bluuebunny/crossref_metadata_2025_split huggingface dataset:
PatientProfiler:A network-based approach to personalized medicine
Authors: Lombardi Veronica , Di Rocco Lorenzo , Meo Eleonora , Venafra Veronica , Di Nisio Elena , Perticaroli Valerio , Nicolaeasa Mihail Lorentz , Cencioni Chiara , Spallotta Francesco , Negri Rodolfo , Sacco Francesca , Perfetto Livia 
Published: February 2025

AbstractDeciphering the intricate mechanisms underlying reprogramming in cancer cells is a crucial challenge in oncology as it holds the key to advance our ability to diagnose and treat cancer patients. For this reason, comprehensive and patient-specific multi-omic characterization of tumor specimens has become increasingly common in clinical practice. While these efforts have advanced our understanding of the molecular mechanisms underlying breast cancer progression, the identification of personalized therapeutic approaches remains a distant goal. The main shortcoming is the absence of a robust computational framework to integrate and interpret the available multi-dimensional data and to drive translational solutions.To fill this gap, we developedPatientProfiler, a computational pipeline that leverages causal interaction data, annotated in our in-house manually-curated resource, SIGNOR, to address how the genetic and molecular background of single patients contributes to the establishment of a malignant phenotype.PatientProfileris an open-source, R-based package composed of several functions that allows multi-omic data analysis and standardization, generation of patient-specific mechanistic models of signal transduction, and extraction of network-based prognostic biomarkers.To benchmark the tool, we retrieved genomic, transcriptomic, (phospho)proteomic, and clinical data derived from 122 treatment-naïve breast cancer biopsies, available at the CPTAC portal. Thanks to this approach, we identified patient-specific mechanistic models (one patient, one network) that recapitulate dysregulated signaling pathways in breast cancer. This collection of models provides valuable insights into the underlying mechanisms of tumorigenesis and disease progression. Moreover, in-depth topological exploration of these networks has allowed us to define seven communities (subnetworks), each associated with a unique transcriptomic signature and a distinct prognostic value.In summary, our work demonstrates thatPatientProfileris a tool for patient-specific network analysis, advancing personalized medicine towards the identification of actionable biomarkers and tailored therapeutic strategies.
High-Throughput Antibody Neutralization Screening in Massively Parallel Droplet Arrays
Authors: Gutierrez-Gonzalez Matias , Fahad Ahmed S. , Delley Cyrille L. , Chung Cheng-Yu , Jin Shuyan , Boyle Nicoleen , de Souza Matheus Oliveira , Pirhanov Azady , Galvez Nicolas M.S. , França Camila T. , Marglous Samantha , Bhagat Evan , Vincent Donovan , Neumeier Daniel , Cao Yi , Doria-Rose Nicole , Reddy Sai T. , Schmidt Aaron G. , Balazs Alejandro B. , Abate Adam R. , DeKosky Brandon J. 
Published: February 2025

AbstractNeutralizing antibodies provide rapid immune defense against infectious diseases, but are difficult to discover at scale because neutralization assays require live reporter cells and soluble monoclonal antibodies. Here we report Droplet Reporter Cell Testing for Neutralization (DrReCT-Neutralization) to screen antibody gene libraries for their ability to neutralize viral infections. We established the necessary engineered cell lines and validated the DrReCT screening platform using synthetic oligoclonal libraries, followed by an example discovery campaign that demonstrated scalable functional antibody data collection against viral diseases.
Miniaturization of Epileptic Abnormal Electrocorticogram Detector Using 3D Convolutional Neural Network
Authors: Yamaji Moemi , Yamamasu Shinjiro , Hirano Yuto , Hayashida Yuki 
Published: February 2025

AbstractEpilepsy is a neurological disorder characterized by sudden and recurrent seizures caused by abnormal electrical activity in the brain. Responsive Neurostimulation (RNS) offers a promising treatment option for patients with drug-resistant epilepsy. Responsive Neurostimulation (RNS) is an implantable device that employs a closed-loop system. It continuously monitors brain activity through electro-corticogram (ECoG) recordings. When the system detects seizure activity, it delivers direct electrical stimulation to the brain to suppress the seizure. Seizure detection algorithms require patient-specific optimization, leading to increased interest in deep learning approaches in recent years. While deeper network architectures generally improve detection accuracy, their implementation in implantable devices is constrained by limited hardware resources and the restricted number of electrode channels available for ECoG monitoring. To ensure the practical feasibility of RNS, it is crucial to systematically minimize both the computational costs of patient-specific deep learning models and the number of connected ECoG electrodes. This study systematically reduced the number of electrode channels and computational costs in seizure detection models by analyzing the spatiotemporal kernels learned by the first convolutional layer of a 3D convolutional neural network (3D CNN) trained on 3D ECoG data. This approach capitalizes on the network’s ability to learn spatial relationships between grid electrodes and the temporal dynamics of ECoG signals. The performance comparison between the downsized seizure detection CNN model and the original CNN model revealed that, for at least some patients, it is possible to maintain inference performance while reducing the model size.
A Systematic Review and Meta-Analysis of the Impact of Tumour Mutation Burden on Survival Outcomes in Solid Tumours
Authors: Meng Aijia , Yuile Alexander , Sim Hao-Wen , Thavaneswaran Subotheni , Noor Humaira , Yeung Jacky , Mehta Ashish , Powell Joseph , Zaman Ashraf 
Published: February 2025

AbstractBackgroundTumour mutation burden (TMB) is an emerging pan-cancer biomarker with potential predictive value for immune checkpoint inhibitor (ICI) therapy outcomes. However, its prognostic significance remains inconsistent due to methodological variability and differing cut-off thresholds. This systematic review and meta-analysis evaluated the impact of TMB on overall survival (OS) and progression-free survival (PFS) across solid tumours.MethodsFollowing PRISMA 2020 guidelines, we systematically searched PubMed, Scopus, ScienceDirect, and Cochrane databases for studies published between 2010 and 2024. Eligible studies reported hazard ratios (HRs) and 95% confidence intervals (CIs) comparing OS and PFS in high versus low TMB cohorts. Heterogeneity was assessed using the I² statistic, and publication bias via funnel plots and Egger’s test.ResultsA total of 5,278 patients across 28 studies were analysed. High TMB was significantly associated with improved OS and PFS, particularly in non-small cell lung cancer (OS: HR = 0.56), gastrointestinal cancers (OS: HR = 0.36), and advanced/recurrent tumours (OS: HR = 0.52). Survival benefits were most pronounced in ICI-treated patients, especially those receiving combination anti-PD-L1/PD-1 and anti-CTLA4 therapy (OS: HR = 0.47; PFS: HR = 0.50). Ultra-high TMB cases had superior outcomes (OS: HR = 0.44) compared to a universal 10 mut/Mb cut-off (OS: HR = 0.58). Variability in TMB measurement across sequencing platforms highlights the need for standardisation.ConclusionHigh TMB is a strong prognostic and predictive biomarker in ICI-treated cancers, yet methodological inconsistencies hinder clinical implementation. Standardising TMB assessment and refining clinically relevant thresholds are essential for optimising its role in precision oncology.PROSPERO registration numberThe protocol of this systematic review is registered on PROSPERO (CRD42024608809).
Restoration of mitochondrial function to metabolically stressed astrocytes by fusion with mesenchymal stromal cells
Authors: Schneider Remy T. , Rowe Matthew R. , Dawson Rebecca H. , Komrskova Katerina , Neuzil Jiri , Berridge Michael V. , Herst Patries M. , McConnell Melanie J. 
Published: February 2025

AbstractMitochondrial networks in eukaryotic cells are dynamic, undergoing fusion, fission, biogenesis and transfer between cells to manage cellular requirements for energy production and biosynthetic components. Mitochondrial transfer has been observed in response to cellular injury and can happen by a variety of mechanisms. To examine whether mitochondria could be restored to injured astrocytes, we established a model of discrete astrocyte-specific, mitochondrial-specific injury in a mixed culture model. Immortalized ρ0astrocytes were generated, then put under lethal metabolic stress by withdrawal of pyruvate and uridine. When cells stressed in this way were grown in the presence of mesenchymal stromal cells, enhanced survival of the ρ0cells was seen, accompanied by the rapid acquisition of an entire mitochondrial networks. Gap-fill ligation and rolling circle amplification for cell-specific mitochondrial genome SNP confirmed that the mitochondrial networks were derived from the mesenchymal stromal donor cells, and both mitochondrial DNA and mitochondrial function were restored to the p0 cells long-term. The presence of two nuclei in the ρ0cells in the early stages of mitochondrial transfer and recovery was observed. This demonstrated that in this instance, the mechanism of mitochondrial rescue was fusion of the ρ0astrocyte and the mesenchymal stromal cell. In support of this, other neural cells were similarly shown to fuse with stressed ρ0astrocytes, suggesting that whole organelles may be donated to restore critical mitochondrial function.
ADrosophilamodel for Costello Syndrome caused by Ras mutation K117R
Authors: Karunaraj Prashath , Cao Emily , Singh Harnoor , Luf Max , Baker Stacey J. , Reddy E Premkumar , Pfleger Cathie M. 
Published: February 2025

ABSTRACTGermline mutations that increase signaling through the Ras pathway can cause developmental disorders called RASopathies. The RASopathy Costello syndrome has been described to present with hallmarks that include short stature, intellectual disability, cardiac issues, and characteristic facial abnormalities and has been associated with gain-of-function mutations in HRas. The most common HRas mutations in Costello Syndrome occur at G12 and G13, but there are also other rare mutation sites such as K117 including HRasK117R. RasK117Rmutations are also found in colorectal cancer.Drosophilastudies modeling gain-of-function in Ras primarily utilize the common cancer-associated mutation G12V, and previousDrosophilaRASopathy models assessing Ras gain-of-function mutations have used human sequences for KRas G12D and HRas G12S. To augment these studies, we characterized the phenotype of engineering the rare gain-of-function mutation K117R in theDrosophilaRas sequence. We report here that constitutive low-level expression of RasK117Rincreased lethality and reduced body size while also causing rough eye and ectopic wing vein phenotypes in those flies that survived to adulthood. Ras pathway inhibitors Trametinib and Rigosertib suppressed the lethality but not the reduced size phenotypes. Trametinib strongly suppressed the K117R wing vein phenotype whereas Rigosertib had only subtle effects. Trametinib is a direct MEK inhibitor. Rigosertib has been reported to have strong effects on PI3K signaling and to indirectly inhibit the Raf-ERK branch. Therefore, this data is consistent with an interpretation that some lethality in the fly RasK117Rmodel depends on elevated signaling through the Raf-ERK branch and potentially some lethality depends on the PI3K branch. In contrast, the lack of effects on the reduced size phenotypes would be consistent with small stature resulting from Raf- and PI3K-independent processes. We propose that this model can be useful for future mechanistic analysis and pharmacological screening and evaluation.
Intratumoral gene delivery of 4-1BBL boosts IL-12-triggered anti-glioblastoma immunity
Authors: Lunavat Taral R. , Nieland Lisa , Looij Sanne M. van de , Reus Alexandra J.E.M. de , Couturier Charles P. , Farran Chadi A. El , Miller Tyler E. , Lill Julia K. , Schübel Maryam , Xiao Tianhe , Ianni Emilio Di , Woods Elliot C. , Sun Yi , Rufino-Ramos David , Solinge Thomas S. van , Mahjoum Shadi , Grandell Emily , Li Mao , Mangena Vamsi , Dunn Gavin P. , Jenkins Russell W. , Mempel Thorsten R. , Breakefield Xandra O. , Breyne Koen 
Published: February 2025

ABSTRACTThe standard of care in high-grade gliomas has remained unchanged in the past 20 years. Efforts to replicate effective immunotherapies in non-cranial tumors have led to only modest therapeutical improvements in glioblastoma (GB).Here, we demonstrate that intratumoral administration of recombinant interleukin-12 (rIL-12) promotes local cytotoxic CD8POST cell accumulation and conversion into an effector-like state, resulting in a dose-dependent survival benefit in preclinical GB mouse models. This tumor-reactive CD8 T cell response is further supported by intratumoral rIL-12-sensing dendritic cells (DCs) and is accompanied by the co-stimulatory receptor 4-1BB expression on both cell types. Given that DCs and CD8POST cells are functionally suppressed in the tumor microenvironments ofde novoand recurrent glioma patients, we tested whether anti-tumor response at the rIL-12-inflamed tumor site could be enhanced with 4-1BBL, the ligand of 4-1BB. 4-1BBL was delivered using an adeno-associated virus (AAV) vector targeting GFAP-expressing cells and resulted in prolonged survival of rIL-12 treated GB-bearing mice.This study establishes that tumor antigen-specific CD8 T cell activity can be directed using an AAV-vector-mediated gene therapy approach, effectively enhancing anti-GB immunity.
APOE4exacerbates glucocorticoid stress hormone-induced tau pathology via mitochondrial dysfunction
Authors: Yu Qing , Du Fang , Goodman Jeffrey , Waites Clarissa L. 
Published: February 2025

AbstractAPOE4is the leading genetic risk factor for Alzheimer’s disease, and chronic stress is a leading environmental risk factor. Studies suggest thatAPOE4confers vulnerability to the behavioral and neuropathological effects of chronic stress, representing a potential mechanism by which this genetic variant accelerates Alzheimer’s onset and progression. Whether and howAPOE4-mediated stress vulnerability manifests in neurons of the hippocampus, a brain region particularly susceptible to stress and Alzheimer’s pathology, remains unexplored.Using a combination ofin vivoandin vitroexperiments in humanizedAPOE4andAPOE3knockin mice and primary hippocampal neurons from these animals, we investigate whether and howAPOE4confers sensitivity to glucocorticoids, the main stress hormones.We find that a major hallmark of stress/glucocorticoid-induced brain damage, tau pathology (i.e., tau accumulation, hyperphosphorylation, and spreading) is exacerbated inAPOE4versusAPOE3mice. Moreover,APOE4animals exhibit underlying mitochondrial dysfunction and enhanced glucocorticoid receptor activation in the hippocampus, factors that likely contribute to tau pathogenesis in both the presence and absence of stress/glucocorticoids. Supporting this concept, we show that opening of the mitochondrial permeability transition pore drives mitochondrial dysfunction and tau pathology inAPOE4mice, and that pharmacological inhibition of pore opening is protective against ApoE4-mediated mitochondrial damage, tau phosphorylation and spreading, and downstream hippocampal synapse loss. These findings shed light on the mechanisms of stress vulnerability inAPOE4carriers and identify the mitochondrial permeability transition pore as a potential therapeutic target for ameliorating Alzheimer’s pathogenesis in this population.
Directed evolution of a SelB variant that does not require a SECIS element for function
Authors: Ishida Satoshi , Gundlach Arno , Kosonocky Clayton W. , Ellington Andrew D. 
Published: February 2025

AbstractIn bacteria the incorporation of selenocysteine is achieved through the interaction of the selenocysteine specific elongation factor (SelB) with selenocysteine-charged tRNASecand a selenocysteine insertion sequence (SECIS) element adjacent to an opal stop codon in a mRNA. The more generalized, SECIS-independent incorporation of selenocysteine is of interest because of the high nucleophilicity of selenium and the greater durability of diselenide bonds. It is likely that during the course of evolution selenocysteine insertion originally arose without the presence of a SECIS element, relying only on SelB. Herein we undertake experiments to evolve an ancestral version of SelB that is SECIS-independent and show that not only can this protein (SelB-v2) generally incorporate selenocysteine across from stop codons, but also that the new, orthogonal translation factor can be repurposed to other amino acids, such as serine. Given the delicate energetic balancing act already performed by EF-Tu, this achievement raises the possibility that greatly expanded genetic codes that relied in part on SelB-based loading can now be contrived.
Mac/Lac-tosylceramide regulates intestinal homeostasis and secretory cell fate commitment by facilitating Notch signaling
Authors: Tang Kebei , Li Xuewen , Hu Jiulong , Shi Jingyuan , Li Yumei , Chen Yansu , Yin Chang , Wang Fengchao , Xi Rongwen 
Published: February 2025

AbstractCell-to-cell communication via Delta-Notch signaling is widely used in various tissues and organs to regulate development and patterning; however, the mechanisms regulating Notch signaling for precise cell fate decisions remain poorly understood. Similar to mammals, the intestinal stem cells (ISCs) in the adultDrosophilamidgut generate both absorptive and secretory cell progeny, guided by differential levels of Notch activation. Here we performed a forward genetic screen inDrosophilaand identified glucosylceramide synthase (GlcT), a rate-limiting enzyme for glycosphingolipid (GSL) production, whose mutation causes the development of secretory cell tumors. Genetic analysis of the GSL synthesis pathway, combined with metabolite rescue experiments, revealed that the tumor formation is linked to a deficiency in Mactosylceramide/Lactosylceramide. This deficiency impaired the endocytic recycling of the Delta, subsequently reducing Notch signaling activation. Conditional knockout ofUGCG, the mammalian ortholog ofGlcT, in mouse small intestine caused an excessive differentiation of goblet cells, phenotypes similar to these caused by Notch inhibition. Our study suggests an evolutionarily conserved role for a specific GSL metabolite in modulating Notch signaling during stem cell fate decisions and provides a molecular connection between ceramide metabolism and Notch signaling in regulating tissue homeostasis and tumor formation.
rTCT: Rodent Triangle Completion Task to facilitate translational study of path integration
Authors: Duncan Stephen , Rehman Sulaiman , Sagen Vladislava , Choi Irene , Lawrence Sami , Kalani Om , Gold Lisette , Goldman Lillian , Ramlo Sophia , Stickel Kylene , Layfield Dylan , Wolbers Thomas , Tiganj Zoran , Newman Ehren L. 
Published: February 2025

AbstractPath integration is navigation in the absence of environmental landmarks and is a primary cognitive mechanism underlying spatial memory. Path integration performance is primarily assessed in humans using the Triangle Completion Task (TCT). In humans, TCT has shown promise for the early diagnosis of Alzheimer’s disease. In rodents, however, path integration is assessed using a wide variety of tasks but none of which currently provide a homologue for the TCT. As rodents are routinely used as preclinical models, homologous path integration tasks that result in comparable performance metrics between species are important. In the present study we developed and tested a novel rodent version of the triangle completion task to enhance cross species comparability of path integration performance. Rats were able to comprehend and perform the task. A group of Alzheimer’s disease model rats (TgF344-AD) exhibited similar path integration performance to their wild-type littermates; however, analysis of behavioural structure suggests use of differing behavioural strategies. This work establishes a novel rodent homologue of the triangle completion task, facilitating enhanced reverse translational study of human path integration.
A Meta-analysis of Perceptual Pseudoneglect reveals the Functional Anatomy of Perceptual Judgements
Authors: Abdul-Nabi Mura , Niemeier Matthias 
Published: February 2025

AbstractMajor evidence for a right-hemisphere dominance of the brain in spatial and/or attentional tasks comes from lesion studies in patients with spatial neglect. However, the neuroanatomy of the different forms of neglect remains a matter of debate, and it remains unclear how dysfunctions in neglect relate to intact processes. In the healthy brain, perceptual pseudoneglect is the equivalent of neglect as observed in paradigms such as the line bisection task. Therefore, the current study investigated the intact functional anatomy of perceptual pseudoneglect using a meta-analysis to compensate for some of the limitations of individual imaging studies. We collated the data from 24 articles that tested 952 participants with a range of paradigms (landmark task, line bisection, grating-scales task, and number line task) obtaining 337 foci. Using Activation Likelihood Estimation (ALE) we identified a right-hemisphere biased network of cortical areas, including superior and intraparietal regions, the intraoccipital sulcus together with other occipital regions, as well as inferior frontal areas that were associated with perceptual pseudoneglect in partial agreement with lesion studies in patients with neglect. The present results are consistent with a framework of neural computations that explains the neural and behavioural asymmetries of perceptual pseudoneglect as due the need for to an integrated representation of spatial information during perceptual judgments.