bluuebunny/crossref_metadata_2025_split huggingface dataset:
GPX3 supports ovarian cancer tumor progressionin vivoand promotes expression of GDF15
Authors: Chang Caroline , Cheng Ya-Yun , Kamlapurkar Shriya , White Sierra R. , Tang Priscilla W. , Elhaw Amal T. , Javed Zaineb , Aird Katherine M. , Mythreye Karthikeyan , Phaëton Rébécca , Hempel Nadine 
Published: January 2024

AbstractObjectiveWe previously reported that high expression of the extracellular glutathione peroxidase GPX3 is associated with poor patient outcome in ovarian serous adenocarcinomas, and that GPX3 protects ovarian cancer cells from oxidative stress in culture. Here we tested if GPX3 is necessary for tumor establishmentin vivoand to identify novel downstream mediators of GPX3’s pro-tumorigenic function.MethodsGPX3 was knocked-down in ID8 ovarian cancer cells by shRNA to test the role of GPX3 in tumor establishment using a syngeneic IP xenograft model. RNA sequencing analysis was carried out in OVCAR3 cells following shRNA-mediated GPX3 knock-down to identify GPX3-dependent gene expression signatures.ResultsGPX3 knock-down abrogated clonogenicity and intraperitoneal tumor developmentin vivo, and the effects were dependent on the level of GPX3 knock-down. RNA sequencing showed that loss of GPX3 leads to decreased gene expression patterns related to pro-tumorigenic signaling pathways. Validation studies identified GDF15 as strongly dependent on GPX3. GDF15, a member of the TGF-β growth factor family, has known oncogenic and immune modulatory activities. Similarly, GPX3 expression positively correlated with pro-tumor immune cell signatures, including regulatory T-cell and macrophage infiltration, and displayed significant correlation with PD-L1 expression.ConclusionsWe show for the first time that tumor produced GPX3 is necessary for ovarian cancer growthin vivoand that it regulates expression of GDF15. The immune profile associated with GPX3 expression in serous ovarian tumors suggests that GPX3 may be an alternate marker of ovarian tumors susceptible to immune check-point inhibitors.
MuPET-Flow: Multiple Ploidy Estimation Tool from Flow cytometry data
Authors: Gómez-Muñoz C. , Fischer G. 
Published: January 2024

ABSTRACTSummaryPloidy, representing the number of homologous chromosome sets, can be estimated from flow cytometry data acquired on cells stained with a fluorescent DNA dye. This estimation relies on a combination of tools that often require scripting, individual sample curation, and additional analyses. To automate the ploidy estimation for multiple flow cytometry files, we developed MuPET-Flow—a Shiny graphical user interface tool. MuPET-Flow allows users to visualize cell fluorescence histograms, detect the peaks corresponding to the different cell cycle phases, perform a linear regression using standards, make ploidy or genome size predictions, and export results as figures and table files. The tool was benchmarked with known ploidy datasets, yielding consistent ploidy results. MuPET-Flow produces ploidy results comparable to those from other available tools; however, MuPET-Flow stands out for its user-friendly interface, which allows the whole process to be carried out in one place, considerably speeding up analysis, particularly in projects involving large numbers of samples.Availability and implementation:https://github.com/CintiaG/MuPET-Flow.
SMARCD1 is a “Goldilocks” metastasis modifier
Authors: Ross Christina , Gong Li-Yun , Jenkins Lisa M. , Ha Ngoc-han , Majocha Megan , Hunter Kent 
Published: January 2024

AbstractBreast cancer is the most frequently diagnosed cancer worldwide, constituting around 15% of all diagnosed cancers in 2023. The predominant cause of breast cancer-related mortality is metastasis to distant essential organs, and a lack of metastasis-targeted therapies perpetuates dismal outcomes for late-stage patients. However, through our use of meiotic genetics to study inherited transcriptional network regulation, we have identified a new class of “Goldilocks” genes that are promising candidates for the development of metastasis-targeted therapeutics. Building upon previous work that implicated the CCR4-NOT RNA deadenylase complex in metastasis, we now demonstrate that the RNA-binding proteins (RNA-BPs) NANOS1, PUM2, and CPSF4 also regulate metastatic potential. Using cell lines, 3D culture, mouse models, and clinical data, we pinpointSmarcd1mRNA as a key target of all three RNA-BPs. Strikingly, both high and low expression ofSmarcd1is associated with positive clinical outcomes, while intermediate expression significantly reduces the probability of survival. Applying the theory of “essential genes” from evolution, we identify an additional 50 genes that span several cellular processes and must be maintained within a discrete window of expression for metastasis to occur. In the case ofSmarcd1, small perturbations in its expression level significantly reduce metastasis in laboratory mouse models and alter splicing programs relevant to the ER+/HER2-enriched breast cancer subtype. The identification of subtype-specific “Goldilocks” metastasis modifier genes introduces a new class of genes and potential catalogue of novel targets that, when therapeutically “nudged” in either direction, may significantly improve late-stage patient outcomes.
Somatic epigenetic drift during shoot branching: a cell lineage-based model
Authors: Chen Yifan , Burian Agata , Johannes Frank 
Published: January 2024

AbstractPlant architecture is shaped by the continuous production of new organs, most of which emerge post-embryonically. This process includes the formation of new lateral branches along existing shoots. Shoot branching is fundamental to plant development, plant-environment interactions, and vegetative propagation. Current empirical evidence supports a “detached meristem” model as the cellular basis of lateral shoot initiation. In this model, a small number of undifferentiated cells are “sampled” from the periphery of the shoot apical meristem (SAM) to act as precursors for axillary buds, which eventually develop into new shoots. Repeated branching thus creates a series of cellular bottlenecks (i.e. somatic drift) that affect howde novogenetic and epigenetic mutations propagate through the plant body during development. Somatic drift could be particularly relevant for epigenetic changes in the form of stochastic DNA methylation gains and losses (i.e. spontaneous epimutations), as they have been shown to arise rapidly with each cell division.Here, we formalize a special case of the “detached meristem” model, where pre-cursor cells are randomly sampled from the SAM periphery in a way that maximizes cell lineage independence. By following a population of SAM cells through repeated branching processes, we show that somatic drift gives rise to a complex mixture of cellular phylogenies, which shape the evolution of cell-to-cell DNA methylation heterogeneity within the SAM over time. This process is dependent on the number of branch points, the strength of somatic drift as well as the epimutation rate. For many realistic cell biological settings, our model predicts that cell-to-cell DNA methylation heterogeneity in the SAM converges to non-zero states during development, suggesting that epigenetic variation is an inherent property of the SAM cell population.Our insights have direct implications for empirical studies of somatic (epi)genomic diversity in long-lived perennial and clonal species using bulk or single-cell sequencing approaches.
The ion channel TRPM8 is a direct target of the immunosuppressant rapamycin in primary sensory neurons
Authors: Arcas José Miguel , Oudaha Khalid , González Alejandro , Fernández-Trillo Jorge , Peralta Francisco Andrés , Castro-Marsal Júlia , Poyraz Seyma , Taberner Francisco , Sala Salvador , de la Peña Elvira , Gomis Ana , Viana Félix 
Published: January 2024

AbstractBackground and PurposeThe mechanistic target of rapamycin (mTOR) signaling pathway is a key regulator of cell growth and metabolism. Its deregulation is implicated in several diseases. The macrolide rapamycin (RAP), a specific inhibitor of mTOR, has immunosuppressive, anti-inflammatory and antiproliferative properties. Recently, we identified tacrolimus, another macrolide immunosuppressant, as a novel activator of TRPM8 ion channels, involved in cold temperature sensing, thermoregulation, tearing and cold pain. We hypothesized that RAP may also have agonist activity on TRPM8.Experimental approachUsing calcium imaging and electrophysiology in transfected HEK293 cells and wildtype orTrpm8KO mouse DRG neurons, we characterized RAP effects on TRPM8. We also examined the effects of RAP on tearing in mice.Key ResultsMicromolar concentrations of RAP activate rat and mouse TRPM8 directly and potentiate cold-evoked responses. These effects were also observed in human TRPM8.In cultured mouse DRG neurons, RAP evoked an increase in intracellular calcium almost exclusively in cold-sensitive neurons. Responses were drastically blunted inTrpm8KO mice or by TRPM8 antagonists. Cutaneous cold thermoreceptor endings were also activated by RAP. Topical application of RAP to the eye surface evokes tearing in mice by a TRPM8-dependent mechanism.Conclusion and implicationsThese results identify TRPM8 cationic channels in sensory neurons as novel molecular targets of the immunosuppressant RAP. These findings may help explain some of its therapeutic effects after topical application to the skin and the eye surface. Moreover, RAP could be used as an experimental tool in the clinic to explore cold thermoreceptors.Bullet point summaryWHAT IS ALREADY KNOWNTRPM8 is a polymodal channel involved in cold detection, thermoregulation, tearing and cold painTacrolimus, a macrolide immunosupressor, is an agonist of cold-activated TRPM8 channelsWHAT THIS STUDY ADDSThe macrolide rapamycin also activates directly TRPM8 channels in mouse sensory neurons and human TRPM8Rapamycin stimulates tearing in mice in a TRPM8-dependent manner CLINICAL SIGNIFICANCERapamycin, an FDA-approved drug, shows agonist activity on TRPM8 channelsBeneficial effects of rapamycin and other macrolides on inflammatory ocular disorders may involve TRPM8 activation
Analyzing the intrastate and interstate swine movement network in the United States
Authors: Cardenas Nicolas C. , Valencio Arthur , Sanchez Felipe , O’Hara Kathleen C. , Machado Gustavo 
Published: January 2024

AbstractDisease prevention and control tactics rely on identifying and restricting animal movement to attenuate the between-premises spread of disease in livestock systems. Therefore, it is essential to uncover between-premises movement dynamics, including shipment distances and network-based control strategies. Here, we analyzed three years of between-premises pig movements, which include 197,022 unique animal shipments, 3,973 premises, and 391,625,374 pigs shipped across 20 U.S. states. We constructed unweighted, directed, temporal networks at 180-day intervals to calculate premises-to-premises movement distances, the size of connected components, network loyalty, and degree distributions, and, based on the out-going contact chains, identified network-based control actions. Our results show that the median distance between premises pig movements was 74.37 km, with median intrastate and interstate movements of 52.71 km and 328.76 km, respectively. On average, 2,842 premises were connected via 6,705 edges, resulting in a weak giant connected component that included 91% of the premises. The premises-level network exhibited loyalty, with a median of 0.65 (IQR: 0.45 – 0.77). Results highlight the effectiveness of node targeting and disease spread; we demonstrated that targeting 25% of farms with the highest degree or betweenness limited spread to 1.23% and 1.7% of premises, respectively. While there is no complete shipment data for the entire U.S., our multi-state movement analysis demonstrated the value and the needs of such data for enhancing the design and implementation of proactive-disease control tactics.
Toward mastering the cell language by learning to generate
Authors: Chen Yixin , Bian Haiyang , Wei Lei , Jia Jinmeng , Dong Xiaomin , Li Yuzhuo , Zhao Yubo , Wu Xinze , Li Chen , Luo Erpai , Xiao Chuxi , Hao Minsheng , Zhang Xuegong 
Published: January 2024

AbstractCells can be viewed as complex stories written by coordinated expression of genes. The success of AI large language models (LLMs) in mastering the human language inspired us to develop a large AI model scMulan with 368 million parameters to generate cell transcriptomics with designated attributes by learning the cell language. We defined a unified c-sentence to incorporate cell transcriptomics and meta-attributes, and pre-trained scMulan on the equivalence of 100 million human cells. Experiments showed that scMulan can generate designated pseudo transcriptomics, predict missing attributes of cells, reconstruct unobserved cells along functional gradients, and can help to identify driving regulators of cell fates. The generated data passed tests of current tools and can reflect the underlying biology.
MORE interpretable multi-omic regulatory networks to characterize phenotypes
Authors: Aguerralde-Martin Maider , Clemente-Císcar Mónica , Conesa Ana , Tarazona Sonia 
Published: January 2024

AbstractThe identification of phenotype-specific regulatory mechanisms is crucial for understanding the molecular basis of diseases and other complex traits. However, the lack of tools capable of constructing multi-omic, condition-specific regulatory networks remains a significant limitation. He re, we introduce MO RE (Multi-Omics Regulation), a novel R package for the inference and comparison of multi-modal regulatory networks publicly available athttps://github.com/BiostatOmics/MORE. MORE supports any number and type of omics layers, integrates prior regulatory knowledge, and employs advanced regression-based modelling and variable selection techniques to identify significant regulators of target features.We evaluated MORE on simulated datasets and benchmarked it against state-of-the-art tools. Our tool exhibited superior accuracy in identifying key regulators, model goodness-of-fit, and computational efficiency. Additionally, we applied MORE to an ovarian cancer dataset to uncover tumour subtype-specific regulatory mechanisms associated with distinct survival outcomes.By providing a comprehensive and user-friendly framework for constructing phenotype-specific regulatory networks, MORE addresses a critical gap in the field of multi-omics data integration. Its versatility and effectiveness make it a valuable resource for advancing our understanding of complex molecular interactions and regulatory systems.
Shoring up the base: the development and regulation of cortical sclerenchyma in grass nodal roots
Authors: McCahill Ian W. , Khahani Bahman , Probert Cassandra F. , Flockhart Eleah L. , Abushal Logayn T. , Gregory Greg A. , Zhang Yu , Baumgart Leo A. , O’Malley Ronan C. , Hazen Samuel P. 
Published: January 2024

ABSTRACTPlants depend on the combined action of a shoot-root-soil system to maintain their anchorage to the soil. Mechanical failure of any component of this system results in lodging, a permanent and irreversible inability to maintain vertical orientation. Models of anchorage in grass crops identify the compressive strength of roots near the soil surface as key determinant of resistance to lodging. Indeed, studies of disparate grasses report a ring of thickened, sclerenchyma cells surrounding the root cortex, present only at the base of nodal roots. Here, in the investigation of the development and regulation of this agronomically important trait, we show that development of these cells is uncoupled from the maturation of other secondary cell wall-fortified cells, and that cortical sclerenchyma wall thickening is stimulated by mechanical forces transduced from the shoot to the root. We also show that exogenous application of gibberellic acid stimulates thickening of lignified cell types in the root, including cortical sclerenchyma, but is not sufficient to establish sclerenchyma identity in cortex cells. Leveraging the ability to manipulate cortex development via mechanical stimulus, we show that cortical sclerenchyma development alters root mechanical properties and improves resistance to lodging. We describe transcriptome changes associated with cortical sclerenchyma development under both ambient and mechanically stimulated conditions and identify SECONDARY WALL NAC7 as a putative regulator of mechanically responsive cortex cell wall development at the root base.
Refining Spatial Proteomics by Mass Spectrometry: An Efficient Workflow Tailored for Archival Tissue
Authors: Daucke Rune , Rift Charlotte V. , Bager Nicolai S. , Saxena Kartikey , Koffeldt Peter R. , Woessmann Jakob , Petrosius Valdemaras , Santoni-Rugiu Eric , Kristensen Bjarne W. , Klausen Pia , Schoof Erwin M. 
Published: January 2024

AbstractBackgroundFormalin-fixed, paraffin-embedded (FFPE) tissue remains the gold standard for extensively archiving biological specimens, providing biobanks with large repositories of retrospective potential. However, while formalin crosslinking is effective at preserving tissue, it poses significant challenges for extracting molecular information, including the proteome. Traditionally, this process required high levels of input material, which, in turn, limited the ability to preserve cell-type heterogeneity and spatial information. To address these limitations, we developed an easily adaptable and highly efficient workflow for extracting deep proteomes from low-input materials, such as biopsies used in routine histopathological diagnostics.MethodsWe compared the extraction efficiency of pancreatic acinar cells identified in FFPE tissue samples stained with conventional hematoxylin-eosin (H&E) against that of cells isolated from tissue samples immunostained for the epithelial cell adhesion molecule (EpCAM) across material inputs ranging from 1,166 to 800,000µm2(estimated to 2 to 1,310 cells in volume). Cells were isolated using laser capture microdissection and subsequently analyzed using Liquid Chromatography-Tandem Mass Spectrometry.ResultsSimilar yields for both methods were observed, with EpCAM-positive cells yielding slightly higher results—approximately 1,200 unique protein groups at the lowest input and up to 5,900 at the highest. In cells isolated from H&E-stained tissue, ∼900 to ∼5,200 protein groups were identified. We decided that the optimal balance for our workflow, ensuring maximum protein identification while minimizing input material, lies within the range of approximately 50,000 to 100,000µm2. With these results, we tested spatial capabilities and biological relevance by isolating cancer cells from biopsies of pancreatic cancer, lung cancer, or glioblastoma, with the first two being stained with EpCAM and the latter being stained against the tumor-suppressor protein p53. We successfully identified tissue-specific protein expressions and observed prominent clustering of all cell populations.DiscussionOur results highlight the feasibility of performing spatial proteomics on FFPE tissue using minimal input material. This adaptable methodology opens up possibilities for investigating cell-type-specific biology while preserving spatial and histological information.
Age and Sex Differences of Virtual Reality Pain Alleviation Therapeutic During Pediatric Burn Care: A Randomized Clinical Trial
Authors: Jones Katarina , Armstrong Megan , Luna John , Thakkar Rajan K , Fabia Renata , Groner Jonathan I , Noffsinger Dana , Ni Ai , Griffin Bronwyn , Xiang Henry 
Published: January 2024

AbstractVirtual reality (VR) effectively alleviates pain for pediatric patients during many medical care procedures, such as venipuncture and burn wound care. Whether VR pain alleviation therapeutics (VR-PAT) differ by a patient’s age or sex remains unresolved. This randomized clinical trial evaluated how age and sex affect VR pain alleviation during dressing care for pediatric burns. Ninety patients aged 6-17 years (inclusive) with burn injuries were recruited from an outpatient burn clinic of an American Burn Association-verified pediatric burn center. Before randomization, expectations of VR helpfulness and need were assessed on a visual analog scale (VAS, 0-100). Participants were randomly assigned to active or passive VR for one burn dressing change. Immediately following the dressing change, participants self-reported pain and the time spent thinking about pain and rated the VR features on the degrees of realism experienced, pleasure/fun, and perceived engagement level. Path analyses assessed how these VR features were interrelated and how they affected self-reported pain by age and sex. Patients aged 6–9 years reported higher mean expectations of VR helpfulness and need (mean=73.6 and 94.5, respectively) than 10–12-year-olds (mean=55.7 and 84.2, respectively) and 13-17-year-olds (mean=68.6 and 77.4, respectively). The path analysis indicated VR engagement and fun were significantly correlated (p-value <0.05). VR engagement significantly negatively impacted overall pain scores during burn dressing (coefficient=-0.45, −0.41; p-value <0.05) and significantly positively impacted time thinking of pain (coefficient=0.38, 0.32; p-value <0.05). Younger patients had the highest expectations of VR pain alleviation’s helpfulness and need. VR game realism, fun, and engagement features were not statistically different between age groups and sexes. VR engagement and thinking of pain during burn dressing significantly positively affected self-reported pain (p-value <0.05), suggesting an analgesic mechanism beyond distraction alone. Younger patients benefited more from VR pain alleviation therapeutics than older patients.
Studies on Geographic Variations and Gender Bias in Thyroid Cancer at National Guard Hospitals in Saudi Arabia
Authors: Alanazi Nawaf , Alabbad Zainab Ibrahim , Almutairi Nahal Hamad , Alhulaymi Rahmah Abdulwahab , Alfalah Jawaher Raed , Alkhalifa Eithar Qasim , Abubaker Rehab Ibrahim , Adeel Kanza , Balghonaim Sarah , Alshayeb Alzahra , Al-Mukhaylid Sarah , Iqbal Zafar 
Published: January 2024

AbstractThyroid cancer (TC) is one of the most prevalent cancers in the world, ranked as ninth worldwide and third in Saudi Arabia. This report reviews the incidence of TC at National Guard Hospitals (Riyadh, Jeddah, and Ahsa), in relation to gender, geographic variation and age. The study design is quantitative cross-sectional retrospective review; data of 2166 patients with TC diagnosed in National Guard Hospitals (Ahsa -Jeddah- Riyadh) in the period of 2015-2021 was received from King Abdullah International Medical Research Center (KAIMRC). Chi- square, t-test, and ANOVA-tests were used in analyzing the relationship between variables. Out of the 2166 patient records, (79.78%) were females, and (46.6%) were in the age group of 40-60 with a mean age of 47.28 years. Riyadh had the highest incidence of TC (49.8%), while Ahsa had the lowest (5.6%). the commonest TC type was papillary (83.5%) followed by follicular (4.0%), medullary (1.2%), anaplastic (1.1%), hurthle cell carcinoma (0.8%) and thyroid lymphoma (0.1%). Females were more suspected to have TC, and the risk of having TC increases as age increases until the age of 60, where it decreases. The registered cases were more in Riyadh, Jeddah and Ahsa, respectively, except for lymphoma and hurthle cell, as they were high in Jeddah. Lymphoma was reported in Jeddah and in males only. The mortality rate was low (2.4%). However, increased death risk was observed in patients diagnosed above the age of 60. Mortality was seen in papillary, anaplastic and a single death case was reported in follicular TC.Research highlightsFemales are at higher risk to develop thyroid cancer than males.The risk of having thyroid cancer increased by age in both genders until the age of 60 where it decreased.The registered cases were higher in Riyadh then Jeddah, and it was the lowest in Ahsa.Lymphoma and hurtle cell were higher in Jeddah.Mortality was low and seen in papillary, anaplastic and a single death case was reported in follicular thyroid cancer.