Effects of extremely preterm birth on cytokine and chemokine responses induced by T-cell activation during infancy.

Objectives: Extremely preterm (EPT; gestational week < 28 + 0, < 1000 g) neonates are vulnerable to infections and necrotising enterocolitis, important contributors to mortality and morbidity. However, knowledge regarding their immune maturation remains limited. We here investigated the longitudinal development of functional T-cell capacity in EPT infants.

Malat1 affects transcription and splicing through distinct pathways in mouse embryonic stem cells.

Malat1 is a long-noncoding RNA with critical roles in gene regulation and cancer metastasis, however its functional role in stem cells is largely unexplored. We here perform a nuclear knockdown of Malat1 in mouse embryonic stem cells, causing the de-regulation of 320 genes and aberrant splicing of 90 transcripts, some of which potentially affecting the translated protein sequence. We find evidence that Malat1 directly interacts with gene bodies and aberrantly spliced transcripts, and that it locates upstream of down-regulated genes at their putative enhancer regions, in agreement with functional genomics data.

Novel candidate genes for environmental stresses response in Synechocystis sp. PCC 6803 revealed by machine learning algorithms.

Cyanobacteria have developed acclimation strategies to adapt to harsh environments, making them a model organism. Understanding the molecular mechanisms of tolerance to abiotic stresses can help elucidate how cells change their gene expression patterns in response to stress. Recent advances in sequencing techniques and bioinformatics analysis methods have led to the discovery of many genes involved in stress response in organisms.

Cold-induced expression of a truncated adenylyl cyclase 3 acts as rheostat to brown fat function.

Promoting brown adipose tissue (BAT) activity innovatively targets obesity and metabolic disease. While thermogenic activation of BAT is well understood, the rheostatic regulation of BAT to avoid excessive energy dissipation remains ill-defined. Here, we demonstrate that adenylyl cyclase 3 (AC3) is key for BAT function.

A Comprehensive Analysis of the Effect of A>I(G) RNA-Editing Sites on Genotoxic Drug Response and Progression in Breast Cancer.

Dysregulated A>I(G) RNA editing, which is mainly catalyzed by ADAR1 and is a type of post-transcriptional modification, has been linked to cancer. A low response to therapy in breast cancer (BC) is a significant contributor to mortality. However, it remains unclear if there is an association between A>I(G) RNA-edited sites and sensitivity to genotoxic drugs.

Upstream land use with microbial downstream consequences: Iron and humic substances link to Legionella spp.

Intensified land use can disturb water quality, potentially increasing the abundance of bacterial pathogens, threatening public access to clean water. This threat involves both direct contamination of faecal bacteria as well as indirect factors, such as disturbed water chemistry and microbiota, which can lead to contamination. While direct contamination has been well described, the impact of indirect factors is less explored, despite the potential of severe downstream consequences on water supply.

Enhanced ROS Production in Mitochondria from Prematurely Aging mtDNA Mutator Mice.

An increase in mitochondrial DNA (mtDNA) mutations and an ensuing increase in mitochondrial reactive oxygen species (ROS) production have been suggested to be a cause of the aging process ("the mitochondrial hypothesis of aging"). In agreement with this, mtDNA-mutator mice accumulate a large amount of mtDNA mutations, giving rise to defective mitochondria and an accelerated aging phenotype. However, incongruously, the rates of ROS production in mtDNA mutator mitochondria have generally earlier been reported to be lower - not higher - than in wildtype, thus apparently invalidating the "mitochondrial hypothesis of aging".

Terrestrial Birth and Body Size Tune UCP1 Functionality in Seals.

The molecular evolution of the mammalian heater protein UCP1 is a powerful biomarker to understand thermoregulatory strategies during species radiation into extreme climates, such as aquatic life with high thermal conductivity. While fully aquatic mammals lost UCP1, most semiaquatic seals display intact UCP1 genes, apart from large elephant seals. Here, we show that UCP1 thermogenic activity of the small-bodied harbor seal is equally potent compared to terrestrial orthologs, emphasizing its importance for neonatal survival on land.

Blood pressure trends following birth in infants born under 25 weeks' gestational age: a retrospective cohort study.

Objective: The aim of our study was to describe postnatal blood pressure (BP) trends and evaluate relevant dynamics and outcomes for a subgroup of extremely preterm (EPT) infants.

Design: Retrospective observational cohort study.

Setting: Patients admitted to Karolinska University Hospital Stockholm.

Triple-Color FluoroSpot Analysis of Polyfunctional Antigen-Specific T Cells by Quantification of Spot-Forming Units and Relative Spot Volumes.

Switching from ELISpot to FluoroSpot enables the analysis of spot-forming units representing cells producing different cytokines as well as the frequencies of spots derived from cells co-secreting multiple cytokines. Due to the fluorescent read-out signal, sophisticated reader instruments can also measure the relative spot volume, making it possible to differentiate between spots generated by cells secreting different levels of one or more cytokines. Here we describe how triple FluoroSpot assays can be used to define polyfunctional T cells secreting multiple cytokines and how different T-cell populations can differ in the levels of cytokines they secrete.

Using PBMCs in a Multiplex FluoroSpot Assay for Detection of Innate Immune Response-Modulating Impurities (IIRMIs).

The ELISA-based monocyte activation test (MAT) facilitates the replacement of the rabbit pyrogen test (RPT) for the detection of Innate Immune Response-Modulating Impurities (IIRMIs) in injectable drugs by activation of monocytes in human peripheral blood mononuclear cells (PBMCs). We describe the use of a triple-color IL-1β/IL-6/TNF-α FluoroSpot assay as a sensitive tool for quantification of the frequencies of IIRMI-activated monocytes as well as determination of the relative amount of pyrogenic cytokine(s) produced by each activated cell.

Dominance reversals: the resolution of genetic conflict and maintenance of genetic variation.

Beneficial reversals of dominance reduce the costs of genetic trade-offs and can enable selection to maintain genetic variation for fitness. Beneficial dominance reversals are characterized by the beneficial allele for a given context (e.g.

Exploring the gut microbiota and its potential as a biomarker in gliomas.

Gut microbiome alterations are associated with various cancers including brain tumours such as glioma and glioblastoma. The gut communicates with the brain via a bidirectional pathway known as the gut-brain axis (GBA) which is essential for maintaining homeostasis. The gut microbiota produces many metabolites including short chain fatty acids (SCFAs) and essential amino acids such as glutamate, glutamine, arginine and tryptophan.

High Degree of Desensitization After 1 Year of Early-Life Peanut Oral Immunotherapy: Small Children Oral Immunotherapy (SmaChO) Randomized Controlled Trial.

Background: The prevalence of peanut allergy is about 2% and mostly lifelong. Studies of oral immunotherapy (OIT) with peanut (the daily oral intake of an initially low and then increasing dose of peanut) often show problematic side effects, but there are indications of better safety and effect in younger children compared with older children and adults.

Objective: To determine the safety and effectiveness of peanut OIT with a slow up-dosing strategy and low maintenance dose in children aged 1 to 3 years who were allergic to peanut, through a 1-year interim analysis.

Evolution of microRNAs in Amoebozoa and implications for the origin of multicellularity.

MicroRNAs (miRNAs) are important and ubiquitous regulators of gene expression in both plants and animals. They are thought to have evolved convergently in these lineages and hypothesized to have played a role in the evolution of multicellularity. In line with this hypothesis, miRNAs have so far only been described in few unicellular eukaryotes.

Hypermigration of macrophages through the concerted action of GRA effectors on NF-κB/p38 signaling and host chromatin accessibility potentiates dissemination.

Mononuclear phagocytes facilitate the dissemination of the obligate intracellular parasite Here, we report how a set of secreted parasite effector proteins from dense granule organelles (GRA) orchestrates dendritic cell-like chemotactic and pro-inflammatory activation of parasitized macrophages. These effects enabled efficient dissemination of the type II lineage, a highly prevalent genotype in humans. We identify novel functions for effectors GRA15 and GRA24 in promoting CCR7-mediated macrophage chemotaxis by acting on NF-κB and p38 MAPK signaling pathways, respectively, with contributions of GRA16/18 and counter-regulation by effector TEEGR.

Differential responses to UCP1 ablation in classical brown versus beige fat, despite a parallel increase in sympathetic innervation.

In the cold, the absence of the mitochondrial uncoupling protein 1 (UCP1) results in hyper-recruitment of beige fat, but classical brown fat becomes atrophied. Here we examine possible mechanisms underlying this phenomenon. We confirm that in brown fat from UCP1-knockout (UCP1-KO) mice acclimated to the cold, the levels of mitochondrial respiratory chain proteins were diminished; however, in beige fat, the mitochondria seemed to be unaffected.

Chp1 is a dedicated chaperone at the ribosome that safeguards eEF1A biogenesis.

Cotranslational protein folding depends on general chaperones that engage highly diverse nascent chains at the ribosomes. Here we discover a dedicated ribosome-associated chaperone, Chp1, that rewires the cotranslational folding machinery to assist in the challenging biogenesis of abundantly expressed eukaryotic translation elongation factor 1A (eEF1A). Our results indicate that during eEF1A synthesis, Chp1 is recruited to the ribosome with the help of the nascent polypeptide-associated complex (NAC), where it safeguards eEF1A biogenesis.

LDO proteins and Vac8 form a vacuole-lipid droplet contact site to enable starvation-induced lipophagy in yeast.

Lipid droplets (LDs) are fat storage organelles critical for energy and lipid metabolism. Upon nutrient exhaustion, cells consume LDs via gradual lipolysis or via lipophagy, the en bloc uptake of LDs into the vacuole. Here, we show that LDs dock to the vacuolar membrane via a contact site that is required for lipophagy in yeast.

Role of G protein-coupled receptor kinases (GRKs) in β -adrenoceptor-mediated glucose uptake.

Truncation of the C-terminal tail of the β -AR, transfection of βARKct or over-expression of a kinase-dead GRK mutant reduces isoprenaline-stimulated glucose uptake, indicating that GRK is important for this response. We explored whether phosphorylation of the β -AR by GRK2 has a role in glucose uptake or if this response is related to the role of GRK2 as a scaffolding protein. CHO-GLUT4myc cells expressing wild-type and mutant β -ARs were generated and receptor affinity for [ H]-CGP12177A and density of binding sites determined together with the affinity of isoprenaline and BRL37344.

J-domain proteins: From molecular mechanisms to diseases.

J-domain proteins (JDPs) are the largest family of chaperones in most organisms, but much of how they function within the network of other chaperones and protein quality control machineries is still an enigma. Here, we report on the latest findings related to JDP functions presented at a dedicated JDP workshop in Gdansk, Poland. The report does not include all (details) of what was shared and discussed at the meeting, because some of these original data have not yet been accepted for publication elsewhere or represented still preliminary observations at the time.

Genotoxin-producing induces tissue-specific types of DNA damage and DNA damage response outcomes.

Introduction: Typhoid toxin-expressing causes DNA damage in the intestinal mucosa , activating the DNA damage response (DDR) in the absence of inflammation. To understand whether the tissue microenvironment constrains the infection outcome, we compared the immune response and DDR patterns in the colon and liver of mice infected with a genotoxigenic strain or its isogenic control strain.

Methods: spatial transcriptomic and immunofluorescence have been used to assess DNA damage makers, activation of the DDR, innate immunity markers in a multiparametric analysis.

Perfluorooctanoate (PFOA) cell-autonomously promotes thermogenic and adipogenic differentiation of brown and white adipocytes.

Perfluorooctanoic acid (PFOA) is a synthetic organofluoride surfactant associated with several toxic effects in humans and animals. Particularly, it has been observed that PFOA treatment of mice results in weight loss associated with recruited brown adipose tissue (BAT), including an increased amount of uncoupling protein 1 (UCP1). The molecular mechanism behind this BAT recruitment is presently unknown.