quantifying-drosophila-melanogaster-eye-phenotypes-computational

Quantifying <i>Drosophila melanogaster</i> Eye Phenotypes: A Computational Approach Integrating ilastik and Flynotyper

The Drosophila melanogaster compound eye is a well-structured and comprehensive array of around 800 ommatidia, exhibiting a symmetrical and hexagonal ...

University of Minnesota

Pancreatic cancer is the worst exocrine gastrointestinal cancer leading to the highest mortality. Recent studies reported that aberrant expression of apurinic/apyrimidinic endodeoxyribonuclease 1 (APE1) is involved in uncontrolled cell growth. However, the molecular mechanism of APE1 biological role remains unrevealed in pancreatic cancer progression. Here, we demonstrate that APE1 accelerates pancreatic cancer cell proliferation through glial cell line-derived neurotrophic factor (GDNF)/glial factor receptor α1 (GFRα1)/Src/ERK axis-cascade signaling. The proliferation of endogenous APE1 expressed-MIA PaCa-2, a human pancreatic carcinoma cell line, was increased by treatment with GDNF, a ligand of GFRα1. Either of downregulated APE1 or GFRα1 expression using small interference RNA (siRNA) inhibited GDNF-induced cancer cell proliferation. The MEK-1 inhibitor PD98059 decreased GDNF-induced MIA PaCa-2 cell proliferation. Src inactivation by either its siRNA or Src inhibitor decreased ERK-phosphorylation in response to GDNF in MIA PaCa-2 cells. Overexpression of GFRα1 in APE1-deficient MIA PaCa-2 cells activated the phosphorylation of Src and ERK. The expression of both APE1 and GFRα1 was gradually increased as progressing pancreatic cancer grades. Our results highlight a critical role for APE1 in GDNF-induced pancreatic cancer cell proliferation through APE1/GFRα1/Src/ERK axis-cascade signaling and provide evidence for future potential therapeutic drug targets for the treatment of pancreatic cancer.

APE1 Promotes Pancreatic Cancer Proliferation through GFRα1/Src/ERK Axis-Cascade Signaling in Response to GDNF.

Mutations in coiled-coil-helix-coiled-coil-helix domain containing 10 (CHCHD10) can cause amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD). However, the underlying mechanisms are unclear. Here, we generate CHCH10-mutant Drosophila melanogaster and HeLa cell lines to model CHCHD10-associated ALS-FTD. The CHCHD10 mutation results in cell toxicity in several tissues and mitochondrial defects. CHCHD10 independently affects the TDP-43 and PINK1 pathways. CHCHD10 expression increases TDP-43 insolubility and mitochondrial translocation. Blocking TDP-43 mitochondrial translocation with a peptide inhibitor reduced CHCHD10-mediated toxicity. While genetic and pharmacological modulation of PINK1 expression and activity of its substrates rescues and mitigates the CHCHD10-induced phenotypes and mitochondrial defects, respectively, in both Drosophila and HeLa cells. Our findings suggest that CHCHD10-induced TDP-43 mitochondrial translocation and chronic activation of PINK1-mediated pathways result in dominant toxicity, providing a mechanistic insight into the CHCHD10 mutations associated with ALS-FTD.

TDP-43 and PINK1 mediate CHCHD10 mutation-induced defects in Drosophila and in vitro.

Author Correction: TDP-43 and PINK1 mediate CHCHD10 mutation-induced defects in Drosophila and in vitro.

Computational fluid dynamics simulations of fibrous filters with 56 combinations of different fiber sizes, packing densities, face velocities, and thicknesses were conducted for developing models that predict pressure drops across nanofiber filters. The accuracy of the simulation method was confirmed by comparing the numerical pressure drops to the experimental data obtained for polyacrylonitrile electrospun nanofiber filters. In the simulations, an aerodynamic slip effect around the surface of the small nanofibers was considered. The results showed that, unlike in the case of conventional filtration theory, pressure drops across the thin layers of electrospun nanofiber filters are not proportional to the thickness. This might be a critical factor for obtaining precise pressure drops across the electrospun nanofiber filters with extremely thin layers. Finally, we derived the product of drag coefficient and Reynolds number as a function of packing density, Knudsen number, and ratio of thickness to fiber diameter to get the correlation equation for pressure drop prediction. The obtained equation predicted the pressure drops across the nanofiber filters with the maximum relative difference of less than 15%.

Modeling pressure drop values across ultra-thin nanofiber filters with various ranges of filtration parameters under an aerodynamic slip effect.

Mutations in coiled-coil-helix-coiled-coil-helix domain containing 10 () have been identified as a genetic cause of amyotrophic lateral sclerosis and/or frontotemporal dementia(ALS-FTD). In our previous studies using in vivo  model expressing CHCHD10, and human cell models expressing CHCHD10, we have identified that the PINK1/Parkin pathway is activated and causes cellular toxicity. Furthermore, we demonstrated that pseudo-substrate inhibitors for PINK1 and mitofusin2 agonists mitigated the cellular toxicity of CHCHD10. Evidences using  genetic, and chemical tools indicate that inhibiting PINK1 would be the most promising treatment for CHCHD10-induced diseases.

Minwoo Baek

Department of Pharmacy Practice and Pharmaceutical Sciences,
College of Pharmacy,
Department of Pharmacy Practice and Pharmaceutical Sciences, College of Pharmacy

University of Minnesota

Quantifying Drosophila melanogaster Eye Phenotypes: A Computational Approach Integrating ilastik and Flynotyper

Minwoo Baek

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Department of Pharmacy Practice and Pharmaceutical Sciences,College of Pharmacy,Department of Pharmacy Practice and Pharmaceutical Sciences, College of Pharmacy

University of Minnesota

Quantifying Drosophila melanogaster Eye Phenotypes: A Computational Approach Integrating ilastik and Flynotyper

Department of Pharmacy Practice and Pharmaceutical Sciences,
College of Pharmacy,
Department of Pharmacy Practice and Pharmaceutical Sciences, College of Pharmacy