MFN2 mutations cause compensatory mitochondrial DNA proliferation.

MFN2 and OPA1 genes encode two dynamin-like GTPase proteins involved in the fusion of the mitochondrial membrane. They have been associated with Charcot–Marie–Tooth disease type 2A and autosomal dominant optic atrophy, respectively. We report a large family with optic atrophy beginning in early childhood, associated with axonal neuropathy and mitochondrial myopathy in adult life. The clinical presentation looks like the autosomal dominant optic atrophy ‘plus’ phenotype linked to OPA1 mutations but is associated with a novel MFN2 missense mutation (c.629A&gt;T, p.D210V). Multiple mitochondrial DNA deletions were found in skeletal muscle and this observation makes MFN2 a novel gene associated with ‘mitochondrial DNA breakage’ syndrome. Contrary to previous studies in patients with Charcot–Marie–Tooth disease type 2A, fibroblasts carrying the MFN2 mutation present with a respiratory chain deficiency, a fragmentation of the mitochondrial network and a significant reduction of MFN2 protein expression. Furthermore, we show for the first time that impaired mitochondrial fusion is responsible for a deficiency to repair stress-induced mitochondrial DNA damage. It is likely that defect in mitochondrial DNA repair is due to variability in repair protein content across the mitochondrial population and is at least partially responsible for mitochondrial DNA instability. <br/

Modified GIANT Dynamic Bandwidth Allocation Algorithm of NG-PON

Gigabit passive optical networks have been widely deployed due to the fact that the cost of their implementation is still decreasing. What is more important, we are facing theproblem with increasing demands on the transmission bandwidth. Regarding this issue, the ITU develops another two standards supporting higher downstream bitrate. The XG-PON standard is the first platform under the developing, and the NG-PON2 is the second standard. The first one provides compatibility and increases the downstream capacity of 10 Gbit/s and the second standard has the same assumptions, but does not have backward compatibility. In this article, we discuss only XG-PON networks. We choose amendment as the dynamic bandwidth allocation algorithms, and we have compared it with the original specification and with our modification. The primary intention of that modification is to reduce the delay of Triple Play (data, video, and voice) services. These services are represented by TCONT (Transmission Container), which is used to improve the PON system upstream bandwidth allocation and transmission status dynamically. As NS-3 simulator does not support the direct mapping of Triple Play services into T-CONT and their labeling. We focus on a delay value for Triple Play services which was reduced by own modification in a GIANT algorithm. On the other hand, we cannot reduce the delay value for VoIP services because it has the highest priority by T-CONT

Subwavelength grating metamaterial waveguides and ring resonators on a silicon nitride platform

We propose and demonstrate subwavelength grating (SWG) metamaterial waveguides and ring resonators on a silicon nitride platform for the first time. The SWG waveguide is engineered such that a large overlap of 53% of the Bloch mode with the top cladding material is achieved, demonstrating excellent potential for applications in evanescent field sensing and light amplification. The devices, which have critical dimensions greater than 100 nm, are fabricated using a commercial rapid turn-around silicon nitride prototyping foundry process using electron beam lithography. Experimental characterization of the fabricated device reveals excellent ring resonator internal quality factor (2.11x10^5) and low propagation loss (~1.5 dB/cm) in the C-band, a significant improvement of both parameters compared to silicon based SWG ring resonators. These results demonstrate the promising prospects of SWG metamaterial structures for silicon nitride based photonic integrated circuits.Comment: 12 pages, 7 figures, submitted to Laser & Photonics Reviews for publicatio

MFN2 mutations cause compensatory mitochondrial DNA proliferation.

MFN2 and OPA1 genes encode two dynamin-like GTPase proteins involved in the fusion of the mitochondrial membrane. They have been associated with Charcot–Marie–Tooth disease type 2A and autosomal dominant optic atrophy, respectively. We report a large family with optic atrophy beginning in early childhood, associated with axonal neuropathy and mitochondrial myopathy in adult life. The clinical presentation looks like the autosomal dominant optic atrophy ‘plus’ phenotype linked to OPA1 mutations but is associated with a novel MFN2 missense mutation (c.629A&gt;T, p.D210V). Multiple mitochondrial DNA deletions were found in skeletal muscle and this observation makes MFN2 a novel gene associated with ‘mitochondrial DNA breakage’ syndrome. Contrary to previous studies in patients with Charcot–Marie–Tooth disease type 2A, fibroblasts carrying the MFN2 mutation present with a respiratory chain deficiency, a fragmentation of the mitochondrial network and a significant reduction of MFN2 protein expression. Furthermore, we show for the first time that impaired mitochondrial fusion is responsible for a deficiency to repair stress-induced mitochondrial DNA damage. It is likely that defect in mitochondrial DNA repair is due to variability in repair protein content across the mitochondrial population and is at least partially responsible for mitochondrial DNA instability. <br/

A review of the deterministic and diffusion approximations for stochastic chemical reaction networks

This work reviews deterministic and diffusion approximations of the stochastic chemical reaction networks and explains their applications. We discuss the added value the diffusion approximation provides for systems with different phenomena, such as a deficiency and a bistability. It is advocated that the diffusion approximation can be considered as an alternative theoretical approach to study the reaction networks rather than a simulation shortcut. We discuss two examples in which the diffusion approximation is able to catch qualitative properties of reaction networks that the deterministic model misses. We provide an explicit construction of the original process and the diffusion approximation such that the distance between their trajectories is controlled and demonstrate this construction for the examples. We also discuss the limitations and potential directions of the developments

Mapping atopic dermatitis and anti–IL-22 response signatures to type 2–low severe neutrophilic asthma

Background: Transcriptomic changes in patients who respond clinically to biological therapies may identify responses in other tissues or diseases. Objective: We sought to determine whether a disease signature identified in atopic dermatitis (AD) is seen in adults with severe asthma and whether a transcriptomic signature for patients with AD who respond clinically to anti–IL-22 (fezakinumab [FZ]) is enriched in severe asthma. Methods: An AD disease signature was obtained from analysis of differentially expressed genes between AD lesional and nonlesional skin biopsies. Differentially expressed genes from lesional skin from therapeutic superresponders before and after 12 weeks of FZ treatment defined the FZ-response signature. Gene set variation analysis was used to produce enrichment scores of AD and FZ-response signatures in the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes asthma cohort. Results: The AD disease signature (112 upregulated genes) encompassing inflammatory, T-cell, TH2, and TH17/TH22 pathways was enriched in the blood and sputum of patients with asthma with increasing severity. Patients with asthma with sputum neutrophilia and mixed granulocyte phenotypes were the most enriched (P < .05). The FZ-response signature (296 downregulated genes) was enriched in asthmatic blood (P < .05) and particularly in neutrophilic and mixed granulocytic sputum (P < .05). These data were confirmed in sputum of the Airway Disease Endotyping for Personalized Therapeutics cohort. IL-22 mRNA across tissues did not correlate with FZ-response enrichment scores, but this response signature correlated with TH22/IL-22 pathways. Conclusions: The FZ-response signature in AD identifies severe neutrophilic asthmatic patients as potential responders to FZ therapy. This approach will help identify patients for future asthma clinical trials of drugs used successfully in other chronic diseases