bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Novel Mouse Model that Recapitulates the Heterogeneity of Human Triple Negative Breast Cancer
Authors: Doha Zinab O. , Wang Xiaoyan , Calistri Nicholas , Eng Jennifer , Daniel Colin J. , Ternes Luke , Kim Eun Na , Pelz Carl , Munks Michael , Betts Courtney , Kirchberger Nell , Kwon Sunjong , Bucher Elmar , Li Xi , Waugh Trent , Pietenpol Jennifer A. , Sanders Melinda E. , Mills Gordon , Chin Koei , Chang Young Hwan , Coussens Lisa M. , Gray Joe W. , Heiser Laura M. , Sears Rosalie C. 
Published: October 2022

AbstractTriple-negative breast cancer (TNBC) patients have a poor prognosis and few treatment options. Mouse models of TNBC are important for development of new targeted therapies, but few TNBC mouse models exist. Here, we developed a novel TNBC murine model by mimicking two common TNBC mutations with high co-occurrence: amplification of the oncogene MYC and deletion of the tumor suppressor PTEN. This Myc;Ptenfl murine model develops TN mammary tumors that display histological and molecular features commonly found in human TNBC. We performed deep omic analyses on Myc;Ptenfl tumors including machine learning for morphologic features, bulk and single-cell RNA-sequencing, multiplex immunohistochemistry and single-cell phenotyping. Through comparison with human TNBC, we demonstrated that this new genetic mouse model develops mammary tumors with differential survival that closely resemble the inter- and intra-tumoral and microenvironmental heterogeneity of human TNBC; providing a unique pre-clinical tool for assessing the spectrum of patient TNBC biology and drug response.Statement of significanceThe development of cancer models that mimic triple-negative breast cancer (TNBC) microenvironment complexities is critical to develop effective drugs and enhance disease understanding. This study addresses a critical need in the field by identifying a murine model that faithfully mimics human TNBC heterogeneity and establishing a foundation for translating preclinical findings into effective human clinical trials.
Brevicidine, a bacterial non-ribosomally produced cyclic antimicrobial lipopeptide with a uniquemodus operandi
Authors: Zhao Xinghong , Zhong Xinyi , Wan Hongping , Liu Lu , Song Xu , Zou Yuanfeng , Li Lixia , Jia Renyong , Lin Juchun , Tang Huaqiao , Ye Gang , Yang Jianqing , Zhao Shan , Lang Yifei , Yin Zhongqiong , Kuipers Oscar P. 
Published: October 2022

AbstractDue to the accelerated appearance of antibiotic-resistant (AMR) pathogens in clinical infections, new first-in-class antibiotics, operating via novel modes of action, are desperately-needed. Brevicidine, a bacterial non-ribosomally produced cyclic lipopeptide, has shown potent and selective antimicrobial activity against Gram-negative pathogens. However, before our investigations, little was known about how brevicidine exerts its potent bactericidal effect against Gram-negative pathogens. In this study, we find that brevicidine has potent antimicrobial activity against AMREnterobacteriaceaepathogens, with a MIC value ranging between 0.5μM (0.8mg/L) and 2μM (3.0mg/L). In addition, brevicidine showed potent anti-biofilm activity against theEnterobacteriaceaepathogens, with same 100% inhibition and 100% eradication concentration of 4μM (6.1mg/L). Further mechanistic studies showed that brevicidine exerts its potent bactericidal activity via interacting with lipopolysaccharide in the outer membrane, targeting phosphatidylglycerol and cardiolipin in the inner membrane, and dissipating the proton motive force of bacteria. This results in metabolic perturbation, including inhibition of adenosine triphosphate synthesis, inhibits the dehydrogenation of nicotinamide adenine dinucleotides, accumulation of reactive oxygen species in bacteria, and inhibition of protein synthesis. Lastly, brevicidine showed a good therapeutic effect in a mouse peritonitis–sepsis model. Our findings pave the way for further research on clinical applications of brevicidine, to combat the prevalent infections caused by AMR Gram-negative pathogens worldwide.
BUB-1 and CENP-C recruit PLK-1 to Control Chromosome Alignment and Segregation During Meiosis I inC. elegansOocytes
Authors: Taylor Samuel J.P. , Borja Laura Bel , Soubigou Flavie , Houston Jack , Cheerambathur Dhanya K. , Pelisch Federico 
Published: October 2022

ABSTRACTPhosphorylation is a key post-translational modification that is utilised in many biological processes for the rapid and reversible regulation of protein localisation and activity. Polo-like kinase 1 (PLK-1) is essential for both mitotic and meiotic cell divisions, with key functions being conserved in eukaryotes. The roles and regulation of PLK-1 during mitosis have been well characterised. However, the discrete roles and regulation of PLK-1 during meiosis have remained obscure. Here, we usedCaenorhabditis elegans (C. elegans)oocytes to show that PLK-1 plays distinct roles in meiotic spindle assembly and/or stability, chromosome alignment and segregation, and polar body extrusion during meiosis I. Furthermore, by a combination of live imaging and biochemical analysis we identified the chromosomal recruitment mechanisms of PLK-1 duringC. elegansoocyte meiosis. The spindle assembly checkpoint kinase BUB-1 directly recruits PLK-1 to the kinetochore and midbivalent while the chromosome arm population of PLK-1 depends on a direct interaction with the centromeric-associated protein CENP-CHCP-4. We found that perturbing both BUB-1 and CENP-CHCP-4recruitment of PLK-1 leads to severe meiotic defects, resulting in highly aneuploid oocytes. Overall, our results shed light on the roles played by PLK-1 during oocyte meiosis and provide a mechanistic understanding of PLK-1 targeting to meiotic chromosomes.
Plant Breeding in the face of climate change
Authors: Messina Carlos D , Cooper Mark 
Published: October 2022

ABSTRACTClimate change will have a net negative and inequitable impact on agriculture. Genetics for crop improvement ranks in the top set of technologies that can contribute to human adaptation to climate change. However, a framework for how to breed crops for climate change adaptation is lacking. Here we propose a framework to develop new genotype (G) x management (M) technologies (G x M) to adapt to climate change, and to transition from current to future G x M technologies in a way that future food security does not come at the expense of current food security. The framework integrate genomic, agronomic, and environmental (E) predictors to accomplish two critical goals: 1-predict emergent phenotypes that stems from the dynamic interplay between G, E and M, and thus enable the breeder to consider the behavior of new genetic and trait combinations in environments that plants have not been exposed or tested before, and 2-identify G x M technologies that could increase food and nutritional security while regenerating natural and production resources. We highlight the need to invest in artificial intelligence and information technologies for breeders to harness multiple sources of information to create G x M technologies to address the diverse cultural and geographically granular societal needs.
Hexanematic crossover in epithelial monolayers depends on cell adhesion and cell density
Authors: Eckert Julia , Ladoux Benoît , Mège René-Marc , Giomi Luca , Schmidt Thomas 
Published: October 2022

AbstractChanges in tissue geometry during developmental processes are associated with collective migration of cells. Recent experimental and numerical results suggest that these changes could leverage on the coexistence of nematic and hexatic orientational order at different length scales. How this multiscale organization is affected by the material properties of the cells and their substrate is presently unknown. In this study, we address these questions in monolayers of Madin-Darby canine kidney cells having various cell densities and molecular repertoires. At small length scales, confluent monolayers are characterized by a prominent hexatic order, independent of the presence of E-cadherin, monolayer density, and underlying substrate stiffness. However, all three properties affect the meso-scale tissue organization. The length scale at which hexatic order transits to nematic order, the “hexanematic” crossover scale, strongly depends on cell-cell adhesions and correlates with monolayer density. Our study demonstrates how epithelial organization is affected by mechanical properties, and provides a robust description of tissue organization during developmental processes.
Inferring pathways of oxidative folding from pre-folding free energy landscapes of disulfide-rich toxins
Authors: Mansbach Rachael A. , Patel Lara A. , Watson Natalya A. , Kubicek-Sutherland Jessica Z. , Gnanakaran S. 
Published: October 2022

AbstractShort, cysteine-rich peptides can exist in stable or metastable structural ensembles due to the number of possible patterns of formation of their disulfide bonds. One interesting subset of this peptide group is the coonotoxins, which are produced by aquatic snails in the familyConidae. Theµconotoxins, which are antagonists and blockers of the voltage-gated sodium channel, exist in a folding spectrum: on one end of the spectrum are more hirudin-like folders, which form disulfide bonds and then reshuffle them, leading to an ensemble of kinetically trapped isomers–and on the other end are more BPTI-like folders–which form the native disulfide bonds one by one in a particular order, leading to a preponderance of conformations existing in a single stable state. In this article, we employ the composite diffusion map approach to study the unified free energy surface of pre-foldingµ-conotoxin equilibrium. We identify the two most important nonlinear collective modes of the unified folding landscape and demonstrate that in the absence of their disulfides, the conotoxins can be thought of as largely disordered polymers. A small increase in the number of hydrophobic residues in the protein shifts the free energy landscape towards hydrophobically collapsed coil conformations responsible for cysteine proximity in hirudin-like folders, compared to semi-extended coil conformations with more distal cysteines in BPTI-like folders. Overall, this work sheds important light on the folding processes and free energy landscapes of cysteinerich peptides and demonstrates the extent to which sequence and length contribute to these landscapes.
Live imaging reveals chromatin compaction transitions and dynamic transcriptional bursting during stem cell differentiation in vivo
Authors: May Dennis , Yun Sangwon , Gonzalez David , Park Sangbum , Chen Yanbo , Lathrop Elizabeth , Cai Biao , Xin Tianchi , Zhao Hongyu , Wang Siyuan , Gonzalez Lauren E. , Cockburn Katie , Greco Valentina 
Published: October 2022

AbstractStem cell differentiation requires dramatic changes in gene expression and global remodeling of chromatin architecture. How and when chromatin remodels relative to the transcriptional, behavioral, and morphological changes during differentiation remain unclear, particularly in an intact tissue context. Here, we develop a quantitative pipeline which leverages fluorescently-tagged histones and longitudinal imaging to track large-scale chromatin compaction changes within individual cells in a live mouse. Applying this pipeline to epidermal stem cells, we reveal that cell-to-cell chromatin compaction heterogeneity within the stem cell compartment emerges independent of cell cycle status, and instead is reflective of differentiation status. Chromatin compaction state gradually transitions over days as differentiating cells exit the stem cell compartment. Moreover, establishing live imaging of keratin-10 nascent RNA, which marks the onset of stem cell differentiation, we find that keratin-10 transcription is highly dynamic and largely precedes the global chromatin compaction changes associated with differentiation. Together, these analyses reveal that stem cell differentiation involves dynamic transcriptional states and gradual chromatin rearrangement.
Targeting tumour-intrinsic neural vulnerabilities of glioblastoma
Authors: Lee Sohyon , Weiss Tobias , Bühler Marcel , Mena Julien , Lottenbach Zuzanna , Wegmann Rebekka , Sun Miaomiao , Bihl Michel , Augustynek Bartłomiej , Baumann Sven , Goetze Sandra , van Drogen Audrey , Pedrioli Patrick , Kirschenbaum Daniel , Vasella Flavio , Rushing Elisabeth J. , Wollscheid Bernd , Hediger Matthias A. , Michael Weller , Snijder Berend 
Published: October 2022

AbstractGlioblastoma is the most common yet deadliest primary brain cancer1. The neural behavior of glioblastoma, including the formation of synaptic circuitry and tumour microtubes, is increasingly understood to be pivotal for disease manifestation2–9. Nonetheless, the few approved treatments for glioblastoma target its oncological nature, while its neural vulnerabilities remain incompletely mapped and clinically unexploited. Here, we systematically survey the neural molecular dependencies and cellular heterogeneity across glioblastoma patients and diverse model systems. In 27 surgical patient samples, we identify cancer cell morphologies indicative of poor prognosis, and discover repurposable neuroactive drugs with anti-glioblastoma efficacy by image-based drug screening. Glioblastoma cells exhibit functional dependencies on highly expressed neuroactive drug targets, while interpretable molecular machine learning (COSTAR) reveals their downstream convergence on AP-1-driven tumour suppression. This drug-target connectivity signature is confirmed by accuratein silicodrug screening on >1 million compounds, as well as by multi-omic profiling of glioblastoma drug responses. Thus, Ca2+-driven AP-1 pathway induction represents a tumour-intrinsic vulnerability at the intersection of oncogenesis and neural activity-dependent signaling. Opportunities for clinical translation of this neural vulnerability are epitomized by the antidepressant Vortioxetine synergizing with current standard of care treatmentsin vivo. Together, the results presented here provide a mechanistic foundation and conceptual framework for the treatment of glioblastoma based on its neural origins.
EquiFold: Protein Structure Prediction with a Novel Coarse-Grained Structure Representation
Authors: Lee Jae Hyeon , Yadollahpour Payman , Watkins Andrew , Frey Nathan C. , Leaver-Fay Andrew , Ra Stephen , Cho Kyunghyun , Gligorijević Vladimir , Regev Aviv , Bonneau Richard 
Published: October 2022

AbstractDesigning proteins to achieve specific functions often requiresin silicomodeling of their properties at high throughput scale and can significantly benefit from fast and accurate protein structure prediction. We introduce EquiFold, a new end-to-end differentiable, SE(3)-equivariant, all-atom protein structure prediction model. EquiFold uses a novel coarse-grained representation of protein structures that does not require multiple sequence alignments or protein language model embeddings, inputs that are commonly used in other state-of-the-art structure prediction models. Our method relies on geometrical structure representation and is substantially smaller than prior state-of-the-art models. In preliminary studies, EquiFold achieved comparable accuracy to AlphaFold but was orders of magnitude faster. The combination of high speed and accuracy make EquiFold suitable for a number of downstream tasks, including protein property prediction and design.
PLK-1 tethered on BUB-1 directs CDC-20 kinetochore recruitment to ensure timely embryonic mitoses
Authors: Houston Jack , Ohta Midori , Gómez-Cavazos J. Sebastián , Deep Amar , Corbett Kevin D. , Oegema Karen , Lara-Gonzalez Pablo , Kim Taekyung , Desai Arshad 
Published: October 2022

ABSTRACTDuring mitosis chromosomes assemble kinetochores in order to dynamically couple with spindle microtubules (Cheeseman, 2014; Musacchio & Desai, 2017). Kinetochores also function as signaling hubs directing mitotic progression by recruiting and controlling the fate of the Anaphase Promoting Complex/Cyclosome (APC/C) activator CDC-20 (Lara-Gonzalez et al., 2017; Lara-Gonzalez, Pines, et al., 2021; Musacchio, 2015). Kinetochores either incorporate CDC-20 into checkpoint complexes that inhibit the APC/C or dephosphorylate CDC-20, which allows it to interact with and activate the APC/C (Kim et al., 2017; Lara-Gonzalez et al., 2017). The importance of these two CDC-20 fates likely depends on biological context. In somatic cells the major mechanism controlling mitotic progression is the spindle checkpoint. By contrast, progression through mitosis during the cell cycles of early embryos is largely checkpoint-independent (Clute & Masui, 1995; Duro & Nilsson, 2021; Gerhart et al., 1984; Zhang et al., 2015). Here, by manipulating CDC-20 phosphorylation status, we show that CDC-20 phosphoregulation controls mitotic duration in the C. elegans embryo and defines a checkpoint-independent temporal mitotic optimum for robust embryogenesis. Flux of CDC-20 through kinetochores for local dephosphorylation requires an ABBA motif on BUB-1 that directly interfaces with the structured WD40 domain of CDC-20 (Di Fiore et al., 2015; Diaz-Martinez et al., 2015; He et al., 2013; Kim et al., 2017). We show that a conserved “STP” motif in BUB-1 that docks the mitotic kinase PLK-1 (Qi et al., 2006) is also necessary to recruit CDC-20 to kinetochores and for timely mitotic progression. The kinase activity of PLK-1 is required for CDC-20 to localize to kinetochores and targets a site within the CDC-20-binding ABBA motif of BUB-1; phosphorylation of this site promotes BUB-1–CDC-20 interaction and mitotic progression. Thus, the BUB-1-bound pool of PLK-1 ensures timely mitosis during embryonic cell cycles by promoting CDC-20 recruitment to the vicinity of kinetochore-localized phosphatase activity.
The formation and closure of macropinocytic cups in a model system
Authors: Lutton Judith E. , Coker Helena L. E. , Paschke Peggy , Munn Christopher J. , King Jason S. , Bretschneider Till , Kay Robert R. 
Published: October 2022

AbstractMacropinocytosis is a conserved endocytic process where cells take up medium into micron-sized vesicles. InDictyostelium, macropinocytic cups form around domains of PIP3 in the plasma membrane and extend by actin polymerization. Using lattice light-sheet microscopy, we describe how cups originate, are supported by an F-actin scaffold and shaped by a ring of actin polymerization, created around PIP3 domains. How cups close is unknown. We find two ways: lip closure, where actin polymerization at the lip is re-directed inwards; and basal closure, where it stretches the cup, eventually causing membrane delamination and vesicle sealing. Cups grow as expanding waves of actin polymerization that travel across the cell surface, capturing new membrane. We propose that cups close when these waves stall. This ‘stalled wave’ hypothesis is tested through a conceptual model, where the interplay of forces from actin polymerization and membrane tension recreates many of our observations.
Chromosome-scale genome assembly of the pink bollworm,Pectinophora gossypiella, a global pest of cotton
Authors: Stahlke Amanda R. , Chang Jennifer , Chudalayandi Sivanandan , Heu Chan C. , Geib Scott M. , Scheffler Brian E. , Childers Anna K. , Fabrick Jeffrey A. 
Published: October 2022

AbstractThe pink bollworm,Pectinophora gossypiella(Saunders) (Lepidoptera: Gelechiidae), is a major global pest of cotton. Current management practices include chemical insecticides, cultural strategies, sterile insect releases, and transgenic cotton producing crystalline (Cry) protein toxins of the bacteriumBacillus thuringiensis(Bt). These strategies have contributed to eradication ofP. gossypiellafrom the cotton growing areas of the United States and northern Mexico. However, this pest has evolved resistance to Bt cotton in Asia, where it remains a critical pest, and the benefits of using transgenic Bt crops have been lost. A complete annotated reference genome is needed to improve global Bt resistance management of the pink bollworm. We generated the first chromosome-level genome assembly for pink bollworm from a Bt-susceptible laboratory strain (APHIS-S) using PacBio continuous long reads for contig generation, Illumina Hi-C for scaffolding, and Illumina whole-genome re-sequencing for error-correction. The psuedohaploid assembly consists of 29 autosomes and the Z sex chromosome. The assembly exceeds the minimum Earth BioGenome Project quality standards, has a low error-rate, is highly contiguous at both the contig and scaffold level (L/N50 of 18/8.26 MB and 14/16.44 MB, respectively), and complete, with 98.6% of lepidopteran single-copy orthologs represented without duplication. The genome was annotated with 50% repeat content and 14,107 protein-coding genes, further assigned to 41,666 functional annotations. This assembly represents the first publicly available complete annotated genome of pink bollworm and will serve as the foundation for advancing molecular genetics of this important pest species.
Estrogen receptor alpha mutations regulate gene expression and cell growth in breast cancer through microRNAs
Authors: Arnesen Spencer , Polaski Jacob T. , Blanchard Zannel , Osborne Kyle S. , Welm Alana L. , O’Connell Ryan M. , Gertz Jason 
Published: October 2022

AbstractEstrogen receptor α (ER) mutations occur in up to 30% of metastatic ER-positive breast cancers. Recent data has shown that ER mutations impact the expression of thousands of genes not typically regulated by wildtype ER. While the majority of these altered genes can be explained by constant activity of mutant ER or genomic changes such as altered ER binding and chromatin accessibility, as much as 33% remain unexplained, indicating the potential for post-transcriptional effects. Here we explored the role of microRNAs in mutant ER-driven gene regulation and identified several microRNAs that are dysregulated in ER mutant cells. These differentially regulated microRNAs target a significant portion of mutant-specific genes involved in key cellular processes. When the activity of microRNAs is altered using mimics or inhibitors, significant changes are observed in gene expression and cellular proliferation related to mutant ER. An in-depth evaluation of miR-301b led us to discover an important role forPRKD3in the proliferation of ER mutant cells. Our findings show that microRNAs contribute to mutant ER gene regulation and cellular effects in breast cancer cells.