Gut microbes exhibit diurnal rhythmicity, and disruptions in this rhythmicity potentially impact host health. In this issue of Cell Host & Microbe, Reitmeier et al. (2020) employ timestamped gut microbiome sequencing data from human subjects coupled with machine learning to identify microbial rhythmicity patterns that predict Type 2 Diabetes incidence.The story of twentieth century biomedical breakthroughs could be told through cholesterol. Revolutions in genetics, molecular biology, genomics, and antibody-based therapies defined cholesterol's impact on human health and cholesterol-lowering strategies. In this issue, Kenny et al. (2020) bring a key twenty-first century biomedical development-the microbiome revolution-to cholesterol.Human milk harbors its own microbiota, but whether the microbes seed the infant gut and are modified by breastfeeding practices is unresolved. In this issue, Fehr et al. (2020) sequence breastmilk and infant stool samples from mother-infant dyads to investigate the co-occurrence of milk-gut bacteria and the impact of breastfeeding practices.In this issue of Cell Host & Microbe, Adebayo et al. (2020) examine the urobiome of older community-dwelling women within the TwinUK Cohort. They define a core genitourinary microbiome for older women with many heritable microbial taxa. Some taxa appear to co-occur, suggesting the existence of specific microbial consortia.Every animal is in constant communication with populations of microbes. In a recent study, O'Donnell and colleagues (2020) uncover an inter-domain conversation, defining a relationship in which a non-pathogenic microbe directly synthesizes a signal that alters host behavior for a mutually beneficial outcome. Almost a third of those undergoing knee replacement for osteoarthritis have poor outcomes despite technically successful surgery. Cyclopamine ic50 Preoperative neuropathic-like pain and/or pain sensitisation may increase the risk of pain following joint replacement. To examine whether preoperative neuropathic-like pain and pain sensitisation predicts pain, function and satisfaction following joint replacement for knee osteoarthritis. Systematic review with meta-analysis. Medline, EMBASE and CINAHL were systematically searched until March 2020. Studies detecting neuropathic-like pain and/or sensitisation using self-report questionnaires prior to knee replacement for osteoarthritis, and relating this to post-operative outcomes were identified. Data extraction, risk of bias assessment and meta-analysis were performed, where appropriate. Five manuscripts, including one preprint, examining six cohorts were included four used painDETECT or modified painDETECT, one the Self-Report Leeds Assessment of Neuropathic Symptoms a sensitisation, predict patients at higher risk of pain following knee replacement.The Krebs cycle-derived metabolite itaconate is highly upregulated in inflammatory macrophages and exerts immunomodulatory effects through cysteine modifications on target proteins. The NLRP3 inflammasome, which cleaves IL-1β, IL-18, and gasdermin D, must be tightly regulated to avoid excessive inflammation. Here we provide evidence that itaconate modifies NLRP3 and inhibits inflammasome activation. Itaconate and its derivative, 4-octyl itaconate (4-OI), inhibited NLRP3 inflammasome activation, but not AIM2 or NLRC4. Conversely, NLRP3 activation was increased in itaconate-depleted Irg1-/- macrophages. 4-OI inhibited the interaction between NLRP3 and NEK7, a key step in the activation process, and "dicarboxypropylated" C548 on NLRP3. Furthermore, 4-OI inhibited NLRP3-dependent IL-1β release from PBMCs isolated from cryopyrin-associated periodic syndrome (CAPS) patients, and reduced inflammation in an in vivo model of urate-induced peritonitis. Our results identify itaconate as an endogenous metabolic regulator of the NLRP3 inflammasome and describe a process that may be exploited therapeutically to alleviate inflammation in NLRP3-driven disorders.Mammalian organs are nourished by nutrients carried by the blood circulation. These nutrients originate from diet and internal stores, and can undergo various interconversions before their eventual use as tissue fuel. Here we develop isotope tracing, mass spectrometry, and mathematical analysis methods to determine the direct sources of circulating nutrients, their interconversion rates, and eventual tissue-specific contributions to TCA cycle metabolism. Experiments with fifteen nutrient tracers enabled extensive accounting for both circulatory metabolic cycles and tissue TCA inputs, across fed and fasted mice on either high-carbohydrate or ketogenic diet. We find that a majority of circulating carbon flux is carried by two major cycles glucose-lactate and triglyceride-glycerol-fatty acid. Futile cycling through these pathways is prominent when dietary content of the associated nutrients is low, rendering internal metabolic activity robust to food choice. The presented in vivo flux quantification methods are broadly applicable to different physiological and disease states. Thalamic circuit imbalance characterized by increased sensorimotor-thalamic connectivity and decreased prefrontal-thalamic connectivity has been consistently observed in adult-onset schizophrenia (AOS), although it is unclear whether this pattern is also a feature of early-onset schizophrenia (EOS). If this is the case, thalamic circuit imbalance can be considered as a core mechanistic defect in schizophrenia, unconfounded by the age of onset. A total of 116 adolescents with EOS (63 drug-naive EOS) and 55 matched healthy controls (HC) were recruited and underwent resting-state functional magnetic resonance imaging scans. To define the specific location of the thalamic subregions in thalamocortical circuit, 16 atlas-based thalamic subdivisions were used in functional connectivity analysis. The EOS group showed increased sensorimotor-thalamic connectivity and decreased prefrontal-cerebello-thalamic connectivity, consistent with AOS. Sensorimotor-thalamic hyperconnectivity was more prominent than prefrontaective of the age of onset, raising the possibility of aberrant but accelerated functional network maturation in EOS. The specific thalamocortical dysconnectivity involving the SN and mPFC may underlie the distinctive features of multi-modal hallucinations and heightened emotional valence of psychosis seen in EOS.