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Blood is a highly complex fluid with rheological properties that have a significant impact on various flow phenomena. In particular, it exhibits a non-Newtonian elongational viscosity that is comparable to polymer solutions. In this study, we investigate the effect of three different anticoagulants, namely EDTA (ethylene diamine tetraacetic acid), heparin, and citrate, on the elongational properties of both human and swine blood. We observe a unique two stage thinning process and a strong dependency of the characteristic relaxation time on the chosen anticoagulant, with the longest relaxation time and thus the highest elongational viscosity being found for the case of citrate. Our findings for the latter are consistent with the physiological values obtained from a dripping droplet of human blood without any anticoagulant. Furthermore, our study resolves the discrepancy found in the literature regarding the reported range of characteristic relaxation times, confirming that the elongational viscosity must be taken into account for a full rheological characterization of blood. These results have important implications for understanding blood flow in various physiological, pathological and technological conditions.

Exposure to early adversity is one of the most important and pervasive risk factors for the development of nearly all major mental disorders across the lifespan. In the search for the mediating mechanisms and processes that underlie long-term stability of these effects, changes to stress-associated hormonal and cellular signalling have emerged as prime candidates. This review summarises evidence showing that experience of early adversity in the form of childhood abuse or neglect and exposure to severe institutional deprivation influences multiple interconnected bio-behavioural, physiological and cellular processes. This paper focusses on dysregulations of hormonal stress regulation, altered DNA methylation pattern, changes to transcriptomic profiles in the context of stress-immune interplay, and mitochondrial biology. Consistent findings that have emerged include a relative cortisol hypoactivity and hyporeactivity in response to challenge, increased activity of pro-inflammatory genes, and altered mitochondrial function. The majority of investigations have focussed on single outcomes, but there is a clear rationale of conceiving the implicated physiological processes as interconnected parts of a wider stress-associated regulatory network, which in turn is connected to behaviour and mental disorders. This calls for integrated and longitudinal investigations to come to a more comprehensive understanding of the role of stress in the biological embedding of experience. The review concludes with considerations of how stress research can contribute to translational efforts through characterising subtypes of mental disorders which arise as a function of early adversity, and have distinct features of behavioral and biological stress processing., Competing Interests: Declaration of Competing Interest none., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The oxytocin receptor gene (OXTR) is of interest when investigating the effects of early adversity on DNA methylation. However, there is heterogeneity regarding the selection of the most promising CpG sites to target for analyses. The goal of this study was to determine functionally relevant clusters of CpG sites within the OXTR CpG island in 113 mother-infant dyads, with 58 of the mothers reporting childhood maltreatment (CM). OXTR DNA methylation was analyzed in peripheral/umbilical blood mononuclear cells. Different complexity reduction approaches were used to reduce the 188 CpG sites into clusters of co-methylated sites. Furthermore, associations between OXTR DNA methylation (cluster- and site-specific level) and OXTR gene expression and CM were investigated in mothers. Results showed that, first, CpG sections differed strongly regarding their statistical utility for research of individual differences in DNA methylation. Second, cluster analyses and Partial Least Squares (PLS) suggested two clusters consisting of intron1/exon2 and the protein-coding region of exon3, respectively, as most strongly associated with outcome measures. Third, cross-validated PLS regression explained 7% of variance in CM, with low cross-validated variance explained for the prediction of gene expression. Fourth, substantial mother-child correspondence was observed in correlation patterns within the identified clusters, but only modest correspondence outside these clusters. This study makes an important contribution to the mapping of the DNA methylation landscape of the OXTR CpG island by highlighting clusters of CpG sites that show desirable statistical properties and predictive value. We provide a Companion Web Application to facilitate the choice of CpG sites., (© 2023. The Author(s).)

PTSD is a prevalent mental disorder that results from exposure to extreme and stressful life events and comes at high costs for both the individual and society. Therapeutic treatment presents the best way to deal with PTSD-the mechanisms underlying change after treatment, however, remain poorly understood. While stress and immune associated gene expression changes have been associated with PTSD development, studies investigating treatment effects at the molecular level so far tended to focus on DNA methylation. Here we use gene-network analysis on whole-transcriptome RNA-Seq data isolated from CD14 + monocytes of female PTSD patients ( N  = 51) to study pre-treatment signatures of therapy response and therapy-related changes at the level of gene expression. Patients who exhibited significant symptom improvement after therapy showed higher baseline expression in two modules involved in inflammatory processes (including notable examples IL1R2 and FKBP5 ) and blood coagulation. After therapy, expression of an inflammatory module was increased, and expression of a wound healing module was decreased. This supports findings reporting an association between PTSD and dysregulations of the inflammatory and the hemostatic system and mark both as potentially treatment sensitive., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Kumsta, Zang, Hummel, Müller, Moser, Herpertz and Kessler.)

MicroRNAs are tissue-specific expressed short RNAs that serve post-transcriptional gene regulation. A specific microRNA can bind to mRNAs of different genes and thereby suppress their protein production. In the context of the complex phenotype of fibromyalgia, we used the Axiom miRNA Target Site Genotyping Array to search genome-wide for DNA variations in microRNA genes, their regulatory regions, and in the 3'UTR of protein-coding genes. To identify disease-relevant DNA polymorphisms, a cohort of 176 female fibromyalgia patients was studied in comparison to a cohort of 162 healthy women. The association between 48,329 markers and fibromyalgia was investigated using logistic regression adjusted for population stratification. Results show that 29 markers had p -values < 1 × 10 -3 , and the strongest association was observed for rs758459 ( p -value of 0.0001), located in the Neurogenin 1 gene which is targeted by hsa-miR-130a-3p. Furthermore, variant rs2295963 is predicted to affect binding of hsa-miR-1-3p. Both microRNAs were previously reported to be differentially expressed in fibromyalgia patients. Despite its limited statistical power, this study reports two microRNA-related polymorphisms which may play a functional role in the pathogenesis of fibromyalgia. For a better understanding of the disease pattern, further functional analyses on the biological significance of microRNAs and microRNA-related polymorphisms are required.

The experience of adversity in childhood has been associated with poor health outcomes in adulthood. In search of the biological mechanisms underlying these effects, research so far focused on alterations of DNA methylation or shifts in transcriptomic profiles. The level of protein, however, has been largely neglected. We utilized mass spectrometry to investigate the proteome of CD14 + monocytes in healthy adults reporting childhood adversity and a control group before and after psychosocial stress exposure. Particular proteins involved in (i) immune processes, such as neutrophil-related proteins, (ii) protein metabolism, or (iii) proteins related to mitochondrial biology, such as those involved in energy production processes, were upregulated in participants reporting exposure to adversity in childhood. This functional triad was further corroborated by protein interaction- and co-expression analyses, was independent of stress exposure, i.e. observed at both pre- and post-stress time points, and became evident especially in females. In line with the mitochondrial allostatic load model, our findings provide evidence for the long-term effects of childhood adversity on mitochondrial biology., (© 2023. The Author(s).)

Post-traumatic stress disorder (PTSD) is a serious mental health condition thought to be mediated by a dysregulated stress response system. Stress, especially chronic stress, affects mitochondrial activity and their efficiency in duplicating their genomes. Human cells contain numerous mitochondria that harbor multiple copies of their own genome, which consist of a mixture of wild type and variant mtDNA - a condition known as mitochondrial heteroplasmy. Number of mitochondrial genomes in a cell and the degree of heteroplasmy may serve as an indicator of mitochondrial allostatic load. Changes in mtDNA copy number and the proportion of variant mtDNA may be related to mental disorders and symptom severity, suggesting an involvement of mitochondrial dysfunction also in PTSD. Therefore, we examined number and composition of mitochondrial DNA before and after six weeks of inpatient psychotherapy treatment in a cohort of 60 female PTSD patients. We extracted DNA from isolated monocytes before and after inpatient treatment and quantified cellular mtDNA using multiplex qPCR. We hypothesized that treatment would lead to changes in cellular mtDNA levels and that change in mtDNA level would be associated with PTSD symptom severity and treatment response. It could be shown that mtDNA copy number and the ratio of variant mtDNA decreased during therapy, however, this change did not correlate with treatment response. Our results suggest that inpatient treatment can reduce signs of mitochondrial allostatic load, which could have beneficial effects on mental health. The quantification of mtDNA and the determination of cellular heteroplasmy could represent valuable biomarkers for the molecular characterization of mental disorders in the future., Competing Interests: Conflicts of interest All authors declare that they have no conflicts of interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: To date, few data on the quality and quantity of online physical education (P.E.) during the COVID-19 pandemic have been published. We assessed activity in online classes and reported allocated curriculum time for P.E. in a multi-national sample of European children (6-18 years)., Methods: Data from two online surveys were analysed. A total of 8395 children were included in the first round (May-June 2020) and 24 302 in the second round (January-February 2021)., Results: Activity levels during P.E. classes were low in spring 2020, particularly among the youngest children and in certain countries. 27.9% of students did not do any online P.E. and 15.7% were hardly ever very active. Only 18.4% were always very active and 14.9% reported being very active quite often. In winter 2020, we observed a large variability in the allocated curriculum time for P.E. In many countries, this was lower than the compulsory requirements. Only 65.7% of respondents had the same number of P.E. lessons than before pandemic, while 23.8% had less P.E., and 6.8% claimed to have no P.E. lessons. Rates for no P.E. were especially high among secondary school students, and in large cities and megapolises., Conclusions: During the COVID-19 pandemic, European children were provided much less P.E. in quantity and quality than before the pandemic. Countermeasures are needed to ensure that these changes do not become permanent. Particular attention is needed in large cities and megapolises. The critical role of P.E. for students' health and development must be strengthened in the school system., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Public Health Association.)

The objective of this work was to perform a series of measurements of radon and thoron exhalation in the underground workings of an experimental coal mine. In the years 2012-2015, experiments on underground coal gasification were carried out in a coal mine, which caused, among other effects, damage to rock mass. Afterward, periodic increases in the concentration of potential alpha energy (PAEC) of radon decay products in the air were found, which could pose a hazard to miners. The question posed was whether the gasification experiment resulted in the increased migration of radon and thoron. If so, did it increase the radiation hazard to miners? The adaptation of the existing instrumentation to the specific conditions was conducted, and a series of measurements were made. It was found that the measured values of radon and thoron exhalation rates ranged from 3.0 up to 38 Bq·m -2 ·h -1 for radon and from 500 up to 2000 Bq·m -2 ·h -1 for thoron.

A telematics device is a vehicle instrument that comes preinstalled by the vehicle manufacturer or can be added later. The device records information about driving behavior, including speed, acceleration, and turning force. When connected to vehicle computers, the device can also provide additional information regarding the mechanical usage and condition of the vehicle. All of this information can be transmitted to a central database via mobile networks. The information provided has led to new services such as Usage Based Insurance (UBI). A range of consultants, industry commentators and academics have produced an abundance of projections on how telematics information will allow the introduction of services from personalized insurance, bespoke entertainment and advertise and vehicle energy optimization, particularly for Electric Vehicles (EVs). In this paper we examine these potential services against a backdrop of nascent regulatory limitations and against the technical capacity of the devices. Using a case study approach, we examine three applications that can use telematics information. We find that the expectations of service providers will be significantly tempered by regulatory and technical hurdles. In our discussion we detail these limitations and suggest a more realistic rollout of ancillary services.

Background: tinnitus is a heterogeneous condition associated with audiological and/or mental disorders. Chronic, severe tinnitus is reported in 1% of the population and it shows a relevant heritability, according to twins, adoptees and familial aggregation studies. The genetic contribution to severe tinnitus is unknown since large genomic studies include individuals with self-reported tinnitus and large heterogeneity in the phenotype. The aim of this study was to identify genes for severe tinnitus in patients with extreme phenotype., Methods: for this extreme phenotype study, we used three different cohorts with European ancestry (Spanish with Meniere disease (MD), Swedes tinnitus and European generalized epilepsy). In addition, four independent control datasets were also used for comparisons. Whole-exome sequencing was performed for the MD and epilepsy cohorts and whole-genome sequencing was carried out in Swedes with tinnitus., Findings: we found an enrichment of rare missense variants in 24 synaptic genes in a Spanish cohort, the most significant being PRUNE2, AKAP9, SORBS1, ITGAX, ANK2, KIF20B and TSC2 (p < 2E -04 ), when they were compared with reference datasets. This burden was replicated for ANK2 gene in a Swedish cohort with 97 tinnitus individuals, and in a subset of 34 Swedish patients with severe tinnitus for ANK2, AKAP9 and TSC2 genes (p < 2E -02 ). However, these associations were not significant in a third cohort of 701 generalized epilepsy individuals without tinnitus. Gene ontology (GO) and gene-set enrichment analyses revealed several pathways and biological processes involved in severe tinnitus, including membrane trafficking and cytoskeletal protein binding in neurons., Interpretation: a burden of rare variants in ANK2, AKAP9 and TSC2 is associated with severe tinnitus. ANK2, encodes a cytoskeleton scaffolding protein that coordinates the assembly of several proteins, drives axonal branching and influences connectivity in neurons., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

The developmental origin of human adults' right hemispheric dominance in response to face stimuli remains unclear, in particular because young infants' right hemispheric advantage in face-selective response is no longer present in preschool children, before written language acquisition. Here we used fast periodic visual stimulation (FPVS) with scalp electroencephalography (EEG) to test 52 preschool children (5.5 years old) at two different levels of face discrimination: discrimination of faces against objects, measuring face-selectivity, or discrimination between individual faces. While the contrast between faces and nonface objects elicits strictly bilateral occipital responses in children, strengthening previous observations, discrimination of individual faces in the same children reveals a strong right hemispheric lateralization over the occipitotemporal cortex. Picture-plane inversion of the face stimuli significantly decreases the individual discrimination response, although to a much smaller extent than in older children and adults tested with the same paradigm. However, there is only a nonsignificant trend for a decrease in right hemispheric lateralization with inversion. There is no relationship between the right hemispheric lateralization in individual face discrimination and preschool levels of readings abilities. The observed difference in the right hemispheric lateralization obtained in the same population of children with two different paradigms measuring neural responses to faces indicates that the level of visual discrimination is a key factor to consider when making inferences about the development of hemispheric lateralization of face perception in the human brain., (© 2019 The Authors. Developmental Science published by John Wiley & Sons Ltd.)

While animal models remain essential for inferring causality, they exhibit important limitations, which restrict the direct translation of findings into new approaches aimed at steering host-microbe interactions for the improvement of human health. Different in vitro models have therefore been developed which incorporate human cell types and microbiota. By virtue of their intricate designs, these models result in human and microbial read-outs reflective of in vivo gut physiology, and present important alternatives to animal models. However, to allow systematic investigations of the interactions between gut microbiota and different human cell types and body systems, ever more complex cell assemblies are necessary which will culminate in the establishment of personalized in vitro models. Such models will allow the unravelling of human-microbe interdependencies and will open exciting new avenues for microbiome-tailored nutrition and drug development., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

In Extended Data Fig. 1a of this Letter, the flow cytometry plot depicting the surface phenotype of AML sample DD08 was a duplicate of the plot for AML sample DD06. Supplementary Data 4 has been added to the Supplementary Information of the original Letter to clarify the proteome data acquisition and presentation. The original Letter has been corrected online.

The branched-chain amino acid (BCAA) pathway and high levels of BCAA transaminase 1 (BCAT1) have recently been associated with aggressiveness in several cancer entities. However, the mechanistic role of BCAT1 in this process remains largely uncertain. Here, by performing high-resolution proteomic analysis of human acute myeloid leukaemia (AML) stem-cell and non-stem-cell populations, we find the BCAA pathway enriched and BCAT1 protein and transcripts overexpressed in leukaemia stem cells. We show that BCAT1, which transfers α-amino groups from BCAAs to α-ketoglutarate (αKG), is a critical regulator of intracellular αKG homeostasis. Further to its role in the tricarboxylic acid cycle, αKG is an essential cofactor for αKG-dependent dioxygenases such as Egl-9 family hypoxia inducible factor 1 (EGLN1) and the ten-eleven translocation (TET) family of DNA demethylases. Knockdown of BCAT1 in leukaemia cells caused accumulation of αKG, leading to EGLN1-mediated HIF1α protein degradation. This resulted in a growth and survival defect and abrogated leukaemia-initiating potential. By contrast, overexpression of BCAT1 in leukaemia cells decreased intracellular αKG levels and caused DNA hypermethylation through altered TET activity. AML with high levels of BCAT1 (BCAT1 high ) displayed a DNA hypermethylation phenotype similar to cases carrying a mutant isocitrate dehydrogenase (IDH mut ), in which TET2 is inhibited by the oncometabolite 2-hydroxyglutarate. High levels of BCAT1 strongly correlate with shorter overall survival in IDH WT TET2 WT , but not IDH mut or TET2 mut AML. Gene sets characteristic for IDH mut AML were enriched in samples from patients with an IDH WT TET2 WT BCAT1 high status. BCAT1 high AML showed robust enrichment for leukaemia stem-cell signatures, and paired sample analysis showed a significant increase in BCAT1 levels upon disease relapse. In summary, by limiting intracellular αKG, BCAT1 links BCAA catabolism to HIF1α stability and regulation of the epigenomic landscape, mimicking the effects of IDH mutations. Our results suggest the BCAA-BCAT1-αKG pathway as a therapeutic target to compromise leukaemia stem-cell function in patients with IDH WT TET2 WT AML.

To date, it is well-established that mitochondrial dysfunction does not only play a vital role in cancer but also in other pathological conditions such as neurodegenerative diseases and inflammation. An important tool for the analysis of cellular metabolism is the application of stable isotope labeled substrates, which allow for the tracing of atoms throughout metabolic networks. While such analyses yield very detailed information about intracellular fluxes, the determination of compartment specific fluxes is far more challenging. Most approaches for the deconvolution of compartmented metabolism use computational models whereas experimental methods are rare. Here, we developed an experimental setup based on selective permeabilization of the cytosolic membrane that allows for the administration of stable isotope labeled substrates directly to mitochondria. We demonstrate how this approach can be used to infer metabolic changes in mitochondria induced by either chemical or genetic perturbations and give an outlook on its potential applications., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Meta-analyses confirm that depression is accompanied by signs of inflammation including increased levels of acute phase proteins, e.g., C-reactive protein, and pro-inflammatory cytokines, e.g., interleukin-6. Supporting the translational significance of this, a meta-analysis showed that anti-inflammatory drugs may have antidepressant effects. Here, we argue that inflammation and depression research needs to get onto a new track. Firstly, the choice of inflammatory biomarkers in depression research was often too selective and did not consider the broader pathways. Secondly, although mild inflammatory responses are present in depression, other immune-related pathways cannot be disregarded as new drug targets, e.g., activation of cell-mediated immunity, oxidative and nitrosative stress (O&NS) pathways, autoimmune responses, bacterial translocation, and activation of the toll-like receptor and neuroprogressive pathways. Thirdly, anti-inflammatory treatments are sometimes used without full understanding of their effects on the broader pathways underpinning depression. Since many of the activated immune-inflammatory pathways in depression actually confer protection against an overzealous inflammatory response, targeting these pathways may result in unpredictable and unwanted results. Furthermore, this paper discusses the required improvements in research strategy, i.e., path and drug discovery processes, omics-based techniques, and systems biomedicine methodologies. Firstly, novel methods should be employed to examine the intracellular networks that control and modulate the immune, O&NS and neuroprogressive pathways using omics-based assays, including genomics, transcriptomics, proteomics, metabolomics, epigenomics, immunoproteomics and metagenomics. Secondly, systems biomedicine analyses are essential to unravel the complex interactions between these cellular networks, pathways, and the multifactorial trigger factors and to delineate new drug targets in the cellular networks or pathways. Drug discovery processes should delineate new drugs targeting the intracellular networks and immune-related pathways.

In this paper, we describe a new, reliable and simple method to determine 210Pb concentration in ice-core samples, based on "Radium 3M" filters (USA). The advantages are well-known chemical yield, simplified retention procedure and measurement by low-energy Ge gamma spectrometry. We compare the results with those obtained by MN 616 LSA-50 filters (Germany). The method permits us to determine activity concentrations down to 30 mBq/l. We proved the efficiency and applicability of the method in the study of ice cores drilled in Livingston Island's glacier in Antarctica.