bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tunnelling nanotubules are druggable mediators of cancer-niche crosstalk
Authors: Hockney Sean , Parker Jess , Tzivelekis Babis , Blair Helen , Dalgarno Kenny , Pal Deepali 
Published: June 2023

AbstractTreatment resistance, conferred onto cancer cells largely by the oncogenic niche, remains a clinically unmet need in leukaemia. Tractable and clinically translatable models that mimic cancer-niche crosstalk remain limited, consequently means of clinically drugging microenvironment-driven cancer treatment resistance remain underexplored. Here we develop a prototype bone marrow (BM) like extracellular matrix (ECM), Vitronectin-Alginate-Laminin (VAL), which comprises animal-free components, displays viscoelastic properties like the human BM, and engrafts a range of patient-derived-xenograft acute lymphoblastic leukaemia (PDX-ALL) samples. We discover that following treatment with oxidative stress-inducing apoptotic therapies, such as dexamethasone, ABT-199 and dexamethasone-ABT-199 combination, PDX-ALL cells reach out to MSC via the formation of tunnelling nanotubes (TNT). Nevertheless, we reveal that ALL-VAL-MSC-TNTs are clinically druggable, as they are absent following treatment with CDH2 antagonist ADH-1, a compound well-tolerated in solid cancer Phase I trials. We ultimately expose a triple drug combination of dexamethasone-ABT-199 and ADH-1, with most synergy area (MSA) scores of >30, that shows high efficacy and disrupts functional cancer-niche-TNTs in 4 different high risk PDX-ALL samples. In summary, here we develop prototype cancer-ECM-niche organoids and using leukaemia as a disease paradigm, we provide proof-of-concept insights enabling the beginning of research into drugging functional cancer cell crosstalk with its surrounding cellular and ECM niche.
Quercetin Suppresses TNBC Cell by Targeting ORM2
Authors: Chen Zhijun 
Published: June 2023

AbstractBackgroundTriple-negative breast cancer (TNBC) is known for its aggressive nature, and Quercetin (QUE) has shown potential anti-cancer effects.MethodsWe determined the IC50 of QUE for inhibiting cell viability in multiple TNBC, non-TNBC, and normal breast cell lines. We compared the expression of ORM2 in TNBC clinical samples and normal tissues. Additionally, we measured ORM2 expression in TNBC and normal breast cell lines. We determined the IC50 of QUE for inhibiting cell viability after ORM2 knockdown. An orthotopic implantation mice model was used to evaluate the treatment effect of QUE. We also conducted molecular docking and amino acid exchange validation to model the binding of QUE to ORM2. Furthermore, we performed a protein-protein interaction network analysis and GO enrichment analysis of differentially expressed genes associated with ORM2 in TNBC.ResultsQUE inhibited the viability of both TNBC and non-TNBC cell lines, but it was specifically associated with worse survival in TNBC patients. We observed higher expression of ORM2 in breast cancer cells compared to normal breast cells. Knockdown of ORM2 reduced the viability of TNBC cells. Treatment with QUE inhibited ORM2 expression and decreased viability in TNBC cells. In the animal model, QUE improved survival and downregulated ORM2 expression in tumors. Enrichment analysis provided insights into the potential functions of ORM2.ConclusionOur findings indicate that QUE directly inhibits TNBC cell viability through its interaction with ORM2. These results contribute to our understanding of the anti-cancer mechanisms of QUE in TNBC and highlight ORM2 as a potential therapeutic target.
A Clear, Legible, Explainable, Transparent, and Elucidative (CLETE) Binary Classification Platform for Tabular Data
Authors: Nasimian Ahmad , Younus Saleena , Tatli Özge , Hammarlund Emma U. , Pienta Kenneth J. , Rönnstrand Lars , Kazi Julhash U. 
Published: June 2023

AbstractTherapeutic resistance continues to impede overall survival rates for those affected by cancer. Although driver genes are associated with diverse cancer types, a scarcity of instrumental methods for predicting therapy response or resistance persists. Therefore, the impetus for designing predictive tools for therapeutic response is crucial and tools based on machine learning open new opportunities. Here, we present an easily accessible platform dedicated to Clear, Legible, Explainable, Transparent, and Elucidative (CLETE) yet wholly modifiable binary classification models. Our platform encompasses both unsupervised and supervised feature selection options, hyperparameter search methodologies, under-sampling and over-sampling methods, and normalization methods, along with fifteen machine learning algorithms. The platform furnishes a k-fold receiver operating curve (ROC) - area under the curve (AUC) and accuracy plots, permutation feature importance, SHapley Additive exPlanations (SHAP) plots, and Local Interpretable Model-agnostic Explanations (LIME) plots to interpret the model and individual predictions. We have deployed a unique custom metric for hyperparameter search, which considers both training and validation scores, thus ensuring a check on under or over-fitting. Moreover, we introduce an innovative scoring method, NegLog2RMSL, which incorporates both training and test scores for model evaluation that facilitates the evaluation of models via multiple parameters. In a bid to simplify the user interface, we provide a graphical interface that sidesteps programming expertise and is compatible with both Windows and Mac OS. Platform robustness has been validated using pharmacogenomic data for 23 drugs across four diseases and holds the potential for utilization with any form of tabular data.
Prenatal Methadone Exposure Leads To Disruptions In Adult-Born Dentate Granule Cell Survival And Female Persistent Fear Responding
Authors: Gamble Meredith E. , Diaz Marvin R. 
Published: June 2023

AbstractMethadone is used for the treatment of opioid use disorder, including in pregnant patients. Research has established several consequences of prenatal exposure to misused opioids, however little work has investigated the effects of prenatal methadone exposure (PME) on the offspring long-term, despite the continued prescription to pregnant individuals. The current study aimed to identify the long-term cognitive impairments arising from PME and assess hippocampal neurogenesis in these adult offspring. Pregnant Sprague Dawley rats were injected with methadone or sterile water twice daily from gestational day 3-20 or were left undisturbed as naïve controls. Adult offspring were tested in one of three behavioral tasks to assess pattern separation, spatial learning and memory, and contextual learning and memory, or were assigned to hippocampal tissue collection. For assessment of neurogenesis, offspring underwent injections of bromodeoxyuridine, and brains were collected at 24hr, 2wks, or 4wks for immunofluorescent staining. Methadone-exposed females, but not males, showed subtle impairments in pattern separation and heightened freezing during the extinction period in the fear conditioning task, and spatial memory in both sexes remained unaffected. Additionally, PME did not alter the rate of dentate granule cell proliferation but did significantly reduce the number of adult-born neuron surviving to a mature phenotype in the PME females at the 4wk timepoint. This work adds to the understanding of PME on offspring long-term and demonstrates female-specific sensitivity to these consequences. Future work is needed to fully investigate the neural disruptions arising from PME, with the goal of better supporting exposed individuals long-term.
A method for storing information in DNA with improved dropout tolerance
Authors: Mortuza Golam , Tobiason Michael D. , Suyehira Kelsey , Hughes William L. , Andersen Tim , Zadegan Reza 
Published: June 2023

AbstractStoring information in synthetic DNA oligomers is attractive for archival purposes due to the favorable physical density, stability, and energy efficiency of this storage medium. However, issues with this medium sometimes cause dropout (i.e., loss of oligomers) which may prevent the recovery of stored information. Here, an improved information storage method derived from the existing “DNA Fountain” method is reported. In this work we have developed and experimentally tested a robust algorithm to write digital data in pools of DNA strands by applying a rateless erasure code (i.e., fountain code), a Reed Solomon code, and an oligomer mapping code. Our new method includes changes to the fountain code, the oligomer mapping code, and the encoding and decoding processes. We have tested and benchmarked our algorithm vs similar algorithms and found that our method increases robustness to dropout, decreases encoding time, and decreases decoding time. The new method was validatedin-vitroby successfully storing and recovering 105,360 bits of information. The advantages of the new method make it more appropriate for applications where information recovery is critical, where substantial sequence loss is expected, and/or where computational resources are limited. Furthermore, the inclusion of the novel oligomer mapping code enabled us to mitigate errors by restricting sequences of repeated bases and enhance security by eliminating start/stop codons, thus minimizing the risk of interaction with living cells.
Structural basis for recognition of unfolded proteins by the ER stress sensor ERN1/IRE1α
Authors: Simpson Mariska S. , Luca Heidi De , Cauthorn Sarah , Luong Phi , Udeshi Namrata D. , Svinkina Tanya , Schmeider Stefanie S. , Carr Steven A. , Grey Michael J. , Lencer Wayne I. 
Published: June 2023

AbstractIRE1α is an endoplasmic reticulum sensor that recognizes misfolded proteins to activate the unfolded protein response (UPR). We used cholera toxin (CTx), which activates IRE1α in cells, to understand how unfolded proteins are recognized. In vitro, the A1 subunit of CTx (CTxA1) bound IRE1α lumenal domain (IRE1αLD). Global unfolding was not required. Instead, IRE1αLDrecognized a 7-residue motif within a metastable region of CTxA1 that was also found in microbial and host proteins involved in IRE1α activation. Binding mapped to a pocket on IRE1αLDnormally occupied by a segment of the IRE1α C-terminal flexible loop implicated in IRE1α regulation. Mutation of the recognition motif blocked CTx-induced IRE1α activation in live cells. These findings describe a mechanism for substrate recognition by IRE1α that induces the UPR.
SMART: reference-free deconvolution for spatial transcriptomics using marker-gene-assisted topic models
Authors: Yang C , Sin DD , Ng RT 
Published: June 2023

AbstractSpatial transcriptomics (ST) offers valuable insights into gene expression patterns within the spatial context of tissue. However, most technologies do not have a single-cell resolution, masking the signal of the individual cell types. Here, we present SMART, a reference-free deconvolution method that simultaneously infers the cell type-specific gene expression profile and the cellular composition at each spot. Unlike most existing methods that rely on having a single-cell RNA-sequencing dataset as the reference, SMART only uses marker gene symbols as the prior knowledge to guide the deconvolution process and outperforms the existing methods in realistic settings when an ideal reference dataset is unavailable. SMART also provides a two-stage approach to enhance its performance on cell subtypes. Allowing the inclusion of covariates, SMART provides condition-specific estimates and enables the identification of cell type-specific differentially expressed genes across conditions, which elucidates biological changes at a single-cell-type resolution.
Putting a new spin on insect jumping performance using 3D modeling and computer simulations of spotted lanternfly nymphs
Authors: Li Chengpei , Xu Aaron J. , Beery Eric , Hsieh S. Tonia , Kane Suzanne Amador 
Published: June 2023

AbstractHow animals jump and land on a variety of surfaces is an ecologically important problem relevant to bioinspired robotics. We investigated this topic in the context of the jumping biomechanics of the planthopperLycorma delicatula(the spotted lanternfly, SLF), an invasive insect in the US that jumps frequently for dispersal, locomotion, and predator evasion. High-speed video was used to analyze jumping by SLF nymphs from take-off to impact on compliant surfaces. These insects used rapid hindleg extensions to achieve high take-off speeds (2.7-3.4 m/s) and accelerations (800-1000 ms-2), with midair trajectories consistent with zero-drag ballistic motion without steering. Despite rotating rapidly (5-45 Hz) in the air about time-varying axes of rotation, they landed successfully in 58.9% of trials; they also attained the most successful impact orientation significantly more often than predicted by chance, consistent with their using attitude control. Notably, these insects were able to land successfully when impacting surfaces at all angles, pointing to the emerging importance of collisional recovery behaviors. To further understand their rotational dynamics, we created realistic 3D rendered models of SLFs and used them to compute their mechanical properties during jumping. Computer simulations based on these models and drag torques estimated from fits to tracked data successfully predicted several features of their measured rotational kinematics. This analysis showed that SLF nymphs are able to use posture changes and drag torques to control their angular velocity, and hence their orientation, thereby facilitating predominately successful landings when jumping.SummaryHigh-speed video revealed that juvenile spotted lanternflies are adept at landing after tumbling rapidly midair during jumping. We present computer simulations and realistic 3D models to help explain these abilities.
Toward transparent taxonomy: an interactive web-tool for evaluating competing taxonomic arrangements
Authors: Vernygora Oksana V. , Sperling Felix A.H. , Dupuis Julian R. 
Published: June 2023

Abstract1. Informative and consistent taxonomy above the species level is essential to communication about evolution, biodiversity, and conservation, and yet the practice of taxonomy is considered opaque and subjective by non-taxonomist scientists and the public alike. While various proposals have tried to make the basis for ranking and inclusiveness of taxa more transparent and objective, widespread adoption of these ideas has lagged.2. Here, we present TaxonomR, an interactive online decision-support tool to evaluate alternative taxonomic classifications. This tool implements an approach that quantifies the criteria commonly used in taxonomic treatments and allows the user to interactively manipulate weightings for different criteria to compare scores for taxonomic groupings under those weights.3. We use the butterfly taxonArgynnisto demonstrate how different weightings applied to common taxonomic criteria result in fundamentally different genus-level classifications that are predominantly used in different continents and geographic regions. These differences are objectively compared and quantified using TaxonomR to evaluate the kinds of criteria that have been emphasized in earlier classifications, and the nature of the support for current alternative taxonomic arrangements.4. The main role of TaxonomR is to make taxonomic decisions transparent via an explicit prioritization scheme. TaxonomR is not a prescriptive application. Rather, it aims to be a tool for facilitating our understanding of alternative taxonomic classifications that can, in turn, potentially support global harmony in biodiversity assessments through evidence-based discussion and community-wide resolution of historically entrenched taxonomic tensions.
Decellularisation and characterisation of porcine pleura for lung tissue engineering
Authors: Vikranth Trisha , Dale Tina , Forsyth Nicholas R 
Published: June 2023

AbstractDecellularisation offers a broad range of biomimetic scaffolds of allogeneic and xenogeneic origins, exhibiting innate tissue-specific characteristics. We explored a physico-chemical method for decellularising porcine pleural membranes (PPM) as potential tissue-engineered surrogates for lung tissue repair. Decellularised PPM (dPPM) was characterised with histology, quantitative assays, mechanical testing, and sterility evaluation. Cytotoxicity and recellularisation assays assessed the biocompatibility of dPPM. Haematoxylin and Eosin staining showed an evident reduction in nuclei in dPPM, confirmed with nuclear staining and analysis (****p < 0.0001). Sulphated glycosaminoglycans (sGAG) and collagen histology demonstrated minimal disruption to the structural assembly of the core extracellular matrix (ECM) in dPPM. Confocal imaging demonstrated realignment of ECM fibres in dPPM against native control. Quantitative analysis defined a significant change in the angular distribution (****p < 0.0001) and coherence of fibre orientations (***p < 0.001) in dPPM versus native ECM. DNA quantification indicated ≥ 85% reduction in native nuclear dsDNA in dPPM (**p < 0.001). Collagen and sGAG quantification indicated reductions of both (**p < 0.001). dPPM displayed increased membrane thickness (*p < 0.05). However, the Youngs modulus (447.8 ± 41.9 kPa) and ultimate tensile strength (5080 ± 2034.5 kPa) of dPPM were comparable with that of native controls at (411.3 ± 8.1 kPa) and (3933.3 ± 1734.5), respectively.In vitrocytotoxicity and scaffold biocompatibility assays demonstrated robust human mesothelial cell line (MeT-5A) attachment and viability. Here, we define a decellularisation protocol for porcine pleura that represents a step forward in their potential application as bioscaffolds in lung tissue engineering.Impact statementDesign and development of ‘off the shelf’ tissue engineered products can rely on decellularisation of native tissue that can be functionalised with cell ingress from surrounding host microenvironment. We describe a reproducible decellularisation method for porcine pleural membranes. Histology, mechanical testing, and biocompatibility studies demonstrated protocol efficiency in adequate removal of native tissue cellularity and retention of gross microarchitecture and bioactivity in the decellularised pleura. The study represents a step forward in establishing an off the shelf potential of decellularised pleura as site-specific mechanical barriers in curtailing prolonged air leaks and promoting spontaneous tissue regeneration with relevant physiological cues.
A 128-ch area-efficient neurochemical-sensing front-end for FSCV recordings of dopamine
Authors: White Kevin A. , Darroudi Mahdieh , Park Jinwoo , Kim Brian N. 
Published: June 2023

AbstractNeurochemical recordings rely on electrochemical reactions of electroactive neurotransmitters such as dopamine, serotonin, and norepinephrine. This electrochemical technique allows for highly sensitive monitoring of neurotransmitters in the brain. Traditionally, single-channel carbon-fiber microelectrode recordings have been considered the gold standard method. However, an alternative approach involves the use of a microelectrode array, which enables high spatiotemporal resolution imaging of electroactive neurotransmitters. To enable neurochemical imaging using a microelectrode array, the development of a high-density current-sensing microchip is necessary. Here, a neurochemical microchip is introduced, featuring a 128-channel current sensing front-end capable of supporting 128 parallel neurochemical measurements. The designed amplifier array employs a highly scalable resistive feedback transimpedance amplifier design. This design allows for a large neurochemical dynamic range of ±5µA with a noise performance as low as 0.22nARMS. With the integration of this microchip,in vivoneurochemical imaging of dopamine can be achieved with high spatiotemporal resolution.
Wound induced small-peptide mediated signalling cascade regulated by OsPSKR, dictates balance between growth and defense in rice
Authors: Harshith C.Y. , Pal Avik , Chakraborty Monoswi , Nair Ashwin , Raju Steffi , Shivaprasad P. V. 
Published: June 2023

AbstractWounding is a general stress in plants that results from various pest and pathogenic infections in addition to environment induced mechanical damages. Plants have sophisticated molecular mechanisms to recognize and respond to pests and pathogens. Although several molecules such as phytohormones, peptides and receptors have been attributed to wound responses in dicots, such mechanisms for monocots probably having distinct wound responses are less understood. Here, we show the involvement of two distinct categories of temporally separated, endogenously derived peptides, namely, plant elicitor peptides (PEPs) and phytosulfokine (PSK), that mediate wound responses in rice. These peptides trigger a dynamic signal relay in which a novel receptor kinase named OsPSKR played a major role. OsPSKR perceived PSK ligand, acting in association with a co-receptor OsSERK1, to activate downstream responses in a kinase activity-dependent manner. Perturbation of OsPSKR expression in rice led to compromised development and constitutive autoimmune phenotypes. These results suggested that OsPSKR maintains the trade-off between growth and exaggerated defense responses, both during homeostasis and wounding. Collectively, these findings indicate the presence of a stepwise peptide-mediated signal relay that regulates the transition from defense to growth upon wounding in monocots.One line summaryEndogenous peptide signalling initiated wound responses through a receptor-like kinase OsPSKR to maintain the balance between growth and defense responses.
Striatonigral distribution of a fluorescent reporter following intracerebral delivery of genome editors
Authors: Neuman Samuel S. , Metzger Jeanette M. , Bondarenko Viktoriya , Wang Yuyuan , Felton Jesi , Levine Jon E. , Saha Krishanu , Gong Shaoqin , Emborg Marina E. 
Published: June 2023

AbstractIntroductionTargeted gene editing is proposed as a therapeutic approach for numerous disorders, including neurological diseases. As the brain is organized into neural networks, it is critical to understand how anatomically connected structures are affected by genome editing. For example, neurons in the substantia nigra pars compacta (SNpc) project to the striatum, and the striatum contains neurons that project to the substantia nigra pars reticulata (SNpr).MethodsHere, we report the effect of injecting genome editors into the striatum of Ai14 reporter mice, which have a LoxP-flanked stop cassette that prevents expression of the red fluorescent protein tdTomato. Two weeks following intracerebral delivery of either synthetic nanocapsules (NCs) containing CRISPR ribonucleoprotein targeting the tdTomato stop cassette or adeno-associated virus (AAV) vectors expressing Cre recombinase, the brains were collected, and the presence of tdTomato was assessed in both the striatum and SN.ResultsTdTomato expression was observed at the injection site in both the NC- and AAV-treated groups and typically colocalized with the neuronal marker NeuN. In the SN, tdTomato-positive fibers were present in the pars reticulata, and SNpr area expressing tdTomato correlated with the size of the striatal genome edited area.ConclusionThese results demonstratein vivoanterograde axonal transport of reporter gene protein products to the SNpr following neuronal genome editing in the striatum.