Miracle-dz/UniFAR-FTUs huggingface dataset:
Identification of blood autosomal cis-expression quantitative trait methylation (cis-eQTMs) in children

Background The identification of expression quantitative trait methylation (eQTMs), defined as correlations between gene expression and DNA methylation levels, might help the biological interpretation of epigenome-wide association studies (EWAS). We aimed to identify autosomal cis-eQTMs in child blood, using data from 832 children of the Human Early Life Exposome (HELIX) project. Methods Blood DNA methylation and gene expression were measured with the Illumina 450K and the Affymetrix HTA v2 arrays, respectively. The relationship between methylation levels and expression of nearby genes (transcription start site (TSS) within a window of 1 Mb) was assessed by fitting 13.6 M linear regressions adjusting for sex, age, and cohort. Results We identified 63,831 autosomal cis-eQTMs, representing 35,228 unique CpGs and 11,071 unique transcript clusters (TCs, genes). 74.3% of these cis-eQTMs were located at <250 kb, 60.0% showed an inverse relationship and 23.9% had at least one genetic variant associated with the methylation and expression levels. They were enriched for active blood regulatory regions. Adjusting for cellular composition decreased the number of cis-eQTMs to 37.7%, suggesting that some of them were cell type-specific. The overlap of child blood cis-eQTMs with those described in adults was small, and child and adult shared cis-eQTMs tended to be proximal to the TSS, enriched for genetic variants and with lower cell type specificity. Only half of the cis-eQTMs could be captured through annotation to the closest gene. Conclusions This catalogue of blood autosomal cis-eQTMs in children can help the biological interpretation of EWAS findings, and is publicly available at https://helixomics.isglobal. org/.
Towards semantic fMRI neurofeedback: navigating among mental states using real-time representational similarity analysis

Objective. Real-time functional magnetic resonance imaging neurofeedback (rt-fMRI-NF) is a non-invasive MRI procedure allowing examined participants to learn to self-regulate brain activity by performing mental tasks. A novel two-step rt-fMRI-NF procedure is proposed whereby the feedback display is updated in real-time based on high-level representations of experimental stimuli (e.g. objects to imagine) via real-time representational similarity analysis of multi-voxel patterns of brain activity. Approach. In a localizer session, the stimuli become associated with anchored points on a two-dimensional representational space where distances approximate between-pattern (dis)similarities. In the NF session, participants modulate their brain response, displayed as a movable point, to engage in a specific neural representation. The developed method pipeline is verified in a proof-of-concept rt-fMRI-NF study at 7 T involving a single healthy participant imagining concrete objects. Based on this data and artificial data sets with similar (simulated) spatio-temporal structure and variable (injected) signal and noise, the dependence on noise is systematically assessed. Main results. The participant in the proof-of-concept study exhibited robust activation patterns in the localizer session and managed to control the neural representation of a stimulus towards the selected target in the NF session. The offline analyses validated the rt-fMRI-NF results, showing that the rapid convergence to the target representation is noise-dependent. Significance. Our proof-of-concept study introduces a new NF method allowing the participant to navigate among different mental states. Compared to traditional NF designs (e.g. using a thermometer display to set the level of the neural signal), the proposed approach provides content-specific feedback to the participant and extra degrees of freedom to the experimenter enabling real-time control of the neural activity towards a target brain state without suggesting a specific mental strategy to the subject.
Cognitive insights from evolutionarily new brain structures in prefrontal cortex

While the disproportionate expansion of lateral prefrontal cortex (LPFC) throughout evolution is commonly accepted, the relationship between evolutionarily new LPFC brain structures and uniquely human cognitive skills is largely unknown. Here, we tested the relationship between variability in evolutionarily new LPFC tertiary sulci and reasoning skills in a pediatric cohort. A novel data-driven approach in independent discovery and replication samples revealed that the depth of specific LPFC tertiary sulci predicts individual differences in reasoning skills beyond age. These findings support a classic, yet untested, theory linking the protracted development of tertiary sulci to late-developing cognitive processes. We conclude by proposing a mechanistic hypothesis relating the depth of LPFC tertiary sulci to anatomical connections. We suggest that deeper LPFC tertiary sulci reflect reduced short-range connections in white matter, which in turn, improve the efficiency of local neural signals underlying cognitive skills such as reasoning that are central to human cognitive development.
Effect of Sulfate on Carbon Monoxide Conversion by a Thermophilic Syngas-Fermenting Culture Dominated by a Desulfofundulus Species

A syngas-degrading enrichment culture, culture T-Syn, was dominated by a bacterium closely related to Desulfofundulus australicus strain AB33T (98% 16S rRNA gene sequence identity). Culture T-Syn could convert high CO concentrations (from pCO ≈ 34 kPa to pCO ≈ 170 kPa), both in the absence and in the presence of sulfate as external electron acceptor. The products formed from CO conversion were H2 and acetate. With sulfate, a lower H2/acetate ratio was observed in the product profile, but CO conversion rates were similar to those in the absence of sulfate. The ability of D. australicus strain AB33T to use CO was also investigated. D. australicus strain AB33T uses up to 40% CO (pCO ≈ 68 kPa) with sulfate and up to 20% CO (pCO ≈ 34 kPa) without sulfate. Comparison of the metagenome-assembled genome (MAG) of the Desulfofundulus sp. from T-Syn culture with the genome of D. australicus strain AB33T revealed high similarity, with an ANI value of 99% and only 32 unique genes in the genome of the Desulfofundulus sp. T-Syn. So far, only Desulfotomaculum nigrificans strain CO-1-SRB had been described to grow with CO with and without sulfate. This work further shows the carboxydotrophic potential of Desulfofundulus genus for CO conversion, both in sulfate-rich and low-sulfate environments.
Sirt3 Attenuates Oxidative Stress Damage and Rescues Cellular Senescence in Rat Bone Marrow Mesenchymal Stem Cells by Targeting Superoxide Dismutase 2

Oxidative stress is one of the main causes of aging. The process of physiological aging is always accompanied by increased levels of endogenous oxidative stress. Exogenous oxidants have contributed to premature cellular senescence. As a deacetylase located in mitochondrial matrix, Sirt3 plays critical roles in mitochondrial energy metabolism, oxidative stress regulation, and cellular senescence. However, it remains unknown whether Sirt3 exerts the analogous role in cellular senescence caused by two different oxidation pathways. In this study, the function of Sirt3 was investigated in age-related natural senescence and H2O2-induced premature senescence of rat bone marrow mesenchymal stem cells (MSCs). Our results showed that Sirt3 expression was significantly decreased in both senescent MSCs, which was concerned with reduced cellular reactive oxygen species (ROS) and aggravated DNA injury. Sirt3 repletion could partly reverse the senescence-associated phenotypic features in natural and premature senescent MSCs. Moreover, Sirt3 replenishment led to the reduction in the levels of cellular ROS by enhancing the expression and activity of superoxide dismutase 2 (SOD2), thus maintaining the balance of intracellular oxidation and antioxidation and ameliorating oxidative stress damage. Altogether, Sirt3 inhibits MSC natural senescence and H2O2-induced premature senescence through alleviating ROS-induced injury and upregulating SOD2 expression and activity. Our research indicates that Sirt3 might contribute to uncovering the novel mechanisms underlying MSC senescence and provide new insights to aging and oxidative stress-related diseases.
CCN3 Signaling Is Differently Regulated in Placental Diseases Preeclampsia and Abnormally Invasive Placenta

Objectives An adequate development of the placenta includes trophoblast differentiation with the processes of trophoblast migration, invasion, cellular senescence and apoptosis which are all crucial to establishing a successful pregnancy. Altered placental development and function lead to placental diseases such as preeclampsia (PE) which is mainly characterized by insufficient trophoblast invasion and abnormally invasive placenta (AIP) disorders (Placenta accreta, increta, or percreta) which are characterized by excessive trophoblast invasion. Both of them will cause maternal and fetal morbidity/mortality. However, the etiology of these diseases is still unclear. Our previous study has shown that the matricellular protein nephroblastoma overexpressed (NOV, CCN3) induces G0/G1 cell cycle arrest, drives trophoblast cells into senescence and activates FAK and Akt kinases resulting in reduced cell proliferation and enhanced migration capability of the human trophoblast cell line SGHPL-5. The present study focuses on whether CCN3 can alter cell cycle-regulated pathways associated with trophoblast senescence and invasion activity in pathological versus gestational age-matched control placentas. Methods Cell cycle regulator proteins were investigated by immunoblotting and qPCR. For localization of CCN3, p16, p21, and Cyclin D1 proteins, co-immunohistochemistry was performed. Results In early-onset PE placentas, CCN3 was expressed at a significantly lower level compared to gestational age-matched controls. The decrease of CCN3 level is associated with an increase in p53, Cyclin E1 and pRb protein expression, whereas the level of cleaved Notch-1, p21, Cyclin D1, pFAK, pAKT, and pmTOR protein decreased. In term AIP placentas, the expression of CCN3 was significantly increased compared to matched term controls. This increase was correlated to an increase in p53, p16, p21, Cyclin D1, cleaved Notch-1, pFAK, pAkt, and pmTOR whereas pRb was significantly decreased. However, in late PE and early AIP placentas, no significant differences in CCN3, p16, p21, Cyclin D1, p53, and cleaved Notch-1 expression were found when matched to appropriate controls. Conclusions CCN3 expression levels are correlated to markers of cell cycle arrest oppositely in PE and AIP by activating the FAK/AKT pathway in AIP or down-regulating in PE. This may be one mechanism to explain the different pathological features of placental diseases, PE and AIP.
Telomere length dynamics in response to DNA damage in malaria parasites

Malaria remains a major cause of morbidity and mortality within the developing world. Recent work has implicated chromosome end stability and the repair of DNA breaks through telomere healing as potent drivers of variant antigen diversification, thus associating basic mechanisms for maintaining genome integrity with aspects of host-parasite interactions. Here we applied long-read sequencing technology to precisely examine the dynamics of telomere addition and chromosome end stabilization in response to double strand breaks within subtelomeric regions. We observed that the process of telomere healing induces the initial synthesis of telomere repeats well in excess of the minimal number required for end stability. However once stabilized, these newly created telomeres appear to function normally, eventually returning to a length nearing that of intact chromosome ends. These results parallel recent observations in humans, suggesting an evolutionarily conserved mechanism for chromosome end repair.
Metabolomic investigation of the pseudouridimycin producer, a prolific streptomycete

We report a metabolomic analysis of Streptomyces sp. ID38640, a soil isolate that produces the bacterial RNA polymerase inhibitor pseudouridimycin. The analysis was performed on the wild type and on ten different pum mutants blocked at different steps in pseudouridimycin biosynthesis. The results indicate that Streptomyces sp. ID38640 is able to produce, in addition to pseudouridimcyin, lydicamycins and deferroxiamines, as previously reported, also the lassopeptide ulleungdin, the non-ribosomal peptide antipain and the osmoprotectant ectoine. The corresponding biosynthetic gene clusters were readily identified in the strain genome. We also detected the known compound pyridindolol, for which we propose a previously unreported biosynthetic gene cluster, as well as three families of unknown metabolites. Remarkably, the levels of the different metabolites varied strongly in the different mutant strains, allowing detection of metabolites not normally seen in the wild type. Three newly constructed pum mutants, along with systematic investigation of the accumulated metabolites, shed further lights on pseudouridimycin biosynthesis. We also show that several Streptomyces strains, harboring the pum biosynthetic gene cluster and unrelated to ID38640, readily produce pseudouridimycin.
A Cell Atlas of Microbe-Responsive Processes in the Zebrafish Intestine

Gut microbial products direct growth, differentiation and development in the animal host. Disruptions to host-microbe interactions have profound health consequences, that include onset of chronic inflammatory illnesses. However, we lack system-wide understanding of cell-specific responses to the microbiome. We profiled transcriptional activity in individual cells from the intestine, and associated tissue, of zebrafish larvae that we raised in the presence, or absence, of a microbiome. We uncovered extensive cellular heterogeneity in the conventional zebrafish intestinal epithelium, including previously undescribed cell types with known mammalian homologs. By comparing conventional to germ-free profiles, we mapped microbial impacts on transcriptional activity in each cell population. We revealed intricate degrees of cellular specificity in host responses to the microbiome, that included regulatory effects on patterning, metabolic and immune activity. For example, we showed that removal of microbes hindered transduction of vascular endothelial growth factor-dependent signals in the developing vasculature, resulting in impaired intestinal vascularization. Our work provides a high-resolution atlas of intestinal cellular composition in the developing fish gut and details the effects of the microbiome on each cell type.
Embedding optimization reveals long-lasting history dependence in neural spiking activity

Information processing can leave distinct footprints on the statistical history dependence in single neuron spiking. Statistical history dependence can be quantified using information theory, but its estimation from experimental recordings is only possible for a reduced representation of past spiking, a so called past embedding. Here, we present a novel embedding-optimization approach that optimizes temporal binning of past spiking to capture most history dependence, while a reliable estimation is ensured by regularization. The approach does not only quantify non-linear and higher-order dependencies, but also provides an estimate of the temporal depth that history dependence reaches into the past. We benchmarked the approach on simulated spike recordings of a leaky integrate-and-fire neuron with long lasting spike-frequency-adaptation, where it accurately estimated history dependence over hundreds of milliseconds. In a diversity of extra-cellular spike recordings, including highly parallel recordings using a Neuropixel probe, we found some neurons with surprisingly strong history dependence, which could last up to seconds. Both aspects, the magnitude and the temporal depth of history dependence, showed interesting differences between recorded systems, which points at systematic differences in information processing between these systems. We provide practical guidelines in this paper and a toolbox for Python3 at https://github.com/Priesemann-Group/hdestimator for readers interested in applying the method to their data. Author summary Even with exciting advances in recording techniques of neural spiking activity, experiments only provide a comparably short glimpse into the activity of only a tiny subset of all neurons. How can we learn from these experiments about the organization of information processing in the brain? To that end, we exploit that different properties of information processing leave distinct footprints on the firing statistics of individual spiking neurons. In our work, we focus on a particular statistical footprint: How much does a single neuron’s spiking depend on its own preceding activity, which we call history dependence. By quantifying history dependence in neural spike recordings, one can, in turn, infer some of the properties of information processing. Because recording lengths are limited in practice, a direct estimation of history dependence from experiments is challenging. The embedding optimization approach that we present in this paper aims at extracting a maximum of history dependence within the limits set by a reliable estimation. The approach is highly adaptive and thereby enables a meaningful comparison of history dependence between neurons with vastly different spiking statistics, which we exemplify on a diversity of spike recordings. In conjunction with recent, highly parallel spike recording techniques, the approach could yield valuable insights on how hierarchical processing is organized in the brain.
Non-lesioned subcortical brain volumes are associated with post-stroke sensorimotor behavior across 28 cohorts worldwide: An ENIGMA Stroke Recovery study

Up to two-thirds of stroke survivors experience persistent sensorimotor impairments. Recovery relies on the integrity of spared brain areas to compensate for damaged tissue. Subcortical regions play critical roles in the control and regulation of sensorimotor circuits. Identifying relationships between sensorimotor behavior and non-lesioned subcortical volumes will reveal new neural targets for improving outcomes. We pooled high-resolution T1-weighted MRI brain scans and behavioral data in 828 individuals with unilateral stroke from 28 cohorts worldwide (age: median 63, interquartile range 19 years; 516 males, 312 females). Cross-sectional analyses using linear mixed-effects models related post-stroke sensorimotor behavior to non-lesioned subcortical volumes. We analyzed subacute (≤90 days) and chronic (≥180 days) stroke; sub-analyses in chronic stroke were performed on class of sensorimotor deficit (impairment, activity limitations) and side of lesioned hemisphere, with exploratory analyses in early stroke (≤21 days) and across time (Bonferroni-corrected, p<0.004). Worse sensorimotor behavior was associated with a smaller ipsilesional thalamic volume in both subacute (n=274, d=0.46) and early stroke (n=179; d=0.68). In chronic stroke (n=404), worse sensorimotor behavior was associated with smaller ipsilesional putamen (d=0.52) and nucleus accumbens (d=0.39) volumes, and a larger ipsilesional lateral ventricle volume (d=-0.42), representing atrophy. In chronic stroke, worse sensorimotor impairment specifically (measured by the Fugl-Meyer Assessment; n=256) was associated with a smaller ipsilesional putamen (d=0.72), and larger lateral ventricle (d=-0.41), while several measures of activity limitations (n=116) showed no significant relationships. Side of lesion (left=214, right=190) had no impact. The full cohort (n=828) revealed associations of sensorimotor behavior with the ipsilesional nucleus accumbens (d=0.23), putamen (d=0.33), thalamus (d=0.33), and lateral ventricle (d=-0.23). This analysis identified significant relationships between sensorimotor behavior and key subcortical regions at different times post-stroke. While further longitudinal studies are needed, these findings may represent brain imaging markers of resilience and reserve and provide putative neuroanatomical targets for improving sensorimotor outcomes post-stroke.
Augmenting Flexibility: Mutual Inhibition Between Inhibitory Neurons Expands Functional Diversity

Rapid, flexible response to an ever-changing environment is critical for an organism’s survival. Recently, multicellular recordings have shown that this rapid, flexible switching between activity patterns is present in neural microcircuits. However, the underlying neural mechanism is not clear. Strikingly, we show in a neural circuit model that mutually inhibitory connections are crucial for rapid and flexible switching between distinct functions without synaptic plasticity. Here, we develop a theoretical framework to explain how inhibitory recurrent circuits give rise to this flexibility and show that mutual inhibition doubles the number of cusp bifurcations in small neural circuits. As a concrete example, we study a commonly observed class of functional motifs we call Coupled Recurrent Inhibitory and Recurrent Excitatory Loops (CRIRELs). These CRIRELs have the advantage of being both multifunctional and controllable, performing a plethora of unique functions. Finally, we demonstrate how mutual inhibition maximizes storage capacity for larger networks.
Comparison of three air samplers for the collection of four nebulized respiratory viruses ‐ Collection of respiratory viruses from air –

Viral respiratory tract infections are a leading cause of morbidity and mortality worldwide. Unfortunately, the transmission routes and shedding kinetics of respiratory viruses remain poorly understood. Air sampling techniques to quantify infectious viruses in the air are indispensable to improve intervention strategies to control and prevent spreading of respiratory viruses. Here, the collection of infectious virus with the six-stage Andersen cascade impactor was optimized with semi-solid gelatin as collection surface. Subsequently, the collection efficiency of the cascade impactor, the SKC BioSampler, and an in-house developed electrostatic precipitator was compared. In an in-vitro setup, influenza A virus, human metapneumovirus, parainfluenza virus type 3 and respiratory syncytial virus were nebulized and the amount of collected infectious virus and viral RNA was quantified with each air sampler. Whereas only low amounts of virus were collected using the electrostatic precipitator, high amounts were collected with the BioSampler and cascade impactor. The BioSampler allowed straight-forward sampling in liquid medium, whereas the more laborious cascade impactor allowed size fractionation of virus-containing particles. Depending on the research question, either the BioSampler or the cascade impactor can be applied in laboratory and field settings, such as hospitals to gain more insight into the transmission routes of respiratory viruses. Practical Implications Respiratory viruses pose a continuous health threat, especially to vulnerable groups such as young children, immunocompromised individuals and the elderly. It is important to understand via which routes these viruses can transmit to and between individuals that are at risk. If we can determine the amount of a certain respiratory virus in the air, then this will help to predict the importance of transmission through the air for this virus. Most currently available air sampling devices have not been designed to collect infectious viruses from the air. Therefore, we here optimized and compared the performance of three air samplers for four different respiratory viruses.