As stem cells undergo differentiation, mitochondrial DNA (mtDNA) copy number is strictly regulated in order that specialized cells can generate appropriate levels of adenosine triphosphate (ATP) ...through oxidative phosphorylation (OXPHOS) to undertake their specific functions. It is not understood whether tumor-initiating cells regulate their mtDNA in a similar manner or whether mtDNA is essential for tumorigenesis. We show that human neural stem cells (hNSCs) increased their mtDNA content during differentiation in a process that was mediated by a synergistic relationship between the nuclear and mitochondrial genomes and results in increased respiratory capacity. Differentiating multipotent glioblastoma cells failed to match the expansion in mtDNA copy number, patterns of gene expression and increased respiratory capacity observed in hNSCs. Partial depletion of glioblastoma cell mtDNA rescued mtDNA replication events and enhanced cell differentiation. However, prolonged depletion resulted in impaired mtDNA replication, reduced proliferation and induced the expression of early developmental and pro-survival markers including POU class 5 homeobox 1 (OCT4) and sonic hedgehog (SHH). The transfer of glioblastoma cells depleted to varying degrees of their mtDNA content into immunocompromised mice resulted in tumors requiring significantly longer to form compared with non-depleted cells. The number of tumors formed and the time to tumor formation was relative to the degree of mtDNA depletion. The tumors derived from mtDNA depleted glioblastoma cells recovered their mtDNA copy number as part of the tumor formation process. These outcomes demonstrate the importance of mtDNA to the initiation and maintenance of tumorigenesis in glioblastoma multiforme.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Pluripotent blastomeres of mammalian pre-implantation embryos and embryonic stem cells (ESCs) are characterized by limited oxidative capacity and great reliance on anaerobic respiration. Early ...pre-implantation embryos and undifferentiated ESCs possess small and immature mitochondria located around the nucleus, have low oxygen consumption and express high levels of glycolytic enzymes. However, as embryonic cells and ESCs lose pluripotency and commit to a specific cell fate, the expression of mtDNA transcription and replication factors is upregulated and the number of mitochondria and mtDNA copies/cell increases. Moreover, upon cellular differentiation, mitochondria acquire an elongated morphology with swollen cristae and dense matrices, migrate into wider cytoplasmic areas and increase the levels of oxygen consumption and ATP production as a result of the activation of the more efficient, aerobic metabolism. Since pluripotency seems to be associated with anaerobic metabolism and a poorly developed mitochondrial network and differentiation leads to activation of mitochondrial biogenesis according to the metabolic requirements of the specific cell type, it is hypothesized that reprogramming of somatic cells towards a pluripotent state, by somatic cell nuclear transfer (SCNT), transcription-induced pluripotency or creation of pluripotent cell hybrids, requires acquisition of mitochondrial properties characteristic of pluripotent blastomeres and ESCs.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The mechanisms that link environmental and intracellular stimuli to mitochondrial functions, including fission/fusion, ATP production, metabolite biogenesis, and apoptosis, are not well understood. ...Here, we demonstrate that the nutrient-sensing mechanistic/mammalian target of rapamycin complex 1 (mTORC1) stimulates translation of mitochondrial fission process 1 (MTFP1) to control mitochondrial fission and apoptosis. Expression of MTFP1 is coupled to pro-fission phosphorylation and mitochondrial recruitment of the fission GTPase dynamin-related protein 1 (DRP1). Potent active-site mTOR inhibitors engender mitochondrial hyperfusion due to the diminished translation of MTFP1, which is mediated by translation initiation factor 4E (eIF4E)-binding proteins (4E-BPs). Uncoupling MTFP1 levels from the mTORC1/4E-BP pathway upon mTOR inhibition blocks the hyperfusion response and leads to apoptosis by converting mTOR inhibitor action from cytostatic to cytotoxic. These data provide direct evidence for cell survival upon mTOR inhibition through mitochondrial hyperfusion employing MTFP1 as a critical effector of mTORC1 to govern cell fate decisions.
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•The mTORC1/4E-BPs/MTFP1/DRP1 axis controls mitochondrial dynamics•Active-site mTOR inhibitors induce mitochondrial hyperfusion and branching•mTORC1 regulates MTFP1 translation and mitochondrial recruitment of DRP1 via 4E-BPs•Uncoupling MTFP1 levels from the mTORC1 axis upon mTOR inhibition leads to apoptosis
Morita et al. show that mTORC1 signaling controls mitochondrial dynamics to govern cell fate decisions. mTORC1 inhibition by asTORi treatment leads to mitochondrial branching and hyperfusion through 4E-BP-dependent suppression of MTFP1 mRNA translation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) originated in Wuhan, China in late 2019, and its resulting coronavirus disease, COVID-19, was declared a pandemic by the World ...Health Organization on March 11, 2020. The rapid global spread of COVID-19 represents perhaps the most significant public health emergency in a century. As the pandemic progressed, a continued paucity of evidence on routes of SARS-CoV-2 transmission has resulted in shifting infection prevention and control guidelines between classically-defined airborne and droplet precautions. During the initial isolation of 13 individuals with COVID-19 at the University of Nebraska Medical Center, we collected air and surface samples to examine viral shedding from isolated individuals. We detected viral contamination among all samples, supporting the use of airborne isolation precautions when caring for COVID-19 patients.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Published prevalence estimates of nonsuicidal self‐injury (NSSI) among nonclinical samples are highly heterogeneous, raising concerns about their reliability and hindering attempts to explore the ...alleged increase in NSSI over time. Accordingly, the objectives of this study were to investigate the influence of methodological factors on heterogeneity in NSSI prevalence estimates, explore changes over time, and estimate overall international NSSI prevalence. Results showed that methodological factors contributed over half (51.6%) of the heterogeneity in prevalence estimates, and, after adjusting for these factors, NSSI prevalence did not increase over time. Overall, pooled NSSI prevalence was 17.2% among adolescents, 13.4% among young adults, and 5.5% among adults. Clearly, development of standardized methodology in NSSI research is crucial if accurate estimates are desired.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Kelp forests (Order Laminariales) form key biogenic habitats in coastal regions of temperate and Arctic seas worldwide, providing ecosystem services valued in the range of billions of dollars ...annually. Although local evidence suggests that kelp forests are increasingly threatened by a variety of stressors, no comprehensive global analysis of change in kelp abundances currently exists. Here, we build and analyze a global database of kelp time series spanning the past half-century to assess regional and global trends in kelp abundances. We detected a high degree of geographic variation in trends, with regional variability in the direction and magnitude of change far exceeding a small global average decline (instantaneous rate of change = −0.018 y−1). Our analysis identified declines in 38% of ecoregions for which there are data (−0.015 to −0.18 y−1), increases in 27% of ecoregions (0.015 to 0.11 y−1), and no detectable change in 35% of ecoregions. These spatially variable trajectories reflected regional differences in the drivers of change, uncertainty in some regions owing to poor spatial and temporal data coverage, and the dynamic nature of kelp populations. We conclude that although global drivers could be affecting kelp forests at multiple scales, local stressors and regional variation in the effects of these drivers dominate kelp dynamics, in contrast to many other marine and terrestrial foundation species.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Autologous olfactory ensheathing cell (OEC) transplantation is a promising therapy for spinal cord injury; however, the efficacy varies between trials in both animals and humans. The main reason for ...this variability is that the purity and phenotype of the transplanted cells differs between studies. OECs are susceptible to modulation with neurotrophic factors, and thus, neurotrophins can be used to manipulate the transplanted cells into an optimal, consistent phenotype. OEC transplantation can be divided into 3 phases: (1) cell preparation, (2) cell administration, and (3) continuous support to the transplanted cells in situ. The ideal behaviour of OECs differs between these 3 phases; in the cell preparation phase, rapid cell expansion is desirable to decrease the time between damage and transplantation. In the cell administration phase, OEC survival and integration at the injury site, in particular migration into the glial scar, are the most critical factors, along with OEC-mediated phagocytosis of cellular debris. Finally, continuous support needs to be provided to the transplantation site to promote survival of both transplanted cells and endogenous cells within injury site and to promote long-term integration of the transplanted cells and angiogenesis. In this review, we define the 3 phases of OEC transplantation into the injured spinal cord and the optimal cell behaviors required for each phase. Optimising functional outcomes of OEC transplantation can be achieved by modulation of cell behaviours with neurotrophins. We identify the key growth factors that exhibit the strongest potential for optimizing the OEC phenotype required for each phase.
The delivery of perfluoroalkyl substances (PFAS) from snowpacks into Lake Hazen, located on Ellesmere Island (Nunavut, Canada, 82° N) indicates that annual atmospheric deposition is a major source of ...PFAS that undergo complex cycling in the High Arctic. Perfluoroalkyl carboxylic acids (PFCA) in snowpacks display odd-even concentration ratios characteristic of long-range atmospheric transport and oxidation of volatile precursors. Major ion analysis in snowpacks suggests that sea spray, mineral dust, and combustion aerosol are all relevant to the fate of PFAS in the Lake Hazen watershed. Distinct drifts of light and dark snow (enriched with light absorbing particles, LAPs) facilitate the study of particle loads on the fate of PFAS in the snowpack. Total PFAS (ΣPFAS, ng m–2) loads are lower in snowpacks enriched with LAPs and are attributed to reductions in snowpack albedo combined with enhanced post-depositional melting. Elevated concentrations of PFCA are observed in the top 5 m of the water column during snowmelt periods compared to ice-covered or ice-free periods. PFAS concentrations in deep waters of the Lake Hazen water column were consistent between snowmelt, ice-free, and ice-covered periods, which is ascribed to the delivery of dense and turbid glacier meltwaters mixing PFAS throughout the Lake Hazen water column. These observations highlight the underlying mechanisms in PFAS cycling in High Arctic Lakes particularly in the context of increased particle loads and melting.
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IJS, KILJ, NUK, PNG, UL, UM
Mitochondrial DNA (mtDNA) copy number is strictly regulated during differentiation so that cells with a high requirement for ATP generated through oxidative phosphorylation have high mtDNA copy ...number, whereas those with a low requirement have few copies. Using immunoprecipitation of DNA methylation on 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC), which distinguish between de novo DNA methylation and demethylation, respectively, we set out to determine whether DNA methylation at exon 2 of the human mtDNA-specific polymerase (DNA polymerase gamma A (POLGA)) regulates cell-specific mtDNA copy number in highly proliferative and terminally differentiated cells. Highly proliferative cancer and pluripotent and multipotent cells possessed low mtDNA copy number and were highly methylated at exon 2 of POLGA in contrast to post-mitotic cells. Unlike neural stem cells, cancer cells were unable to differentiate and remained extensively DNA methylated at exon 2 of POLGA. However, mtDNA depletion of cancer cells reduced DNA methylation at exon 2 of POLGA as they replenished mtDNA to form tumours in mice. Glioblastoma cells treated with the DNA demethylation agent 5-azacytidine over 28 days of astrocyte-induced differentiation demethylated exon 2 of POLGA leading to increased mtDNA copy number and expression of the astrocyte endpoint marker glial fibrillary acidic protein (GFAP). However, the demethylation agent vitamin C (VitC) was unable to sustain increased mtDNA copy number and differentiation, as was the case when VitC was withdrawn after short-term treatment. These data demonstrate that DNA demethylation of POLGA is an essential regulator of mtDNA copy number and cellular fate and that cancer cells are only able to modulate DNA methylation of POLGA and mtDNA copy number in the presence of a DNA demethylation agent that inhibits de novo methyltransferase 1 activity.
To determine the cognitive effects of long-term dietary soy isoflavones in a daily dose comparable to that of traditional Asian diets.
In the double-blind Women's Isoflavone Soy Health trial, healthy ...postmenopausal women were randomly allocated to receive daily 25 g of isoflavone-rich soy protein (91 mg of aglycone weight of isoflavones: 52 mg of genistein, 36 mg of daidzein, and 3 mg glycitein) or milk protein-matched placebo. The primary cognitive endpoint compared between groups at 2.5 years was change from baseline on global cognition, a composite of the weighted sum of 14 neuropsychological test score changes. Secondary outcomes compared changes in cognitive factors and individual tests.
A total of 350 healthy postmenopausal women aged 45-92 years enrolled in this trial; 313 women with baseline and endpoint cognitive test data were included in intention-to-treat analyses. Adherence in both groups was nearly 90%. There was no significant between-group difference on change from baseline in global cognition (mean standardized improvement of 0.42 in the isoflavone group and 0.31 in the placebo group; mean standardized difference 0.11, 95% confidence interval CI -0.13 to 0.35). Secondary analyses indicated greater improvement on a visual memory factor in the isoflavone group (mean standardized difference 0.33, 95% CI 0.06-0.60) but no significant between-group differences on 3 other cognitive factors or individual test scores, and no significant difference within a subgroup of younger postmenopausal women.
For healthy postmenopausal women, long-term dietary soy isoflavone supplementation in a dose comparable to that of traditional Asian diets has no effect on global cognition but may improve visual memory.
This study provides Class I evidence that long-term dietary supplementation with isoflavone-rich soy protein does not improve global cognition of healthy postmenopausal women.
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