. Thirdly, due to the influence of the extreme weather, the Gaussianity of the reduced turbulent fluctuations in typhoon wind is easily disturbed, resulting in the obvious non-Gaussian features.Originality/valueThis paper employs the mathematical model of uniformly modulated non-stationary process to characterize typhoon wind speeds and then proposes a straightforward and efficient method for estimating the EPSD of typhoon wind. The accuracy and efficacy of the presented estimation method are verified using the field-measured wind speed data from Typhoon Rammasun. The proposed EPSD estimation method for typhoon wind exhibits suitability for engineering applications owing to its simplicity and computational efficiency.
Uncertainty analysis of MHD oscillatory flow of ternary nanofluids through a diverging channel: a comparative study of nanofluid composites
Authors: Jaismitha B. , Sasikumar J. 
Published: November 2024

Purpose
This study aims to investigate the heat and mass transfer characteristics of a temperature-sensitive ternary nanofluid in a porous medium with magnetic field and the Soret–Dufour effect through a tapered asymmetric channel. The ternary nanofluid consists of Boron Nitride Nanotubes (BNNT), silver (Ag) and copper (Cu) nanoparticles, with a focus on understanding the thermal behaviour and performance across mono, hybrid and tri-hybrid nanofluids. This paper also examines the thermal behaviour of MHD oscillatory nanofluid flow and carries out an uncertainty analysis of the model using the Taguchi method.

Design/methodology/approach
The governing equations for this system are transformed into coupled linear partial differential equations using non-similarity transformations and solved numerically with the Crank–Nicolson scheme. The impact of temperature sensitivity at three distinct temperatures (5°C, 20°C and 60°C) is incorporated to analyse variations in viscosity and Prandtl number. The study also examines the combined effects of Soret–Dufour numbers and thermal radiation on heat and mass transfer within the nanofluid.

Findings
The results demonstrate that the inclusion of BNNT, Ag and Cu nanoparticles significantly enhances heat and mass transfer rate, with copper nanoparticles showing superior performance in terms of skin friction and heat transfer rates. The Soret and Dufour effects play critical roles in modulating heat and mass diffusion within tri-hybrid nanofluids. The study reveals that temperature sensitivity alters heat and mass transfer characteristics depending on the temperature range, with pronounced variations at elevated temperatures. The influence of thermal radiation and the Peclet number is found to significantly impact temperature distribution and overall heat transfer performance within the asymmetric channel.

Originality/value
To the best of the authors’ knowledge, this study is the first to analyse the heat and mass diffusion in a ternary nanofluid composed of BNNT, Ag and Cu nanoparticles, considering porous media, oscillatory flow and thermal radiation within a tapered asymmetric channel. The research extends to a novel examination of temperature sensitivity in mono, hybrid and tri-hybrid nanofluids at varying temperature gradients. Furthermore, a comparative analysis of skin friction and heat transfer rates between copper, alumina and ferro composites is presented for optimising the nanofluid performance.