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Mitochondrial dysfunction elicits stress responses that safeguard cellular homeostasis against metabolic insults. Mitochondrial integrated stress response (ISR mt ) is a major response to mitochondrial (mt)DNA expression stress (mtDNA maintenance, translation defects), but the knowledge of dynamics or interdependence of components is lacking. We report that in mitochondrial myopathy, ISR mt progresses in temporal stages and development from early to chronic and is regulated by autocrine and endocrine effects of FGF21, a metabolic hormone with pleiotropic effects. Initial disease signs induce transcriptional ISR mt (ATF5, mitochondrial one-carbon cycle, FGF21, and GDF15). The local progression to 2 nd metabolic ISR mt stage (ATF3, ATF4, glucose uptake, serine biosynthesis, and transsulfuration) is FGF21 dependent. Mitochondrial unfolded protein response marks the 3 rd ISR mt stage of failing tissue. Systemically, FGF21 drives weight loss and glucose preference, and modifies metabolism and respiratory chain deficiency in a specific hippocampal brain region. Our evidence indicates that FGF21 is a local and systemic messenger of mtDNA stress in mice and humans with mitochondrial disease., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Digitalization is a global trend becoming ever more important to our connected and sustainable society. This trend also affects industry where the Industrial Internet of Things is an important part, and there is a need to conserve spectrum as well as energy when communicating data to a fog or cloud back-end system. In this paper we investigate the benefits of fog computing by proposing a novel distributed learning model on the sensor device and simulating the data stream in the fog, instead of transmitting all raw sensor values to the cloud back-end. To save energy and to communicate as few packets as possible, the updated parameters of the learned model at the sensor device are communicated in longer time intervals to a fog computing system. The proposed framework is implemented and tested in a real world testbed in order to make quantitative measurements and evaluate the system. Our results show that the proposed model can achieve a 98% decrease in the number of packets sent over the wireless link, and the fog node can still simulate the data stream with an acceptable accuracy of 97%. We also observe an end-to-end delay of 180 ms in our proposed three-layer framework. Hence, the framework shows that a combination of fog and cloud computing with a distributed data modeling at the sensor device for wireless sensor networks can be beneficial for Industrial Internet of Things applications.

Objective: To validate new mitochondrial myopathy serum biomarkers for diagnostic use., Methods: We analyzed serum FGF21 (S-FGF21) and GDF15 from patients with (1) mitochondrial diseases and (2) nonmitochondrial disorders partially overlapping with mitochondrial disorder phenotypes. We (3) did a meta-analysis of S-FGF21 in mitochondrial disease and (4) analyzed S-Fgf21 and skeletal muscle Fgf21 expression in 6 mouse models with different muscle-manifesting mitochondrial dysfunctions., Results: We report that S-FGF21 consistently increases in primary mitochondrial myopathy, especially in patients with mitochondrial translation defects or mitochondrial DNA (mtDNA) deletions (675 and 347 pg/mL, respectively; controls: 66 pg/mL, p < 0.0001 for both). This is corroborated in mice (mtDNA deletions 1,163 vs 379 pg/mL, p < 0.0001). However, patients and mice with structural respiratory chain subunit or assembly factor defects showed low induction (human 335 pg/mL, p < 0.05; mice 335 pg/mL, not significant). Overall specificities of FGF21 and GDF15 to find patients with mitochondrial myopathy were 89.3% vs 86.4%, and sensitivities 67.3% and 76.0%, respectively. However, GDF15 was increased also in a wide range of nonmitochondrial conditions., Conclusions: S-FGF21 is a specific biomarker for muscle-manifesting defects of mitochondrial translation, including mitochondrial transfer-RNA mutations and primary and secondary mtDNA deletions, the most common causes of mitochondrial disease. However, normal S-FGF21 does not exclude structural respiratory chain complex or assembly factor defects, important to acknowledge in diagnostics., Classification of Evidence: This study provides Class III evidence that elevated S-FGF21 accurately distinguishes patients with mitochondrial myopathies from patients with other conditions, and FGF21 and GDF15 mitochondrial myopathy from other myopathies., (© 2016 American Academy of Neurology.)

Mitochondrial dysfunction affects cellular energy metabolism, but less is known about the consequences for cytoplasmic biosynthetic reactions. We report that mtDNA replication disorders caused by TWINKLE mutations-mitochondrial myopathy (MM) and infantile onset spinocerebellar ataxia (IOSCA)-remodel cellular dNTP pools in mice. MM muscle shows tissue-specific induction of the mitochondrial folate cycle, purine metabolism, and imbalanced and increased dNTP pools, consistent with progressive mtDNA mutagenesis. IOSCA-TWINKLE is predicted to hydrolyze dNTPs, consistent with low dNTP pools and mtDNA depletion in the disease. MM muscle also modifies the cytoplasmic one-carbon cycle, transsulfuration, and methylation, as well as increases glucose uptake and its utilization for de novo serine and glutathione biosynthesis. Our evidence indicates that the mitochondrial replication machinery communicates with cytoplasmic dNTP pools and that upregulation of glutathione synthesis through glucose-driven de novo serine biosynthesis contributes to the metabolic stress response. These results are important for disorders with primary or secondary mtDNA instability and offer targets for metabolic therapy., (Copyright © 2016 Elsevier Inc. All rights reserved.)

USF1 (upstream stimulatory factor 1) is a transcription factor associated with familial combined hyperlipidemia and coronary artery disease in humans. However, whether USF1 is beneficial or detrimental to cardiometabolic health has not been addressed. By inactivating USF1 in mice, we demonstrate protection against diet-induced dyslipidemia, obesity, insulin resistance, hepatic steatosis, and atherosclerosis. The favorable plasma lipid profile, including increased high-density lipoprotein cholesterol and decreased triglycerides, was coupled with increased energy expenditure due to activation of brown adipose tissue (BAT). Usf1 inactivation directs triglycerides from the circulation to BAT for combustion via a lipoprotein lipase-dependent mechanism, thus enhancing plasma triglyceride clearance. Mice lacking Usf1 displayed increased BAT-facilitated, diet-induced thermogenesis with up-regulation of mitochondrial respiratory chain complexes, as well as increased BAT activity even at thermoneutrality and after BAT sympathectomy. A direct effect of USF1 on BAT activation was demonstrated by an amplified adrenergic response in brown adipocytes after Usf1 silencing, and by augmented norepinephrine-induced thermogenesis in mice lacking Usf1. In humans, individuals carrying SNP (single-nucleotide polymorphism) alleles that reduced USF1 mRNA expression also displayed a beneficial cardiometabolic profile, featuring improved insulin sensitivity, a favorable lipid profile, and reduced atherosclerosis. Our findings identify a new molecular link between lipid metabolism and energy expenditure, and point to the potential of USF1 as a therapeutic target for cardiometabolic disease., (Copyright © 2016, American Association for the Advancement of Science.)

Haematopoietic progenitor cells show special sensitivity to mitochondrial DNA (mtDNA) mutagenesis, which suggests that increased mtDNA mutagenesis could underlie anemias. Here we show that elevated mtDNA mutagenesis in mice with a proof-reading deficient mtDNA polymerase (PolG) leads to incomplete mitochondrial clearance, with asynchronized iron loading in erythroid precursors, and increased total and free cellular iron content. The resulting Fenton chemistry leads to oxidative damage and premature destruction of erythrocytes by splenic macrophages. Our data indicate that mitochondria actively contribute to their own elimination in reticulocytes and modulate iron loading. Asynchrony of this sequence of events causes severe mitochondrial anaemia by depleting the organism of red blood cells and the bone marrow of iron. Our findings account for the anaemia development in a progeroid mouse model and may have direct relevance to the anemias associated with human mitochondrial disease and ageing.

Nutrient availability is the major regulator of life and reproduction, and a complex cellular signaling network has evolved to adapt organisms to fasting. These sensor pathways monitor cellular energy metabolism, especially mitochondrial ATP production and NAD(+)/NADH ratio, as major signals for nutritional state. We hypothesized that these signals would be modified by mitochondrial respiratory chain disease, because of inefficient NADH utilization and ATP production. Oral administration of nicotinamide riboside (NR), a vitamin B3 and NAD(+) precursor, was previously shown to boost NAD(+) levels in mice and to induce mitochondrial biogenesis. Here, we treated mitochondrial myopathy mice with NR. This vitamin effectively delayed early- and late-stage disease progression, by robustly inducing mitochondrial biogenesis in skeletal muscle and brown adipose tissue, preventing mitochondrial ultrastructure abnormalities and mtDNA deletion formation. NR further stimulated mitochondrial unfolded protein response, suggesting its protective role in mitochondrial disease. These results indicate that NR and strategies boosting NAD(+) levels are a promising treatment strategy for mitochondrial myopathy., (© 2014 The Authors. Published under the terms of the CC BY license.)

Somatic stem cell (SSC) dysfunction is typical for different progeroid phenotypes in mice with genomic DNA repair defects. MtDNA mutagenesis in mice with defective Polg exonuclease activity also leads to progeroid symptoms, by an unknown mechanism. We found that Polg-Mutator mice had neural (NSC) and hematopoietic progenitor (HPC) dysfunction already from embryogenesis. NSC self-renewal was decreased in vitro, and quiescent NSC amounts were reduced in vivo. HPCs showed abnormal lineage differentiation leading to anemia and lymphopenia. N-acetyl-L-cysteine treatment rescued both NSC and HPC abnormalities, suggesting that subtle ROS/redox changes, induced by mtDNA mutagenesis, modulate SSC function. Our results show that mtDNA mutagenesis affected SSC function early but manifested as respiratory chain deficiency in nondividing tissues in old age. Deletor mice, having mtDNA deletions in postmitotic cells and no progeria, had normal SSCs. We propose that SSC compartment is sensitive to mtDNA mutagenesis, and that mitochondrial dysfunction in SSCs can underlie progeroid manifestations., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Brominated flame retardants (BFRs) have been found in Arctic wildlife, lake sediment, and air. To identify the atmospheric BFR deposition history on Svalbard, Norway, we analyzed 19 BFRs, including hexabromocyclododecane (HBCD), 1,2-bis(2,4,6-tribromophenoxy)ethane (BTBPE), decabromodiphenyl ethane (DBDPE), pentabromoethylbenzene (PBEB), and 15 polybrominated diphenyl ether congeners (PBDE) in the upper 34 m of an ice core (representing 1953-2005) from Holtedahlfonna, the western-most ice sheet on Svalbard. All of the non-PBDE compounds were detected in nearly continuous profiles in the core. Seven PBDEs were not observed above background (28, 47, 66, 100, 99, 154, 153), while 4 were found in 1 or 2 of 6 segments (17, 85, 138, 183). BDEs-49, 71, 190, 209 had nearly continuous profiles but only BDE-209 in large amounts. The greatest inputs were HBCD and BDE-209, 910, and 320 pg cm(-2) yr(-1) from 1995-2005. DBDPE, BTBPE, and PBEB show nearly continuous input growth in recent core segments, but all were <6 pg cm(-2) yr(-1). Long-range atmospheric processes may have moved these particle-bound BFRs to the site, probably during the Arctic haze season. Average air mass trajectories over 10 years show >75% of atmospheric flow to Holtedahlfonna coming from Eurasia during haze periods (March and April).

Fifty heterosexual male patients with histologically verified genital warts of short duration (less than 3 months) were randomly allocated to treatment with either 0.25% or 0.5% idoxuridine cream. The application of the cream to the warts was performed twice daily for an initial period of 14 days, whereafter patients with partial improvement or no response were retreated in the same way for another period of 14 days. Patients not completely healed after 28 days were regarded as treatment failures and withdrawn from the study. After the initial treatment period of 14 days, 19 of 25 patients (76%) treated with 0.5% idoxuridine cream, and 9 of 25 patients (36%) treated with 0.25% idoxuridine cream were completely healed. This difference is significant (p less than 0.01). The corresponding figures at the second follow-up examination (28 days after start of the study) were 19 of 25 (76%) and 13 of 25 (52%), respectively. At the last follow-up examination three months after start of treatment, four patients treated with 0.5% idoxuridine cream and five patients treated with 0.25% idoxuridine cream had a relapse. Thus, the overall rate of complete healing was 15 of 25 (60%) for the patients treated with 0.5% idoxuridine cream and 8 of 25 (32%) for those treated with 0.25% idoxuridine cream. The difference is significant (p less than 0.01). No adverse reactions were observed or reported by the patients.

The continuously increasing incidence of vulvovaginal candidiasis necessitated a search for novel therapeutic modalities. Butoconazole nitrate (BN) a new imidazole, has been singled out for clinical studies since, in experimental vaginal candidiasis, it proved more effective than either miconazole nitrate (MN) or clotrimazole. One hundred and thirty volunteers with vaginal candidiasis, verified by wet mount and positive fungal culture, were randomly assigned to receive daily, for 6 days, either 1% BN (44 patients), or 2% BN (45 patients) vaginal cream or 2% MN (41 patients) vaginal cream. The patients were comparable regarding age (85% were 18-39 years of age), gravidity and parity. Twenty-five per cent had a recent history of unsuccessfully treated fungal vaginitis. Eight days after completion of treatment, negative fungal cultures were found in 98% of the patients using 2% BN, in 91% of patients using 1% BN and in 83% using 2% MN. The recurrence rate of the disease was low; about 80% of patients using 1% and 2% BN and 68% of those using 2% MN were culture-negative 30 days after conclusion of treatment. Rapid relief of clinical symptoms was experienced by patients in all three treatment groups. No significant side effects of the treatment were observed in any of the treatment groups.