| 1. |
- Carroll, Christopher, et al.
(författare)
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Hypoxia Generated by Avian Embryo Growth Induces the HIF-α Response and Critical Vascularization
- 2021
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Ingår i: Frontiers in Ecology and Evolution. - : Frontiers Media SA. - 2296-701X. ; 9, s. 1-15
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Tidskriftsartikel (refereegranskat)abstract
- Cancer research has transformed our view on cellular mechanisms for oxygen sensing. It has been documented that these mechanisms are important for maintaining animal tissues and life in environments where oxygen (O2) concentrations fluctuate. In adult animals, oxygen sensing is governed by the Hypoxia Inducible Factors (HIFs) that are stabilized at low oxygen concentrations (hypoxia). However, the importance of hypoxia itself during development and for the onset of HIF-driven oxygen sensing remains poorly explored. Cellular responses to hypoxia associates with cell immaturity (stemness) and proper tissue and organ development. During mammalian development, the initial uterine environment is hypoxic. The oxygenation status during avian embryogenesis is more complex since O2 continuously equilibrates across the porous eggshell. Here, we investigate HIF dynamics and use microelectrodes to determine O2 concentrations within the egg and the embryo during the first four days of development. To determine the increased O2 consumption rates, we also obtain the O2 transport coefficient (DO2) of eggshell and associated inner and outer shell membranes, both directly (using microelectrodes in ovo for the first time) and indirectly (using water evaporation at 37.5°C for the first time). Our results demonstrate a distinct hypoxic phase (<5% O2) between day 1 and 2, concurring with the onset of HIF-α expression. This phase of hypoxia is demonstrably necessary for proper vascularization and survival. Our indirectly determined DO2 values are about 30% higher than those determined directly. A comparison with previously reported values indicates that this discrepancy may be real, reflecting that water vapor and O2 may be transported through the eggshell at different rates. Based on our obtained DO2 values, we demonstrate that increased O2 consumption of the growing embryo appears to generate the phase of hypoxia, which is also facilitated by the initially small gas cell and low membrane permeability. We infer that the phase of in ovo hypoxia facilitates correct avian development. These results support the view that hypoxic conditions, in which the animal clade evolved, remain functionally important during animal development. The study highlights that insights from the cancer field pertaining to the cellular capacities by which both somatic and cancer cells register and respond to fluctuations in O2 concentrations can broadly inform our exploration of animal development and success.
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| 2. |
- Haxen, Emma R., et al.
(författare)
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“Hypoxic” Silurian oceans suggest early animals thrived in a low-O2 world
- 2023
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Ingår i: Earth and Planetary Science Letters. - 0012-821X. ; 622
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Tidskriftsartikel (refereegranskat)abstract
- Atmospheric oxygen (O2) concentrations likely remained below modern levels until the Silurian–Devonian, as indicated by several recent studies. Yet, the background redox state of early Paleozoic oceans remains poorly constrained, hampering our understanding of the relationship between early animal evolution and O2. Here, we present a multi-proxy analysis of redox conditions in the Caledonian foreland basin to Baltica from the early to the mid-Silurian. Our results indicate that anoxic to severely hypoxic bottom waters dominated during deposition of the Silurian sediments cored in the Sommerodde-1 well (Bornholm, Denmark), and regional comparison suggests that these conditions persisted across the Baltoscandian foreland basin. Indeed, even during times of relative oxygenation, ichnological observations indicate that conditions were, at most, very weakly oxic. The results suggest that dissolved O2 was generally scarce in the bottom waters of the extensive Silurian seaway between Baltica and Avalonia, even between Paleozoic “Anoxic Events”. In light of delayed oxygenation of the atmosphere–hydrosphere system, it may be time to consider that early animals were adapted to “hypoxia” and thrived through ∼100 million years of low-O2 conditions after the Cambrian.
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| 3. |
- Nasimian, Ahmad, et al.
(författare)
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AlphaML : A clear, legible, explainable, transparent, and elucidative binary classification platform for tabular data
- 2024
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Ingår i: Patterns. - 2666-3899. ; 5:1
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Tidskriftsartikel (refereegranskat)abstract
- Leveraging the potential of machine learning and recognizing the broad applications of binary classification, it becomes essential to develop platforms that are not only powerful but also transparent, interpretable, and user friendly. We introduce alphaML, a user-friendly platform that provides clear, legible, explainable, transparent, and elucidative (CLETE) binary classification models with comprehensive customization options. AlphaML offers feature selection, hyperparameter search, sampling, and normalization methods, along with 15 machine learning algorithms with global and local interpretation. We have integrated a custom metric for hyperparameter search that considers both training and validation scores, safeguarding against under- or overfitting. Additionally, we employ the NegLog2RMSL scoring method, which uses both training and test scores for a thorough model evaluation. The platform has been tested using datasets from multiple domains and offers a graphical interface, removing the need for programming expertise. Consequently, alphaML exhibits versatility, demonstrating promising applicability across a broad spectrum of tabular data configurations.
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| 4. |
- Niklasson, Camilla U., et al.
(författare)
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Hypoxia inducible factor-2 alpha importance for migration, proliferation, and self-renewal of trunk neural crest cells
- 2021
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Ingår i: Developmental Dynamics. - : Wiley. - 1058-8388 .- 1097-0177. ; 250:2, s. 191-236
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Tidskriftsartikel (refereegranskat)abstract
- Background: The neural crest is a transient embryonic stem cell population. Hypoxia inducible factor (HIF)-2 α is associated with neural crest stem cell appearance and aggressiveness in tumors. However, little is known about its role in normal neural crest development.Results: Here, we show that HIF-2 α is expressed in trunk neural crest cells of human, murine, and avian embryos. Knockdown as well as overexpression of HIF-2 α in vivo causes developmental delays, induces proliferation, and self-renewal capacity of neural crest cells while decreasing the proportion of neural crest cells that migrate ventrally to sympathoadrenal sites. Reflecting the in vivo phenotype, transcriptome changes after loss of HIF-2 α reveal enrichment of genes associated with cancer, invasion, epithelial-to-mesenchymal transition, and growth arrest.Conclusions: Taken together, these results suggest that expression levels of HIF-2 α must be strictly controlled during normal trunk neural crest development and that dysregulated levels affects several important features connected to stemness, migration, and development.
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| 5. |
- Philipsen, Mai H., et al.
(författare)
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Mapping the chemistry of hair strands by mass spectrometry imaging - A Review
- 2021
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Ingår i: Molecules. - : MDPI AG. - 1420-3049 .- 1420-3049. ; 26:24
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Tidskriftsartikel (refereegranskat)abstract
- Hair can record chemical information reflecting our living conditions, and, therefore, strands of hair have become a potent analytical target within the biological and forensic sciences. While early efforts focused on analyzing complete hair strands in bulk, high spatial resolution mass spectrometry imaging (MSI) has recently come to the forefront of chemical hair-strand analysis. MSI techniques offer a localized analysis, requiring fewer de-contamination procedures per default and making it possible to map the distribution of analytes on and within individual hair strands. Applying the techniques to hair samples has proven particularly useful in investigations quantifying the exposure to, and uptake of, toxins or drugs. Overall, MSI, combined with optimized sample preparation protocols, has improved precision and accuracy for identifying several elemental and molecular species in single strands of hair. Here, we review different sample preparation protocols and use cases with a view to make the methodology more accessible to researchers outside of the field of forensic science. We conclude that-although some challenges remain, including contamination issues and matrix effects-MSI offers unique opportunities for obtaining highly resolved spatial information of several compounds simultaneously across hair surfaces.
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| 6. |
- Alcott, Lewis J., et al.
(författare)
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Development of Iron Speciation Reference Materials for Palaeoredox Analysis
- 2020
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Ingår i: Geostandards and Geoanalytical Research. - : Wiley. - 1639-4488 .- 1751-908X. ; 44:3, s. 581-591
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Tidskriftsartikel (refereegranskat)abstract
- The development and application of geochemical techniques to identify redox conditions in modern and ancient aquatic environments has intensified over recent years. Iron (Fe) speciation has emerged as one of the most widely used procedures to distinguish different redox regimes in both the water column and sediments, and is the main technique used to identify oxic, ferruginous (anoxic, Fe(II) containing) and euxinic (anoxic, sulfidic) water column conditions. However, an international sediment reference material has never been developed. This has led to concern over the consistency of results published by the many laboratories that now utilise the technique. Here, we report an interlaboratory comparison of four Fe speciation reference materials for palaeoredox analysis, which span a range of compositions and reflect deposition under different redox conditions. We provide an update of extraction techniques used in Fe speciation and assess the effects of both test portion mass, and the use of different analytical procedures, on the quantification of different Fe fractions in sedimentary rocks. While atomic absorption spectroscopy and inductively coupled plasma-optical emission spectrometry produced comparable Fe measurements for all extraction stages, the use of ferrozine consistently underestimated Fe in the extraction step targeting mixed ferrous–ferric minerals such as magnetite. We therefore suggest that the use of ferrozine is discontinued for this Fe pool. Finally, we report the combined data of four independent Fe speciation laboratories to characterise the Fe speciation composition of the reference materials. These reference materials are available to the community to provide an essential validation of in-house Fe speciation measurements.
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| 7. |
- Brown, Joel S., et al.
(författare)
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Updating the Definition of Cancer
- 2023
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Ingår i: Molecular cancer research : MCR. - 1557-3125. ; 21:11, s. 1142-1147
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Tidskriftsartikel (refereegranskat)abstract
- Most definitions of cancer broadly conform to the current NCI definition: "Cancer is a disease in which some of the body's cells grow uncontrollably and spread to other parts of the body." These definitions tend to describe what cancer "looks like" or "does" but do not describe what cancer "is" or "has become." While reflecting past insights, current definitions have not kept pace with the understanding that the cancer cell is itself transformed and evolving. We propose a revised definition of cancer: Cancer is a disease of uncontrolled proliferation by transformed cells subject to evolution by natural selection. We believe this definition captures the essence of the majority of previous and current definitions. To the simplest definition of cancer as a disease of uncontrolled proliferation of cells, our definition adds in the adjective "transformed" to capture the many tumorigenic processes that cancer cells adopt to metastasize. To the concept of uncontrolled proliferation of transformed cells, our proposed definition then adds "subject to evolution by natural selection." The subject to evolution by natural selection modernizes the definition to include the genetic and epigenetic changes that accumulate within a population of cancer cells that lead to the lethal phenotype. Cancer is a disease of uncontrolled proliferation by transformed cells subject to evolution by natural selection.
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| 8. |
- Bukkuri, Anuraag, et al.
(författare)
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A life history model of the ecological and evolutionary dynamics of polyaneuploid cancer cells
- 2022
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Therapeutic resistance is one of the main reasons for treatment failure in cancer patients. The polyaneuploid cancer cell (PACC) state has been shown to promote resistance by providing a refuge for cancer cells from the effects of therapy and by helping them adapt to a variety of environmental stressors. This state is the result of aneuploid cancer cells undergoing whole genome doubling and skipping mitosis, cytokinesis, or both. In this paper, we create a novel mathematical framework for modeling the eco-evolutionary dynamics of state-structured populations and use this framework to construct a model of cancer populations with an aneuploid and a PACC state. Using in silico simulations, we explore how the PACC state allows cancer cells to (1) survive extreme environmental conditions by exiting the cell cycle after S phase and protecting genomic material and (2) aid in adaptation to environmental stressors by increasing the cancer cell’s ability to generate heritable variation (evolvability) through the increase in genomic content that accompanies polyploidization. In doing so, we demonstrate the ability of the PACC state to allow cancer cells to persist under therapy and evolve therapeutic resistance. By eliminating cells in the PACC state through appropriately-timed PACC-targeted therapies, we show how we can prevent the emergence of resistance and promote cancer eradication.
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| 9. |
- Bukkuri, Anuraag, et al.
(författare)
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A mathematical investigation of polyaneuploid cancer cell memory and cross-resistance in state-structured cancer populations
- 2023
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Ingår i: Scientific Reports. - 2045-2322. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- The polyaneuploid cancer cell (PACC) state promotes cancer lethality by contributing to survival in extreme conditions and metastasis. Recent experimental evidence suggests that post-therapy PACC-derived recurrent populations display cross-resistance to classes of therapies with independent mechanisms of action. We hypothesize that this can occur through PACC memory, whereby cancer cells that have undergone a polyaneuploid transition (PAT) reenter the PACC state more quickly or have higher levels of innate resistance. In this paper, we build on our prior mathematical models of the eco-evolutionary dynamics of cells in the 2N+ and PACC states to investigate these two hypotheses. We show that although an increase in innate resistance is more effective at promoting cross-resistance, this trend can also be produced via PACC memory. We also find that resensitization of cells that acquire increased innate resistance through the PAT have a considerable impact on eco-evolutionary dynamics and extinction probabilities. This study, though theoretical in nature, can help inspire future experimentation to tease apart hypotheses surrounding how cross-resistance in structured cancer populations arises.
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| 10. |
- Bukkuri, Anuraag, et al.
(författare)
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Modeling cancer’s ecological and evolutionary dynamics
- 2023
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Ingår i: Medical Oncology. - : Springer Science and Business Media LLC. - 1357-0560 .- 1559-131X. ; 40:4
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Tidskriftsartikel (refereegranskat)abstract
- In this didactic paper, we present a theoretical modeling framework, called the G-function, that integrates both the ecology and evolution of cancer to understand oncogenesis. The G-function has been used in evolutionary ecology, but has not been widely applied to problems in cancer. Here, we build the G-function framework from fundamental Darwinian principles and discuss how cancer can be seen through the lens of ecology, evolution, and game theory. We begin with a simple model of cancer growth and add on components of cancer cell competition and drug resistance. To aid in exploration of eco-evolutionary modeling with this approach, we also present a user-friendly software tool. By the end of this paper, we hope that readers will be able to construct basic G function models and grasp the usefulness of the framework to understand the games cancer plays in a biologically mechanistic fashion.
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