Insights into mitochondrial dysfunction: aging, amyloid-β, and tau-A deleterious trio

Significance: Alzheimer's disease (AD) is an age-related progressive neurodegenerative disorder mainly affecting elderly individuals. The pathology of AD is characterized by amyloid plaques (aggregates of amyloid-β [Aβ]) and neurofibrillary tangles (aggregates of tau), but the mechanisms underlying this dysfunction are still partially unclear. Recent Advances: A growing body of evidence supports mitochondrial dysfunction as a prominent and early, chronic oxidative stress-associated event that contributes to synaptic abnormalities and, ultimately, selective neuronal degeneration in AD. Critical Issues: In this review, we discuss on the one hand whether mitochondrial decline observed in brain aging is a determinant event in the onset of AD and on the other hand the close interrelationship of this organelle with Aβ and tau in the pathogenic process underlying AD. Moreover, we summarize evidence from aging and Alzheimer models showing that the harmful trio "aging, Aβ, and tau protein" triggers mitochondrial dysfunction through a number of pathways, such as impairment of oxidative phosphorylation (OXPHOS), elevation of reactive oxygen species production, and interaction with mitochondrial proteins, contributing to the development and progression of the disease. Future Directions: The aging process may weaken the mitochondrial OXPHOS system in a more general way over many years providing a basis for the specific and destructive effects of Aβ and tau. Establishing strategies involving efforts to protect cells at the mitochondrial level by stabilizing or restoring mitochondrial function and energy homeostasis appears to be challenging, but very promising route on the horizon

Winter is coming: food web structure and seasonality in a subtropical freshwater coastal-lake

Indexación: Web of Science; Scopus.Food web studies provide a useful tool to assess the organization and complexity of natural communities. Nevertheless, the seasonal dynamics of food web properties, their environmental correlates, and potential association with community diversity and stability remain poorly studied. Here, we condensed an incomplete 6-year community dataset of a subtropical coastal lake to examine how monthly variation in diversity impacts food web structure over an idealized time series for an averaged year. Phytoplankton, zooplankton, macroinvertebrates, and fish were mostly resolved to species level (n = 120 trophospecies). Our results showed that the seasonal organization of the food web could be aggregated into two clusters of months grouped here as ‘summer’ and ‘winter’. During ‘winter’, the food web decreases in size and complexity, with the number of trophospecies dropping from 106 to 82 (a 22.6% decrease in the number of nodes) and the trophic interactions from 1,049 to 637 between month extremes (a 39.3% drop in the number of links). The observed simplification in food web structure during ‘winter’ suggests that community stability is more vulnerable to the impact of any change during this period.http://onlinelibrary.wiley.com/doi/10.1002/ece3.3031/epd

Protein Kinase CK2 Regulates Nerve/Glial Antigen (NG)2-Mediated Angiogenic Activity of Human Pericytes

Protein kinase CK2 is a crucial regulator of endothelial cell proliferation, migration and sprouting during angiogenesis. However, it is still unknown whether this kinase additionally affects the angiogenic activity of other vessel-associated cells. In this study, we investigated the effect of CK2 inhibition on primary human pericytes. We found that CK2 inhibition reduces the expression of nerve/glial antigen (NG)2, a crucial factor which is involved in angiogenic processes. Reporter gene assays revealed a 114 bp transcriptional active region of the human NG2 promoter, whose activity was decreased after CK2 inhibition. Functional analyses demonstrated that the pharmacological inhibition of CK2 by CX-4945 suppresses pericyte proliferation, migration, spheroid sprouting and the stabilization of endothelial tubes. Moreover, aortic rings of NG2−/− mice showed a significantly reduced vascular sprouting when compared to rings of NG2+/+ mice, indicating that NG2 is an important regulator of the angiogenic activity of pericytes. In vivo, implanted Matrigel plugs containing CX-4945-treated pericytes exhibited a lower microvessel density when compared to controls. These findings demonstrate that CK2 regulates the angiogenic activity of pericytes through NG2 gene expression. Hence, the inhibition of CK2 represents a promising anti-angiogenic strategy, because it does not only target endothelial cells, but also vessel-associated pericytes

Evaluation of T2Candida Panel for detection of Candida in peritoneal dialysates

Fungal peritonitis in the peritoneal dialysis population is difficult to diagnose promptly due to the inherently slow cultivation-based methods currently required for identification of peritonitis pathogens. Because of the moderate risk for severe complications, the need for rapid diagnostics is considerable. One possible solution to this unmet need is the T2Candida Panel, a new technology designed to detect the most common pathogenic Candida spp. directly from whole blood specimens in as little as a few hours. We hypothesized that this technology could be applied to the detection of Candida in peritoneal dialysate, a matrix not currently approved by the Food and Drug Administration for testing by this system. Remnant dialysate samples from three healthy (noninfected) pediatric peritoneal dialysis patients were spiked with Candida glabrata, serially diluted, and tested in triplicate with unaltered dialysate specimens. The assay detected C. glabrata in 100% of spiked dialysate samples across the full spectrum of dilutions tested, and no assay inhibition or cross-reactivity was noted. These findings suggest one of possibly more applications of this technology. The positive clinical implications of this test will continue to be realized as its use is validated in peritoneal dialysate and other patient specimen types

Promoting the health of refugee women: a scoping literature review incorporating the social ecological model

The health of refugee women after settlement in a new country, can be adversely or positively affected by individual, interpersonal, community, and organizational factors. While much of the previous literature highlights these factors individually, there is a lack of comprehensive synthesis regarding how the factors interact to influence the health of refugee women. We conducted a thematic analysis in our literature review to elucidate how providers can work with refugee women to prevent adverse health outcomes and intervene at multiple levels to improve their health outcomes after resettlement. We reviewed peer-reviewed literature from 2009 to 2019 from Google Scholar, JSTOR, Global Health, PubMed, CINAHL, Sociological Abstracts, and Social Service Abstracts, and also used citation chaining, to identify relevant information pertaining to refugee women’s health. The key terms used for our literature review were, health care, violence, social support, and mental health. In total, we included 52 articles, 3 books, and 8 other sources. We found that refugee women are vulnerable to violence during migration and typically have high rates of post-traumatic stress disorder. There were also concerns of secondary victimization by providers after resettlement. We also found that social support is an important factor for reducing isolation, and improving access to health care, as well as improving mental health outcomes. However, social support was often difficult to maintain, and was moderated by factors such as English language fluency. Health care was influenced by health literacy, cultural difference, communication concerns, and access issues. The findings suggest that at the individual and interpersonal levels there is a need to address language barriers, improve provider-patient communication, and provide appropriate medical and mental health screenings. At the organizational level, interorganizational communication and awareness are vital. At the community level, providers can work with community leaders, to educate, create dialogue and collaboration, to help facilitate understanding and bolster community social support. Improved communication and knowledge about the unique needs and concerns of refugee women through an integrated, multi-system approach is necessary to improve their health outcomes

CK2 Activity Mediates the Aggressive Molecular Signature of Glioblastoma Multiforme by Inducing Nerve/Glial Antigen (NG)2 Expression

Nerve/glial antigen (NG)2 expression crucially determines the aggressiveness of glioblastoma multiforme (GBM). Recent evidence suggests that protein kinase CK2 regulates NG2 expression. Therefore, we investigated in the present study whether CK2 inhibition suppresses proliferation and migration of NG2-positive GBM cells. For this purpose, CK2 activity was suppressed in the NG2-positive cell lines A1207 and U87 by the pharmacological inhibitor CX-4945 and CRISPR/Cas9- mediated knockout of CK2α. As shown by quantitative real-time PCR, luciferase-reporter assays, flow cytometry and western blot, this significantly reduced NG2 gene and protein expression when compared to vehicle-treated and wild type controls. In addition, CK2 inhibition markedly reduced NG2-dependent A1207 and U87 cell proliferation and migration. The Cancer Genome Atlas (TCGA)- based data further revealed not only a high expression of both NG2 and CK2 in GBM but also a positive correlation between the mRNA expression of the two proteins. Finally, we verified a decreased NG2 expression after CX-4945 treatment in patient-derived GBM cells. These findings indicate that the inhibition of CK2 represents a promising approach to suppress the aggressive molecular signature of NG2-positive GBM cells. Therefore, CX-4945 may be a suitable drug for the future treatment of NG2-positive GBM

Interplay of cis and trans mechanisms driving transcription factor binding and gene expression evolution

Noncoding regulatory variants play a central role in the genetics of human diseases and in evolution. Here we measure allele-specific transcription factor binding occupancy of three liver-specific transcription factors between crosses of two inbred mouse strains to elucidate the regulatory mechanisms underlying transcription factor binding variations in mammals. Our results highlight the pre-eminence of cis-acting variants on transcription factor occupancy divergence. Transcription factor binding differences linked to cis-acting variants generally exhibit additive inheritance, while those linked to trans-acting variants are most often dominantly inherited. Cis-acting variants lead to local coordination of transcription factor occupancies that decay with distance; distal coordination is also observed and may be modulated by long-range chromatin contacts. Our results reveal the regulatory mechanisms that interplay to drive transcription factor occupancy, chromatin state, and gene expression in complex mammalian cell states.We thank the CRUK—CI Genomics, BRU, and Bioinformatics Cores for technical assistance and the EMBL-EBI systems team for management of computational resources. This research was supported by the European Molecular Biology Laboratory (E.S.W., D.T., J.C.M., P.F.), Cancer Research UK (B.M.S., T.F.R., F.C., C.F., A.R., D.T.O.), the BOLD ITN (B.M.S.), Darwin Fellowship (A.K.), the Wellcome Trust (WT202878/B/16/Z, WT108749/Z/15/Z) (P.F.), (WT202878/A/16/Z) (D.T.O), (WT095606) (A.C.F.-S) and (WT098051) (P.F., D.T.O.), EMBO Long-term (ALTF1518-2012) and Advanced Fellowships (aALTF1672-2014) (E.S.W.), and by the European Research Council (award 615584) and EMBO Young Investigator Programme (D.T.O.)

A Comparison of Radio Axis with Host Galaxy Plane Axis in Seyfert Galaxies

We use the radio axis as an indicator of the orientation of the obscuring torus in Seyfert galaxies, and analyze the difference between the position angles of extended radio structures and host galaxy major axis of Seyfert 1 and Seyfert 2 galaxies. We find that Seyfert 1's are less likely to have extended radio structures along the host galaxy major axis, while Seyfert 2's have these structures distributed in most directions. We also find a zone of avoidance in the distribution of position angles; both Seyfert 1's and Seyfert 2's seem to avoid close alignment between the radio axis and the host galaxy plane axis. These results are analyzed from the point of view of a model in which Seyfert 1's have their obscuring torus axis aligned preferentially along the host galaxy disk axis, and Seyfert 2's have their torus axis laying at an intermediate angle between the galaxy disk and its axis.Comment: 9 pages of text, 10 figures and 1 table. Accepted for publication in the Ap

Mesoscale Numerical Investigations of Air Traffic Emissions over the North Atlantic during SONEX Flight 8: A Case Study

Chemical data from flight 8 of NASA's Subsonic Assessment (SASS) Ozone and Nitrogen Oxide Experiment (SONEX) exhibited signatures consistent with aircraft emissions, stratospheric air, and surface-based pollution. These signatures are examined in detail, focussing on the broad aircraft emission signatures that are several hundred kilometers in length. A mesoscale meteorological model provides high resolution wind data that are used to calculate backward trajectories arriving at locations along the flight track. These trajectories are compared to aircraft locations in the North Atlantic Flight Corridor over a 27-33 hour period. Time series of flight level NO and the number of trajectory/aircraft encounters within the NAFC show excellent agreement. Trajectories arriving within the stratospheric and surface-based pollution regions are found to experience very few aircraft encounters. Conversely, there are many trajectory/aircraft encounters within the two chemical signatures corresponding to aircraft emissions. Even many detailed fluctuations of NO within the two aircraft signature regions correspond to similar fluctuations in aircraft encountered during the previous 27-33 hours. Results indicate that high resolution meteorological modeling, when coupled with detailed aircraft location data, is useful for understanding chemical signatures from aircraft emissions at scales of several hundred kilometers