Mitochondrial dysfunction and cancer metastasis

Abstract Mitochondria have an essential role in powering cells by generating ATP following the metabolism of pyruvate derived from glycolysis. They are also the major source of generating reactive oxygen species (ROS), which have regulatory roles in cell death and proliferation. Mutations in mitochondrial DNA (mtDNA) and dysregulation of mitochondrial metabolism have been frequently described in human tumors. Although the role of oxidative stress as the consequence of mtDNA mutations and/or altered mitochondrial functions has been demonstrated in carciongenesis, a causative role of mitochondria in tumor progression has only been demonstrated recently. Specifically, the subject of this mini-review focuses on the role of mitochondria in promoting cancer metastasis. Cancer relapse and the subsequent spreading of cancer cells to distal sites are leading causes of morbidity and mortality in cancer patients. Despite its clinical importance, the underlying mechanisms of metastasis remain to be elucidated. Recently, it was demonstrated that mitochondrial oxidative stress could actively promote tumor progression and increase the metastatic potential of cancer cells. The purpose of this mini-review is to summarize current investigations of the roles of mitochondria in cancer metastasis. Future development of diagnostic and therapeutic strategies for patients with advanced cancer will benefit from the new knowledge of mitochondrial metabolism in epithelial cancer cells and the tumor stroma

Regulation of Mitochondrial Complex I Biogenesis in Drosophila Flight Muscles

The flight muscles of Drosophila are highly enriched with mitochondria, but the mechanism by which mitochondrial complex I (CI) is assembled in this tissue has not been described. We report the mechanism of CI biogenesis in Drosophila flight muscles and show that it proceeds via the formation of ∼315, ∼550, and ∼815 kDa CI assembly intermediates. Additionally, we define specific roles for several CI subunits in the assembly process. In particular, we show that dNDUFS5 is required for converting an ∼700 kDa transient CI assembly intermediate into the ∼815 kDa assembly intermediate. Importantly, incorporation of dNDUFS5 into CI is necessary to stabilize or promote incorporation of dNDUFA10 into the complex. Our findings highlight the potential of studies of CI biogenesis in Drosophila to uncover the mechanism of CI assembly in vivo and establish Drosophila as a suitable model organism and resource for addressing questions relevant to CI biogenesis in humans

Sex and gender differences in technology needs and preferences among informal caregivers of persons with dementia

Background: Dementia is a major public health concern associated with significant caregiver demands and there are technologies available to assist with caregiving. However, there is a paucity of information on caregiver needs and preferences for these technologies, particularly from a sex and gender perspective. To address this gap in research, the objectives of this study are to examine (1) the knowledge of technology, (2) perceived usefulness of technology, (3) feature preferences when installing and using technology and (4) sex and gender influences on technology needs and preferences among family caregivers of persons with dementia (PWD) across North America. Methods: A secondary analysis was conducted on an existing cross-sectional survey with family caregivers of PWDs. Respondents were recruited through the Alzheimer Society of Canada, the Victorian Order of Nurses and Adult Day Programs and other Canadian health care provision institutes. Descriptive statistics, bivariate and multivariate analyses were used to describe the study sample, uncover differences between male and female caregivers and examine sex and gender influences on caregivers’ technology needs and preferences. Results: A total of 381 eligible responses were received over a nine-month data collection period. The majority of respondents did not know much about and never used any technologies to assist with caregiving. “Being easy to install”, “easy to learn how to use” and “cost” were identified as the most important features when purchasing and setting up technology, while “reliability” was identified as the most important feature when using technology. Most respondents were willing to pay up to $500 to acquire individual technologies. Controlling for other socio-demographic variables, female respondents were more likely to have some or more knowledge about technology for caregiving while male respondents were more willing to pay higher amounts for these technologies compared to their female counterparts

Adsorptive properties and on-demand magnetic response of lignin@Fe3O4 nanoparticles at castor oil–water interfaces

Lignin@Fe3O4 nanoparticles adsorb at oil–water interfaces, form Pickering emulsions, induce on-demand magnetic responses to break emulsions, and can sequester oil from water. Lignin@Fe3O4 nanoparticles were prepared using a pH-induced precipitation method and were fully characterized. These were used to prepare Pickering emulsions with castor oil/Sudan red G dye and water at various oil/water volume ratios and nanoparticle concentrations. The stability and demulsification of the emulsions under different magnetic fields generated with permanent magnets (0–540 mT) were investigated using microscopy images and by visual inspection over time. The results showed that the Pickering emulsions were more stable at the castor oil/water ratio of 50/50 and above. Increasing the concentration of lignin@Fe3O4 improved the emulsion stability and demulsification rates with 540 mT applied magnetic field strength. The adsorption of lignin@Fe3O4 nanoparticles at the oil/water interface using 1-pentanol evaporation through Marangoni effects was demonstrated, and magnetic manipulation of a lignin@Fe3O4 stabilized castor oil spill in water was shown. Nanoparticle concentration and applied magnetic field strengths were analyzed for the recovery of spilled oil from water; it was observed that increasing the magnetic strength increased oil spill motion for a lignin@Fe3O4 concentration of up to 0.8 mg mL−1 at 540 mT. Overall, this study demonstrates the potential of lignin-magnetite nanocomposites for rapid on-demand magnetic responses to externally induced stimuli

Within the fold: assessing differential expression measures and reproducibility in microarray assays

BACKGROUND: 'Fold-change' cutoffs have been widely used in microarray assays to identify genes that are differentially expressed between query and reference samples. More accurate measures of differential expression and effective data-normalization strategies are required to identify high-confidence sets of genes with biologically meaningful changes in transcription. Further, the analysis of a large number of expression profiles is facilitated by a common reference sample, the construction of which must be carefully addressed. RESULTS: We carried out a series of 'self-self' hybridizations in which aliquots of the same RNA sample were labeled separately with Cy3 and Cy5 fluorescent dyes and co-hybridized to the same microarray. From this, we can analyze the intensity-dependent behavior of microarray data, define a statistically significant measure of differential expression that exploits the structure of the fluorescent signals, and measure the inherent reproducibility of the technique. We also devised a simple procedure for identifying and eliminating low-quality data for replicates within and between slides. We examine the properties required of a universal reference RNA sample and show how pooling a small number of samples with a diverse representation of expressed genes can outperform more complex mixtures as a reference sample. CONCLUSION: Analysis of cell-line samples can identify systematic structure in measured gene-expression levels. A general procedure for analyzing cDNA microarray data is proposed and validated. We show that pooled reference samples should be based not only on the expression of individual genes in each cell line but also on the expression levels of genes within cell lines

Candida albicans Ethanol Stimulates Pseudomonas aeruginosa WspR-Controlled Biofilm Formation as Part of a Cyclic Relationship Involving Phenazines

In chronic infections, pathogens are often in the presence of other microbial species. For example, Pseudomonas aeruginosa is a common and detrimental lung pathogen in individuals with cystic fibrosis (CF) and co-infections with Candida albicans are common. Here, we show that P. aeruginosa biofilm formation and phenazine production were strongly influenced by ethanol produced by the fungus C. albicans. Ethanol stimulated phenotypes that are indicative of increased levels of cyclic- di-GMP (c-di-GMP), and levels of c-di-GMP were 2-fold higher in the presence of ethanol. Through a genetic screen, we found that the diguanylate cyclase WspR was required for ethanol stimulation of c-di-GMP. Multiple lines of evidence indicate that ethanol stimulates WspR signaling through its cognate sensor WspA, and promotes WspR-dependent activation of Pel exopolysaccharide production, which contributes to biofilm maturation. We also found that ethanol stimulation of WspR promoted P. aeruginosa colonization of CF airway epithelial cells. P. aeruginosa production of phenazines occurs both in the CF lung and in culture, and phenazines enhance ethanol production by C. albicans. Using a C.albicans adh1/adh1 mutant with decreased ethanol production, we found that fungal ethanol strongly altered the spectrum of P. aeruginosa phenazines in favor of those that are most effective against fungi. Thus, a feedback cycle comprised of ethanol and phenazines drives this polymicrobial interaction, and these relationships may provide insight into why co-infection with both P. aeruginosa and C. albicans has been associated with worse outcomes in cystic fibrosis

Video and Synthetic MRI Pre-training of 3D Vision Architectures for Neuroimage Analysis

Transfer learning represents a recent paradigm shift in the way we build artificial intelligence (AI) systems. In contrast to training task-specific models, transfer learning involves pre-training deep learning models on a large corpus of data and minimally fine-tuning them for adaptation to specific tasks. Even so, for 3D medical imaging tasks, we do not know if it is best to pre-train models on natural images, medical images, or even synthetically generated MRI scans or video data. To evaluate these alternatives, here we benchmarked vision transformers (ViTs) and convolutional neural networks (CNNs), initialized with varied upstream pre-training approaches. These methods were then adapted to three unique downstream neuroimaging tasks with a range of difficulty: Alzheimer's disease (AD) and Parkinson's disease (PD) classification, "brain age" prediction. Experimental tests led to the following key observations: 1. Pre-training improved performance across all tasks including a boost of 7.4% for AD classification and 4.6% for PD classification for the ViT and 19.1% for PD classification and reduction in brain age prediction error by 1.26 years for CNNs, 2. Pre-training on large-scale video or synthetic MRI data boosted performance of ViTs, 3. CNNs were robust in limited-data settings, and in-domain pretraining enhanced their performances, 4. Pre-training improved generalization to out-of-distribution datasets and sites. Overall, we benchmarked different vision architectures, revealing the value of pre-training them with emerging datasets for model initialization. The resulting pre-trained models can be adapted to a range of downstream neuroimaging tasks, even when training data for the target task is limited

The role of CO2 variability and exposure time for biological impacts of ocean acidification

Biological impacts of ocean acidification have mostly been studied using future levels of CO without consideration of natural variability or how this modulates both duration and magnitude of CO exposure. Here we combine results from laboratory studies on coral reef fish with diurnal in situ CO data from a shallow coral reef, to demonstrate how natural variability alters exposure times for marine organisms under increasingly high-CO conditions. Large in situ CO variability already results in exposure of coral reef fish to short-term CO levels higher than laboratory-derived critical CO levels (∼600 μatm). However, we suggest that the in situ exposure time is presently insufficient to induce negative effects observed in laboratory studies. Our results suggest that both exposure time and the magnitude of CO levels will be important in determining the response of organisms to future ocean acidification, where both will increase markedly with future increases in CO. Key Points Seawater CO2 variability alters in situ CO2 exposure time and magnitude Fish are presently exposed to short-term CO2 levels above critical values Acidification experiments should consider both CO2 level and exposure time

Maternal corticotropin-releasing hormone is associated with LEP DNA methylation at birth and in childhood: an epigenome-wide study in Project Viva

BackgroundCorticotropin-releasing hormone (CRH) plays a central role in regulating the secretion of cortisol which controls a wide range of biological processes. Fetuses overexposed to cortisol have increased risks of disease in later life. DNA methylation may be the underlying association between prenatal cortisol exposure and health effects. We investigated associations between maternal CRH levels and epigenome-wide DNA methylation of cord blood in offsprings and evaluated whether these associations persisted into mid-childhood.MethodsWe investigated mother-child pairs enrolled in the prospective Project Viva pre-birth cohort. We measured DNA methylation in 257 umbilical cord blood samples using the HumanMethylation450 Bead Chip. We tested associations of maternal CRH concentration with cord blood cells DNA methylation, adjusting the model for maternal age at enrollment, education, maternal race/ethnicity, maternal smoking status, pre-pregnancy body mass index, parity, gestational age at delivery, child sex, and cell-type composition in cord blood. We further examined the persistence of associations between maternal CRH levels and DNA methylation in children's blood cells collected at mid-childhood (n = 239, age: 6.7-10.3 years) additionally adjusting for the children's age at blood drawn.ResultsMaternal CRH levels are associated with DNA methylation variability in cord blood cells at 96 individual CpG sites (False Discovery Rate <0.05). Among the 96 CpG sites, we identified 3 CpGs located near the LEP gene. Regional analyses confirmed the association between maternal CRH and DNA methylation near LEP. Moreover, higher maternal CRH levels were associated with higher blood-cell DNA methylation of the promoter region of LEP in mid-childhood (P < 0.05, β = 0.64, SE = 0.30).ConclusionIn our cohort, maternal CRH was associated with DNA methylation levels in newborns at multiple loci, notably in the LEP gene promoter. The association between maternal CRH and LEP DNA methylation levels persisted into mid-childhood