Mitochondrial DNA Inheritance in Humans : Mix, Match, and Survival of the Fittest

Mitochondrial DNA (mtDNA) sequence variation and maternal inheritance are valuable tools in assessing ancestry of different human populations and for clinical practice. A new study (Wei et al., 2019) reports that the fate of new mtDNA variants in the female germline is non-random as they report functional selection and matching to nuclear ancestry to shape human mtDNA variation.Non peer reviewe

Asiakastyytyväisyys Punkaharjun Lomakeskuksessa

Tämän opinnäytetyön tavoitteena on kartoittaa asiakkaiden tyytyväisyys Punkaharjun Lomakeskuksen palveluun ja palveluiden laatuun omistajanvaihdoksen ja sitä seuranneiden kehitystöiden jälkeen. Opinnäytetyön toimeksiantaja on Finland EasyHoliday Oy, joka toimii operaattoriyhtiönä Punkaharjun Lomakeskuksessa; majoitus- ja ravintolatoiminnassa, Kesämaan huvipuistossa ja ohjelmapalveluissa. Työn teoreettinen viitekehys koostuu palvelun laadusta ja asiakastyytyväisyydestä. Työssä käsitellään palvelun määritelmää, laadun näkökulmia ja ulottuvuuksia sekä koettua kokonaislaatua. Asiakastyytyväisyyden osalta käsitellään asiakastyytyväisyyden määritelmää, asiakastyytyväisyyteen vaikuttavia tekijöitä sekä asiakastyytyväisyystutkimusta. Opinnäytetyössä käytettiin kvantitatiivista tutkimusmenetelmää ja tutkimusaineisto kerättiin kyselylomakkeella. Kyselylomakkeita jaettiin asiakkaille kesä-elokuussa 2011 ja vastauksia saatiin yhteensä 43. Tutkimuksen tulokset analysoitiin SPSS -tilasto-ohjelmalla. Tuloksien perusteella asiakkaat olivat pääasiassa tyytyväisiä Punkaharjun Lomakeskuksen palveluihin ja tiloihin sekä henkilökuntaan. Tyytyväisimpiä asiakkaat olivat vastaanotto- ja Kesämaan henkilökunnan ystävällisyyteen ja palvelualttiuteen, Kesämaan viihtyisyyteen, ravintola Punkaharju Paviljongin viihtyisyyteen sekä matkailualueen yleiseen viihtyisyyteen. Tyytymättömimpiä asiakkaat olivat siivous- ja huoltohenkilökunnan ystävällisyyteen ja palvelualttiuteen sekä loma-asunnon varustelu- ja kuntotasoon. Asiakastyytyväisyyskyselyn tulosten pohjalta saatiin kehitysehdotuksia ja -suuntia, joilla Punkaharjun Lomakeskuksen palveluita voidaan entisestään parantaa. Kehitysehdotukset koskivat muun muassa loma-asuntojen kunto- ja varustelutasoa sekä matkailualueen yleistä kunnossapitoa

Mitochondrial roles in disease : a box full of surprises

This commentary inaugurates a new review series in EMBO Molecular Medicine focused on mitochondrial diseases. This area of medicine, which actually encompasses most disease areas, has long since come of age and is now positioned for the next leap toward the development of effective therapies. The aims of the review series are to offer a comprehensive overview of this exciting area of medicine and research and to provide timely discussions for clinicians and investigators on the new discoveries elucidating how mitochondrial metabolism contributes to an expanding group of complex, heterogeneous, and difficult-to-tackle diseases.Peer reviewe

Quantitative solid-phase assay to measure deoxynucleoside triphosphate pools

deoxynucleoside triphosphate (dNTPs) are the reduced nucleotides used as the building blocks and energy source for deoxyribonucleic acid (DNA) replication and maintenance in all living systems. They are present in highly regulated amounts and ratios in the cell, and their balance has been implicated in the most important cell processes, from determining the fidelity of DNA replication to affecting cell fate. Furthermore, many cancer drugs target biosynthetic enzymes in dNTP metabolism, and mutations in genes directly or indirectly affecting these pathways that are the cause of devastating diseases. The accurate and systematic measurement of these pools is key to understanding the mechanisms behind these diseases and their treatment. We present a new method for measuring dNTP pools from biological samples, utilizing the current state-of-the-art polymerase method, modified to a solid-phase setting and optimized for larger scale measurements.Peer reviewe

Integrative omics approaches provide biological and clinical insights : examples from mitochondrial diseases

High-throughput technologies for genomics, transcriptomics, proteomics, and metabolomics, and integrative analysis of these data, enable new, systems-level insights into disease pathogenesis. Mitochondrial diseases are an excellent target for hypothesis-generating omics approaches, as the disease group is mechanistically exceptionally complex. Although the genetic background in mitochondrial diseases is in either the nuclear or the mitochondrial genome, the typical downstream effect is dysfunction of the mitochondrial respiratory chain. However, the clinical manifestations show unprecedented variability, including either systemic or tissue-specific effects across multiple organ systems, with mild to severe symptoms, and occurring at any age. So far, the omics approaches have provided mechanistic understanding of tissue-specificity and potential treatment options for mitochondrial diseases, such as metabolome remodeling. However, no curative treatments exist, suggesting that novel approaches are needed. In this Review, we discuss omics approaches and discoveries with the potential to elucidate mechanisms of and therapies for mitochondrial diseases.Peer reviewe

Atomistic Molecular Dynamics Simulations of Mitochondrial DNA Polymerase gamma : Novel Mechanisms of Function and Pathogenesis

DNA polymerase gamma (Pol gamma) is a key component of the mitochondrial DNA replisome and an important cause of neurological diseases. Despite the availability of its crystal structures, the molecular mechanism of DNA replication, the switch between polymerase and exonuclease activities, the site of replisomal interactions, and functional effects of patient mutations that do not affect direct catalysis have remained elusive. Here we report the first atomistic classical molecular dynamics simulations of the human Pol gamma replicative complex. Our simulation data show that DNA binding triggers remarkable changes in the enzyme structure, including (1) completion of the DNA-binding channel via a dynamic subdomain, which in the apo form blocks the catalytic site, (2) stabilization of the structure through the distal accessory beta-subunit, and (3) formation of a putative transient replisome-binding platform in the "intrinsic processivity" subdomain of the enzyme. Our data indicate that noncatalytic mutations may disrupt replisomal interactions, thereby causing Pol gamma-associated neurodegenerative disorders.Peer reviewe

Reply to 'Letter to Editor by Finsterer J and Zarrouk-Mahjoub S : Phenotypic manifestations of the m.8969G > A variant'

Peer reviewe

Mitochondrial spongiotic brain disease: astrocytic stress and harmful rapamycin and ketosis effect

Mitochondrial DNA (mtDNA) depletion syndrome (MDS) is a group of severe, tissue-specific diseases of childhood with unknown pathogenesis. Brain-specific MDS manifests as devastating spongiotic encephalopathy with no curative therapy. Here, we report cell type-specific stress responses and effects of rapamycin treatment and ketogenic diet (KD) in mice with spongiotic encephalopathy mimicking human MDS, as these interventions were reported to improve some mitochondrial disease signs or symptoms. Thesemice with astrocyte-specific knockout of Twnk gene encoding replicative mtDNA helicase Twinkle (TwKO(astro)) show wide-spread cell-autonomous astrocyte activation and mitochondrial integrated stress response (ISRmt) induction with major metabolic remodeling of the brain. Mice with neuronal-specific TwKO show no ISRmt. Both KD and rapamycin lead to rapid deterioration and weight loss of TwKO(astro) and premature trial termination. Although rapamycin had no robust effects on TwKO(astro) brain pathology, KD exacerbated spongiosis, gliosis, and ISRmt. Our evidence emphasizes that mitochondrial disease treatments and stress responses are tissue- and disease specific. Furthermore, rapamycin and KD are deleterious in MDS-linked spongiotic encephalopathy, pointing to a crucial role of diet and metabolism for mitochondrial disease progression.Peer reviewe

Cost-effectiveness of whole-exome sequencing in progressive neurological disorders of children

Objectives: To clarify the diagnostic utility and the cost-effectiveness of whole-exome sequencing (WES) as a routine early-diagnostic tool in children with progressive neurological disorders. Methods: Patients with infantile-onset severe neurological diseases or childhood-onset progressive neurological disorders were prospectively recruited to this WES study, in the pediatric neurology clinic at Helsinki University Hospital during 2016-2018. A total of 48 patients underwent a singleton WES. A control group of 49 children underwent traditional diagnostic examinations and were retrospectively collected from the hospital records. Their use of health care services, related to the diagnostic process, was gathered. Incremental cost-effectiveness ratio (ICER) per additional diagnosis was calculated from the health care provider perspective. Bootstrapping methods were used to estimate the uncertainty of cost-effectiveness outcomes. Results: WES provided a better diagnostic yield (38%) than diagnostic pathway that did not prioritize WES in early diagnosis (25%). WES outperformed other diagnostic paths especially when made early, within one year of first admission (44%). Cost-effectiveness in our results are conservative, affected by WES costs during 2016-18. Conclusions: WES is an efficient and cost-effective diagnostic tool that should be prioritized in early diagnostic path of children with progressive neurological disorders. The progressively decreasing price of the test improves cost-effectiveness further. (C) 2021 The Authors. Published by Elsevier Ltd on behalf of European Paediatric Neurology Society.Peer reviewe