bluuebunny/crossref_metadata_2025_split huggingface dataset:
SUMO Inhibition Plus CD40 Agonism Increases Anti-Tumor Immunogenicity Through Interferon Mediated Macrophage Activation
Authors: Li Kevin , Courelli Asimina , Lee Hyojae James , de Mendoza Tatiana Hurtado , Martsinkovskiy Alexei , Mose Evangeline , Patel Jay , Ng Izzy , Sun Siming , Tharuka Mohottige Don Neranjan , Tiriac Hervé , Chen Yuan , Lowy Andrew M. 
Published: December 2024

AbstractResistance to immunotherapy is a cardinal feature of pancreatic ductal adenocarcinoma (PDAC). Inhibition of Small Ubiquitin-like MOdifier (SUMO), a post-translational modification with important immune regulatory functions, augments responsiveness to immunotherapy in non-PDAC models via pro-immunogenic effects on myeloid cells, cancer cells, and T-cells. Recently, it has been reported that SUMO inhibition has direct immunogenic effects on PDAC. Here, we report that the novel combination of SUMO inhibition with a small molecule, TAK-981, plus antibody-mediated CD40 agonism improves survival in an aggressive orthotopic mouse model of PDAC by enhancing anti-tumoral immunogenicity. This combination amplifies CD8+ T-cell tumor infiltration and induces significant changes among macrophages. TAK-981 also leads to enhanced cancer specific MHC-I expression bothin vitroandin vivoby augmenting interferon signaling. We show that the improvement in survival is mediated by macrophages. Our findings show that SUMO inhibition complements CD40 agonism to enhance immune activity in PDAC via interferon signaling, improving survival in an aggressive pre-clinical model of PDAC and translating previous findings to a characteristically immunosuppressive and highly aggressive solid malignancy.
BindingGYM: A Large-Scale Mutational Dataset Toward Deciphering Protein-Protein Interactions
Authors: Lu Wei , Zhang Jixian , Gu Ming , Zheng Shuangjia 
Published: December 2024

AbstractProtein-protein interactions are crucial for drug discovery and understanding biological mechanisms. Despite significant advances in predicting the structures of protein complexes, led by AlphaFold3, determining the strength of these interactions accurately remains a challenge. Traditional low-throughput experimental methods do not generate sufficient data for comprehensive benchmarking or training deep learning models. Deep mutational scanning (DMS) experiments provide rich, high-throughput data; however, they are often used incompletely, neglecting to consider the binding partners, and on a per-study basis without assessing the generalization capabilities of fine-tuned models across different assays. To address these limitations, we collected over ten million raw DMS data points and refined them to half a million high-quality points from twenty-five assays, focusing on protein-protein interactions. We intentionally excluded non-PPI DMS data pertaining to intrinsic protein properties, such as fluorescence or catalytic activity. Our dataset meticulously pairs binding energies with thesequencesandstructures of all interacting partnersusing a comprehensive pipeline, recognizing that interactions inherently involve at least two proteins. This curated dataset serves as a foundation for benchmarking and training the next generation of deep learning models focused on protein-protein interactions, thereby opening the door to a plethora of high-impact applications including understanding cellular networks and advancing drug target discovery and development.
Scaling diversity, abundance and energy: The Equilibrium Theory of Biodiversity Dynamics
Authors: Storch David , Okie Jordan G. 
Published: December 2024

AbstractThis preprint of a book chapter presents the newly proposed Equilibrium Theory of Biodiversity Dynamics (ETBD), whose aim is to conceptualize large-scale dynamics of species richness via addressing the population size-dependence of speciation and extinction rates, the resulting diversity-dependence of these rates, and their modulation by the environment. It provides the most general framework for understanding large-scale biodiversity patterns such as the latitudinal diversity gradient (LDG) and temporal patterns of biodiversity changes. The theory has been published elsewhere in its full form that includes all the derivations (Okie & Storch 2004, American Naturalisthttps://doi.org/10.1086/733103), but here it is presented in a simpler and user-friendly way, focusing on its major implications comprising macroecological scaling relationships between energy (or resource) availability, species richness and community abundance.
Deep Ensemble Model for Quantitative Optical Property and Chromophore Concentration Images of Biological Tissues
Authors: Yan Bingbao , Song Bowen , Ge Chang , Yin Xinman , Jia Wenchao , Mu Gen , Zhao Yanyu 
Published: December 2024

AbstractThe ability to quantify widefield tissue optical properties (OPs, i.e., absorption and scattering) has major implications on the characterization of various physiological and disease processes. However, conventional image processing methods for tissue optical properties are either limited to qualitative analysis, or have tradeoffs in speed and accuracy. The key to quantification of optical properties is the extraction of amplitude maps from reflectance images under sinusoidal illumination of different spatial frequencies. Conventional three-phase demodulation (TPD) method has been demonstrated for the mapping of OPs, but it requires as many as 14 measurement images for accurate OP extraction, which leads to limited throughput and hinders practical translation. Although single-phase demodulation (SPD) method has been proposed to map OPs with a single measurement image, it is typically subject to image artifacts and decreased measurement accuracy. To tackle those challenges, here we develop a deep ensemble model (DEM) that can map tissue optical properties with high accuracy in a single snapshot, increasing the measurement speed by 14× compared to conventional TPD method. The proposed method was validated with measurements on an array of optical phantoms,ex vivotissues, andin vivotissues. The errors for OP extraction were 0.83 ± 5.0% for absorption and 0.40 ± 1.9% for reduced scattering, dramatically lower than that of the state-of-the-art SPD method (2.5 ± 15% for absorption and -1.2 ± 11% for reduced scattering). It was further demonstrated that while trained with data from a single wavelength, the DEM can be directly applied to other wavelengths and effectively obtain optical property and chromophore concentration images of biological tissues. Together, these results highlight the potential of DEM to enable new capabilities for quantitative monitoring of tissue physiological and disease processes.
MerQuaCo: a computational tool for quality control in image-based spatial transcriptomics
Authors: Martin Naomi , Olsen Paul , Quon Jacob , Campos Jazmin , Cuevas Nasmil Valera , Nagra Josh , VanNess Marshall , Maltzer Zoe , Gelfand Emily C , Oyama Alana , Gary Amanda , Wang Yimin , Alaya Angela , Ruiz Augustin , Reynoldson Cade , Bielstein Cameron , Pom Christina Alice , Huang Cindy , Slaughterbeck Cliff , Liang Elizabeth , Alexander Jason , Ariza Jeanelle , Malone Jocelin , Melchor Jose , Colbert Kaity , Brouner Krissy , Shulga Lyudmila , Reding Melissa , Latimer Patrick , Sanchez Raymond , Barta Stuard , Egdorf Tom , Madigan Zachary , Pagan Chelsea M , Close Jennie L , Long Brian , Kunst Michael , Lein Ed S , Zeng Hongkui , McMillen Delissa , Waters Jack 
Published: December 2024

ABSTRACTImage-based spatial transcriptomics platforms are powerful tools often used to identify cell populations and describe gene expression in intact tissue. Spatial experiments return large, high-dimension datasets and several open-source software packages are available to facilitate analysis and visualization. Spatial results are typically imperfect. For example, local variations in transcript detection probability are common. Software tools to characterize imperfections and their impact on downstream analyses are lacking so the data quality is assessed manually, a laborious and often a subjective process. Here we describe imperfections in a dataset of 641 fresh-frozen adult mouse brain sections collected using the Vizgen MERSCOPE. Common imperfections included the local loss of tissue from the section, tissue outside the imaging volume due to detachment from the coverslip, transcripts missing due to dropped images, varying detection probability through space, and differences in transcript detection probability between experiments. We describe the incidence of each imperfection and the likely impact on the accuracy of cell type labels. We develop MerQuaCo, open-source code that detects and quantifies imperfections without user input, facilitating the selection of sections for further analysis with existing packages. Together, our results and MerQuaCo facilitate rigorous, objective assessment of the quality of spatial transcriptomics results.
Whole mitochondrial genome analysis ofAedes aegyptireveal association withWolbachiainfection
Authors: Gupta Bhavna , Sumitha Melveettil Kishor , Pandiyan G Navaneetha , Kalimuthu Mariapillai , Paramasivan Rajaiah , Rahi Manju 
Published: December 2024

AbstractThe mitochondrial genomes (mitogenomes) of nineAedes aegyptisamples from India were analysed along with 34 mitogenomes from global samples retrieved from GenBank. The mitogenome size of Indian samples ranged from 15,730 bp to 16,374 bp. A total of 199 genetic variants were identified among Indian samples, with the majority (90%) occurring in protein-coding genes, followed by rRNA and tRNA genes. Phylogenetic analysis of the 43 genomes revealed two major clades. The similar clustering pattern was observed in the traditional mitochondrial markers for which extensive global data is available, indicating that individual mitochondrial markers ofAe. aegyptishare the common genealogy as reflected by the complete mitogenome. In addition to exploring genetic diversity, we investigated the relationship of these two mitochondrial clades withWolbachiainfection. Our analysis revealed thatWolbachia-infected samples were predominantly located within one of the mitochondrial clades, suggesting a potential association between specific mitochondrial lineage andWolbachiainfection. This analysis demonstrates the extent of genetic diversity inAe. aegyptimitogenome and highlights how this diversity is associated withWolbachiainfection, a maternally inherited endosymbiont. These findings have implications for the effectiveness ofWolbachia-based mosquito control strategies.
Protein2Text: Providing Rich Descriptions for Protein Sequences
Authors: Dotan Edo , Lyubman Iris , Bacharach Eran , Pupko Tal , Belinkov Yonatan 
Published: December 2024

AbstractUnderstanding the functionality of proteins has been a focal point of biological research due to their critical roles in various biological processes. Unraveling protein functions is essential for advancements in medicine, agriculture, and biotechnology, enabling the development of targeted therapies, engineered crops, and novel biomaterials. However, this endeavor is challenging due to the complex nature of proteins, requiring sophisticated experimental designs and extended timelines to uncover their specific functions. Public large language models (LLMs), though proficient in natural language processing, struggle with biological sequences due to the unique and intricate nature of biochemical data. These models often fail to accurately interpret and predict the functional and structural properties of proteins, limiting their utility in bioinformatics. To address this gap, we introduce BetaDescribe, a collection of models designed to generate detailed and rich textual descriptions of proteins, encompassing properties such as function, catalytic activity, involvement in specific metabolic pathways, subcellular localizations, and the presence of particular domains. The trained BetaDescribe model receives protein sequences as input and outputs a textual description of these properties. BetaDescribe’s starting point was the LLAMA2 model, which was trained on trillions of tokens. Next, we trained our model on datasets containing both biological and English text, allowing biological knowledge to be incorporated. We demonstrate the utility of BetaDescribe by providing descriptions for proteins that share little to no sequence similarity to proteins with functional descriptions in public datasets. We also show that BetaDescribe can be harnessed to conductin-silicomutagenesis procedures to identify regions important for protein functionality without needing homologous sequences for the inference. Altogether, BetaDescribe offers a powerful tool to explore protein functionality, augmenting existing approaches such as annotation transfer based on sequence or structure similarity.
Zymoseptoria triticistealth infection is facilitated by stage-specific down-regulation of a β-glucanase
Authors: Rebaque Diego , Carrasco-López Cristian , Krishnan Parvathy , López Gemma , López-Cobos Sergio , de Salas Felipe , Meile Lukas , Lorrain Cécile , Largo-Gosens Asier , McDonald Bruce A. , Vilaplana Francisco , Martinez Maria Jesus , Mélida Hugo , Molina Antonio , Sánchez-Vallet Andrea 
Published: December 2024

AbstractPlant cell walls constitute a major defence barrier against pathogens, although it is unclear how specific cell wall components impact pathogen colonisation. Pathogens secrete cell wall degrading enzymes (CWDEs) to facilitate plant colonisation, but damaged, infected cells are often a source of cell wall-derived oligosaccharides that trigger host immunity. The mechanisms by which pathogens minimize the release of cell wall-derived oligosaccharides while colonizing the host remain to be elucidated. We combined biochemical, molecular genetics and transcriptomic analyses to functionally characterize a glycoside hydrolase (ZtGH45) from the wheat pathogenZymoseptoria tritici.ZtGH45gene is expressed during the necrotrophic phase of the fungus, coinciding with an accumulation of wheat β-1,3/1,4-mixed-linked glucan (MLG)-derived oligosaccharides. We show that overexpression ofZtGH45enhances β-1,3/1,4-glucan hydrolysis and the derived oligosaccharides trigger an immune response in wheat, which hindersZ. triticivirulence. The results demonstrate that tight regulation ofZtGH45is critical for the infection process to prevent early accumulation of MLG oligosaccharides that would prematurely induce host immunity counterbalancing fungal virulence. We suggest that the balance between plant cell wall degradation by fungal CWDE and the release of immunogenic wall-derived oligosaccharides governs the outcome of host invasion by pathogens.
ERGA-BGE Reference Genome of the Striped Field Mouse (Apodemus agrarius), a Widespread and Abundant Species in Central and Eastern Europe
Authors: Janžekovič Franc , Buzan Elena , Bončina Aja , Escudero Nuria , Fernández Rosa , Böhne Astrid , Monteiro Rita , Aguilera Laura , Gut Marta , Ferreira Francisco Câmara , Cruz Fernando , Gómez-Garrido Jèssica , Alioto Tyler S. , Haggerty Leanne , Martin Fergal , De Panis Diego 
Published: December 2024

AbstractThe reference genome ofApodemus agrariusprovides a valuable resource for phylogenetic studies of rodents, particularly mice, and for understanding factors that influence the geographical distribution of the species across East Asia and East Europe. A total of 25 contiguous chromosomal pseudomolecules were assembled from the genome sequence (23 autosomes and 2 sex chromosomes). This chromosome-level assembly encompasses 2.6 Gb, composed of 242 contigs and 60 scaffolds, with contig and scaffold N50 values of 35 Mb and 119 Mb, respectively.
Epigenetic remodeling and 3D chromatin reorganization governed by NKX2-1 drive neuroendocrine prostate cancer
Authors: Lu Xiaodong , Keo Viriya , Cheng Irina , Xie Wanqing , Gritsina Galina , Wang Juan , Jin Qiushi , Jin Peng , Yue Feng , Sanda Martin G. , Corces Victor , Altemose Nicolas , Zhao Jonathan C. , Yu Jindan 
Published: December 2024

ABSTRACTA significant number of castration-resistant prostate cancer (CRPC) evolve into a neuroendocrine (NE) subtype termed NEPC, leading to resistance to androgen receptor (AR) pathway inhibitors and poor clinical outcomes. Through Hi-C analyses of a panel of patient-derived xenograft tumors, here we report drastically different 3D chromatin architectures between NEPC and CRPC samples. Such chromatin re-organization was faithfully recapitulated in vitro on isogenic cells undergoing NE transformation (NET). Mechanistically, neural transcription factor (TF) NKX2-1 is selectively and highly expressed in NEPC tumors and is indispensable for NET across various models. NKX2-1 preferentially binds to gene promoters, but it interacts with chromatin-pioneering factors such as FOXA2 at enhancer elements through chromatin looping, further strengthening FOXA2 binding at NE enhancers. Conversely, FOXA2 mediates regional DNA demethylation, attributing to NE enhancer priming and inducing NKX2-1 expression, forming a feed-forward loop. Single-cell multiome analyses of isogenic cells over time-course NET cells identify individual cells amid luminal-to-NE transformation, exhibiting intermediate epigenetic and transcriptome states. Lastly, NKX2-1/FOXA2 interacts with, and recruits CBP/p300 proteins to activate NE enhancers, and pharmacological inhibitors of CBP/p300 effectively blunted NE gene expression and abolished NEPC tumor growth. Thus, our study reports a hierarchical network of TFs governed by NKX2-1 in regulating the 2D and 3D chromatin re-organization during NET and uncovers a promising therapeutic approach to eradicate NEPC.
Bayesian Perspective for Orientation Estimation in Cryo-EM and Cryo-ET
Authors: Xu Sheng , Balanov Amnon , Bendory Tamir 
Published: December 2024

AbstractAccurate orientation estimation is a crucial component of 3D molecular structure reconstruction, both in single-particle cryo-electron microscopy (cryo-EM) and in the increasingly popular field of cryo-electron tomography (cryo-ET). The dominant method, which involves searching for an orientation with maximum cross-correlation relative to given templates, falls short, particularly in low signal-to-noise environments. In this work, we propose a Bayesian framework to develop a more accurate and flexible orientation estimation approach, with the minimum mean square error (MMSE) estimator as a key example. This method effectively accommodates varying structural conformations and arbitrary rotational distributions. Through simulations, we demonstrate that our estimator consistently outperforms the cross-correlation-based method, especially in challenging conditions with low signal-to-noise ratios, and offer a theoretical framework to support these improvements. We further show that integrating our estimator into the iterative refinement in the 3D reconstruction pipeline markedly enhances overall accuracy, revealing substantial benefits across the algorithmic workflow. Finally, we show empirically that the proposed Bayesian approach enhances robustness against the “Einstein from Noise” phenomenon, reducing model bias and improving reconstruction reliability. These findings indicate that the proposed Bayesian framework could substantially advance cryo-EM and cryo-ET by enhancing the accuracy, robustness, and reliability of 3D molecular structure reconstruction, thereby facilitating deeper insights into complex biological systems.
Role of Dynamin 2 in mitochondrial fission and cell cycle regulation:Dysregulation of a miR-124-3p-STAT3-DNM2-Drp1-RGCC pathway connects fission and cell proliferation in pulmonary arterial hypertension
Authors: Dasgupta Asish , Chen Kuang-Hueih , Wu Danchen , Yerramilli V. Siddartha , Lima Patricia D.A. , Martin Ashley Y. , Ott Benjamin P. , Mewburn Jeffrey D. , Tian Lian , Al-Qazazi Ruaa , Emon Isaac M. , Colpman Pierce , Jefferson Lindsay , Noordhof Curtis , Jones Oliver , Hindmarch Charles C.T. , Archer Stephen L. 
Published: December 2024

AbstractIntroductionDynamin-related protein 1 (Drp1) activation increases mitochondrial fission and cell cycle progression in hyperproliferative cells, termedmitotic fission. However, the diameter of a fission apparatus comprised solely of Drp1 and its binding partners appears insufficient to complete fission. Moreover, the mechanism linking fission to cell cycle progression is unknown, suggesting an additional mediator in the terminal steps of mitotic fission.HypothesisThe large GTPase, dynamin 2 (DNM2), interacts with Drp1 to complete mitochondrial fission and regulate cell cycle progression.CorollaryDNM2 is epigenetically upregulated in pulmonary arterial smooth muscle cells in pulmonary arterial hypertension (PAH PASMC).MethodsMitochondrial morphology, protein colocalization and mitochondrial fission sites were assessed using super-resolution microscopy. Protein-protein interaction was confirmed using immunoprecipitation. The role of DNM2’s GTPase domain in mitochondrial targeting was studied by heterologous expression of truncated constructs. Transcriptomic changes from silencing DNM2 in PAH PASMC were measured by RNA-seq. DNM2 expression was quantified in normal and PAH PASMC and lungs from PAH patients and rats with monocrotaline (MCT) and SU5416/hypoxia (Su/Hx)-induced PAH. The effects of manipulating DNM2 on cell proliferation, cell cycle progression and apoptosis were assessed by flow cytometry. siRNA targeting DNM2 was nebulized to rats with MCT-PAH.ResultsDNM2 is increased in PAH PASMC in humans and rodents and interacts with Drp1 via its GTPase domain, permitting mitochondrial translocation. Silencing DNM2 in PAH PASMC inhibits fission and slows cell proliferation by causing G1/G0 phase blockade. Augmenting DNM2 in normal PASMC induces fission and accelerates proliferation. siDNM2 downregulates the positive cell cycle regulator, Regulator of Cell Cycle (RGCC), in PAH PASMC. Moreover, siRGCC causes G1/G0 cell cycle arrest. miR-124-3p negatively regulates DNM2 and is decreased in PAH PASMC. Augmenting miR-124-3p in PAH PASMC decreases DNM2, inhibits proliferation and induces apoptosis. STAT3 is also negatively regulated by miR-124-3p and siSTAT3 reduces DNM2 and mitochondrial fission in PAH PASMC. Nebulized siDNM2 regresses PAH in MCT-PAH.ConclusionDNM2’s GTPase domain binds Drp1, mediating mitochondrial translocation and tighter mitochondrial fission. DNM2 is upregulated in PAH by miR-124a-3p deficiency and STAT3 activation. The miR-124a-3p-STAT3-DNM2-Drp1-RGCC pathway underlies accelerated mitotic fission in PAH and offers novel therapeutic targets.