bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterization of non-monotonic relationships between tumor mutational burden and clinical outcomes
Authors: Anaya Jordan , Kung Julia , Baras Alexander S. 
Published: January 2024

ABSTRACTPotential clinical biomarkers are often assessed with Cox regressions or their ability to differentiate two groups of patients based on a single cutoff. However, both of these approaches assume a monotonic relationship between the potential biomarker and survival. Tumor mutational burden (TMB) is currently being studied as a predictive biomarker for immunotherapy, and a single cutoff is often used to divide patients. In this study we introduce a two-cutoff approach that allows splitting of patients when a non-monotonic relationship is present, and explore the use of neural networks to model more complex relationships of TMB to outcome data. Using real-world data we find that while in most cases the true relationship between TMB and survival appears monotonic, that is not always the case and researchers should be made aware of this possibility.SignificanceWhen a non-monotonic relationship to survival is present it is not possible to divide patients by a single value of a predictor. Neural networks allow for complex transformations and can be used to correctly split patients when a non-monotonic relationship is present.
Cell polarity proteins promote macropinocytosis in response to metabolic stress
Authors: Lambies Guillem , Lee Szu-Wei , Duong-Polk Karen , Aza-Blanc Pedro , Maganti Swetha , Dawson David W. , Commisso Cosimo 
Published: January 2024

AbstractMacropinocytosis has emerged as a nutrient-scavenging pathway that cancer cells exploit to survive the nutrient-deprived conditions of the tumor microenvironment. Cancer cells are especially reliant on glutamine for their survival, and in pancreatic ductal adenocarcinoma (PDAC) cells, glutamine deficiency can enhance the stimulation of macropinocytosis, allowing the cells to escape metabolic stress through the production of extracellular-protein-derived amino acids. Here, we identify the atypical protein kinase C (aPKC) enzymes, PKCζ and PKCι, as novel regulators of macropinocytosis. In normal epithelial cells, aPKCs are known to regulate cell polarity in association with the scaffold proteins Par3 and Par6, controlling the function of several targets, including the Par1 kinases. In PDAC cells, we identify that each of these cell polarity proteins are required for glutamine stress-induced macropinocytosis. Mechanistically, we find that the aPKCs are regulated by EGFR signaling or by the transcription factor CREM to promote the relocation of Par3 to microtubules, facilitating macropinocytosis in a dynein-dependent manner. Importantly, we determine that cell fitness impairment caused by aPKC depletion is rescued by the restoration of macropinocytosis and that aPKCs support PDAC growthin vivo. These results identify a previously unappreciated role for cell polarity proteins in the regulation of macropinocytosis and provide a better understanding of the mechanistic underpinnings that control macropinocytic uptake in the context of metabolic stress.
A dynamicWUSCHEL/ Layer 1 interplay directs shoot apical meristem formation during regeneration
Authors: Kumar Manoj , Ayzenshtat Dana , Zemach Hanita , Belausov Eduard , Williams Leor Eshed , Bocobza Samuel 
Published: January 2024

AbstractDe novoshoot apical meristem (SAM) organogenesis during regeneration in tissue culture has been investigated for several decades, but the precise mechanisms governing early-stage cell fate specification remain elusive. In contrast to SAM establishment during embryogenesis,in vitroSAM formation occurs without positional cues, and is characterized by spontaneous cellular patterning. Here, we have elucidated the initial stages of SAM organogenesis and the molecular mechanisms that orchestrate gene patterning to establish SAM homeostasis. We found that SAM organogenesis in tobacco calli initiates with protuberance formation followed by the formation of an intact L1 layer covering the nascent protuberance. Acquisition of L1 cellular identity is indispensable for de novo SAM formation, which also requiresWUSCHEL(WUS) and the cellular capacity to direct anticlinal cell divisions. An intriguing finding is thatTONNEAU1silencing prevents the exclusive occurrence of anticlinal divisions in the outermost layer of the protuberances and suppresses the acquisition of L1 cellular identity, ultimately impeding regeneration. This study exposes an intricate interplay between L1 andWUSexpression and that any disruption in this interplay compromises shoot formation. It further provides a novel molecular framework for the characterization ofWUS/L1 interplay-mediated shoot apical meristem formation during regeneration.
Neural space-time model for dynamic scene recovery in multi-shot computational imaging systems
Authors: Cao Ruiming , Divekar Nikita , Nuñez James , Upadhyayula Srigokul , Waller Laura 
Published: January 2024

AbstractComputational imaging reconstructions from multiple measurements that are captured sequentially often suffer from motion artifacts if the scene is dynamic. We propose a neural space-time model (NSTM) that jointly estimates the scene and its motion dynamics. Hence, we can both remove motion artifacts and resolve sample dynamics. We demonstrate NSTM in three computational imaging systems: differential phase contrast microscopy, 3D structured illumination microscopy, and rolling-shutter DiffuserCam. We show that NSTM can recover subcellular motion dynamics and thus reduce the misinterpretation of living systems caused by motion artifacts.
Pharmacogenomics Guided Spaceflight: the intersection between space-flown drugs and space genes
Authors: Nelson Theodore M. , Rose Julianna K. , Walter Claire E. , Cervantes-Navarro Gresia L. , Schmidt Caleb M. , Lin Richard , Alexander Emma , Zheng Jiang Tao , Glicksberg Benjamin S. , Schmidt Julian C. , Overbey Eliah , Rana Brinda , Patel Hemal , Schmidt Michael A. , Mason Christopher E. 
Published: January 2024

AbstractTen years ago, it was predicted that the multi-omics revolution would also revolutionize space pharmacogenomics. Current barriers related to the findable, accessible, interoperable, and reproducible use of space-flown pharmaceutical data have contributed to a lack of progress beyond application of earth-based principles. To directly tackle these challenges, we have produced a novel database of all the drugs flown into space, compiled from publicly available ontological and spaceflight-related datasets, to exemplify analyses for describing significant spaceflight-related targets. By focusing on mechanisms perturbed by spaceflight, we have provided a novel avenue for identifying the most relevant changes within the drug absorption, distribution, metabolism, and excretion pathways. We suggest a set of space genes, by necessity limited to available tissue types, that can be expanded and modified based on future tissue-specific and mechanistic-specific high-throughput assays. In sum, we provide the justification and a definitive starting point for pharmacogenomics guided spaceflight as a foundation of precision medicine, which will enable long-term human habitation of the Moon, Mars, and beyond.Graphical Abstract
Mountain pine beetle spread in forests with varying host resistance
Authors: Brush Micah , Lewis Mark A. 
Published: January 2024

AbstractIn the last few decades, mountain pine beetle (MPB) have spread into novel regions in Canada. An important aspect seldom captured in models of MPB spread is host resistance. Lodgepole pine, the predominant host of MPB, varies in resistance across the landscape. There is evidence for a genetic component of resistance, as well as evidence that hosts in areas where MPB has not been present historically are at risk of increased susceptibility. In addition to the spatially varying resistance of the primary host species, the eastward spread of MPB has brought them into jack pine forests. Host resistance in jack pine remains uncertain, but experiments indicate jack pine could be a suitable host. We develop a model of pine beetle spread that links pine beetle population dynamics and forest structure and resistance. We find that beetle outbreaks in the model are characterized by large transient outbreaks that move through the forest. We show how the speed of these outbreaks changes with host resistance and find that biologically plausible values for host resistance are able to stop the wave from advancing. We also find that near the threshold of resistance where the wave is able to advance, small changes in host resistance dramatically decrease the severity of the outbreak. These results indicate that planting trees selected for higher MPB resistance on the landscape may be able to slow or even stop the local spread of MPB. In terms of further eastward spread, our results indicate future outbreaks may move more quickly and be more severe if novel lodgepole pine hosts are indeed more susceptible to beetle attacks, although more research is needed into the susceptibility of jack pine.
Design of a Cereblon construct for crystallographic and biophysical studies of protein degraders
Authors: Kroupova Alena , Spiteri Valentina A. , Furihata Hirotake , Darren Darren , Ramachandran Sarath , Rutter Zoe J. , Chakraborti Sohini , Haubrich Kevin , Pethe Julie , Gonzales Denzel , Wijaya Andre , Rodriguez-Rios Maria , Lynch Dylan M. , Farnaby William , Nakasone Mark A. , Zollman David , Ciulli Alessio 
Published: January 2024

AbstractThe ubiquitin E3 ligase cereblon (CRBN) is the target of therapeutic drugs thalidomide and lenalidomide and is recruited by most targeted protein degraders (PROTACs and molecular glues) in clinical development. Biophysical and structural investigation of CRBN has been limited by current constructs that either require co-expression with the adaptor DDB1 or inadequately represent full-length protein, with high-resolution structures of degraders ternary complexes remaining rare. We present the design of CRBNmidi, a construct that readily expresses fromE. coliwith high yields as soluble, stable protein without DDB1. We benchmark CRBNmidifor wild-type functionality through a suite of biophysical techniques and solve high-resolution co-crystal structures of its binary and ternary complexes with degraders. We qualify CRBNmidias an enabling tool to accelerate structure-based discovery of the next generation of CRBN based therapeutics.One sentence summaryA novel Cereblon construct (CRBNmidi) allows structural and biophysical enablement of ligand and degrader design
Effects of local and landscape factors on paddy field arthropod diversity: from species to communities
Authors: Ou Jia-Ang , Huang Chi-Lun , Tsai Chi-Wei , Ho Chuan-Kai 
Published: January 2024

AbstractAgricultural landscapes are dynamic mosaics where environmental conditions vary across spatial scales. Identifying the spatial scales of environmental variables relevant to biodiversity is therefore essential for safeguarding biodiversity and the ecosystem services they provide. Although species richness is a useful aggregate metric the captures the responses of biodiversity as a whole, few studies have examined how species-specific responses to environmental variables give rise to community-level patterns. Failure to account for the heterogeneity in species responses may undermine potential processes that structure biodiversity. In this study, we sampled paddy-field inhabiting arthropods across the first growing season and examined how local (organic farming, water depth, and crop height) and landscape factors (forest cover and connectivity) affect their abundance and distribution. We built a spatio-temporally explicit joint species distribution model (JSDM) to answer three main questions. 1) How do species differ in their response to local and landscapes factors. 2) Can trophic guild explain the variation in species responses to environmental covariates, and 3) How do species-specific responses scale-up to structure species richness at the community-level? Our results show that the mean importance of environmental covariates was low overall (mean R2= 0.21), suggesting the prevalence of stochasticity in structuring species abundances. However, environmental importance varied substantially across species (highest R2= 0.87 and lowest R2= 0.01) and that trophic guild explained only approximately 15% of species responses, which indicates high idiosyncrasy in species responses both within and among guilds. At the community-level, we found that species richness responds negligibly to local factors while increasing with forest cover at the landscape scale. The importance of each environmental covariate was reflected by the variability of species responses. Lastly, we found no evidence of dispersal limitation in structuring species abundances. Taken together, our study suggests that many paddy field arthropods exhibit transient dynamics and that environmental effects are highly species-specific, even within the same trophic guild. Most importantly, our study highlights the need to understand biodiversity from the species level to understand the processes that structure them in dynamic mosaic landscapes.
Dynamic Visualization of DNA Methylation in Cell Cycle Genes during iPSC Cardiac Differentiation
Authors: Li Ning , Nguyen Ba Thong , Zhang Zhenhe , MacLellan W. Robb , Zhang Yiqiang 
Published: January 2024

ABSTRACTBackgroundEpigenetic DNA methylation is an essential mechanism controlling gene expression and cellular function. Existing analyses with conventional assays have generated significant insights into static states of DNA methylation, but were unable to visualize the dynamics of epigenetic regulation.AimWe utilized a genomic DNA methylation reporter (GMR) system to track changes in DNA methylation during cardiac differentiation.Methods and ResultsThe promoter region ofCdk1(Cyclin-dependent kinase 1) orSox2(SRY-Box Transcription Factor 2) gene was cloned upstream of the small nuclear ribonucleoprotein polypeptide N (Snrpn) minimal promoter followed by a fluorescent reporter gene. Mouse induced pluripotent stem cells (iPSCs) carrying Sox2 GMR rapidly lost fluorescent reporter signal upon the induction of differentiation. Cdk1 GMR reporter signal was strong in undifferentiated iPSCs, and gradually decreased during directed cardiomyocyte (CM) differentiation. RT-qPCR and pyrosequencing demonstrated that the reduction ofSox2andCdk1was regulated by hypermethylation of their CpG regions during cardiac differentiation. The present study demonstrated the dynamic DNA methylation along the course of cell cycle withdrawal during CM differentiation.ConclusionThe GMR reporter system can be a useful tool to monitor real-time epigenetic DNA modification at single-cell resolution.
The neocortical infrastructure for language involves region-specific patterns of laminar gene expression
Authors: Wong Maggie M.K. , Sha Zhiqiang , Lütje Lukas , Kong Xiang-Zhen , Velthuijs Niels , van Heukelum Sabrina , van de Berg Wilma D.J. , Jonkman Laura E. , Fisher Simon E. , Francks Clyde 
Published: January 2024

AbstractThe language network of the human brain has core components in the inferior frontal cortex and superior/middle temporal cortex, with left-hemisphere dominance in most people. Functional specialization and interconnectivity of these neocortical regions is likely to be reflected in their molecular and cellular profiles. Excitatory connections between cortical regions arise and innervate according to layer-specific patterns. Here we generated a new gene expression dataset from human postmortem cortical tissue samples from core language network regions, using spatial transcriptomics to discriminate gene expression across cortical layers. Integration of these data with existing single-cell expression data identified 56 genes that showed differences in laminar expression profiles between frontal and temporal language cortex together with upregulation in layer II/III and/or layer V/VI excitatory neurons. Based on data from large-scale genome-wide screening in the population, DNA variants within these 56 genes showed set-level associations with inter-individual variation in structural connectivity between left-hemisphere frontal and temporal language cortex, and with predisposition to dyslexia. The axon guidance genesSLIT1andSLIT2were consistently implicated. These findings identify region-specific patterns of laminar gene expression as a feature of the brain’s language network.
Signatures of adaptation at key insecticide resistance loci inAnopheles gambiaein Southern Ghana revealed by low-coverage WGS
Authors: Dennis Tristan P.W. , Essandoh John , Mable Barbara K. , Viana Mafalda S. , Yawson Alexander E. , Weetman David. 
Published: January 2024

AbstractResistance to insecticides and adaptation to a diverse range of environments present challenges toAnopheles gambiae s.l.mosquito control efforts in sub-Saharan Africa. Whole-genome-sequencing is often employed for identifying the genomic basis underlying adaptation inAnopheles, but remains expensive for large-scale surveys. Low-coverage whole-genome-sequencing (lcWGS) can identify regions of the genome involved in adaptation at a lower cost, but is currently untested inAnophelesmosquitoes. Here, we use lcWGS to investigate population genetic structure and identify signatures of local adaptation inAnophelesmosquitoes across southern Ghana. In contrast to previous analyses, we find no structuring by ecoregion, withAnopheles coluzziiandAnopheles gambiaepopulations largely displaying the hallmarks of large, unstructured populations. However, we find signatures of selection at insecticide resistance (IR) loci that appear ubiquitous across ecoregions inAn. coluzzii,and strongest in forest ecoregions inAn. gambiae. In the IR geneCyp9k1, we find species-specific alleles under selection, suggesting interspecific variation in the precise mechanism of resistance conferred byCyp9k1. Our study highlights resistance candidate genes in this region, and validates lcWGS, potentially to very low coverage levels, for population genomics and exploratory surveys for adaptation inAnophelestaxa.
Mappingin silicogenetic networks of theKMT2Dtumour suppressor gene to uncover novel functional associations and cancer cell vulnerabilities
Authors: Takemon Yuka , Pleasance Erin D. , Gagliardi Alessia , Hughes Christopher S. , Csizmok Veronika , Wee Kathleen , Trinh Diane L. , Huff Ryan D. , Mungall Andrew J. , Moore Richard A. , Chuah Eric , Mungall Karen L. , Lewis Eleanor , Nelson Jessica , Lim Howard J. , Renouf Daniel J. , Jones Steven JM. , Laskin Janessa , Marra Marco A. 
Published: January 2024

AbstractLoss-of-function (LOF) alterations in tumour suppressor genes cannot be directly targeted. Approaches characterising gene function and vulnerabilities conferred by such mutations are required. Here, we computationally map genetic networks ofKMT2D, a tumour suppressor gene frequently mutated in several cancer types. UsingKMT2Dloss-of-function (KMT2DLOF) mutations as a model, we illustrate the utility ofin silicogenetic networks in uncovering novel functional associations and vulnerabilities in cancer cells with LOF alterations affecting tumour suppressor genes. We revealed genetic interactors with functions in histone modification, metabolism, and immune response, and synthetic lethal (SL) candidates, including some encoding existing therapeutic targets. Analysing patient data from The Cancer Genome Atlas and the Personalized OncoGenomics Project, we showed, for example, elevated immune checkpoint response markers inKMT2DLOFcases, possibly supportingKMT2DLOFas an immune checkpoint inhibitor biomarker. Our study illustrates how tumour suppressor gene LOF alterations can be exploited to reveal potentially targetable cancer cell vulnerabilities.
Development of immobilized antibody-based affinity grid strategy and application in on-grid purification of target proteins for high-resolution cryo-EM
Authors: Zhao Qiaoyu , Hong Xiaoyu , Wang Yanxing , Zhang Shaoning , Ding Zhanyu , Meng Xueming , Song Qianqian , Hong Qin , Jiang Wanying , Shi Xiangyi , Cai Tianxun , Cong Yao 
Published: January 2024

AbstractIn cryo-electron microscopy (cryo-EM), sample preparation, especially for rare or fragile macromolecular assemblies and those suffering from air-water interface denaturation and particle orientation distribution problems, is a major bottleneck. Here, we developed and characterized an immobilized antibody-based affinity grid (IAAG) strategy based on the high-affinity PA tag/NZ-1 antibody epitope tag system. We used Pyr-NHS as a linker to immobilize NZ-1 Fab on the graphene oxide or carbon covered grid surface. We showed that the IAAG grid can enrich the PA-tagged target proteins, and overcome preferred orientation problems. Furthermore, we demonstrated that our IAAG strategy can be utilized for on-grid purification of low-abundance target complexes from cell lysates and enables atomic resolution cryo-EM. This approach greatly streamlines the purification process, reduces the need for large quantities of biological samples, and addresses common challenges encountered in cryo-EM sample preparation. Collectively, our IAAG strategy provides an efficient and robust means for combined sample purification and vitrification feasible for high-resolution cryo-EM. This approach also has the potential for broader applicability in cryo-EM and cryo-ET.
The mitochondrialorf117Shagene desynchronizes pollen development and causes pollen abortion in the Arabidopsis Sha CMS
Authors: Dehaene Noémie , Boussardon Clément , Andrey Philippe , Charif Delphine , Brandt Dennis , Gilouppe Taillefer Clémence , Nietzel Thomas , Ricou Anthony , Simon Matthieu , Tran Joseph , Vezon Daniel , Camilleri Christine , Arimura Shin-ichi , Schwarzländer Markus , Budar Françoise 
Published: January 2024

AbstractCytoplasmic male sterility (CMS) is of major agronomical relevance in hybrid breeding. In gametophytic CMS, abortion of pollen is determined by the grain genotype, while in sporophytic CMS, it is determined by the mother plant genotype. While several CMS mechanisms have been dissected at the molecular level, gametophytic CMS has not been straightforwardly accessible. We used the gametophytic Sha-CMS in Arabidopsis to characterize the cause and process of pollen abortion by implementingin vivobiosensing in single pollen and mitoTALEN mutagenesis. We obtained conclusive evidence thatorf117Shais the CMS-causing gene, despite distinct characteristics from other CMS-genes. We measured thein vivocytosolic ATP content in single pollen, followed pollen development and analyzed pollen mitochondrial volume in two genotypes that differed only by the presence of theorf117Shalocus. Our results show that the Sha-CMS is not triggered by ATP deficiency. Instead, we observed desynchronization of a pollen developmental program. Pollen death occurred independently in pollen grains at diverse stages and was preceded by mitochondrial swelling. We conclude that pollen death is grain-autonomous in Sha-CMS and propose that mitochondrial permeability transition, which was previously described as a hallmark of developmental and environmental-triggered cell death programs, precedes pollen death in Sha-CMS.HighlightThe Arabidopsis CMS-causing geneorf117Shadoes not limit pollen ATP supply. Pollen-centered approaches show desynchronization of development and mitochondrial swelling before pollen death, which occurred at diverse stages.