Regulation of the dystrophin-associated glycoprotein complex composition by the metabolic properties of muscle fibres

The dystrophin-glycoprotein complex (DGC) links the muscle cytoskeleton to the extracellular matrix and is responsible for force transduction and protects the muscle fibres from contraction induced damage. Mutations in components of the DGC are responsible for muscular dystrophies and congenital myopathies. Expression of DGC components have been shown to be altered in many myopathies. In contrast we have very little evidence of whether adaptive changes in muscle impact on DGC expression. In this study we investigated connection between muscle fibre phenotype and the DGC. Our study reveals that the levels of DGC proteins at the sarcolemma differ in highly glycolytic muscle compared to wild-type and that these changes can be normalised by the super-imposition of an oxidative metabolic programme. Importantly we show that the metabolic properties of the muscle do not impact on the total amount of DGC components at the protein level. Our work shows that the metabolic property of a muscle fibre is a key factor in regulating the expression of DGC proteins at the sarcolemma

Correlated dynamics in egocentric communication networks

We investigate the communication sequences of millions of people through two different channels and analyze the fine grained temporal structure of correlated event trains induced by single individuals. By focusing on correlations between the heterogeneous dynamics and the topology of egocentric networks we find that the bursty trains usually evolve for pairs of individuals rather than for the ego and his/her several neighbors thus burstiness is a property of the links rather than of the nodes. We compare the directional balance of calls and short messages within bursty trains to the average on the actual link and show that for the trains of voice calls the imbalance is significantly enhanced, while for short messages the balance within the trains increases. These effects can be partly traced back to the technological constrains (for short messages) and partly to the human behavioral features (voice calls). We define a model that is able to reproduce the empirical results and may help us to understand better the mechanisms driving technology mediated human communication dynamics.Comment: 7 pages, 6 figure

Weighted temporal event graphs

The times of temporal-network events and their correlations contain information on the function of the network and they influence dynamical processes taking place on it. To extract information out of correlated event times, techniques such as the analysis of temporal motifs have been developed. We discuss a recently-introduced, more general framework that maps temporal-network structure into static graphs while retaining information on time-respecting paths and the time differences between their consequent events. This framework builds on weighted temporal event graphs: directed, acyclic graphs (DAGs) that contain a superposition of all temporal paths. We introduce the reader to the temporal event-graph mapping and associated computational methods and illustrate its use by applying the framework to temporal-network percolation

Prompt impact of first prospective statin mega-trials on postoperative lipid management of CABG patients:A 20-year follow-up in a single hospital

Background: The long-term success of coronary artery bypass grafting (CABG) depends on secondary prevention. Vast evidence provided by the results of cholesterol mega-trials over two decades has shown that effective reduction of LDL cholesterol improves the prognosis of patients with coronary heart disease. However, the implementation of these results into the clinical practice has turned out to be challenging. We analysed how the information derived from clinical statin trials and international recommendations affected the local treatment practices of dyslipidaemia of CABG patients during a 20-year time period. Methods: The cohort includes all CABG patients (n = 953) treated in Kanta-Häme Central Hospital during the time period 1990-2009. At the postoperative visits in the cardiology outpatient clinic, each patient's statin prescription was recorded, and blood lipids were determined. Results: During 1990-1994, 12.0 % of patients were on statins and during the following 5-year time periods the proportion was 57.2, 82.2 and 96.8 %, respectively. During the 20-year observation period (1990-2009), the effective statin dose increased progressively during these 5-year periods up to 36-fold, while the mean concentration of LDL cholesterol decreased from 3.7 to 2.1 mmol/l and that of apolipoprotein B from 1.3 to 0.8 g/l. In the very last year of follow-up, the mean concentrations of LDL-C and apoB were 1.83 mmol/l and 0.78 g/l, respectively. The most prominent increase in statin use and dosage took place during 1994-1996 and 2003-2005, respectively. Conclusions: Among CABG patients the lipid-lowering efficacy of statin therapy improved dramatically since 1994. This progress was accompanied by significant and favourable changes of lipid and apolipoprotein-B values. This study shows that it is possible to effectively improve lipid treatment policy once the results of relevant trials are available, and that this may happen even before international or national guidelines have been updated.BioMed Central open acces

Towards resolving taxonomic uncertainties in wolf, dog and jackal lineages of Africa, Eurasia and Australasia

Successful conservation depends on accurate taxonomy. Currently, the taxonomy of canids in Africa, Eurasia and Australasia is unstable as recent molecular and morphological studies have questioned earlier phenetic classifications. We review available information on several taxa of Old World and Australasian Canis with phylogenetic uncertainties (namely, African jackals, Asian wolves and Australasian dogs), in order to assess the validity of suggested scientific names and provide a scientific basis for reaching a taxonomic consensus primarily based on molecular data, but also including morphology, biogeography and behavioural ecology. We identify major knowledge gaps, provide recommendations for future research and discuss conservation implications of an updated taxonomic framework. Recent molecular studies indicate that the former Afro-Eurasian 'golden jackal' represents two distinct lineages, the golden jackal (Canis aureus) from Eurasia and the African wolf (C. lupaster) from Africa. Phylogenetic research also indicates that the side-striped and black-backed jackals form a monophyletic group that branched earlier than Canis, Cuon and Lycaon, which should be reassigned to the genus Lupulella as L. adusta and L. mesomelas, respectively. The Himalayan/Tibetan and Indian wolf lineages appear to have diverged earlier and are distinct from all other grey wolves (C. lupus) based on mitochondrial and nuclear genome data. However, until genome-wide data from multiple individuals across the range clarify relationships with other taxa, we suggest referring to the Himalayan/Tibetan wolf lineage as Canis lupus chanco. We support the currently accepted nomenclature for the Indian wolf Canis lupus pallipes for the wolf populations found on the Indian subcontinent and possibly also in south-western Asia (exact geographical boundary pending). The information presented here provides a current and consistent taxonomic framework for use by conservationists and other practitioners, but it is also intended to stimulate further research to resolve current uncertainties affecting the taxonomy of Old World canids.Peer reviewe

Machine Learning of Bone Marrow Histopathology Identifies Genetic and Clinical Determinants in Patients with MDS

Publisher Copyright: ©2021 American Association for Cancer Research.In myelodysplastic syndrome (MDS) and myeloproliferative neoplasm (MPN), bone marrow (BM) histopathology is assessed to identify dysplastic cellular morphology, cellularity, and blast excess. Yet, other morphologic findings may elude the human eye. We used convolutional neural networks to extract morphologic features from 236 MDS, 87 MDS/MPN, and 11 control BM biopsies. These features predicted genetic and cytogenetic aberrations, prognosis, age, and gender in multivariate regression models. Highest prediction accuracy was found for TET2 [area under the receiver operating curve (AUROC) = 0.94] and spliceosome mutations (0.89) and chromosome 7 monosomy (0.89). Mutation prediction probability correlated with variant allele frequency and number of affected genes per pathway, demonstrating the algorithms' ability to identify relevant morphologic patterns. By converting regression models to texture and cellular composition, we reproduced the classical del(5q) MDS morphology consisting of hypolobulated megakaryocytes. In summary, this study highlights the potential of linking deep BM histopathology with genetics and clinical variables. SIGNIFICANCE: Histopathology is elementary in the diagnostics of patients with MDS, but its high-dimensional data are underused. By elucidating the association of morphologic features with clinical variables and molecular genetics, this study highlights the vast potential of convolutional neural networks in understanding MDS pathology and how genetics is reflected in BM morphology.See related commentary by Elemento, p. 195.Peer reviewe

Old Wolrd Canis spp. with taxonomic ambiguity: Workshop conclusions and recommendations Vairao, Portugal, 28th-30th May 2019

Non peer reviewe

Core binding factors are necessary for natural killer cell development, and cooperate with Notch signaling during T cell specification

CBF{beta} is the non-DNA binding subunit of the core binding factors (CBFs). Mice with reduced CBF{beta} levels display profound, early defects in T but not B cell development. Here we show that CBF{beta} is also required at very early stages of natural killer (NK) cell development. We also demonstrate that T cell development aborts during specification, as the expression of Gata3 and Tcf7, which encode key regulators of T lineage specification, is substantially reduced, as are functional thymic progenitors. Constitutively active Notch or IL-7 signaling cannot restore T cell expansion or differentiation of CBF{beta} insufficient cells, nor can overexpression of Runx1 or CBF{beta} overcome a lack of Notch signaling. Therefore the ability of the prethymic cell to respond appropriately to Notch is dependent on CBF{beta}, and both signals converge to activate the T cell developmental program

Aging and serum exomiR content in women-effects of estrogenic hormone replacement therapy

Exosomes participate in intercellular messaging by transporting bioactive lipid-, protein-and RNA-molecules and -complexes. The contents of the exosomes reflect the physiological status of an individual making exosomes promising targets for biomarker analyses. In the present study we extracted exosome microRNAs (exomiRs) from serum samples of premenopausal women (n = 8) and monozygotic postmenopausal twins (n = 10 female pairs), discordant for the use of estrogenic hormone replacement therapy (HRT), in order to see whether the age or/and the use of HRT associates with exomiR content. A total of 241 exomiRs were detected by next generation sequencing, 10 showing age, 14 HRT and 10 age + HRT-related differences. When comparing the groups, differentially expressed miRs were predicted to affect cell proliferation processes showing inactivation with younger age and HRT usage. MiR-106-5p, -148a-3p, -27-3p, -126-5p, -28-3p and -30a-5p were significantly associated with serum 17 beta-estradiol. MiRs formed two hierarchical clusters being indicative of positive or negative health outcomes involving associations with body composition, serum 17 beta-estradiol, fat-, glucose-and inflammatory markers. Circulating exomiR clusters, obtained by NGS, could be used as indicators of metabolic and inflammatory status affected by hormonal changes at menopause. Furthermore, the individual effects of HRT-usage could be evaluated based on the serum exomiR signature

Hormone replacement therapy enhances IGF-1 signaling in skeletal muscle by diminishing miR-182 and miR-223 expressions: a study on postmenopausal monozygotic twin pairs

MiRNAs are fine-tuning modifiers of skeletal muscle regulation, but knowledge of their hormonal control is lacking. We used a co-twin case-control study design, that is, monozygotic postmenopausal twin pairs discordant for estrogen-based hormone replacement therapy (HRT) to explore estrogen-dependent skeletal muscle regulation via miRNAs. MiRNA profiles were determined from vastus lateralis muscle of nine healthy 54-62-years-old monozygotic female twin pairs discordant for HRT (median 7 years). MCF-7 cells, human myoblast cultures and mouse muscle experiments were used to confirm estrogen's causal role on the expression of specific miRNAs, their target mRNAs and proteins and finally the activation of related signaling pathway. Of the 230 miRNAs expressed at detectable levels in muscle samples, qPCR confirmed significantly lower miR-182, miR-223 and miR-142-3p expressions in HRT using than in their nonusing co-twins. Insulin/IGF-1 signaling emerged one common pathway targeted by these miRNAs. IGF-1R and FOXO3A mRNA and protein were more abundantly expressed in muscle samples of HRT users than nonusers. In vitro assays confirmed effective targeting of miR-182 and miR-223 on IGF-1R and FOXO3A mRNA as well as a dose-dependent miR-182 and miR-223 down-regulations concomitantly with up-regulation of FOXO3A and IGF-1R expression. Novel finding is the postmenopausal HRT-reduced miRs-182, miR-223 and miR-142-3p expression in female skeletal muscle. The observed miRNA-mediated enhancement of the target genes' IGF-1R and FOXO3A expression as well as the activation of insulin/IGF-1 pathway signaling via phosphorylation of AKT and mTOR is an important mechanism for positive estrogen impact on skeletal muscle of postmenopausal women