TMEM41B and VMP1 are scramblases and regulate the distribution of cholesterol and phosphatidylserine

TMEM41B and VMP1 are integral membrane proteins of the endoplasmic reticulum (ER) and regulate the formation of autophagosomes, lipid droplets (LDs), and lipoproteins. Recently, TMEM41B was identified as a crucial host factor for infection by all coronaviruses and flaviviruses. The molecular function of TMEM41B and VMP1, which belong to a large evolutionarily conserved family, remains elusive. Here, we show that TMEM41B and VMP1 are phospholipid scramblases whose deficiency impairs the normal cellular distribution of cholesterol and phosphatidylserine. Their mechanism of action on LD formation is likely to be different from that of seipin. Their role in maintaining cellular phosphatidylserine and cholesterol homeostasis may partially explain their requirement for viral infection. Our results suggest that the proper sorting and distribution of cellular lipids are essential for organelle biogenesis and viral infection.     

Antagonism of the ATP-gated P2X7 receptor: a potential therapeutic strategy for cancer

Purinergic Signalling - The P2X receptor 7 (P2X7R) is a plasma membrane receptor sensing extracellular ATP associated with a wide variety of cellular functions. It is most commonly expressed on...     

Sports Participation and Positive Correlates in African American,Latino, and White Girls

The purpose of the study was to examine relations among sports participation and positive correlates across African American, Latino, and White girls. Positive correlate variables were self-perceptions (self-worth, body attractiveness, athletic competence), less depression, and participation in extracurricular activities. The sample comprised 372 girls (mean age = 12.03 years). Data were analyzed using multiple-sample structural equation models, controlling for age and income. Across all ethnic groups, greater sports participation was significantly related to higher self-worth, body attractiveness, and athletic competence, and to more extracurricular activity. Among Latino and White girls only, greater sports participation also was related to less depression. There were significant age and income influences on the positive correlates. Findings confirm the existence of significant relationships between organized sports participation and positive correlates among early adolescent African American, Latino, and White girls. Despite a few ethnic differences in relationships, the current study revealed more similarities than differences.     

The mitochondria targeted antioxidant MitoQ protects against fluoroquinolone-induced oxidative stress and mitochondrial membrane damage in human Achilles tendon cells

Tendinitis and tendon rupture during treatment with fluoroquinolone antibiotics is thought to be mediated via oxidative stress. This study investigated whether ciprofloxacin and moxifloxacin cause oxidative stress and mitochondrial damage in cultured normal human Achilles’ tendon cells and whether an antioxidant targeted to mitochondria (MitoQ) would protect against such damage better than a non-mitochondria targeted antioxidant. Human tendon cells from normal Achilles’ tendons were exposed to 0–0.3 mm antibiotic for 24 h and 7 days in the presence of 1 µm MitoQ or an untargeted form, idebenone. Both moxifloxacin and ciprofloxacin resulted in up to a 3-fold increase in the rate of oxidation of dichlorodihydrofluorescein, a marker of general oxidative stress in tenocytes (p<0.0001) and loss of mitochondrial membrane permeability (p<0.001). In cells treated with MitoQ the oxidative stress was less and mitochondrial membrane potential was maintained. Mitochondrial damage to tenocytes during fluoroquinolone treatment may be involved in tendinitis and tendon rupture.     

Structure-Activity Relationships Among a New Class of Antiviral Heterosubstituted 2′,3′-Dideoxynucleoside Analogues

Abstract

3′-Oxa-4′-thiocytidine nucleoside analogues 14–17 were prepared from oxathiolanes 10 and 11, and evaluated for activity against HIV-1 and HBV in vitro. The nucleoside analogues were found to possess potent activities against HIV-1 in a panel of cell lines. Compound 16 is moderately active against HBV in 2.2.15 cells.     

‘Illuminating the broader context’: anthropological and historical knowledge at the International Criminal Tribunal for Rwanda

Historians and anthropologists have been among the experts called to enlighten non‐Rwandan judges at the International Criminal Tribunal for Rwanda. Given that the Tribunal's regulations provide little guidance on who qualifies as an expert and that judges are not bound by national rules of evidence, judges exercise considerable discretion on who may provide expert testimony. By considering judges' scepticism towards repetitive expert testimony and that experts have changed their opinion because of information revealed in the course of the trials, this article seeks to convey the distinct characteristics of this innovative context and re‐evaluate the assumption that anthropologists and historians are inevitably engaged in an epistemological contest with law when they act as experts in criminal trials.     

Importin‐7 Mediates Nuclear Trafficking of DNA in Mammalian Cells

Eukaryotic cells have the ability to uptake and transport endogenous and exogenous DNA in their nuclei, however little is known about the specific pathways involved. Here we show that the nuclear transport receptor importin 7 (imp7) supports nuclear import of supercoiled plasmid DNA and human mitochondrial DNA in a Ran and energy‐dependent way. The imp7‐dependent pathway was specifically competed by excess DNA but not by excess of maltose‐binding protein fused with the classical nuclear localizing signal (NLS) or the M9 peptides. Transport of DNA molecules complexed with poly‐l ‐lysine was impaired in intact cells depleted of imp7, and DNA complexes remained localized in the cytoplasm. Poor DNA nuclear import in cells depleted of imp7 directly correlated with lower gene expression levels in these cells compared to controls. Inefficient nuclear import of transfected DNA induced greater upregulation of the interferon pathway, suggesting that rapid DNA nuclear import may prevent uncontrolled activation of the innate immune response. Our results provide evidence that imp7 is a non‐redundant component of an intrinsic pathway in mammalian cells for efficient accumulation of exogenous and endogenous DNA in the nucleus, which may be critical for the exchange of genetic information between mitochondria and nuclear genomes and to control activation of the innate immune response .     

The Contribution of Non-Conventional T Cells and NK Cells in the Mycobacterial-Specific IFNγ Response in Bacille Calmette-Guérin (BCG)-Immunized Infants

Background

The Mycobacterium bovis Bacille Calmette-Guérin (BCG) vaccine is given to >120 million infants each year worldwide. Most studies investigating the immune response to BCG have focused on adaptive immunity. However the importance of TCR-gamma/delta (γδ) T cells and NK cells in the mycobacterial-specific immune response is of increasing interest.

Methods

Participants in four age-groups were BCG-immunized. Ten weeks later, in vitro BCG-stimulated blood was analyzed for NK and T cell markers, and intracellular IFNgamma (IFNγ) by flow cytometry. Total functional IFNγ response was calculated using integrated median fluorescence intensity (iMFI).

Results

In infants and children, CD4 and CD4-CD8- (double-negative (DN)) T cells were the main IFNγ-expressing cells representing 43-56% and 27-37% of total CD3+ IFNγ+ T cells respectively. The iMFI was higher in DN T cells compared to CD4 T cells in all age groups, with the greatest differences seen in infants immunized at birth (p=0.002) or 2 months of age (p<0.0001). When NK cells were included in the analysis, they accounted for the majority of total IFNγ-expressing cells and, together with DN Vδ2 γδ T cells, had the highest iMFI in infants immunized at birth or 2 months of age.

Conclusion

In addition to CD4 T cells, NK cells and DN T cells, including Vδ2 γδ T cells, are the key populations producing IFNγ in response to BCG immunization in infants and children. This suggests that innate immunity and unconventional T cells play a greater role in the mycobacterial immune response than previously recognized and should be considered in the design and assessment of novel tuberculosis vaccines.