Direct neuronal reprogramming of NDUFS4 patient cells identifies the unfolded protein response as a novel general reprogramming hurdle

Mitochondria account for essential cellular pathways, from ATP production to nucleotide metabolism, and their deficits lead to neurological disorders and contribute to the onset of age -related diseases. Direct neuronal reprogramming aims at replacing neurons lost in such conditions, but very little is known about the impact of mitochondrial dysfunction on the direct reprogramming of human cells. Here, we explore the effects of mitochondrial dysfunction on the neuronal reprogramming of induced pluripotent stem cell (iPSC)derived astrocytes carrying mutations in the NDUFS4 gene, important for Complex I and associated with Leigh syndrome. This led to the identification of the unfolded protein response as a major hurdle in the direct neuronal conversion of not only astrocytes and fibroblasts from patients but also control human astrocytes and fibroblasts. Its transient inhibition potently improves reprogramming by influencing the mitochondriaendoplasmic-reticulum-stress-mediated pathways. Taken together, disease modeling using patient cells unraveled novel general hurdles and ways to overcome these in human astrocyte-to-neuron reprogramming

NF-κB inhibition prevents acute shear stress-induced inflammation in the saphenous vein graft endothelium

The long saphenous vein (LSV) is commonly used as a conduit in coronary artery bypass grafting. However, long term patency remains limited by the development of vascular inflammation, intimal hyperplasia and accelerated atherosclerosis. The impact of acute exposure of venous endothelial cells (ECs) to acute arterial wall shear stress (WSS) in the arterial circulation, and the subsequent activation of inflammatory pathways, remain poorly defined. Here, we tested the hypothesis that acute exposure of venous ECs to high shear stress is associated with inflammatory responses that are regulated by NF-κB both in-vitro and ex-vivo. Analysis of the LSV endothelium revealed that activation of NF-κB occurred within 30 min after exposure to arterial rates of shear stress. Activation of NF-κB was associated with increased levels of CCL2 production and enhanced binding of monocytes in LSVECs exposed to 6 h acute arterial WSS. Consistent with this, ex vivo exposure of LSVs to acute arterial WSS promoted monocyte interactions with the vessel lumen. Inhibition of the NF-κB pathway prevented acute arterial WSS-induced CCL2 production and reduced monocyte adhesion, both in vitro and in human LSV ex vivo, demonstrating that this pathway is necessary for the induction of the acute arterial WSS-induced pro-inflammatory response. We have identified NF-κB as a critical regulator of acute endothelial inflammation in saphenous vein in response to acute arterial WSS. Localised endothelial-specific inhibition of the NF-κB pathway may be beneficial to prevent vein graft inflammation and consequent failure

Towards Urban Geopolitics of Encounter: Spatial Mixing in Contested Jerusalem

The extent to which 'geographies of encounter' facilitate tolerance of diversity and difference has long been a source of debate in urban studies and human geography scholarship. However, to date this contestation has focused primarily on hyper-diverse cities in the global north-west. Adapting this debate to the volatile conditions of the nationally-contested city, this paper explores intergroup encounters between Israelis and Palestinians in Jerusalem. The paper suggests that in the context of hyper-polarisation of the nationally-contested urban space, the study of encounter should focus on macro-scale structural forces. In Jerusalem, we stress the role of ethnonationality and neoliberalism as key producers of its asymmetric and volatile yet highly resilient geography of intergroup encounters. In broader sense, as many cities worldwide experience a resurgence of ethnonationalism, illuminating the structural production of encounter may demarcate a broader function for reading contemporary urban geopolitics

Role of coding and non-coding variants in mitochondrial disease genes.

After whole exome sequencing, around half of mitochondrial disease patients remain without genetic diagnosis. Focusing on them, I described two novel disease genes, MDH2 and UQCRFS1, encoding for a Krebs cycle enzyme and subunit of mitochondrial complex III, respectively. In addition, I performed RNA-sequencing as a complementary tool to whole exome sequencing, increasing the diagnostic yield and improving variant annotation. This expanded the genetic spectrum of mitochondrial disease and encourages implementation of RNA-sequencing in future diagnostics.&nbsp

Genetic basis of mitochondrial diseases.

Mitochondrial disorders are monogenic disorders characterized by a defect in oxidative phosphorylation and caused by pathogenic variants in one of over 340 different genes. The implementation of whole exome sequencing has led to a revolution in their diagnosis, duplicated the number of associated disease genes, and significantly increased the diagnosed fraction. However, the genetic etiology of a substantial fraction of patients exhibiting mitochondrial disorders remains unknown, highlighting limitations in variant detection and interpretation, which calls for improved computational and DNA sequencing methods, as well as the addition of OMICS tools. More intriguingly, this also suggests that some pathogenic variants lie outside of the protein-coding genes and that the mechanisms beyond the Mendelian inheritance and the mtDNA are of relevance. This review covers the current status of the genetic basis of mitochondrial diseases, discusses current challenges and perspectives, and explores the contribution of factors beyond the protein-coding regions and monogenic inheritance in the expansion of the genetic spectrum of disease

ncRNAs: New players in mitochondrial health and disease?

The regulation of mitochondrial proteome is unique in that its components have origins in both mitochondria and nucleus. With the development of OMICS technologies, emerging evidence indicates an interaction between mitochondria and nucleus based not only on the proteins but also on the non-coding RNAs (ncRNAs). It is now accepted that large parts of the non-coding genome are transcribed into various ncRNA species. Although their characterization has been a hot topic in recent years, the function of the majority remains unknown. Recently, ncRNA species microRNA (miRNA) and long-non coding RNAs (lncRNA) have been gaining attention as direct or indirect modulators of the mitochondrial proteome homeostasis. These ncRNA can impact mitochondria indirectly by affecting transcripts encoding for mitochondrial proteins in the cytoplasm. Furthermore, reports of mitochondria-localized miRNAs, termed mitomiRs, and lncRNAs directly regulating mitochondrial gene expression suggest the import of RNA to mitochondria, but also transcription from the mitochondrial genome. Interestingly, ncRNAs have been also shown to hide small open reading frames (sORFs) encoding for small functional peptides termed micropeptides, with several examples reported with a role in mitochondria. In this review, we provide a literature overview on ncRNAs and micropeptides found to be associated with mitochondrial biology in the context of both health and disease. Although reported, small study overlap and rare replications by other groups make the presence, transport, and role of ncRNA in mitochondria an attractive, but still challenging subject. Finally, we touch the topic of their potential as prognosis markers and therapeutic targets

Corrigendum: ncRNAs: New players in mitochondrial health and disease?(Frontiers in Genetics, (2020), 11, (95), 10.3389/fgene.2020.00095).

In the original article, there weremistakes in Figure 5 and Figure 6 as published. Figures are stating miR-167b instead of the correct miR-147b. The corrected Figure 5 and Figure 6 appear below. The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated. (Figure presented.)

The Upper Cretaceous geodynamic evolution of the Adriatic-Dinaric carbonate platform(s)

Jelaska Vladimir, Gusic Ivan, Jurkovšek Bogdan, Ogorelec Bojan, Cosovic V., Sribar L., Toman M. The Upper Cretaceous geodynamic evolution of the Adriatic-Dinaric carbonate platform(s). In: Géologie Méditerranéenne. Tome 21, numéro 3-4, 1994. Perimediterranean carbonate platforms. First International Meeting. Marseille – France (5-8 septembre 1994) sous la direction de Jean-Pierre Masse. pp. 89-91

The Upper Cretaceous geodynamic evolution of the Adriatic-Dinaric carbonate platform(s)

Jelaska Vladimir, Gusic Ivan, Jurkovšek Bogdan, Ogorelec Bojan, Cosovic V., Sribar L., Toman M. The Upper Cretaceous geodynamic evolution of the Adriatic-Dinaric carbonate platform(s). In: Géologie Méditerranéenne. Tome 21, numéro 3-4, 1994. Perimediterranean carbonate platforms. First International Meeting. Marseille – France (5-8 septembre 1994) sous la direction de Jean-Pierre Masse. pp. 89-91