Simulation study of dose enhancement in a cell due to nearby carbon and oxygen in particle radiotherapy

The aim of this study is to investigate the dose-deposition enhancement by alpha-particle irradiation in a cellular model using carbon and oxygen chemical compositions.A simulation study was performed to study dose enhancement due to carbon and oxygen for a human cell where Geant4 code used for the alpha-particle irradiation to the cellular phantom. The characteristic of dose enhancement in the nucleus and cytoplasm by the alpha-particle radiation was investigated based on concentrations of the carbon and oxygen compositions and was compared with those by gold and gadolinium.The results show that both the carbon and oxygen-induced dose enhancement was found to be more effective than those of gold and gadolinium. We found that the dose-enhancement effect was more dominant in the nucleus than in the cytoplasm if carbon or oxygen is uniformly distributed in a whole cell. In the condition that the added chemical composition was inserted only into the cytoplasm, the effect of the dose enhancement in nucleus becomes weak.We showed that high-stopping-power materials offer a more effective dose-enhancement efficacy and suggest that the carbon nanotubes and oxygenation are promising candidates for dose utilization as dose enhancement tools in particle therapy.Comment: 19 pages, 6 figures, 4 tables. presented to 7th KOREA-JAPAN Joint Meeting on Medical Physics (2014.09.25) accepted to Journal of the Korean Physical Society (2015.03.10

Mitofusin 2 is essential for IP3-mediated SR/Mitochondria metabolic feedback in ventricular myocytes

Aim: Endothelin-1 (ET-1) and angiotensin II (Ang II) are multifunctional peptide hormones that regulate the function of the cardiovascular and renal systems. Both hormones increase the intracellular production of inositol-1,4,5-trisphosphate (IP$_3$) by activating their membrane-bound receptors. We have previously demonstrated that IP$_3$-mediated sarcoplasmic reticulum (SR) Ca$^{2+}$ release results in mitochondrial Ca$^{2+}$ uptake and activation of ATP production. In this study, we tested the hypothesis that intact SR/mitochondria microdomains are required for metabolic IP$_3$-mediated SR/mitochondrial feedback in ventricular myocytes. Methods: As a model for disrupted mitochondrial/SR microdomains, cardio-specific tamoxifen-inducible mitofusin 2 (Mfn2) knock out (KO) mice were used. Mitochondrial Ca$^{2+}$ uptake, membrane potential, redox state, and ATP generation were monitored in freshly isolated ventricular myocytes from Mfn2 KO mice and their control wild-type (WT) littermates. Results: Stimulation of ET-1 receptors in healthy control myocytes increases mitochondrial Ca$^{2+}$ uptake, maintains mitochondrial membrane potential and redox balance leading to the enhanced ATP generation. Mitochondrial Ca$^{2+}$ uptake upon ET-1 stimulation was significantly higher in interfibrillar (IFM) and perinuclear (PNM) mitochondria compared to subsarcolemmal mitochondria (SSM) in WT myocytes. Mfn2 KO completely abolished mitochondrial Ca$^{2+}$ uptake in IFM and PNM mitochondria but not in SSM. However, mitochondrial Ca2+ uptake induced by beta-adrenergic receptors activation with isoproterenol (ISO) was highest in SSM, intermediate in IFM, and smallest in PNM regions. Furthermore, Mfn2 KO did not affect ISO-induced mitochondrial Ca$^{2+}$ uptake in SSM and IFM mitochondria; however, enhanced mitochondrial Ca$^{2+}$ uptake in PNM. In contrast to ET-1, ISO induced a decrease in ATP levels in WT myocytes. Mfn2 KO abolished ATP generation upon ET-1 stimulation but increased ATP levels upon ISO application with highest levels observed in PNM regions. Conclusion: When the physical link between SR and mitochondria by Mfn2 was disrupted, the SR/mitochondrial metabolic feedback mechanism was impaired resulting in the inability of the IP$_3$-mediated SR Ca$^{2+}$ release to induce ATP production in ventricular myocytes from Mfn2 KO mice. Furthermore, we revealed the difference in Mfn2-mediated SR-mitochondrial communication depending on mitochondrial location and type of communication (IP$_3$R-mRyR1 vs. ryanodine receptor type 2-mitochondrial calcium uniporter)

Mitofusin 2 is essential for IP3-mediated SR/mitochondria metabolic feedback in ventricular myocytes

Aim: Endothelin-1 (ET-1) and angiotensin II (Ang II) are multifunctional peptide hormones that regulate the function of the cardiovascular and renal systems. Both hormones increase the intracellular production of inositol-1,4,5-trisphosphate (IP$_3$) by activating their membrane-bound receptors. We have previously demonstrated that IP$_3$-mediated sarcoplasmic reticulum (SR) Ca$^{2+}$ release results in mitochondrial Ca$^{2+}$ uptake and activation of ATP production. In this study, we tested the hypothesis that intact SR/mitochondria microdomains are required for metabolic IP$_3$-mediated SR/mitochondrial feedback in ventricular myocytes. Methods: As a model for disrupted mitochondrial/SR microdomains, cardio-specific tamoxifen-inducible mitofusin 2 (Mfn2) knock out (KO) mice were used. Mitochondrial Ca$^{2+}$ uptake, membrane potential, redox state, and ATP generation were monitored in freshly isolated ventricular myocytes from Mfn2 KO mice and their control wild-type (WT) littermates. Results: Stimulation of ET-1 receptors in healthy control myocytes increases mitochondrial Ca$^{2+}$ uptake, maintains mitochondrial membrane potential and redox balance leading to the enhanced ATP generation. Mitochondrial Ca$^{2+}$ uptake upon ET-1 stimulation was significantly higher in interfibrillar (IFM) and perinuclear (PNM) mitochondria compared to subsarcolemmal mitochondria (SSM) in WT myocytes. Mfn2 KO completely abolished mitochondrial Ca$^{2+}$ uptake in IFM and PNM mitochondria but not in SSM. However, mitochondrial Ca2+ uptake induced by beta-adrenergic receptors activation with isoproterenol (ISO) was highest in SSM, intermediate in IFM, and smallest in PNM regions. Furthermore, Mfn2 KO did not affect ISO-induced mitochondrial Ca$^{2+}$ uptake in SSM and IFM mitochondria; however, enhanced mitochondrial Ca$^{2+}$ uptake in PNM. In contrast to ET-1, ISO induced a decrease in ATP levels in WT myocytes. Mfn2 KO abolished ATP generation upon ET-1 stimulation but increased ATP levels upon ISO application with highest levels observed in PNM regions. Conclusion: When the physical link between SR and mitochondria by Mfn2 was disrupted, the SR/mitochondrial metabolic feedback mechanism was impaired resulting in the inability of the IP$_3$-mediated SR Ca$^{2+}$ release to induce ATP production in ventricular myocytes from Mfn2 KO mice. Furthermore, we revealed the difference in Mfn2-mediated SR-mitochondrial communication depending on mitochondrial location and type of communication (IP$_3$R-mRyR1 vs. ryanodine receptor type 2-mitochondrial calcium uniporter)

Mitochondrial Dynamism and Mitochondrial Quality Control in the Heart

Mitochondrial health is essential to heart function. Unlike fibroblasts and many other type of cells that constantly undergo mitochondrial fission and fusion, adult cardiomyocyte mitochondria are hypo-dynamic. Yet, mitochondrial dynamism proteins are abundantly expressed in the adult heart and how cardiac mitochondrial fission and fusion relate to organelle quality control is unclear. Here, we performed parallel studies in cultured murine embryonic fibroblasts (MEFs) and in vivo mouse hearts to uncover distinct effects on mitophagy of acutely inhibiting Drp1-mediated mitochondrial fission versus mitofusin-mediated mitochondrial fusion. Our results showed that Drp1 ablation evoked dilated cardiomyopathy with mitochondrial enlargement, increased MPTP-mediated cell death, and loss of mitochondria due to increased Parkin-mediated mitophagy. Mfn1/Mfn2 deletion provoked eccentric remodeling with mitochondrial fragmentation and accumulation of defective mitochondria due to suppressed Parkin-mediated mitophagy. Taken together, we discovered that inhibiting mitochondrial fission and fusion had opposing effects on mitophagy, cell viability, and cardiac remodeling, and thus unraveled their non-canonical roles during in vivo cardiac mitochondrial quality control in an integrated homeostatic pathway. Given the importance of mitochondrial fission and fusion in maintaining mitochondrial health to properly fuel cardiac contraction, it is intriguing that no genetic mutations in mitochondrial dynamism factors have been discovered to cause human cardiac diseases. Here, we performed Mfn2 gene sequencing in a cohort of 286 patients with unexplained cardiac hypertrophy and found 6 nonsynonymous mutations. By bioinformatics prediction and statistical analysis, we identified R400Q as the most damaging variant. Functional studies in multiple experimental systems showed that human Mfn2-Q400 interrupted tethering-mediated sarcoplasmic reticular-mitochondrial calcium signaling and caused ventricular concentric hypertrophy with normal cardiac contractility, which recapitulated the patient phenotype. These findings demonstrated the pathological potential of Mfn2-Q400, linking Mfn2 mutations to a novel category of mitochondrial cardiomyopathy

The Good, the Bad, and the Missing: Neural Code Generation for Machine Learning Tasks

Machine learning (ML) has been increasingly used in a variety of domains, while solving ML programming tasks poses unique challenges because of the fundamentally different nature and construction from general programming tasks, especially for developers who do not have ML backgrounds. Automatic code generation that produces a code snippet from a natural language description can be a promising technique to accelerate ML programming tasks. In recent years, although many deep learning-based neural code generation models have been proposed with high accuracy, the fact that most of them are mainly evaluated on general programming tasks calls into question their effectiveness and usefulness in ML programming tasks. In this paper, we set out to investigate the effectiveness of existing neural code generation models on ML programming tasks. For our analysis, we select six state-of-the-art neural code generation models, and evaluate their performance on four widely used ML libraries, with newly-created 83K pairs of natural-language described ML programming tasks. Our empirical study reveals some good, bad, and missing aspects of neural code generation models on ML tasks, with a few major ones listed below. (Good) Neural code generation models perform significantly better on ML tasks than on non-ML tasks. (Bad) Most of the generated code is semantically incorrect. (Bad) Code generation models cannot significantly improve developers' completion time. (Good) The generated code can help developers write more correct code by providing developers with clues for using correct APIs. (Missing) The observation from our user study reveals the missing aspects of code generation for ML tasks, e.g., decomposing code generation for divide-and-conquer into two tasks: API sequence identification and API usage generation.Comment: 20 page

Efficient Mining of Anticancer Peptides from Gut Metagenome

Abstract The gut microbiome plays a crucial role in modulating host health and disease. It serves as a vast reservoir of functional molecules that hold great potential for clinical applications. One specific area of interest is identifying anticancer peptides (ACPs) for innovative cancer therapies. However, ACPs discovery is hindered by a heavy reliance on experimental methodologies. To overcome this limitation, we here employed a novel approach by leveraging the overlap between ACPs and antimicrobial peptides (AMPs). By combining well‐established AMP prediction methods with mining techniques in metagenomic cohorts, a total of 40 potential ACPs is identified. Out of the identified ACPs, 39 demonstrated inhibitory effects against at least one cancer cell line, exhibiting significant differences from known ACPs. Moreover, the therapeutic potential of the two most promising peptides in a mouse xenograft cancer model is evaluated. Encouragingly, the peptides exhibit effective tumor inhibition without any detectable toxic effects. Interestingly, both peptides display uncommon secondary structures, highlighting its distinctive characteristics. This findings highlight the efficacy of the multi‐center mining approach, which effectively uncovers novel ACPs from the gut microbiome. This approach has significant implications for expanding treatment options not only for CRC, but also for other cancer types

Two rare human mitofusin 2 mutations alter mitochondrial dynamics and induce retinal and cardiac pathology in Drosophila.

Mitochondrial fusion is essential to organelle homeostasis and organ health. Inexplicably, loss of function mutations of mitofusin 2 (Mfn2) specifically affect neurological tissue, causing Charcot Marie Tooth syndrome (CMT) and atypical optic atrophy. As CMT-linked Mfn2 mutations are predominantly within the GTPase domain, we postulated that Mfn2 mutations in other functional domains might affect non-neurological tissues. Here, we defined in vitro and in vivo consequences of rare human mutations in the poorly characterized Mfn2 HR1 domain. Human exome sequencing data identified 4 rare non-synonymous Mfn2 HR1 domain mutations, two bioinformatically predicted as damaging. Recombinant expression of these (Mfn2 M393I and R400Q) in Mfn2-null murine embryonic fibroblasts (MEFs) revealed incomplete rescue of characteristic mitochondrial fragmentation, compared to wild-type human Mfn2 (hMfn2); Mfn2 400Q uniquely induced mitochondrial fragmentation in normal MEFs. To compare Mfn2 mutation effects in neurological and non-neurological tissues in vivo, hMfn2 and the two mutants were expressed in Drosophila eyes or heart tubes made deficient in endogenous fly mitofusin (dMfn) through organ-specific RNAi expression. The two mutants induced similar Drosophila eye phenotypes: small eyes and an inability to rescue the eye pathology induced by suppression of dMfn. In contrast, Mfn2 400Q induced more severe cardiomyocyte mitochondrial fragmentation and cardiac phenotypes than Mfn2 393I, including heart tube dilation, depressed fractional shortening, and progressively impaired negative geotaxis. These data reveal a central functional role for Mfn2 HR1 domains, describe organ-specific effects of two Mfn2 HR1 mutations, and strongly support prospective studies of Mfn2 400Q in heritable human heart disease of unknown genetic etiology