Mitochondrial retinopathies

The retina is an exquisite target for defects of oxidative phosphorylation (OXPHOS) associated with mitochondrial impairment. Retinal involvement occurs in two ways, retinal dystrophy (retinitis pigmentosa) and subacute or chronic optic atrophy, which are the most common clinical entities. Both can present as isolated or virtually exclusive conditions, or as part of more com-plex, frequently multisystem syndromes. In most cases, mutations of mtDNA have been found in association with mitochondrial retinopathy. The main genetic abnormalities of mtDNA include mutations associated with neurogenic muscle weakness, ataxia and retinitis pigmentosa (NARP) sometimes with earlier onset and increased severity (maternally inherited Leigh syndrome, MILS), single large-scale deletions determining Kearns–Sayre syndrome (KSS, of which retinal dystrophy is a cardinal symptom), and mutations, particularly in mtDNA-encoded ND genes, associated with Leber hereditary optic neuropathy (LHON). However, mutations in nuclear genes can also cause mito-chondrial retinopathy, including autosomal recessive phenocopies of LHON, and slowly progressive optic atrophy caused by dominant or, more rarely, recessive, mutations in the fusion/mitochondrial shaping protein OPA1, encoded by a nuclear gene on chromosome 3q29

A tunable rf SQUID manipulated as flux and phase qubit

We report on two different manipulation procedures of a tunable rf SQUID. First, we operate this system as a flux qubit, where the coherent evolution between the two flux states is induced by a rapid change of the energy potential, turning it from a double well into a single well. The measured coherent Larmor-like oscillation of the retrapping probability in one of the wells has a frequency ranging from 6 to 20 GHz, with a theoretically expected upper limit of 40 GHz. Furthermore, here we also report a manipulation of the same device as a phase qubit. In the phase regime, the manipulation of the energy states is realized by applying a resonant microwave drive. In spite of the conceptual difference between these two manipulation procedures, the measured decay times of Larmor oscillation and microwave-driven Rabi oscillation are rather similar. Due to the higher frequency of the Larmor oscillations, the microwave-free qubit manipulation allows for much faster coherent operations.Comment: Proceedings of Nobel Symposium "Qubits for future quantum computers", Goeteborg, Sweden, May 25-28, 2009; to appear in Physica Script

Therapeutic Options in Hereditary Optic Neuropathies

Options for the effective treatment of hereditary optic neuropathies have been a long time coming. The successful launch of the antioxidant idebenone for Leber’s Hereditary Optic Neuropathy (LHON), followed by its introduction into clinical practice across Europe, was an important step forward. Nevertheless, other options, especially for a variety of mitochondrial optic neuropathies such as dominant optic atrophy (DOA), are needed, and a number of pharmaceutical agents, acting on different molecular pathways, are currently under development. These include gene therapy, which has reached Phase III development for LHON, but is expected to be developed also for DOA, whilst most of the other agents (other antioxidants, anti-apoptotic drugs, activators of mitobiogenesis, etc.) are almost all at Phase II or at preclinical stage of research. Here, we review proposed target mechanisms, preclinical evidence, available clinical trials with primary endpoints and results, of a wide range of tested molecules, to give an overview of the field, also providing the landscape of future scenarios, including gene therapy, gene editing, and reproductive options to prevent transmission of mitochondrial DNA mutations

A second case with the V374A KCND3 pathogenic variant in an Italian patient with early-onset spinocerebellar ataxia

Background and Objectives To date, approximately 20 heterozygous mainly loss-of-function variants in KCND3 have been associated with spinocerebellar ataxia (SCA) type 19 and 22, a clinically heterogeneous group of neurodegenerative disorders. We aimed at reporting the second patients with the V374A KCND3 mutation from an independent family, confirming its pathogenic role. Methods We describe the clinical history of a patient with SCA and conducted genetic investigations including mitochondrial DNA analysis and exome sequencing. Results This male patient was reported to have unstable gait with tremors at the lower limbs and dysarthric speech since childhood. A neurologic examination also showed dysarthria, nystagmus, action tremor, dysmetria, and weak deep tendon reflexes. He had marked cerebellar atrophy at brain MRI, more evident at vermis. Molecular analysis, including exome sequencing and an in silico panel analysis of genes associated with SCA, revealed the c.1121T>C [p.V374A] mutation in KCND3. Discussion This report consolidates the pathogenicity of the V374A KCND3 mutation and suggests that the ataxic paroxysmal exacerbations are not a key phenotypic feature of this mutation

Missense PDSS1 mutations in CoenzymeQ10 synthesis cause optic atrophy and sensorineural deafness

CoenzymeQ10 is one of the main cellular antioxidants and an essential lipid involved in numerous cell reactions, such as energy production and apoptosis modulation. A large number of enzymes are involved in CoQ10 biosynthesis. Mutations in the genes encoding for these enzymes cause a CoQ10 deficiency, characterized by neurological and systemic symptoms. Here we describe two young sisters with sensorineural deafness followed by optic atrophy, due to a novel homozygous pathogenic variant in PDSS1. The visual system seems to be mainly involved when the first steps of CoQ10 synthesis are impaired (PDSS1, PDSS2, and COQ2 deficiency)

Static flux bias of a flux qubit using persistent current trapping

Qubits based on the magnetic flux degree of freedom require a flux bias, whose stability and precision strongly affect the qubit performance, up to a point of forbidding the qubit operation. Moreover, in the perspective of multiqubit systems, it must be possible to flux-bias each qubit independently, hence avoiding the traditional use of externally generated magnetic fields in favour of on-chip techniques that minimize cross-couplings. The solution discussed in this paper exploits a persistent current, trapped in a superconducting circuit integrated on chip that can be inductively coupled with an individual qubit. The circuit does not make use of resistive elements that can be detrimental for the qubit coherence. The trapping procedure allows to control and change stepwise the amount of stored current; after that, the circuit can be completely disconnected from the external sources. We show in a practical case how this works and how to drive the bias circuit at the required value.Comment: 5 figures submitted to Superconductor Science and Technolog

Effect of cosmic rays on the resonant gravitational wave detector NAUTILUS at temperature T=1.5 K

The interaction between cosmic rays and the gravitational wave bar detector NAUTILUS is experimentally studied with the aluminum bar at temperature of T=1.5 K. The results are compared with those obtained in the previous runs when the bar was at T=0.14 K. The results of the run at T = 1.5 K are in agreement with the thermo-acoustic model; no large signals at unexpected rate are noticed, unlike the data taken in the run at T = 0.14 K. The observations suggest a larger efficiency in the mechanism of conversion of the particle energy into vibrational mode energy when the aluminum bar is in the superconductive status.Comment: 7 pages, 3 figures, 2 tables. Accepted by Physics Letters

Increasing the bandwidth of resonant gravitational antennas: The case of Explorer

Resonant gravitational wave detectors with an observation bandwidth of tens of hertz are a reality: the antenna Explorer, operated at CERN by the ROG collaboration, has been upgraded with a new read-out. In this new configuration, it exhibits an unprecedented useful bandwidth: in over 55 Hz about its frequency of operation of 919 Hz the spectral sensitivity is better than 10^{-20} /sqrt(Hz) . We describe the detector and its sensitivity and discuss the foreseable upgrades to even larger bandwidths.Comment: 4 pages- 4 figures Acceted for publication on Physical Review Letter

Chromatic Pupillometry in Isolated Rapid Eye Movement Sleep Behavior Disorder

Background: Melanopsin retinal ganglion cell (mRGC)-mediated pupillary light reflex (PLR) abnormalities have been documented in several neurodegenerative disorders including Parkinson's disease. Overall, isolated rapid eye movement (REM) sleep behavior disorder (iRBD) represents the strongest prodromal risk factor for impending α-synucleinopathies. Objectives: To quantitatively compare PLR and mRGC-mediated contribution to PLR in 16 iRBD patients and 16 healthy controls. Methods: iRBD and controls underwent extensive neuro-ophthalmological evaluation and chromatic pupillometry. In iRBD, PLR metrics were correlated with clinical variables and with additional biomarkers including REM atonia index (RAI), DaTscan, and presence of phosphorylated-α-synuclein (p-α-syn) deposition in skin biopsy. Results: We documented higher baseline pupil diameter and decreased rod-transient PLR amplitude in iRBD patients compared to controls. PLR rod-contribution correlated with RAI. Moreover, only iRBD patients with evidence of p-α-syn deposition at skin biopsy showed reduced PLR amplitude compared to controls. Conclusion: The observed PLR abnormalities in iRBD might be considered as potential biomarkers for the risk stratification of phenoconversion of the disease. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Mechanical Activation of Adipose Tissue and Derived Mesenchymal Stem Cells : Novel Anti-Inflammatory Properties

The adipose tissue is a source of inflammatory proteins, such as TNF, IL-6, and CXCL8. Most of their production occurs in macrophages that act as scavengers of dying adipocytes. The application of an orbital mechanical force for 6-10 min at 97 g to the adipose tissue, lipoaspirated and treated according to Coleman procedures, abolishes the expression of TNF-\u3b1 and stimulates the expression of the anti-inflammatory protein TNF-stimulated gene-6 (TSG-6). This protein had protective and anti-inflammatory effects when applied to animal models of rheumatic diseases. We examined biopsy, lipoaspirate, and mechanically activated fat and observed that in addition to the increased TSG-6, Sox2, Nanog, and Oct4 were also strongly augmented by mechanical activation, suggesting an effect on stromal cell stemness. Human adipose tissue-derived mesenchymal stem cells (hADSCs), produced from activated fat, grow and differentiate normally with proper cell surface markers and chromosomal integrity, but their anti-inflammatory action is far superior compared to those mesenchymal stem cells (MSCs) obtained from lipoaspirate. The expression and release of inflammatory cytokines from THP-1 cells was totally abolished in mechanically activated adipose tissue-derived hADSCs. In conclusion, we report that the orbital shaking of adipose tissue enhances its anti-inflammatory properties, and derived MSCs maintain such enhanced activity