bluuebunny/crossref_metadata_2025_split huggingface dataset:
Computational modeling of drug response identifies mutant-specific constraints for dosing panRAF and MEK inhibitors in melanoma
Authors: Goetz Andrew , Shanahan Frances , Brooks Logan , Lin Eva , Mroue Rana , Cruz Darlene Dela , Hunsaker Thomas , Czech Bartosz , Dixit Purushottam , Segal Udi , Martin Scott , Foster Scott A. , Gerosa Luca 
Published: August 2024

AbstractPurpose: This study explores the potential of preclinicalin vitrocell line response data and computational modeling in identifying optimal dosage requirements of pan-RAF (Belvarafenib) and MEK (Cobimetinib) inhibitors in melanoma treatment. Our research is motivated by the critical role of drug combinations in enhancing anti-cancer responses and the need to close the knowledge gap around selecting effective dosing strategies to maximize their potential. Results: In a drug combination screen of 43 melanoma cell lines, we identified unique dosage landscapes of panRAF and MEK inhibitors for NRAS vs BRAF mutant melanomas. Both experienced benefits, but with a notably more synergistic and narrow dosage range for NRAS mutant melanoma. Computational modeling and molecular experiments attributed the difference to a mechanism of adaptive resistance by negative feedback. We validatedin vivotranslatability ofin vitrodose-response maps by accurately predicting tumor growth in xenografts. Then, we analyzed pharmacokinetic and tumor growth data from Phase 1 clinical trials of Belvarafenib with Cobimetinib to show that the synergy requirement imposes stricter precision dose constraints in NRAS mutant melanoma patients. Conclusion: Leveraging pre-clinical data and computational modeling, our approach proposes dosage strategies that can optimize synergy in drug combinations, while also bringing forth the real-world challenges of staying within a precise dose range.Simple SummaryCombining drugs is crucial for enhancing anti-cancer responses. However, the potential of pre-clinical data in identifying suitable combinations and dosage is often underutilized. In this study, we leverage preclinicalin vitrocell line drug response data and computational modeling of signal transduction and of pharmacokinetics to elucidate distinct dose requirements for the combination of pan-RAF and MEK inhibitors in melanoma. Our findings reveal a more synergistic, but narrower dosing landscape in NRAS vs BRAF mutant melanoma, which we linked to a mechanism of adaptive resistance through negative feedback. Further, our analysis suggests the importance of drug dosing strategies to optimize synergy based on mutational context, yet highlights the real-world challenges of maintaining a narrow dose range. This approach establishes a framework for translational investigation of drug responses in the refinement of combination therapy, balancing the potential for synergy and practical feasibility in cancer treatment planning.
Reproductive state controls transcription in the murine liver, with implications for breast cancer liver metastasis
Authors: Ozaki Michelle K. , Zhang Yi , Bartlett Alexandra Q. , de Wilde Elise , Guan Xiangnan , Yang Alex , Xia Zheng , Schedin Pepper 
Published: August 2024

AbstractLiver biology is functionally linked to lactation, as liver size and metabolic output increase during lactation to support synthesis of breast milk. Upon weaning, the rodent liver returns to baseline homeostasis via hepatocyte cell death, in a process considered liver involution. To explore liver biology changes across a lactation-wean cycle, we employed transcriptomic profiling. We identified elevated hepatocyte proliferation and anabolic metabolism gene signatures during lactation, consistent with the liver being a major producer of substrates needed for milk production. Rapid loss of these capacities upon weaning correlated with catabolic metabolism, lysosomal-mediated cell death, and an influx of immune suppressive cells. Furthermore, we identified that the transcriptional profiles associated with liver involution share similarities with the gene expression patterns of liver pre-metastatic niches. This work identifies features of reproductive control of liver biology that sets a foundation for better understanding the potential role of the liver in maternal health.
A role for YAP-mediated regulation of invadopodia in HNSCC cells
Authors: Jerrell Rachel J. , Marchlewski Dayton D. , Parekh Aron 
Published: August 2024

ABSTRACTThe objective of this study was to determine whether nuclear translocation of the transcriptional coactivator Yes-associated protein (YAP) was sensitive to extracellular matrix (ECM) rigidity and promoted Rho-associated kinase 2 (ROCK2) expression to affect invadopodia maturation and ECM degradation. ECM rigidity mimicking head and neck squamous cell carcinoma (HNSCC) tumor mechanical properties was simulated in vitro using a well-established model based on fibronectin-conjugated polyacrylamide gels (PAAs). The ratio of nuclear to cytoplasmic YAP and overall cellular ROCK2 levels were evaluated in HNSCC cells using quantitative immunofluorescence. YAP-mediated ROCK2 expression in HNSCC cells was determined using nested PCR and Western blot in response to the YAP inhibitor verteporfin. Invadopodia and ECM degradation were evaluated in HNSCC cells with siRNA-mediated inhibition of YAP using quantitative immunofluorescence in invadopodia assays. Both YAP nuclear translocation and ROCK2 cellular levels increased with ECM rigidity. Inhibition of YAP activity with verteporfin decreased ROCK2 gene and protein expression. Knockdown of YAP with siRNA inhibited the formation of mature invadopodia and ECM degradation but not total invadopodia (i.e., mature and immature or not degrading). Our study suggests that tumor-associated ECM rigidity can promote mechanically-induced transcriptional regulation to control proteolytic activity by affecting invadopodia maturation.
Evolution and Diversification of the Aposematic Poison Frog,Oophaga pumilio,in Bocas del Toro
Authors: Aguilar-Gómez Diana , Freeborn Layla , Yuan Lin , Smith Lydia L. , Guzman Alex , Vaughn Andrew H. , Steigerwald Emma , Stuckert Adam , Yang Yusan , Linderoth Tyler , MacManes Matthew , Richards-Zawacki Corinne , Nielsen Rasmus 
Published: August 2024

AbstractThe aposematic strawberry poison frog,Oophaga pumilio, is an iconic model system for studying the evolution and maintenance of color variation. Through most of its range, this frog is red with blue limbs. However, frogs from the Bocas del Toro Province, Panama, show striking variance in color and pattern, both sympatrically and allopatrically. This observation contradicts standard models of the evolution of aposematism and has led to substantial speculation about its evolutionary and molecular causes. Since the enigma ofO. pumiliophenotypic variation is partly unresolved because of its large, ∼ 6.7 Gb genome, we here sequence exomes from 347 individuals from ten populations and map a number of genetic factors responsible for the color and pattern variation. Thekitgene is the primary candidate underlying the blue-red polymorphism in Dolphin Bay, where an increase in melanosomes is correlated with blue coloration. Additionally, thettc39bgene, a known enhancer of yellow-to-red carotenoid conversion in birds, is the primary factor behind the yellow-red polymorphism in the Bastimentos West area. The causal genetic regions show evidence of selective sweeps acting locally to spread the rare phenotype. Our analyses suggest an evolutionary model in which selection is driving the formation of new morphs in a dynamic system resulting from a trade-off between predation avoidance, intraspecific competition, and mate choice.
Expanding the Distribution and Phylogenetic Insights ofChrysobrycon mojicaiin the Peruvian Amazon: Morphological and Molecular Analyses with Taxonomic Corrections
Authors: Chuctaya Junior , Ruiz-Tafur Morgan , Faustino-Fuster Dario , Meza-Vargas Vanessa , Garcia-Davila Carmen , Castro-Ruiz Diana , Angulo Carlos , Vanegas-Ríos James Anyelo 
Published: August 2024

AbstractThis study focuses on the genusChrysobrycon, particularlyChrysobrycon mojicai, which was initially described in the Amacayacu National Natural Park in Colombia. Here, we document a new geographical record ofC. mojicaiin various locations of the Peruvian Amazon, including the Nanay, Putumayo, Tapiche, and Tigre Rivers basins. Based on morphological, morphometric, and molecular analyses, we confirm the presence ofC. mojicaiin these new locations, expanding its known distribution. Morphological features such as the distinct shape of the hypertrophied scales and the specific arrangement of teeth were used to confirm its identity. Molecular data, obtained through cytochrome oxidase I (COI) gene sequencing, provide additional validation and contribute to understanding its phylogenetic relationships within the Stevardiini tribe. Our phylogenetic analysis reveals unresolved relationships within the tribe, particularly in the genusGephyrocharax, and highlights discrepancies in the current taxonomic framework, withC. mojicaishowing close genetic affinity toC. myersifrom the Pachitea River basin. The study also presents morphometric information of the holotype of C. mojicai, specifically the percentages of measurements relative to the head, which were not included in the original description. It also includes ecological observations of the habitats whereC. mojicaiwas collected, noting its presence in blackwater and mixed water streams characterized by fluctuating water levels and specific physical and chemical parameters. Additionally, the study restricts the distribution ofC. guahibofor Colombia and invalidates the COI sequence ofHysteronotus megalostomusavailable in molecular databases. This research not only expands the known distribution ofC. mojicaibut also underscores the need for further taxonomic and ecological studies to resolve existing ambiguities within the Stevardiini subfamily.
Peucedanol ameliorates LPS-induced inflammation in RAW264.7 cells and CLP-induced sepsis in mice by inhibiting TLR4/myD88/NF-κB pathway
Authors: Yao Qi , Chang Bo-tao 
Published: August 2024

AbstractBackgroundPreviously, it has reported that Peucedanol (PEU) possesses anti-bacterial activity. However, its effect and mechanism against inflammation remains unclear.MethodsIsothermal titration calorimetry (ITC) was used to assess binding affinities of PEU to pathogen associated molecular patterns (PAMPs) Kdo2-Lipid A (KLA), oligodeoxynucleotide 1826 (ODN 1826), and peptidoglycan (PGN). A lipopolysaccharide (LPS)-induced RAW264.7 cell inflammation model and a cecum ligation and a puncture (CLP)-induced mouse sepsis model were used to assess efficacy and mechanism of PEUin vitroandin vivo. 16S ribosomal RNA (16S rRNA) sequencing was used to assay characteristics of intestinal flora of the sepsis mice.ResultsPEU had a moderate binding to KLA and ODN 1826. PEU significantly reduced supernatant tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6), and downregulated protein expressions of toll-like receptor 4 (TLR4), myeloid differentiation primary response gene 8 (MyD88), and nuclear factor kappa-B (NF-κB) in the LPS-treated cells. PEU remarkably increased the survival rate, reduced the serum TNF-α and IL-6 levels, attenuated the CLP-induced pathological damage of intestine, increased proliferation-related proteins Bmi1 and Lgr5. Further, the anti-inflammatory effects of PEU were not significantly abolished in the present of chloroquine (CQ). Meanwhile, PEU significantly increased Chao1 index of the intestinal flora at the early stage of sepsis. In addition, PEU significantly changed composition of the flora at both phylum and genus levels. Moreover, PEU significantly affected metabolism-related pathways such as tricarboxylic acid (TCA) cycle, fatty acid degradation, secondary bile acid biosynthesis, and others.ConclusionsTaken together, PEU significantly inhibits LPS-induced inflammationin vitroand CLP-induced sepsisin vivo. Further, its anti-inflammatory effect is independent of the TLR4/myD88/NF-κB pathway. In addition, PEU improves the intestinal flora imbalance at the early stage of sepsis.
Constraint Induced Movement Therapy Confers only a Transient Behavioral Benefit but Enduring Functional Circuit-Level Changes after Experimental TBI
Authors: Paydar Afshin , Khorasani Laila , Harris Neil G. 
Published: August 2024

AbstractAlthough the behavioral outcome of Constraint-Induced Movement Therapy (CIMT) is well known, and that a combination of CIMT and arm use training potentiates the effect, there has been limited study of the brain circuits involved that respond to therapy. An understanding of CIMT from a brain network level would be useful for guiding the duration of effective therapy, the type of training regime to potentiate the outcome, as well as brain regional targets that might be amenable for direct neuromodulation. Here we investigated the effect of CIMT therapy alone unconfounded by additional rehabilitation training in order to determine the impact of intervention at the circuit level. Adult rats were injured by controlled cortical impact injury and studied before and then after 2wks of CIMT or noCIMT at 1-3wks post-injury using a combination of forelimb behavioral tasks and task-based and resting state functional magnetic resonance imaging at 3 and 7wks post-injury and compared to sham rats. There was no difference in behavior or functional imaging between CIMT and noCIMT after injury before intervention so that data are unlikely to be confounded by differences in injury severity. CIMT produced only a transient reduction in limb deficits compared to noCIMT immediately after the intervention, but no difference thereafter. However, CIMT resulted in a persistent reduction in contralesional limb-evoked activation and a corresponding ipsilesional cortical plasticity compared to noCIMT that endured 4wks after intervention. This was associated with a significant amelioration of intra and inter-hemispheric connectivity present in the noCIMT group at 7wks post-injury.
Two distinct chromatin modules regulate proinflammatory gene expression
Authors: Seufert Isabelle , Gerosa Irene , Varamogianni-Mamatsi Vassiliki , Vladimirova Anastasiya , Sen Ezgi , Mantz Stefanie , Rademacher Anne , Schumacher Sabrina , Liakopoulos Panagiotis , Kolovos Petros , Anders Simon , Mallm Jan-Philipp , Papantonis Argyris , Rippe Karsten 
Published: August 2024

AbstractVarious mechanisms have been proposed to explain gene activation and co-regulation, including enhancer-promoter interactions via chromatin looping and the enrichment of transcription factors into hubs or condensates. However, these conclusions often stem from analyses of individual loci, and genome-wide studies exploring mechanistic differences with coupled gene expression are lacking. In this study, we dissected the proinflammatory gene expression program induced by TNFα in primary human endothelial cells using NGS- and imaging-based techniques. Our findings, enabled by our novel RWireX approach for single-cell ATAC-seq analysis, revealed two distinct regulatory chromatin modules: autonomous links of co-accessibility (ACs) between separated sites, and domains of contiguous co-accessibility (DCs) with increased local transcription factor binding. Genes in ACs and DCs exhibited different transcriptional bursting kinetics, highlighting the existence of two structurally and functionally distinct regulatory chromatin modules in the proinflammatory response. These findings provide a novel mechanistic framework for understanding how cells achieve rapid and precise gene expression control.Graphical abstractHighlightsTwo distinct, non-mutually exclusive chromatin modules, ACs and DCs, that regulate proinflammatory gene expression were identified based on deep scATAC-seq.ACs represent long-range genomic interactions with regulation occurring more by transcription burst frequency.DCs are regions of increased local transcription factor binding that can modulate transcription burst size.The AC/DC model integrates sequencing-based evidence for chromatin looping with microscopy observations of transcription factor hubs/condensates into a unified model.Our findings provide a novel framework for understanding how cells achieve rapid and precise gene expression control.
Generating Synthetic Task-based Brain Fingerprints for Population Neuroscience Using Deep Learning
Authors: Serin Emin , Ritter Kerstin , Schumann Gunter , Banaschewski Tobias , Marquand Andre , Walter Henrik ,   the environMENTAL consortium
Published: August 2024

AbstractTask-based functional magnetic resonance imaging (tb-fMRI) provides valuable insights into individual differences in the neural basis of cognitive functions because it links specific cognitive tasks to their evoked neural responses. Yet, it is challenging to scale to population-level data due to its cognitive demands, variations in task design across studies, and a limited number of tasks acquired in typical large-scale studies. Here, we present DeepTaskGen, a convolutional neural network (CNN) approach that enables us to generate synthetic task-based contrast maps from resting-state fMRI (rs-fMRI) data. Our method outperforms several benchmarks, exhibiting superior reconstruction performance while retaining inter-individual variation essential for biomarker development. We showcase DeepTaskGen by generating synthetic task images from the UK Biobank cohort, achieving competitive or greater performance compared to actual task contrast maps and resting-state connectomes for predicting a wide range of demographic, cognitive, and clinical variables. This approach will facilitate the study of individual differences and the generation of task-related biomarkers by enabling the generation of arbitrary functional cognitive tasks from readily available rs-fMRI data.
High-throughput gene expression analysis with TempO-LINC sensitively resolves complex brain, lung and kidney heterogeneity at single-cell resolution
Authors: Eastburn Dennis J. , White Kevin S. , Jayne Nathan D. , Camiolo Salvatore , Montis Gioele , Ha Seungeun , Watson Kendall G. , Yeakley Joanne M. , McComb Joel , Seligmann Bruce 
Published: August 2024

AbstractWe report the development and performance of a novel genomics platform, TempO-LINC, for conducting high-throughput transcriptomic analysis on single cells and nuclei. TempO-LINC works by adding cell-identifying molecular barcodes onto highly selective and high-sensitivity gene expression probes within fixed cells, without having to first generate cDNA. Using an instrument-free combinatorial-indexing approach, all probes within the same fixed cell receive an identical barcode, enabling the reconstruction of single-cell gene expression profiles across as few as several hundred cells and up to 100,000+ cells per run. The TempO-LINC approach is easily scalable based on the number of barcodes and rounds of barcoding performed; however, for the experiments reported in this study, the assay utilized over 5.3 million unique barcodes. TempO-LINC has a robust protocol for fixing and banking cells and displays high-sensitivity gene detection from multiple diverse sample types. We show that TempO-LINC has an observed multiplet rate of less than 1.1% and a cell capture rate of ∼50%. Although the assay can accurately profile the whole transcriptome (19,683 human or 21,400 mouse genes), it can be targeted to measure only actionable/informative genes and molecular pathways of interest – thereby reducing sequencing requirements. In this study, we applied TempO-LINC to profile the transcriptomes of 89,722 cells across multiple sample types, including nuclei from mouse lung, kidney and brain tissues. The data demonstrated the ability to identify and annotate at least 50 unique cell populations and positively correlate expression of cell type-specific molecular markers within them. TempO-LINC is a robust new single-cell technology that is ideal for large-scale applications/studies across thousands of samples with high data quality.
Implementation of a Goals-of-Care Communication Priming Intervention Tailored to Outpatient Stroke Survivors: A Pilot Study
Authors: Abedini Nauzley C. , Kross Erin K. , Engelberg Ruth A. , Garzio Gigi , Creutzfeldt Claire J. 
Published: August 2024

AbstractBackgroundGoals-of-care conversations (GOCC) are important but infrequent after stroke. Serious illness communication priming guides like the Jumpstart Guide can increase GOCC, but have not been evaluated in the stroke population.MethodsWe conducted a randomized pilot study to evaluate feasibility and acceptability of the Jumpstart Guide adapted for outpatient stroke survivors, their surrogates, and clinicians. We recruited stroke survivors ≥60 years presenting for care at a single academically-affiliated stroke clinic. We enrolled surrogates if the patient had communication or cognitive impairment. Patients/surrogates were randomized to intervention (patient/surrogate and clinician received pre-visit Jumpstart Guide) or control arms. We assessed feasibility of participant enrollment, survey completion and extraction of GOCC documentation from the electronic medical record. We assessed acceptability using patient/surrogate and clinician surveys.ResultsWe enrolled 15/24 (63%) eligible patients or surrogates. We randomized 5 patients alone and 3 patients with surrogates to the intervention arm, and 5 patients alone and 2 patients with surrogates to the control arm. Six clinicians were enrolled for the 8 intervention encounters. Patient characteristics in both groups were similar with mean age 74.7 years, 10/15 male, 12/15 white, and 10/15 with acute ischemic stroke. Most patients/surrogates (7/8 intervention vs 7/7 control) and all intervention clinicians completed post-visit surveys. Most intervention participants reported successful pre-visit receipt of the Jumpstart Guide (6/7 patient/surrogates; 6/8 clinicians). Of these, all intervention patients/surrogates and 5/6 clinicians stated they would “definitely” or “probably” recommend it to others. Two intervention vs no control patients had newly documented GOCC post-visit. Intervention patients/surrogates more frequently reported discussing GOCC during their clinic visit (6/7 intervention vs 4/7 control).ConclusionsImplementation of a stroke-specific GOCC priming guide (Jumpstart Guide) in an outpatient stroke clinic is feasible and acceptable. A large randomized controlled trial is needed to evaluate its efficacy in improving outpatient stroke clinic GOCC.