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Disease Models & Mechanisms Mar 2022Cancer continues to be a leading cause of death worldwide, largely due to metastases and cachexia. It is a complex disease that is commonly associated with a variety of...
Cancer continues to be a leading cause of death worldwide, largely due to metastases and cachexia. It is a complex disease that is commonly associated with a variety of comorbidities. With global increases in ageing populations and obesity, multimorbidity is a rapidly growing clinical issue in the context of cancer. Cancer is also genetically heterogeneous, with a tumour's unique profile determining its incidence of metastasis, degree of cachexia and response to therapeutics. These complexities of human cancer are difficult to replicate in animal models and are, in part, responsible for the failures in translational cancer research. In this Perspective, we highlight the fruit fly, Drosophila melanogaster, as a powerful model organism to investigate multimorbidity and tumour diversity. We also highlight how harnessing these complexities in Drosophila can, potentially, enhance cancer research and advance therapeutic discoveries.
Topics: Animals; Cachexia; Disease Models, Animal; Drosophila; Drosophila melanogaster; Neoplasms
PubMed: 35344038
DOI: 10.1242/dmm.049513 -
Proceedings of the National Academy of... Aug 2023Loss-of-function mutations in the (Kv1.1) gene cause episodic ataxia type 1 (EA1), a neurological disease characterized by cerebellar dysfunction, ataxic attacks,...
Loss-of-function mutations in the (Kv1.1) gene cause episodic ataxia type 1 (EA1), a neurological disease characterized by cerebellar dysfunction, ataxic attacks, persistent myokymia with painful cramps in skeletal muscles, and epilepsy. Precision medicine for EA1 treatment is currently unfeasible, as no drug that can enhance the activity of Kv1.1-containing channels and offset the functional defects caused by mutations has been clinically approved. Here, we uncovered that niflumic acid (NFA), a currently prescribed analgesic and anti-inflammatory drug with an excellent safety profile in the clinic, potentiates the activity of Kv1.1 channels. NFA increased Kv1.1 current amplitudes by enhancing the channel open probability, causing a hyperpolarizing shift in the voltage dependence of both channel opening and gating charge movement, slowing the OFF-gating current decay. NFA exerted similar actions on both homomeric Kv1.2 and heteromeric Kv1.1/Kv1.2 channels, which are formed in most brain structures. We show that through its potentiating action, NFA mitigated the EA1 mutation-induced functional defects in Kv1.1 and restored cerebellar synaptic transmission, Purkinje cell availability, and precision of firing. In addition, NFA ameliorated the motor performance of a mouse model of EA1 and restored the neuromuscular transmission and climbing ability in (Kv1.1) mutant flies (). By virtue of its multiple actions, NFA has strong potential as an efficacious single-molecule-based therapeutic agent for EA1 and serves as a valuable model for drug discovery.
Topics: Animals; Mice; Myokymia; Drosophila melanogaster; Ataxia; Drosophila; Kv1.2 Potassium Channel
PubMed: 37487086
DOI: 10.1073/pnas.2207978120 -
The European Journal of Neuroscience Jan 2020A key feature of circadian rhythms is the sleep/wake cycle. Sleep causes reduced responsiveness to the environment, which puts animals in a particularly vulnerable... (Review)
Review
A key feature of circadian rhythms is the sleep/wake cycle. Sleep causes reduced responsiveness to the environment, which puts animals in a particularly vulnerable state; yet sleep has been conserved throughout evolution, indicating that it fulfils a vital purpose. A core function of sleep across species has not been identified, but substantial advances in sleep research have been made in recent years using the genetically tractable model organism, Drosophila melanogaster. This review describes the universality of sleep, the regulation of sleep, and current theories on the function of sleep, highlighting a historical and often overlooked theory called the Free Radical Flux Theory of Sleep. Additionally, we summarize our recent work with short-sleeping Drosophila mutants and other genetic and pharmacological tools for manipulating sleep which supports an antioxidant theory of sleep and demonstrates a bi-directional relationship between sleep and oxidative stress.
Topics: Animals; Circadian Rhythm; Drosophila; Drosophila Proteins; Drosophila melanogaster; Sleep
PubMed: 30295966
DOI: 10.1111/ejn.14197 -
Current Opinion in Cell Biology Feb 2020Beginning with Turing's seminal work [1], decades of research have demonstrated the fundamental ability of biochemical networks to generate and sustain the formation of... (Review)
Review
Beginning with Turing's seminal work [1], decades of research have demonstrated the fundamental ability of biochemical networks to generate and sustain the formation of patterns. However, it is increasingly appreciated that biochemical networks also both shape and are shaped by physical and mechanical processes [2, 3, 4]. One such process is fluid flow. In many respects, the cytoplasm, membrane and actin cortex all function as fluids, and as they flow, they drive bulk transport of molecules throughout the cell. By coupling biochemical activity to long-range molecular transport, flows can shape the distributions of molecules in space. Here, we review the various types of flows that exist in cells, with the aim of highlighting recent advances in our understanding of how flows are generated and how they contribute to intracellular patterning processes, such as the establishment of cell polarity.
Topics: Actomyosin; Animals; Cell Polarity; Cytoplasm; Drosophilidae
PubMed: 31760155
DOI: 10.1016/j.ceb.2019.10.005 -
ELife Mar 2024A complete map of the external sense organs shows how fruit fly larvae detect different aspects of their environment.
A complete map of the external sense organs shows how fruit fly larvae detect different aspects of their environment.
Topics: Animals; Larva; Drosophila; Drosophila Proteins; Sense Organs; Emotions; Drosophila melanogaster
PubMed: 38456840
DOI: 10.7554/eLife.96708 -
Cells Sep 2020Animals face the dual threat of virus infections hijacking cellular function and transposons proliferating in germline genomes. For insects, the deeply conserved RNA... (Review)
Review
Animals face the dual threat of virus infections hijacking cellular function and transposons proliferating in germline genomes. For insects, the deeply conserved RNA interference (RNAi) pathways and other chromatin regulators provide an important line of defense against both viruses and transposons. For example, this innate immune system displays adaptiveness to new invasions by generating cognate small RNAs for targeting gene silencing measures against the viral and genomic intruders. However, within the Dipteran clade of insects, Drosophilid fruit flies and Culicids mosquitoes have evolved several unique mechanistic aspects of their RNAi defenses to combat invading transposons and viruses, with the Piwi-piRNA arm of the RNAi pathways showing the greatest degree of novel evolution. Whereas central features of Piwi-piRNA pathways are conserved between Drosophilids and Culicids, multiple lineage-specific innovations have arisen that may reflect distinct genome composition differences and specific ecological and physiological features dividing these two branches of Dipterans. This perspective review focuses on the most recent findings illuminating the Piwi/piRNA pathway distinctions between fruit flies and mosquitoes, and raises open questions that need to be addressed in order to ameliorate human diseases caused by pathogenic viruses that mosquitoes transmit as vectors.
Topics: Animals; Argonaute Proteins; Culicidae; Drosophila Proteins; Drosophilidae; RNA Interference; RNA, Small Interfering; Signal Transduction; Virus Diseases
PubMed: 32992598
DOI: 10.3390/cells9102180 -
PLoS Computational Biology Jun 2022Measuring mechanical parameters in tissues, such as the elastic modulus of cell-cell junctions, is essential to decipher the mechanical control of morphogenesis....
Measuring mechanical parameters in tissues, such as the elastic modulus of cell-cell junctions, is essential to decipher the mechanical control of morphogenesis. However, their in vivo measurement is technically challenging. Here, we formulated an image-based statistical approach to estimate the mechanical parameters of epithelial cells. Candidate mechanical models are constructed based on force-cell shape correlations obtained from image data. Substitution of the model functions into force-balance equations at the cell vertex leads to an equation with respect to the parameters of the model, by which one can estimate the parameter values using a least-squares method. A test using synthetic data confirmed the accuracy of parameter estimation and model selection. By applying this method to Drosophila epithelial tissues, we found that the magnitude and orientation of feedback between the junction tension and shrinkage, which are determined by the spring constant of the junction, were correlated with the elevation of tension and myosin-II on shrinking junctions during cell rearrangement. Further, this method clarified how alterations in tissue polarity and stretching affect the anisotropy in tension parameters. Thus, our method provides a novel approach to uncovering the mechanisms governing epithelial morphogenesis.
Topics: Animals; Drosophila; Drosophila melanogaster; Epithelial Cells; Epithelium; Intercellular Junctions; Morphogenesis
PubMed: 35737656
DOI: 10.1371/journal.pcbi.1010209 -
Genome Biology and Evolution Aug 2021The vinegar fly Drosophila melanogaster is a pivotal model for invertebrate development, genetics, physiology, neuroscience, and disease. The whole family Drosophilidae,...
The vinegar fly Drosophila melanogaster is a pivotal model for invertebrate development, genetics, physiology, neuroscience, and disease. The whole family Drosophilidae, which contains over 4,400 species, offers a plethora of cases for comparative and evolutionary studies. Despite a long history of phylogenetic inference, many relationships remain unresolved among the genera, subgenera, and species groups in the Drosophilidae. To clarify these relationships, we first developed a set of new genomic markers and assembled a multilocus data set of 17 genes from 704 species of Drosophilidae. We then inferred a species tree with highly supported groups for this family. Additionally, we were able to determine the phylogenetic position of some previously unplaced species. These results establish a new framework for investigating the evolution of traits in fruit flies, as well as valuable resources for systematics.
Topics: Animals; Drosophila; Drosophila melanogaster; Phylogeny
PubMed: 34343293
DOI: 10.1093/gbe/evab179 -
Current Biology : CB Aug 2021Many animals rely on taste to identify nutritious foods and to avoid the consumption of harmful substances. The tastes of macronutrients, as well as of non-caloric...
Many animals rely on taste to identify nutritious foods and to avoid the consumption of harmful substances. The tastes of macronutrients, as well as of non-caloric micronutrients such as sodium and calcium, contribute to the regulation of ingestive behavior. Whether vitamins also affect feeding behavior through taste is less clear. Here, we show that the fly Drosophila melanogaster has a strong preference for consuming a vitamin-containing diet: both sexes show a preference for folic acid, whereas only females show a preference for riboflavin. Females show a preference with vitamin concentrations as low as ∼10 nM - at least 50,000-fold lower than the concentration needed for sucrose preference. This female vitamin preference requires inputs from external and internal taste organs, suggesting that post-ingestive signals, in the absence of gustatory input, are insufficient to actuate preferential consumption of vitamin-containing diets. Our studies demonstrate that vitamin perception is an important determinant of feeding behavior.
Topics: Animals; Drosophila; Drosophila melanogaster; Female; Male; Taste; Taste Perception; Vitamins
PubMed: 34375595
DOI: 10.1016/j.cub.2021.06.046 -
ELife Feb 2022New imaging approaches question a long-standing model for how the eyes of fruit flies acquire their geometric patterning.
New imaging approaches question a long-standing model for how the eyes of fruit flies acquire their geometric patterning.
Topics: Animals; Drosophila; Drosophila Proteins; Drosophila melanogaster; Eye
PubMed: 35225787
DOI: 10.7554/eLife.77309