bluuebunny/crossref_metadata_2025_split huggingface dataset:
Stromal KITL/SCF promotes pancreas tissue homeostasis and restrains tumor progression
Authors: Oñate M. Kathrina , Oon Chet , Bhattacharyya Sohinee , Low Vivien , Chen Canping , Zhao Xiaofan , Yan Ziqiao , Hang Yan , Kim Seung K. , Xia Zheng , Sherman Mara H. 
Published: July 2024

AbstractComponents of normal tissue architecture serve as barriers to tumor progression. Inflammatory and wound-healing programs are requisite features of solid tumorigenesis, wherein alterations to immune and non-immune stromal elements enable loss of homeostasis during tumor evolution. The precise mechanisms by which normal stromal cell states limit tissue plasticity and tumorigenesis, and which are lost during tumor progression, remain largely unknown. Here we show that healthy pancreatic mesenchyme expresses the paracrine signaling molecule KITL, also known as stem cell factor, and identify loss of stromal KITL during tumorigenesis as tumor-promoting. Genetic inhibition of mesenchymal KITL in the contexts of homeostasis, injury, and cancer together indicate a role for KITL signaling in maintenance of pancreas tissue architecture, such that loss of the stromal KITL pool increased tumor growth and reduced survival of tumor-bearing mice. Together, these findings implicate loss of mesenchymal KITL as a mechanism for establishing a tumor-permissive microenvironment.Statement of significanceBy analyzing transcriptional programs in healthy and tumor-associated pancreatic mesenchyme, we find that a sub-population of mesenchymal cells in healthy pancreas tissue express the paracrine signaling factor KITL. Loss of mesenchymal KITL is an accompanying and permissive feature of pancreas tumor evolution, with potential implications for cancer interception.
Proteomic analysis of unicellular cyanobacteriumCrocosphaera subtropicaATCC 51142 under extended light or dark growth
Authors: Panda Punyatoya , Giri Swagarika J. , Sherman Louis , Kihara Daisuke , Aryal Uma K. 
Published: July 2024

AbstractThe daily light-dark cycle is a recurrent and predictable environmental phenomenon to which many organisms, including cyanobacteria, have evolved to adapt. Understanding how cyanobacteria alter their metabolic attributes in response to subjective light or dark growth may provide key features for developing strains with improved photosynthetic efficiency and applications in enhanced carbon sequestration and renewable energy. Here, we undertook a label-free proteomic approach to investigate the effect of extended light (LL) or extended dark (DD) conditions on the unicellular cyanobacteriumCrocosphaera subtropicaATCC 51142. We quantified 2287 proteins, of which 603 proteins were significantly different between the two growth conditions. These proteins represent several biological processes, including photosynthetic electron transport, carbon fixation, stress responses, translation, and protein degradation. One significant observation is the regulation of over two dozen proteases, including ATP dependent Clp-proteases (endopeptidases) and metalloproteases, the majority of which were upregulated in LL compared to DD. This suggests that proteases play a crucial role in the regulation and maintenance of photosynthesis, especially the PSI and PSII components. The higher protease activity in LL indicates a need for more frequent degradation and repair of certain photosynthetic components, highlighting the dynamic nature of protein turnover and quality control mechanisms in response to prolonged light exposure. The results enhance our understanding of howCrocosphaera subtropicaATCC51142 adjusts its molecular machinery in response to extended light or dark growth conditions.
Identification and characterization of anti-epileptic compounds from Papaver somniferum using quantification techniques (GC-MS, FTIR), integrated network pharmacology, molecular docking, and molecular dynamics simulations
Authors: Shahzadi Kiran , Rasool Danish , Irshad Faiza , khalid Ammara , Aslam Sehar , Nazir Aisha 
Published: July 2024

AbstractEpilepsy is a common neurological condition identified by repetitive seizures that affect the overall quality of life. Existing anti-epileptic drugs have undesirable side effects, necessitating safer alternatives. This study develops an integrated computational framework to discover potential anti-epileptic leads fromPapaver somniferum(opium poppy). Literature and databases were mined to compile all chemicals from Papaver somniferum. PubChem provided structural data, and compounds satisfying drug-likeness and bioavailability criteria were selected. GeneCards, DisGeNET and SwissTargetPrediction identified 344 target genes of the compounds and common targets with epilepsy. Network pharmacology analyses were performed. Cytoscape constructed a compound-target network comprising 5 active constituents and 22 shared targets. Degree distributions revealed molecular interactions. STRING elucidated target connectivity. Hub targets were identified using CytoHubba. GO and KEGG enrichment on 123 targets recognized biological roles and pathways. DAVID and Hiplot characterized functional annotations. Cytoscape visualized a compound-target-pathway association network involving targets, pathways, and compounds related to epilepsy. GC-MS identified 25 compounds in the Papaver somniferum extract. FTIR characterized functional groups. Molecular docking scored compound affinities for 10 targets. Autodock Vina docked 15 constituents into binding pockets. Interactions were validated using Desmond MD simulations of IL6 with scoulerine over 100 ns, assessing RMSD, RMSF, interactions. RMSD/RMSF plots and histograms characterized protein/ligand stability and flexibility. This integrativeInsilicoandInvitroframework facilitates prioritizing Papaver somniferum constituents for epilepsy. Network analyses provided systems-level understanding of multi-target mechanisms. Molecular modeling established structure-activity relationships, validating predicted interactions. Compounds with good ADMET profiles, network centrality, docking scores, and stable simulations emerge as candidates warranting further examination for safer anti-epileptic therapy.
Sepsis-induced NET formation requires MYD88 but is independent of GSDMD and PAD4
Authors: Englert Hanna , Rangaswamy Chandini , Divivier Mylène , Göbel Josephine , Hermans-Borgmeyer Irm , Borgmeyer Uwe , Mowen Kerri A. , Beerens Manu , Frye Maike , Mailer Reiner K. , Gelderblom Mathias , Stavrou Evi X. , Preston Roger J. S. , Schneider Stefan W. , Fuchs Tobias A. , Renné Thomas 
Published: July 2024

ABSTRACTNeutrophils are peripheral blood-circulating leukocytes that play a pivotal role in host defense against bacterial pathogens which upon activation, they release web-like chromatin structures called neutrophil extracellular traps (NETs).Here, we analyzed and compared the importance of myeloid differentiation factor 88 (MYD88), peptidyl arginine deiminase 4 (PAD4), and gasdermin D (GSDMD) for NET formationin vivofollowing sepsis and neutrophilia challenge. Injection of lipopolysaccharide (LPS)/E. colior the transgenic expression of granulocyte colony-stimulating factor (G-CSF), each induced NET-mediated lethal vascular occlusions in mice with combined genetic deficiency inDnase1 andDnase1l3(D1/D1l3−/−). In accordance with the signaling of toll-like receptors,Myd88/D1/D1l3−/−animals were protected from the formation of lethal intravascular NETs during septic conditions. However, this protection was not observed during neutrophilia. It was unexpected to find that bothGsdmd/D1/D1l3−/−andPad4/D1/D1l3−/−mice were fully capable of forming NETs upon LPS/E.coli challenge. Sepsis equally triggered a similar inflammatory response in these mice characterized by formation of DNA-rich thrombi, vessel occlusions, and mortality from pulmonary embolism, compared toD1/D1l3−/−mice. Pharmacologic GSDMD inhibitors did not reduce PMA-stimulated NET formation inex vivomodels either. Similarly, neither Pad4 nor GSDMD deficiency affected intravascular occlusive NET formation upon neutrophilia challenge. The magnitude of NET production, multi-organ damage, and lethality were comparable to those observed in challenged control mice.In conclusion, our data indicate that NET formation during experimental sepsis and neutrophilia is regulated by distinct stimulus-dependent pathways that may be independent of canonical PAD4 and GSDMD.Key points:-Sepsis triggers vaso-occlusive NET formation inDnase1/Dnase1l3-deficient mice in a myeloid differentiation factor 88-dependent manner-Peptidyl arginine deiminase 4 and gasdermin D are dispensable for NET formation in sepsis and neutrophilia models-Myeloid differentiation factor 88, peptidyl arginine deiminase 4 and gasdermin D differ in their importance for NET formationin vivo
Fucosylated and non-fucosylated α2,3 sialosides were detected on the bovine mammary gland tissues
Authors: Hiono Takahiro , Morita Tatsuru , Kosenda Keigo , Otani Yuki , Ichii Osamu , Isoda Norikazu , Sakoda Yoshihiro 
Published: July 2024

AbstractReceptors for high pathogenicity avian influenza viruses (HPAIVs) in the mammary glands of dairy cattle were detected using various recombinant hemagglutinins (rHAs). Results demonstrated the presence of fucosylated and non-fucosylated α2,3 sialosides, which were typically targeted by the HA of clade 2.3.4.4b HPAIVs.
The dual Ras Association (RA) Domains of Drosophila Canoe have differential roles in linking cell junctions to the cytoskeleton during morphogenesis
Authors: McParland Emily D. , Gurley Noah J. , Wolfsberg Leah R. , Butcher T. Amber , Bhattarai Abhi , Jensen Corbin C. , Johnson Ruth I. , Slep Kevin C. , Peifer Mark 
Published: July 2024

AbstractDuring embryonic development and adult homeostasis epithelial cells must change shape and move without disrupting the tissue’s dynamic architecture. This requires robust linkage of cell-cell adherens junctions to the force-generating actomyosin cytoskeleton. Drosophila Canoe and mammalian Afadin play key roles in this linkage. One central task for the field is defining how upstream inputs from Ras-family GTPases regulate Canoe and Afadin. They are unusual in that they share two tandem Ras-association (RA) domains, which, when deleted, virtually eliminate Canoe function. Previous work in vitro suggested RA1 and RA2 differ in their ability to bind GTPases, but their individual functions in vivo remain unknown. Combining bioinformatic and biochemical approaches, we find that both RA1 and RA2 bind to active Rap1 with similar affinities, and that conserved N-terminal extensions play a role in binding. We created Drosophilacanoemutants to test RA1 and RA2 function in vivo. Despite their similar affinities for Rap1, RA1 and RA2 play strikingly different roles. Deleting RA1 virtually eliminates Canoe function in morphogenesis, while mutants lacking RA2 are viable and fertile but have defects in junctional reinforcement in embryos and during pupal eye development. These data significantly expand our understanding of how adherens junction:cytoskeletal linkage is regulated.
Efficient integration of spatial omics data for joint domain detection, matching, and alignment with stMSA
Authors: Shu Han , Chen Jing , Xu Chang , Hu Jialu , Wang Yongtian , Peng Jiajie , Jiang Qinghua , Shang Xuequn , Wang Tao 
Published: July 2024

AbstractSpatial omics (SO) is a powerful methodology that enables the study of genes, proteins, and other molecular features within the spatial context of tissue architecture. With the growing availability of SO datasets, researchers are eager to extract biological insights from larger datasets for a more comprehensive understanding. However, existing approaches focus on batch effect correction, often neglecting complex biological patterns in tissue slices, complicating feature integration and posing challenges when combining transcriptomics with other omics layers. Here, we introduce stMSA (SpaTial Multi-Slice/omics Analysis), a deep graph contrastive learning model that incorporates graph auto-encoder techniques. stMSA is specifically designed to produce batch-corrected representations while retaining the distinct spatial patterns within each slice, considering both intra- and inter-batch relationships during integration. Extensive evaluations show that stMSA outperforms state-of-the-art methods in distinguishing tissue structures across diverse slices, even when faced with varying experimental protocols and sequencing technologies. Furthermore, stMSA effectively deciphers complex developmental trajectories by integrating spatial proteomics and transcriptomics data, and excels in cross-slice matching and alignment for 3D tissue reconstruction.
Impact of preanalytical factors on liquid biopsy in the canine cancer model
Authors: Megquier Kate , Husted Christopher , Rhoades Justin , White Michelle E. , Genereux Diane P. , Chen Frances L. , Xiong Kan , Kwon Euijin , Swofford Ross , Painter Corrie , Adalsteinsson Viktor , London Cheryl A. , Gardner Heather L. , Karlsson Elinor K. 
Published: July 2024

ABSTRACTWhile liquid biopsy has potential to transform cancer diagnostics through minimally-invasive detection and monitoring of tumors, the impact of preanalytical factors such as the timing and anatomical location of blood draw is not well understood. To address this gap, we leveraged pet dogs with spontaneous cancer as a model system, as their compressed disease timeline facilitates rapid diagnostic benchmarking. Key liquid biopsy metrics from dogs were consistent with existing reports from human patients. The tumor content of samples was higher from venipuncture sites closer to the tumor and from a central vein. Metrics also differed between lymphoma and non-hematopoietic cancers, urging cancer-type-specific interpretation. Liquid biopsy was highly sensitive to disease status, with changes identified soon after post chemotherapy administration, and trends of increased tumor fraction and other metrics observed prior to clinical relapse in dogs with lymphoma or osteosarcoma. These data support the utility of pet dogs with cancer as a relevant system for advancing liquid biopsy platforms.
Effects of ketamine on GABAergic and glutamatergic activity in the mPFC: biphasic recruitment of GABA function in antidepressant-like responses
Authors: Fogaça Manoela V. , Daher Fernanda , Picciotto Marina R. 
Published: July 2024

AbstractMajor depressive disorder (MDD) is associated with disruptions in glutamatergic and GABAergic activity in the medial prefrontal cortex (mPFC), leading to altered synaptic formation and function. Low doses of ketamine rapidly rescue these deficits, inducing fast and sustained antidepressant effects. While it is suggested that ketamine produces a rapid glutamatergic enhancement in the mPFC, the temporal dynamics and the involvement of GABA interneurons in its sustained effects remain unclear. Using simultaneous photometry recordings of calcium activity in mPFC pyramidal and GABA neurons, as well as chemogenetic approaches inGad1-Cremice, we explored the hypothesis that initial effects of ketamine on glutamate signaling trigger subsequent enhancement of GABAergic responses, contributing to its sustained antidepressant responses. Calcium recordings revealed a biphasic effect of ketamine on activity of mPFC GABA neurons, characterized by an initial transient decrease (phase 1, <30 min) followed by an increase (phase 2, >60 min), in parallel with a transient increase in excitation/inhibition levels (10 min) and lasting enhancement of glutamatergic activity (30-120 min). Previous administration of ketamine enhanced GABA neuron activity during the sucrose splash test (SUST) and novelty suppressed feeding test (NSFT), 24 h and 72 h post-treatment, respectively. Chemogenetic inhibition of GABA interneurons during the surge of GABAergic activity (phase 2), or immediately before the SUST or NSFT, occluded ketamine’s behavioral actions. These results indicate that time-dependent modulation of GABAergic activity is required for the sustained antidepressant-like responses induced by ketamine, suggesting that approaches to enhance GABAergic plasticity and function are promising therapeutic targets for antidepressant development.
‘Tuning’ of ribosome levels mediated by RNase I and hibernating ribosomes
Authors: Minami Atsushi , Tanzawa Takehito , Yang Zhuohao , Funatsu Takashi , Kuzuyama Tomohisa , Yoshida Hideji , Kato Takayuki , Ogawa Tetsuhiro 
Published: July 2024

AbstractRibosomes consume vast energy to synthesize proteins, so controlling the ribosome abundance is a significant concern for cells. Ribonucleases mediate ribosome degradation in response to stresses, while some ribosomes deactivate translational activity and protect themselves from degradation, called ribosome hibernation. RNase T2 is an endoribonuclease found in almost all organisms, and they are thought to be involved in the degradation of ribosomal RNA. Although it was recently reported that the activity ofEscherichia coliRNase T2, called RNase I, depends on the environmental conditions, the regulation mechanism remains elusive. Here, we report how rRNA degradation by RNase I is regulated by hibernating ribosomes. Combining the biochemical, cryo-electron microscopy, and single-molecule analyses, we found that hibernating ribosome is an inhibitor by forming a complex with RNase I. Moreover, RNase I does not bind to the translating ribosome, so rRNA is protected. On the other hand, RNase I degrades the rRNA of each subunit dissociated from stalled ribosomes on aberrant mRNA bytrans-translation. Under stress conditions, and even in the actively growing phase, some ribosomes are stalling or pausing. Although such ribosomes were thought to be recycled after being rescued, our results add a new insight that they are not recycled but degraded. These findings have broad implications for understanding the regulation of ribosome levels, which is critical for cellular homeostasis and response to environmental stresses.
Ranking Single Fluorescent Protein Based Calcium Biosensor Performance by Molecular Dynamics Simulations
Authors: Berksoz Melike , Atilgan Canan 
Published: July 2024

ABSTRACTGenetically Encoded Fluorescent Biosensors (GEFBs) have become indispensable tools for visualizing biological processes in vivo. A typical GEFB is composed of a sensory domain (SD) which undergoes a conformational change upon ligand binding and a genetically fused fluorescent protein (FP). Ligand binding in the SD allosterically modulates the chromophore environment and changes its spectral properties. Single fluorescent (FP)-based biosensors, a subclass of GEFBs, offer a simple experimental setup; they are easy to produce in living cells, structurally stable and simple due to their single-wavelength operation. However, they pose a significant challenge for structure optimization, especially concerning the length and residue content of linkers between the FP and SD which affect how well the chromophore responds to conformational change in the SD. In this work, we use classical all-atom molecular dynamics simulations to analyze the dynamic properties of a series of calmodulin-based calcium biosensors, all with different FP-SD interaction interfaces and varying degrees of calcium binding dependent fluorescence change. Our results indicate that biosensor performance can be predicted based on distribution of water molecules around the chromophore and shifts in hydrogen bond occupancies between the ligand-bound and ligand-free sensor structures.
Understanding human amygdala function with artificial neural networks
Authors: Jang Grace , Kragel Philip A. 
Published: July 2024

AbstractThe amygdala is a cluster of subcortical nuclei that receives diverse sensory inputs and projects to the cortex, midbrain and other subcortical structures. Numerous accounts of amygdalar contributions to social and emotional behavior have been offered, yet an overarching description of amygdala function remains elusive. Here we adopt a computationally explicit framework that aims to develop a model of amygdala function based on the types of sensory inputs it receives, rather than individual constructs such as threat, arousal, or valence. Characterizing human fMRI signal acquired as participants viewed a full-length film, we developed encoding models that predict both patterns of amygdala activity and self-reported valence evoked by naturalistic images. We use deep image synthesis to generate artificial stimuli that distinctly engage encoding models of amygdala subregions that systematically differ from one another in terms of their low-level visual properties. These findings characterize how the amygdala compresses high-dimensional sensory inputs into low-dimensional representations relevant for behavior.
Multimodal weakly supervised learning to identify disease-specific changes in single-cell atlases
Authors: Litinetskaya Anastasia , Shulman Maiia , Hediyeh-zadeh Soroor , Moinfar Amir Ali , Curion Fabiola , Szałata Artur , Omidi Alireza , Lotfollahi Mohammad , Theis Fabian J. 
Published: July 2024

AbstractMultimodal analysis of single-cell samples from healthy and diseased tissues at various stages provides a comprehensive view that identifies disease-specific cells, their molecular features and aids in patient stratification. Here, we present MultiMIL, a novel weakly-supervised multimodal model designed to construct multimodal single-cell references and prioritize phenotype-specific cells via patient classification. MultiMIL effectively integrates single-cell modalities, even when they only partially overlap, providing robust representations for downstream analyses such as phenotypic prediction and cell prioritization. Using a multiple-instance learning approach, MultiMIL aggregates cell-level measurements into sample-level representations and identifies disease-specific cell states through attention-based scoring. We demonstrate that MultiMIL accurately identifies disease-specific cell states in blood and lung samples, identifying novel disease-associated genes and achieving superior patient classification accuracy compared to existing methods. We anticipate MultiMIL will become an essential tool for querying single-cell multiomic atlases, enhancing our understanding of disease mechanisms and informing targeted treatments.
Marsupial immune protection is shaped by enhancer sharing and gene cluster duplication of cathelicidin antimicrobial peptides
Authors: Park Jongbeom , Ke Wenfan , Kaage Aellah , Feigin Charles Y. , Pritykin Yuri , Donia Mohamed S. , Mallarino Ricardo 
Published: July 2024

AbstractMarsupial neonates are born with immature immune systems, making them vulnerable to pathogens. While neonates receive maternal protection, they can also independently combat pathogens, though the mechanisms remain unknown. Using the sugar glider (Petaurus breviceps) as a model, we investigated immunological defense strategies of marsupial neonates. Cathelicidins – a family of antimicrobial peptides expanded in the genomes of marsupials – are highly expressed in developing neutrophils. Sugar glider cathelicidins reside in two genomic clusters and their coordinated expression is achieved by enhancer sharing within clusters and long-range physical interactions between clusters. These cathelicidins modulate immune responses and have potent antimicrobial effects, sufficient to provide protection in a mouse model of sepsis. Lastly, cathelicidins have a complex evolutionary history, where marsupials and monotremes are the only tetrapods that retained two cathelicidin clusters. Thus, cathelicidins are critical mediators of marsupial immunity, and their evolution reflects the life history-specific immunological needs of these animals.