High-throughput quantum photonic devices emitting indistinguishable photons in the telecom C-band.

Single indistinguishable photons at telecom C-band wavelengths are essential for quantum networks and the future quantum internet. However, high-throughput technology for single-photon generation at 1550 nm remained a missing building block to overcome present limitations in quantum communication and information technologies. Here, we demonstrate the high-throughput fabrication of quantum-photonic integrated devices operating at C-band wavelengths based on epitaxial semiconductor quantum dots. Our technique enables the deterministic integration of single pre-selected quantum emitters into microcavities based on circular Bragg gratings. Respective devices feature the triggered generation of single photons with ultra-high purity and record-high photon indistinguishability. Further improvements in yield and coherence properties will pave the way for implementing single-photon non-linear devices and advanced quantum networks at telecom wavelengths.

On-Demand Generation of Indistinguishable Photons in the Telecom C-Band Using Quantum Dot Devices.

Semiconductor quantum dots (QDs) enable the generation of single and entangled photons, which are useful for various applications in photonic quantum technologies. Specifically for quantum communication via fiber-optical networks, operation in the telecom C-band centered around 1550 nm is ideal. The direct generation of QD-photons in this spectral range with high quantum-optical quality, however, remained challenging. Here, we demonstrate the coherent on-demand generation of indistinguishable photons in the telecom C-band from single QD devices consisting of InAs/InP QD-mesa structures heterogeneously integrated with a metallic reflector on a silicon wafer. Using pulsed two-photon resonant excitation of the biexciton-exciton radiative cascade, we observe Rabi rotations up to pulse areas of 4π and a high single-photon purity in terms of g(2)(0) = 0.005(1) and 0.015(1) for exciton and biexciton photons, respectively. Applying two independent experimental methods, based on fitting Rabi rotations in the emission intensity and performing photon cross-correlation measurements, we consistently obtain preparation fidelities at the π-pulse exceeding 80%. Finally, performing Hong-Ou-Mandel-type two-photon interference experiments, we obtain a photon-indistinguishability of the full photon wave packet of up to 35(3)%, representing a significant advancement in the photon-indistinguishability of single photons emitted directly in the telecom C-band.

Ultra-small mode area V-groove waveguide design for on-chip single-photon emission.

We numerically investigate the figures of merit for single-photon emission in a planar GaAs-on-insulator waveguide featuring a V-groove geometry. Thanks to a field enhancement effect arising due to boundary conditions of this waveguide, the structure features an ultra-small mode area enabling a factor of a maximum 2.8 times enhancement of the Purcell factor for quantum dot and a more significant 7 times enhancement for the atomic-size solid-state emitters with the aligned dipole orientation. In addition, the coupling efficiency to the fundamental quasi-TE mode is also improved. To take into account potential on-chip integration, we further show that the V-groove mode profile can be converted using a tapering section to the mode profile of a standard ridge waveguide while maintaining both the high Purcell factor and the good fundamental mode coupling efficiency.

Performance of the nanopost single-photon source: beyond the single-mode model.

We present a detailed analysis of the physics governing the collection efficiency and the Purcell enhancement of the nanopost single-photon source. We show that a standard single-mode Fabry-Pérot model is insufficient to describe the device performance, which benefits significantly from scattering from the fundamental mode to radiation modes. We show how the scattering mechanism decouples the collection efficiency from the Purcell enhancement, such that maximum collection efficiency is obtained off-resonance. Finally, we discuss how this scattering mechanism can be beneficial for future single-photon source designs.

Odd- and even-numbered medium-chained fatty acids protect against glutathione depletion in very long-chain acyl-CoA dehydrogenase deficiency.

Recent trials have reported the ability of triheptanoin to improve clinical outcomes for the severe symptoms associated with long-chain fatty acid oxidation disorders, including very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency. However, the milder myopathic symptoms are still challenging to treat satisfactorily. Myopathic pathogenesis is multifactorial, but oxidative stress is an important component. We have previously shown that metabolic stress increases the oxidative burden in VLCAD-deficient cell lines and can deplete the antioxidant glutathione (GSH). We investigated whether medium-chain fatty acids provide protection against GSH depletion during metabolic stress in VLCAD-deficient fibroblasts. To investigate the effect of differences in anaplerotic capacity, we included both even-(octanoate) and odd-numbered (heptanoate) medium-chain fatty acids. Overall, we show that modulation of the concentration of medium-chain fatty acids in culture media affects levels of GSH retained during metabolic stress in VLCAD-deficient cell lines but not in controls. Lowered glutamine concentration in the culture media during metabolic stress led to GSH depletion and decreased viability in VLCAD deficient cells, which could be rescued by both heptanoate and octanoate in a dose-dependent manner. Unlike GSH levels, the levels of total thiols increased after metabolic stress exposure, the size of this increase was not affected by differences in cell culture medium concentrations of glutamine, heptanoate or octanoate. Addition of a PPAR agonist further exacerbated stress-related GSH-depletion and viability loss, requiring higher concentrations of fatty acids to restore GSH levels and cell viability. Both odd- and even-numbered medium-chain fatty acids efficiently protect VLCADdeficient cells against metabolic stress-induced antioxidant depletion.

Bright Quantum Dot Single-Photon Emitters at Telecom Bands Heterogeneously Integrated on Si.

Whereas the Si photonic platform is highly attractive for scalable optical quantum information processing, it lacks practical solutions for efficient photon generation. Self-assembled semiconductor quantum dots (QDs) efficiently emit photons in the telecom bands (1460-1625 nm) and allow for heterogeneous integration with Si. In this work, we report on a novel, robust, and industry-compatible approach for achieving single-photon emission from InAs/InP QDs heterogeneously integrated with a Si substrate. As a proof of concept, we demonstrate a simple vertical emitting device, employing a metallic mirror beneath the QD emitter, and experimentally obtained photon extraction efficiencies of ∼10%. Nevertheless, the figures of merit of our structures are comparable with values previously only achieved for QDs emitting at shorter wavelength or by applying technically demanding fabrication processes. Our architecture and the simple fabrication procedure allows for the demonstration of high-purity single-photon generation with a second-order correlation function at zero time delay, g (2)(τ = 0) < 0.02, without any corrections at continuous wave excitation at the liquid helium temperature and preserved up to 50 K. For pulsed excitation, we achieve the as-measured g (2)(0) down to 0.205 ± 0.020 (0.114 ± 0.020 with background coincidences subtracted).

Design and fabrication of ridge waveguide-based nanobeam cavities for on-chip single-photon sources.

We report on the design of nanohole/nanobeam cavities in ridge waveguides for on-chip, quantum-dot-based single-photon generation. Our design overcomes limitations of a low-refractive-index-contrast material platform in terms of emitter-mode coupling efficiency and yields an outcoupling efficiency of 0.73 to the output ridge waveguide. Importantly, this high coupling efficiency is combined with broadband operation of 9 nm full-width half-maximum. We provide an explicit design procedure for identifying the optimum geometrical parameters according to the developed design. Besides, we fabricate and optically characterize a proof-of-concept waveguide structure. The results of the microphotoluminescence measurements provide evidence for cavity-enhanced spontaneous emission from the quantum dot, thus supporting the potential of our design for on-chip single-photon sources applications.

Use of Molecular Genetic Analyses in Danish Routine Newborn Screening.

Historically, the analyses used for newborn screening (NBS) were biochemical, but increasingly, molecular genetic analyses are being introduced in the workflow. We describe the application of molecular genetic analyses in the Danish NBS programme and show that second-tier molecular genetic testing is useful to reduce the false positive rate while simultaneously providing information about the precise molecular genetic variant and thus informing therapeutic strategy and easing providing information to parents. When molecular genetic analyses are applied as second-tier testing, valuable functional data from biochemical methods are available and in our view, such targeted NGS technology should be implemented when possible in the NBS workflow. First-tier NGS technology may be a promising future possibility for disorders without a reliable biomarker and as a general approach to increase the adaptability of NBS for a broader range of genetic diseases, which is important in the current landscape of quickly evolving new therapeutic possibilities. However, studies on feasibility, sensitivity, and specificity are needed as well as more insight into what views the general population has towards using genetic analyses in NBS. This may be sensitive to some and could have potentially negative consequences for the NBS programme.

Bioenergetic and Proteomic Profiling of Immune Cells in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients: An Exploratory Study.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a heterogeneous, debilitating, and complex disease. Along with disabling fatigue, ME/CFS presents an array of other core symptoms, including autonomic nervous system (ANS) dysfunction, sustained inflammation, altered energy metabolism, and mitochondrial dysfunction. Here, we evaluated patients' symptomatology and the mitochondrial metabolic parameters in peripheral blood mononuclear cells (PBMCs) and plasma from a clinically well-characterised cohort of six ME/CFS patients compared to age- and gender-matched controls. We performed a comprehensive cellular assessment using bioenergetics (extracellular flux analysis) and protein profiles (quantitative mass spectrometry-based proteomics) together with self-reported symptom measures of fatigue, ANS dysfunction, and overall physical and mental well-being. This ME/CFS cohort presented with severe fatigue, which correlated with the severity of ANS dysfunction and overall physical well-being. PBMCs from ME/CFS patients showed significantly lower mitochondrial coupling efficiency. They exhibited proteome alterations, including altered mitochondrial metabolism, centred on pyruvate dehydrogenase and coenzyme A metabolism, leading to a decreased capacity to provide adequate intracellular ATP levels. Overall, these results indicate that PBMCs from ME/CFS patients have a decreased ability to fulfill their cellular energy demands.

Variants in the ethylmalonyl-CoA decarboxylase (ECHDC1) gene: a novel player in ethylmalonic aciduria?

Ethylmalonic acid (EMA) is a major and potentially cytotoxic metabolite associated with short-chain acyl-CoA dehydrogenase (SCAD) deficiency, a condition whose status as a disease is uncertain. Unexplained high EMA is observed in some individuals with complex neurological symptoms, who carry the SCAD gene (ACADS) variants, c.625G>A and c.511C>T. The variants have a high allele frequency in the general population, but are significantly overrepresented in individuals with elevated EMA. This has led to the idea that these variants need to be associated with variants in other genes to cause hyperexcretion of ethylmalonic acid and possibly a diseased state. Ethylmalonyl-CoA decarboxylase (ECHDC1) has been described and characterized as an EMA metabolite repair enzyme, however, its clinical relevance has never been investigated. In this study, we sequenced the ECHDC1 gene (ECHDC1) in 82 individuals, who were reported with unexplained high EMA levels due to the presence of the common ACADS variants only. Three individuals with ACADS c.625G>A variants were found to be heterozygous for ECHDC1 loss-of-function variants. Knockdown experiments of ECHDC1, in healthy human cells with different ACADS c.625G>A genotypes, showed that ECHDC1 haploinsufficiency and homozygosity for the ACADS c.625G>A variant had a synergistic effect on cellular EMA excretion. This study reports the first cases of ECHDC1 gene defects in humans and suggests that ECHDC1 may be involved in elevated EMA excretion in only a small group of individuals with the common ACADS variants. However, a direct link between ECHDC1/ACADS deficiency, EMA and disease could not be proven.

Open-geometry modal method based on transverse electric and transverse magnetic mode expansion for orthogonal curvilinear coordinates.

A vectorial modal method is presented based on transverse magnetic and transverse electric mode expansion, which significantly simplifies the evaluation of the operator matrix. The method, which features a true open boundary condition, is introduced for an orthogonal curvilinear coordinate system with the specific examples of circular and elliptical geometries presented. We validate the method by considering challenging problems, such as the calculation of spontaneous emission rates, of modal reflection coefficients and of the effect of the emitter spatial misalignment on the spontaneous emission ß factor. Results are compared with literature.

Time-bin entangled photon pairs from quantum dots embedded in a self-aligned cavity.

We introduce a scalable photonic platform that enables efficient generation of entangled photon pairs from a semiconductor quantum dot. Our system, which is based on a self-aligned quantum dot- micro-cavity structure, erases the need for complex steps of lithography and nanofabrication. We experimentally show collection efficiency of 0.17 combined with a Purcell enhancement of up to 1.7. We harness the potential of our device to generate photon pairs entangled in time bin, reaching a fidelity of 0.84(5) with the maximally entangled state. The achieved pair collection efficiency is 4 times larger than the state-of-the art for this application. The device, which theoretically supports pair extraction efficiencies of nearly 0.5 is a promising candidate for the implementation of bright sources of time-bin, polarization- and hyper entangled photon pairs in a straightforward manner.

Bezafibrate activation of PPAR drives disturbances in mitochondrial redox bioenergetics and decreases the viability of cells from patients with VLCAD deficiency.

Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is the most common inborn long-chain fatty acid oxidation (FAO) disorder. VLCAD deficiency is characterized by distinct phenotypes. The severe phenotypes are potentially life-threatening and affect the heart or liver, with a comparatively milder phenotype characterized by myopathic symptoms. There is an unmet clinical need for effective treatment options for the myopathic phenotype. The molecular mechanisms driving the gradual decrease in mitochondrial function and associated alterations of muscle fibers are unclear. The peroxisome proliferator-activated receptor (PPAR) pan-agonist bezafibrate is a potent modulator of FAO and multiple other mitochondrial functions and has been proposed as a potential medication for myopathic cases of long-chain FAO disorders. In vitro experiments have demonstrated the ability of bezafibrate to increase VLCAD expression and activity. However, the outcome of small-scale clinical trials has been controversial. We found VLCAD deficient patient fibroblasts to have an increased oxidative stress burden and deranged mitochondrial bioenergetic capacity, compared to controls. Applying heat stress under fasting conditions to bezafibrate pretreated patient cells, caused a marked further increase of mitochondrial superoxide levels. Patient cells failed to maintain levels of the essential thiol peptide antioxidant glutathione and experienced a decrease in cellular viability. Our findings indicate that chronic PPAR activation is a plausible initiator of long-term pathogenesis in VLCAD deficiency. Our findings further implicate disruption of redox homeostasis as a key pathogenic mechanism in VLCAD deficiency and support the notion that a deranged thiol metabolism might be an important pathogenic factor in VLCAD deficiency.

Riboflavin Deficiency-Implications for General Human Health and Inborn Errors of Metabolism.

As an essential vitamin, the role of riboflavin in human diet and health is increasingly being highlighted. Insufficient dietary intake of riboflavin is often reported in nutritional surveys and population studies, even in non-developing countries with abundant sources of riboflavin-rich dietary products. A latent subclinical riboflavin deficiency can result in a significant clinical phenotype when combined with inborn genetic disturbances or environmental and physiological factors like infections, exercise, diet, aging and pregnancy. Riboflavin, and more importantly its derivatives, flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), play a crucial role in essential cellular processes including mitochondrial energy metabolism, stress responses, vitamin and cofactor biogenesis, where they function as cofactors to ensure the catalytic activity and folding/stability of flavoenzymes. Numerous inborn errors of flavin metabolism and flavoenzyme function have been described, and supplementation with riboflavin has in many cases been shown to be lifesaving or to mitigate symptoms. This review discusses the environmental, physiological and genetic factors that affect cellular riboflavin status. We describe the crucial role of riboflavin for general human health, and the clear benefits of riboflavin treatment in patients with inborn errors of metabolism.

Increased antioxidant response in medium-chain acyl-CoA dehydrogenase deficiency: does lipoic acid have a protective role?

BACKGROUND: Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency (MCADD) is the most frequent fatty acid oxidation (FAO) defect in humans. MCAD-deficient fibroblasts are more resistant to oxidative stress-induced cell death than other FAO defects and healthy controls. METHODS: Herein we investigate the antioxidant response and mitochondrial function in fibroblasts from MCAD-deficient patients (c.985 A>G/c.985 A>G) and healthy controls. RESULTS: MCAD-deficient fibroblasts showed increased level of mitochondrial superoxide, while lipids were less oxidatively damaged, and higher amount of manganese superoxide dismutase were detected compared to healthy controls, showing forceful antioxidant system in MCADD. We showed increased maximal respiration and reserve capacity in MCAD-deficient fibroblasts compared to controls, indicating more capacity through the tricarboxylic acid (TCA) cycle and subsequently respiratory chain. This led us to study the pyruvate dehydrogenase complex (PDC), the key enzyme in the glycolysis releasing acetyl-CoA to the TCA cycle. MCAD-deficient fibroblasts displayed not only significantly increased PDC but also increased lipoylated PDC protein levels compared to healthy controls. CONCLUSIONS: Based on these findings, we raise the interesting hypothesis that increased PDC-bound lipoic acid, synthesized from accumulated octanoic acid in MCADD, may affect the cellular antioxidant pool in MCADD.

Danish expanded newborn screening is a successful preventive public health programme.

INTRODUCTION: Newborn screening is a public health programme for early diagnosis of treatable diseases. METHODS: The subjects included were newborns born 2002-2019. Expanded newborn screening (eNBS) for metabolic diseases was introduced as a pilot project from 2002 to 2009, followed by routine screening with informed dissent. A total of 967,780 newborns were screened; 82,930 were unscreened. Furthermore, a historic cohort of clinically diagnosed children born in the 1992-2001 period was included. Children in the unscreened and historic cohorts were evaluated for the same diseases as were the screened children. Dried blood spot samples were collected locally and sent for screening analyses. We recorded newborns with true and false positive results as well as false negative results and their clinical signs at screening and at the last follow-up. RESULTS: A total of 603 samples were screen positive: 354 false positives and 249 true positives (222 newborns and 27 mothers). The positive predictive value (PPV) was 41% for the entire screening period; 62% for 2018. The false positive rate (FPR) was 0.036% overall; 0.024% for 2018. The overall prevalence of diseases was 1:3,900; in the historic cohort, the prevalence of the same diseases was 1:8,300; 7.3% had symptoms at the time of screening. At follow-up, 93% of the children had no clinically significant sequelae. Among 82,930 unscreened newborns, 27 (1:3,000) had eNBS panel diseases, some with severe manifestations. CONCLUSIONS: This update of eNBS in Denmark confirms that eNBS is a successful preventive public health programme. Early treatment in a latent phase of disease is effective and screening should be extended to other diseases not currently in the programme. FUNDING: The work was supported by grants from The Ronald McDonald Børnefond, Danmarks Sundhedsfond, Direktør Ib Henriksens Fond, Ragnhild Ibsens Legat til Medicinsk Forskning, Gerda og Aage Haenschs Fond, Dronning Louises Børnehospitals Forskningsfond, Læge Sofus Carl Emil Friis og Hustru Olga Doris Friis's Legat, Aase and Ejnar Danielsens Fond, Oda og Hans Svenningsens Fond, Fonden af 1870, Vanførefonden, Fonden til Lægevidenskabens Fremme and Danish Medical Research Council. TRIAL REGISTRATION: not relevant.

[Psychological, neurological and cell-mediated mechanisms by mindfulness-based therapy].

In this review, we present clinical studies on mindfulness-based therapy (MBT) with a focus on mediating mechanisms for its health promoting effects. These constitute awareness, self-compassion, regulation of dysfunctional patterns of thoughts and emotions, neural network and cellular processes. Among cellular processes are inflammation, oxidative stress, mitochondrial dysfunction and telomere shortening, which all contribute to the molecular pathophysiology of several of today's lifestyle diseases. Finally, we address applications, where strong evidence exists for the clinical impact of MBT.

[Myalgic encephalomyelitis or chronic fatigue syndrome].

In this review, we discuss the myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), which is characterised by extreme mental and physical fatigue with associated symptoms of pain, disturbed sleep, cognitive and autonomic dysfunction, as well as post-exertional malaise. This con-dition is often preceded by an infection, severe physiological and/or psychological strain. Over the last decades, research has demonstrated mitochondrial, neuroendocrine, immuno-logical, and metabolic perturbations in patients with ME/CFS, giving hope for the development of new biomarkers and new treatment modalities.

Mitochondrial fatty acid oxidation and the electron transport chain comprise a multifunctional mitochondrial protein complex.

Three mitochondrial metabolic pathways are required for efficient energy production in eukaryotic cells: the electron transfer chain (ETC), fatty acid ß-oxidation (FAO), and the tricarboxylic acid cycle. The ETC is organized into inner mitochondrial membrane supercomplexes that promote substrate channeling and catalytic efficiency. Although previous studies have suggested functional interaction between FAO and the ETC, their physical interaction has never been demonstrated. In this study, using blue native gel and two-dimensional electrophoreses, nano-LC-MS/MS, immunogold EM, and stimulated emission depletion microscopy, we show that FAO enzymes physically interact with ETC supercomplexes at two points. We found that the FAO trifunctional protein (TFP) interacts with the NADH-binding domain of complex I of the ETC, whereas the electron transfer enzyme flavoprotein dehydrogenase interacts with ETC complex III. Moreover, the FAO enzyme very-long-chain acyl-CoA dehydrogenase physically interacted with TFP, thereby creating a multifunctional energy protein complex. These findings provide a first view of an integrated molecular architecture for the major energy-generating pathways in mitochondria that ensures the safe transfer of unstable reducing equivalents from FAO to the ETC. They also offer insight into clinical ramifications for individuals with genetic defects in these pathways.