MPV17 encodes an inner mitochondrial membrane protein and is mutated in infantile hepatic mitochondrial DNA depletion

The mitochondrial (mt) DNA depletion syndromes (MDDS) are genetic disorders characterized by a severe, tissue-specific decrease of mtDNA copy number, leading to organ failure. There are two main clinical presentations: myopathic (OMIM 609560) and hepatocerebral (OMIM 251880). Known mutant genes, including TK2, SUCLA2, DGUOK and POLG, account for only a fraction of MDDS cases. We found a new locus for hepatocerebral MDDS on chromosome 2p21-23 and prioritized the genes on this locus using a new integrative genomics strategy. One of the top-scoring candidates was the human ortholog of the mouse kidney disease gene Mpv17. We found disease-segregating mutations in three families with hepatocerebral MDDS and demonstrated that, contrary to the alleged peroxisomal localization of the MPV17 gene product, MPV17 is a mitochondrial inner membrane protein, and its absence or malfunction causes oxidative phosphorylation (OXPHOS) failure and mtDNA depletion, not only in affected individuals but also in Mpv17-/- mice.     

The structural intolerance of the PrP α-fold for polar substitution of the helix-3 methionines

The conversion of the cellular prion protein (PrP^C) into its disease-associated form (PrP^Sc) involves a major conformational change and the accumulation of sulfoxidized methionines. Computational and synthetic approaches have shown that this change in the polarity of M206 and M213 impacts the C-terminal domain native α-fold allowing the flexibility required for the structural conversion. To test the effect in the full-length molecule with site-specificity, we have generated M-to-S mutations. Molecular dynamics simulations show that the replacement indeed perturbs the native state. When this mutation is placed at the conserved methionines of HaPrP(23–231), only substitutions at the Helix-3 impair the α-fold, stabilizing a non-native state with perturbed secondary structure, loss of native tertiary contacts, increased surface hydrophobicity, reduced thermal stability and an enhanced tendency to aggregate into protofibrillar polymers. Our work supports that M206 and M213 function as α-fold gatekeepers and suggests that their redox state regulate misfolding routes.     

From Permanence to Total Availability: A Quantum Conceptual Upgrade

We consider the classical concept of time of permanence and observe that its quantum equivalent is described by a bona fide self-adjoint operator. Its interpretation, by means of the spectral theorem, reveals that we have to abandon not only the idea that quantum entities would be characterizable in terms of spatial trajectories but, more generally, that they would possess the very attribute of spatiality. Consequently, a permanence time shouldn’t be interpreted as a “time” in quantum mechanics, but as a measure of the total availability of a quantum entity in participating to a process of creation of a spatial localization.     

Emerging topics and new perspectives on HLA-G

Following the Fifth International Conference on non-classical HLA-G antigens (HLA-G), held in Paris in July 2009, we selected some topics which focus on emerging aspects in the setting of HLA-G functions. In particular, HLA-G molecules could play a role in: (1) various inflammatory disorders, such as multiple sclerosis, intracerebral hemorrhage, gastrointestinal, skin and rheumatic diseases, and asthma, where they may act as immunoregulatory factors; (2) the mechanisms to escape immune surveillance utilized by several viruses, such as human cytomegalovirus, herpes simplex virus type 1, rabies virus, hepatitis C virus, influenza virus type A and human immunodeficiency virus 1 (HIV-1); and (3) cytokine/chemokine network and stem cell transplantation, since they seem to modulate cell migration by the downregulation of chemokine receptor expression and mesenchymal stem cell activity blocking of effector cell functions and the generation of regulatory T cells. However, the immunomodulatory circuits mediated by HLA-G proteins still remain to be clarified.     

Ephemeral Properties and the Illusion of Microscopic Particles

Founding our analysis on the Geneva-Brussels approach to quantum mechanics, we use conventional macroscopic objects as guiding examples to clarify the content of two important results of the beginning of twentieth century: Einstein?CPodolsky?CRosen??s reality criterion and Heisenberg??s uncertainty principle. We then use them in combination to show that our widespread belief in the existence of microscopic particles is only the result of a cognitive illusion, as microscopic particles are not particles, but are instead the ephemeral spatial and local manifestations of non-spatial and non-local entities.     

Spin and Wind Directions I: Identifying Entanglement in Nature and Cognition

We present a cognitive psychology experiment where participants were asked to select pairs of spatial directions that they considered to be the best example of Two different wind directions. Data are shown to violate the CHSH version of Bell’s inequality with the same magnitude as in typical Bell-test experiments with entangled spins. Wind directions thus appear to be conceptual entities connected through meaning, in human cognition, in a similar way as spins appear to be entangled in experiments conducted in physics laboratories. This is the first part of a two-part article. In the second part (Aerts et al. in Found Sci, 2017) we present a symmetrized version of the same experiment for which we provide a quantum modeling of the collected data in Hilbert space.     

Anti-Candida activity of 1–18 fragment of the frog skin peptide esculentin-1b: in vitro and in vivo studies in a Caenorhabditis elegans infection model

Candida albicans represents one of the most prevalent species causing life-threatening fungal infections. Current treatments to defeat Candida albicans have become quite difficult, due to their toxic side effects and the emergence of resistant strains. Antimicrobial peptides (AMPs) are fascinating molecules with a potential role as novel anti-infective agents. However, only a few studies have been performed on their efficacy towards the most virulent hyphal phenotype of this pathogen. The purpose of this work is to evaluate the anti-Candida activity of the N-terminal 1–18 fragment of the frog skin AMP esculentin-1b, Esc(1–18), under both in vitro and in vivo conditions using Caenorhabditis elegans as a simple host model for microbial infections. Our results demonstrate that Esc(1–18) caused a rapid reduction in the number of viable yeast cells and killing of the hyphal population. Esc(1–18) revealed a membrane perturbing effect which is likely the basis of its mode of action. To the best of our knowledge, this is the first report showing the ability of a frog skin AMP-derived peptide (1) to kill both growing stages of Candida; (2) to promote survival of Candida-infected living organisms and (3) to inhibit transition of these fungal cells from the roundish yeast shape to the more dangerous hyphal form at sub-inhibitory concentrations.     

Positional identification of TNFSF4, encoding OX40 ligand, as a gene that influences atherosclerosis susceptibility

Ath1 is a quantitative trait locus on mouse chromosome 1 that renders C57BL/6 mice susceptible and C3H/He mice resistant to diet-induced atherosclerosis. The quantitative trait locus region encompasses 11 known genes, including Tnfsf4 (also called Ox40l or Cd134l), which encodes OX40 ligand. Here we report that mice with targeted mutations of Tnfsf4 had significantly (P 相似文献