bluuebunny/crossref_metadata_2025_split huggingface dataset:
AngioMT: An in silico platform for digital sensing of oxygen transport through heterogenous microvascular networks
Authors: Mathur Tanmay , Tronolone James J. , Jain Abhishek 
Published: January 2023

ABSTRACTMeasuring the capacity of microvascular networks in delivering soluble oxygen and nutrients to its organs is essential in health, disease, and surgical interventions. Here, a finite element methodbased oxygen transport program, AngioMT, is designed and validated to predict spatial oxygen distribution and other physiologically relevant transport metrics within both the vascular network and the surrounding tissue. The software processes acquired images of microvascular networks and produces a digital mesh which is used to predict vessel and tissue oxygenation. The image-to-physics translation by AngioMT correlated with results from commercial software, however only AngioMT could provide predictions within the solid tissue in addition to vessel oxygenation. AngioMT predictions were sensitive and positively correlated to spatial heterogeneity and extent of vascularization of 500 different vascular networks formed with variable vasculogenic conditions. The predictions of AngioMT cross-correlate with experimentally-measured oxygen distributionsin vivo. The computational power of the software is increased by including calculations of higher order reaction mechanisms, and the program includes defining additional organ and tissue structures for a more physiologically relevant analysis of tissue oxygenation in complex co-cultured systems, orin vivo. AngioMT may serve as a digital performance measuring tool of vascular networks in microcirculation, experimental models of vascularized tissues and organs, and in clinical applications, such as organ transplants.
CrossTx: Cross-cell line Transcriptomic Signature Predictions
Authors: Chrysinas Panagiotis , Chen Changyou , Gunawan Rudiyanto 
Published: January 2023

AbstractMotivationPredicting the cell response to chemical compounds is central to drug discovery, drug repurposing, and personalized medicine. To this end, large datasets of drug response signatures have been curated, most notably the Connectivity Map (CMap) from the Library of Integrated Network-based Cellular Signatures (LINCS) project. A multitude ofin silicoapproaches have also been formulated to leverage drug signature data for accelerating novel therapeutics. However, the majority of the available data are from immortalized cancer cell lines. Cancer cells display markedly different responses to compounds, not only when compared to normal cells, but also among cancer types. Strategies for predicting drug signatures in unseen cells—cell lines not in the reference datasets—are still lacking.ResultsIn this work we developed a computational strategy, called CrossTx, for predicting drug transcriptomic signatures of an unseen target cell line using drug transcriptome data of reference cell lines and background transcriptome data of the target cells. Our strategy involves the combination of predictor and corrector steps. Briefly, the Predictor applies averaging (mean) or linear regression model to the reference dataset to generate cell line-agnostic drug signatures. The Corrector generates target-specific drug signatures by projecting cell line-agnostic signatures from the Predictor onto the transcriptomic latent space of the target cell line using Principal Component Analysis (PCA) and/or an Autoencoder (AE). We tested different combinations of Predictor-Corrector algorithms in an application to the CMap dataset to demonstrate the performance of our approach.ConclusionCrossTx is an efficacious and generalizable method for predicting drug signatures in an unseen target cell line. Among the combinations tested, we found that the best strategy is to employ Mean as the Predictor and PCA followed by AE (PCA+AE) as the Corrector. Still, the combination of Mean and PCA (without AE) is an attractive strategy because of its computationally efficiency and simplicity, while offering only slightly less accurate drug signature predictions than the best performing combination.Availability and implementationhttp://www.github.com/cabsel/crosstxContactrgunawan@buffalo.edu
HOGVAX: Exploiting Peptide Overlaps to Maximize Population Coverage in Vaccine Design with Application to SARS-CoV-2
Authors: Schulte Sara C. , Dilthey Alexander T. , Klau Gunnar W. 
Published: January 2023

AbstractPeptide vaccines present a safe and cost-efficient alternative to traditional vaccines. Their efficacy depends on the peptides included in the vaccine and the ability of major histocompatibility complex (MHC) molecules to bind and present these peptides. Due to the high diversity of MHC alleles, their diverging peptide binding specificities, and physical constraints on the maximum length of peptide vaccine constructs, choosing a set of peptides that effectively achieve immunization across a large proportion of the population is challenging.Here, we present HOGVAX, a combinatorial optimization approach to select peptides that maximize population coverage. The key idea behind HOGVAX is to exploit overlaps between peptide sequences to include a large number of peptides in limited space and thereby also cover rare MHC alleles. We formalize the vaccine design task as a theoretical problem, which we call the Maximum Scoring k-Superstring Problem (MSKS). We show that MSKS is NP-hard, reformulate it into a graph problem using the hierarchical overlap graph (HOG), and present a haplotype-aware variant of MSKS to take linkage disequilibrium between MHC loci into account. We give an integer linear programming formulation for the graph problem and provide an open source implementation.We demonstrate on a SARS-CoV-2 case study that HOGVAX-designed vaccine formulations contain significantly more peptides than vaccine sequences built from concatenated peptides. We predict over 98% population coverage and high numbers of per-individual presented peptides, leading to robust immunity against new pathogens or viral variants.
Six3acts independently ofPax6to provide an essential contribution to lens development
Authors: Manohar Sumanth , Nakayama Takuya , Fisher Marilyn , Grainger Robert M. 
Published: January 2023

ABSTRACTThe Six3 transcription factor is essential for forebrain and eye development, andSIX3mutations cause the congenital disorder holoprosencephaly. We created asix3mutant inXenopus tropicaliswith a mild holoprosencephaly phenotype, and unlike mouseSix3mutants that are headless/eyeless, theXenopusmutant forms some eye structures, allowing direct study of Six3 function in eye formation. We focus here on striking deficits in lens formation. Early lens induction occurs normally in the mutant, e.g., the essential eye genepax6, is activated in lens ectoderm, persisting in the eye to a late developmental stage, but in many embryos the lens fails to form. We found thatbmp4, bmp7.1, smad7, dll1, dlc, mab21l1and/ormab21l2, previously unknown assix3eye targets, are downregulated in the mutant. We show thatsix3is required for lens formation, acting primarily in developing retina during neurulation through BMP and Notch signaling, and thatmab21l1/mab21l2regulate(s) this BMP activity. This work reveals previously unrecognized essential roles forsix3in eye development, identifying its key role in signaling needed for lens formation, and acting independently ofpax6activity.SUMMARY STATEMENTThis study identifies thesix3transcription factor as the mediator of key inductive signals driving lens formation, acting independently ofpax6in early phases of lens formation.
Simultaneous interneuron labeling reveals population-level interactions among parvalbumin, somatostatin, and pyramidal neurons in cortex
Authors: Potter Christian , Bassi Constanza , Runyan Caroline A. 
Published: January 2023

SummaryCortical interneurons shape network activity in cell type-specific ways, and are also influenced by interactions with other cell types. These specific cell-type interactions are understudied, as transgenic labeling methods typically restrict labeling to one neuron type at a time. Although recent methods have enabled post-hoc identification of cell types, these are not available to many labs. Here, we present a method to distinguish between two red fluorophoresin vivo, which allowed imaging of activity in somatostatin (SOM), parvalbumin (PV), and putative pyramidal neurons (PYR) in mouse association cortex. We compared population events of elevated activity and observed that the PYR network state corresponded to the ratio between mean SOM and PV neuron activity, demonstrating the importance of simultaneous labeling to explain dynamics. These results extend previous findings in sensory cortex, as activity became sparser and less correlated when the ratio between SOM and PV activity was high.
HYENA detects oncogenes activated by distal enhancers in cancer
Authors: Yu Anqi , Yesilkanal Ali E. , Thakur Ashish , Wang Fan , Yang Yang , Phillips William , Wu Xiaoyang , Muir Alexander , He Xin , Spitz Francois , Yang Lixing 
Published: January 2023

AbstractSomatic structural variations (SVs) in cancer can shuffle DNA content in the genome, relocate regulatory elements, and alter genome organization. Enhancer hijacking occurs when SVs relocate distal enhancers to activate proto-oncogenes. However, most enhancer hijacking studies have only focused on protein-coding genes. Here, we develop a computational algorithm “HYENA” to identify candidate oncogenes (both protein-coding and non-coding) activated by enhancer hijacking based on tumor whole-genome and transcriptome sequencing data. HYENA detects genes whose elevated expression is associated with somatic SVs by using a rank-based regression model. We systematically analyze 1,146 tumors across 25 types of adult tumors and identify a total of 108 candidate oncogenes including many non-coding genes. A long non-coding RNATOB1-AS1is activated by various types of SVs in 10% of pancreatic cancers through altered 3-dimensional genome structure. We find that high expression ofTOB1-AS1can promote cell invasion and metastasis. Our study highlights the contribution of genetic alterations in non-coding regions to tumorigenesis and tumor progression.
Polyploid yeast are dependent on elevated levels of Mps1 for successful chromosome segregation
Authors: Meyer Régis E , Sartin Ashlea , Gish Madeline , Harsha Jillian , Wilkie Emily , Haworth Dawson , LaVictoire Rebecca , Alberola Isabel , Chuong Hoa H , Gorbsky Gary J , Dawson Dean S 
Published: January 2023

AbstractTumor cell lines with elevated chromosome numbers frequently have correlated elevations of Mps1 expression and these tumors are more dependent on Mps1 activity for their survival than control cell lines. Mps1 is a conserved kinase involved in controlling aspects of chromosome segregation in mitosis and meiosis. The mechanistic explanation for the Mps1-addiction of aneuploid cells is unknown. To address this question, we explored Mps1-dependence in yeast cells with increased sets of chromosomes. These experiments revealed that in yeast, increasing ploidy leads to delays and failures in orienting chromosomes on the mitotic spindle. Yeast cells with elevated numbers of chromosomes proved vulnerable to reductions of Mps1 activity. Cells with reduced Mps1 activity exhibit an extended prometaphase with longer spindles and delays in orienting the chromosomes. One known role of Mps1 is in recruiting Bub1 to the kinetochore in meiosis. We found that the Mps1-addiction of polyploid yeast cells is due in part to its role in Bub1 recruitment. Together, the experiments presented here demonstrate that increased ploidy renders cells more dependent on Mps1 for orienting chromosomes on the spindle. The phenomenon described here may be relevant in understanding why hyper-diploid cancer cells exhibit elevated reliance on Mps1 expression for successful chromosome segregation.Author summaryLosing or gaining chromosomes during cell division leads to aneuploidy (an abnormal number of chromosomes) and can contribute to cancer and other diseases. Indeed, most cells in solid tumors carry abnormally elevated numbers of chromosomes. Mps1 is a regulator of the machinery that distributes chromosomes to daughter cells. In tumors with elevated chromosome numbers the expression of Mps1 is often also elevated. In some aneuploid tumor cell lines these elevated Mps1 levels have been shown to be critical for survival tumor survival. To determine how cells with higher ploidy become dependent on Mps1, we explored Mps1-dependence in yeast cells with increased numbers of chromosomes. We report that yeast cells with elevated chromosome number are sensitive to reductions Mps1 expression. In cells with high ploidy and reduced levels of Mps1, the progression of the cell cycle is delayed and the ability of the cells to properly orient and segregate their chromosomes on the spindle is greatly reduced.
Rationally designed inhibitors of the Musashi protein-RNA interaction by hotspot mimicry
Authors: Bai Nan , Adeshina Yusuf , Bychkov Igor , Xia Yan , Gowthaman Ragul , Miller Sven A. , Gupta Abhishek K. , Johnson David K. , Lan Lan , Golemis Erica A. , Makhov Petr B. , Xu Liang , Pillai Manoj M. , Boumber Yanis , Karanicolas John 
Published: January 2023

AbstractRNA-binding proteins (RBPs) are key post-transcriptional regulators of gene expression, and thus underlie many important biological processes. Here, we developed a strategy that entails extracting a “hotspot pharmacophore” from the structure of a protein-RNA complex, to create a template for designing small-molecule inhibitors and for exploring the selectivity of the resulting inhibitors. We demonstrate this approach by designing inhibitors of Musashi proteins MSI1 and MSI2, key regulators of mRNA stability and translation that are upregulated in many cancers. We report this novel series of MSI1/MSI2 inhibitors is specific and active in biochemical, biophysical, and cellular assays. This study extends the paradigm of “hotspots” from protein-protein complexes to protein-RNA complexes, supports the “druggability” of RNA-binding protein surfaces, and represents one of the first rationally-designed inhibitors of non-enzymatic RNA-binding proteins. Owing to its simplicity and generality, we anticipate that this approach may also be used to develop inhibitors of many other RNA-binding proteins; we also consider the prospects of identifying potential off-target interactions by searching for other RBPs that recognize their cognate RNAs using similar interaction geometries. Beyond inhibitors, we also expect that compounds designed using this approach can serve as warheads for new PROTACs that selectively degrade RNA-binding proteins.
A Cellular Platform for Production of C4Monomers
Authors: Davis Matthew A. , Yu Vivian Yaci , Fu Beverly , Wen Miao , Koleski Edward J. , Silverman Joshua , Berdan Charles A. , Nomura Daniel K. , Chang Michelle C. Y. 
Published: January 2023

ABSTRACTLiving organisms carry out a wide range of remarkable functions, including the synthesis of thousands of simple and complex chemical structures for cellular growth and maintenance. The manipulation of this reaction network has allowed for the genetic engineering of cells for targeted chemical synthesis, but it remains challenging to alter the program underlying their fundamental chemical behavior. By taking advantage of the unique ability of living systems to use evolution to find solutions to complex problems, we have achieved ~95% theoretical yield of three C4commodity chemicals,n-butanol, 1,3-butanediol, and 4-hydroxy-2-butanone. Genomic sequencing of the evolved strains identifiedpcnBandrpoBCas two gene loci that are able to alter carbon flow by remodeling the transcriptional landscape of the cell, highlighting the potential of synthetic pathways as a tool to identify metabolic control points.
Early rise and persistent inhibition of electromyography during failed stopping
Authors: Fisher Mitchell , Trinh Hoa , O’Neill Jessica , Greenhouse Ian 
Published: January 2023

ABSTRACTReactively canceling movements is a vital feature of the motor system to ensure safety. This behavior can be studied in the laboratory using the stop signal task. There remains ambiguity about whether a “point-of-no-return” exists, after which a response cannot be aborted. A separate question concerns whether motor system inhibition associated with attempted stopping persists when stopping is unsuccessful. We address these two questions using electromyography (EMG) in two stop signal task experiments. Experiment 1 (n = 24) involved simple right and left index finger responses in separate task blocks. Experiment 2 (n = 28) involved a response choice between the right index and pinky fingers. To evaluate the approximate point-of-no-return, we measured EMG in responding fingers during the 100 ms preceding the stop signal and observed significantly greater EMG amplitudes during failed than successful stop trials in both experiments. Thus, EMG differentiated failed from successful stopping prior to the stop signal, regardless of whether there was a response choice. To address whether motor inhibition persists after failed stopping, we assessed EMG peak-to-offset durations and slopes (i.e., the rate of EMG decline) for go, failed stop, and successful stop (partial response EMG) trials. EMG peak-to-offset was shorter and steeper in failed stop trials compared to go and successful stop partial response EMG trials, suggesting motor inhibition persists even when failing to stop. These findings indicate EMG is sensitive to a point at which participants can no longer successfully stop an ongoing movement and suggest the peak-to-offset time of response-related EMG activity during failed stopping reflects stopping-related inhibition.
DNA G-quadruplex is a transcriptional control device that regulates memory
Authors: Marshall Paul R. , Zhao Qiongyi , Davies Joshua , Liau Wei-Siang , Lee Yujin , Basic Dean , Periyakaruppiah Ambika , Zajaczkowski Esmi L. , Leighton Laura J. , Madugalle Sachithrani U. , Musgrove Mason , Kielar Marcin , Gong Hao , Ren Haobin , Kaczmarczyk Lech , Jackson Walker S. , Chen Alon , Spitale Robert C. , Bredy Timothy W. 
Published: January 2023

AbstractThe conformational state of DNA fine-tunes the transcriptional rate and abundance of RNA. Here we report that DNA G-quadruplex (G4-DNA) accumulates in neurons in an experience-dependent manner, and that this is required for the transient silencing and activation of genes that are critically involved in learning and memory. In addition, site-specific resolution of G4-DNA by dCas9-mediated deposition of the helicase DHX36 impairs fear extinction memory. Dynamic DNA structure states therefore represent a key molecular mechanism underlying memory consolidation.One-Sentence SummaryG4-DNA is a molecular switch that enables the temporal regulation of the gene expression underlying the formation of fear extinction memory.
The role of catalytic and regulatory domains of human PrimPol in DNA binding and synthesis
Authors: Boldinova Elizaveta O. , Baranovskiy Andrey G. , Gagarinskaya Diana I. , Makarova Alena V. , Tahirov Tahir H. 
Published: January 2023

ABSTRACTHuman PrimPol possesses DNA primase and DNA polymerase activities and restarts stalled replication forks protecting cells against DNA damage in nuclei and mitochondria. The zinc-binding motif (ZnFn) of the C-terminal domain (CTD) of PrimPol is required for DNA primase activity but the mechanism is not clear. In this work, we biochemically demonstrate that PrimPol initiatesde novoDNA synthesis incis-orientation, when the N-terminal catalytic domain (NTD) and the CTD of one molecule take part in catalysis. The modeling studies revealed that PrimPol uses a similar mode of initiating NTP coordination as the human primase. The ZnFn motif residue Arg417 is required for binding the 5’-triphosphate group that stabilizes the PrimPol complex with a DNA template-primer. We found that PrimPol is able to efficiently initiate DNA synthesis in the absence of the link between the two domains. The ability of the NTD alone to prime DNA synthesis and a regulatory role of the RPA-binding motif in the modulation of PrimPol binding to DNA are also demonstrated.
A mechanism of melanogenesis mediated by E-cadherin downregulation and its involvement in solar lentigines
Authors: Inoue Daigo , Narita Tomomi , Ishikawa Keiko , Maeno Katsuyuki , Motoyama Akira , Ono Takayuki , Aoki Hirofumi , Shibata Takako 
Published: January 2023

AbstractBackgroundIntensive studies have revealed pleiotropic melanocytic factors for age spot formation. In particular, dysfunctional keratinocyte differentiation is thought to be an upstream cause of age spot formation. Although keratinocyte differentiation is mediated by a cell-cell contact factor, E-cadherin, its involvement in age spots remains unknown. To find the origin of age spots and an integrated solution, we focused on E-cadherin.MethodsImmunofluorescent staining with cutaneous tissues and cultured cells was performed. Keratinocytes treated with siRNAs were cocultured with melanocytes. With the supernatants of the keratinocyte culture, secretion factors were identified using proteomic analysis. For the activity of melanogenesis and the ingredient screening, a quantitative PCR was performed. For the behavioral analysis of melanocytes, time-lapse imaging of melanocytes was done by confocal laser scanning microscopy.ResultsIn age spots, E-cadherin expression in the epidermis was downregulated, suggesting that E-cadherin is implicated in age spot formation. E-cadherin knockdown (E-cad-KD) keratinocytes not only promoted the secretion of melanocytic/inflammatory factors, but also increased melanogenesis by upregulating the expression of melanogenesis factors. Furthermore, live imaging showed E-cadherin downregulation detained melanocyte dynamics and accelerated melanin-uptake. Finally, we identified Rosa multiflora fruit extract as a solution for upregulating E-cadherin in keratinocytes.ConclusionOur findings showed that E-cadherin downregulation triggers various downstream melanocytic processes such as secretion of melanocytic factors and melanogenesis. Additionally, we showed that Rosa multiflora fruit extract upregulates E-cadherin expression in keratinocytes.