Communications Biology最新文献

Differences in the ϒ-aminobutyric acid (GABA) system contribute to an excitatory-inhibitory imbalance in autism, particularly affecting sensory processing. However, the brain's broader response to interventions targeting GABA pathways in individuals with autism remains poorly understood. This study tested the hypothesis that GABAergic control of information transfer across large-scale brain functional networks is altered in autism. We conducted a phase-amplitude coupling (PAC) analysis of resting-state EEG signals within and between these networks. Responses were compared after double-blind, randomized oral administration of either a placebo or 15/30 mg of arbaclofen, a GABA_B receptor agonist. Twenty-four non-autistic (9 males; 19-53 years) and 15 autistic participants (9 males; 20-51 years) completed 93 study visits. Autistic participants exhibited significantly higher theta-beta PAC, especially within the limbic network. High-dose arbaclofen shifted PAC metrics in visual and somatomotor networks towards non-autistic levels, but had minimal effects on networks related to higher cognitive functions. Interestingly, altered PAC within and between networks in the limbic system of autistic participants was normalized by low-dose arbaclofen, yet reemerged after high-dose administration. These findings provide compelling evidence for altered GABAergic responsivity in autism, helping explain some of the challenges in prescribing medications for autistic individuals, such as paradoxical reactions and dose sensitivity.

Glycogen Storage Disease Type III (GSDIII) is a rare genetic disorder caused by mutations in the AGL gene, leading to a deficiency in the glycogen debranching enzyme. This results in the accumulation of abnormal glycogen in various tissues, causing a range of symptoms, including liver enlargement and hypoglycemia. Current animal models do not fully recapitulate the severe phenotypes observed in patients, highlighting the need for improved model systems. To the best of our knowledge, this study presents the first Caenorhabditis elegans model of GSDIII, which successfully exhibits disease-relevant traits, including glycogen accumulation. Using this model, we developed a computational approach based on high-throughput screening methods, enabling the identification of key genetic modulators. Notably, we demonstrate that glycogen accumulation can be rescued by genetic and pharmacological inhibition of CHK1, a gene involved in cell cycle regulation and DNA damage response, in a variant-specific manner. These findings suggest that targeting CHK1 may represent a promising therapeutic strategy for treating GSDIII, particularly when considering specific AGL mutations.

Microcystis is one of the most common bloom-forming cyanobacteria colonizing freshwater ecosystems worldwide. This genus remarkably produces numerous bio-active accessory metabolites, which are believed to be potentially involved in different ecological and/or physiological processes. However, their genuine contribution to the evolutionary success of Microcystis blooms remains undetermined. To better depict the potential relationship between the local genetic diversity of blooming Microcystis populations and their respective associated chemical diversity, we conducted a joint genomic and metabolomic analysis of 65 Microcystis strains collected from various lakes in France and surrounding Western European countries. Interestingly, both core and pan-gene phylogenetic analysis place 57 of these strains in 11 distinct genotypes with at least 2 genomes, being widely distributed along the entire Microcystis phylogeny and presenting specific signatures of accessory metabolite biosynthesis. The direct chemical analysis of metabolite diversity produced by these strains, cultured under laboratory conditions, reveals the production of stable metabolite cocktails, with minimal variations over replication, growth phases and culture conditions. Remarkably, these strains belonging to 11 different genotypes correspond to 13 distinct chemotypes according to an accurate one-chemotype-for-one-genotype rule. Furthermore, these genotypes also appear distinguishable regarding their respective ecotoxicological traits and might be considered as specific toxico-ecotypes. Overall, our investigations reveal that the production of accessory metabolites constitute well conserved chemical traits across the different Microcystis genotypes, suggesting these molecules may be involved in key adaptive and selective processes, that still remain under-explored.

Macrophage polarization shapes immune responses in inflammation and fibrosis, yet the epigenetic mechanisms restraining pathogenic states remain unclear. Here, we identify lysine-specific demethylase 7 A (KDM7A) as an epigenetic suppressor of a profibrotic macrophage (Fib-Mac). Using macrophage assays, single-cell RNA sequencing of Kdm7a-knockout mice, and lung tissue from fibrosis patients, we show that Kdm7a loss drives transcriptional and metabolic reprogramming toward Fib-Mac states. Kdm7a-knockout mice exhibit exacerbated bleomycin-induced lung fibrosis with the expansion of Fib-Mac populations. Mechanistically, we identify toll-like receptor 8 (TLR8) as a suppressor of Fib-Mac polarization whose expression is regulated by KDM7A via the repressive mark H3K27me2 at its enhancer. Notably, macrophage Kdm7a and Tlr8 expression declines with age in male mice, consistent with clinical risk patterns. These findings uncover an epigenetic mechanism restraining disease-driving macrophage states and suggest the KDM7A-TLR8 axis as a potential therapeutic target in fibrotic disorders.

Reporter gene assays are widely employed to investigate activation of G-protein-coupled receptors (GPCRs). However, the increasing complexity of GPCR signaling-particularly the capability of many receptors to couple with multiple Gα subunits-has created a growing need for reliable methods to dissect individual Gα-mediated pathways. Recent insights into the crosstalk and interdependence among Gα subfamilies have further complicated our understanding of the overarching GPCR signaling landscape. While previous studies have linked specific Gα-proteins to distinct transcriptional response elements, the precise specificity of these associations remains unclear. Here, we systematically identified the relationship between Gα proteins and four commonly used GPCR-regulated response elements-CRE, SRE, NFAT-RE, and SRF-RE-using a panel of Gα knockout (KO) cell lines. Contrary to the traditional model of near-exclusive Gα-response element pairings, our results reveal that each reporter is modulated by multiple Gα subfamilies. Each response element exhibited varying degrees of activation by different Gα proteins, with CRE being predominantly regulated by Gα_s/olf, and SRE, NFAT-RE, and SRF-RE primarily regulated by Gα_q/11. Based on these results, we provide an updated framework that redefines the subfamily-specific Gα regulation of downstream transcriptional responses and underscores the need for caution when interpreting reporter assays to assess Gα-protein activity.

The primary somatosensory cortex (SI) is traditionally regarded as a sensory encoding region, yet growing evidence implicates it may also work in the maintenance and manipulation of tactile working memory (TWM), and interact with frontoparietal (FP) pathway under varying task demands. Here, we use high-field fMRI and a custom pneumatic tactile stimulation device to examine neural dynamics across distinct WM phases during a retro-cue task. We manipulate task demand during the delay phase (complex/simple retro-cues) and the retrieval phase (recall/non-recall) while isolating encoding, delay, and retrieval phases. Functional connectivity results reveal increased functional coupling between SI and FP regions as task demand increases. Moreover, effective connectivity results show the high-demand task selectively modulates excitatory connections from the posterior parietal cortex (PPC) to SI during maintenance, and from PPC to dorsolateral prefrontal cortex (dlPFC) as well as from dlPFC to SI during manipulation. These results demonstrate that SI engages in demand-dependent excitatory interactions with FP regions, supporting its central role throughout the whole TWM process.

Thalamic neurons discharge tonically during wakefulness and rapid-eye-movement (REM) sleep, but switch to burst firing during non-REM (NREM) sleep. It has been hypothesized that NREM thalamic bursts do not serve as a cortical "wake-up" signal due to their periodic and synchronized nature. Here, we analyze the simultaneously recorded polysomnographic signals, field potentials, and spiking activity of neurons in the ventral anterior and centromedian thalamic nuclei of two female non-human primates during naturally occurring vigilance states. These nuclei receive GABAergic output from the basal ganglia, with discharge rate decreasing during NREM sleep. Despite this reduction in inhibitory input, NREM bursting increases significantly as reported for glutamate-driven thalamic nuclei.  The NREM bursts are neither periodic nor tightly synchronized. However, delta and sleep-spindle EEG activity and thalamic field potentials time-locked to burst onset during NREM sleep markedly differ from those observed during wakefulness and REM sleep. These results suggest that the basal ganglia modulate, rather than drive, their thalamic targets. Additionally, unique state-dependent thalamocortical dynamics, rather than the periodicity or tight synchrony of the thalamic bursts, are sufficient to account for why NREM thalamic bursts do not awaken the cortex.

A high infiltration of tumor-associated macrophages (TAMs) in hepatocellular carcinoma (HCC) is associated with a negative prognosis for patients. Kupffer cells (KCs) constitute a stationary tissue-resident macrophage subset of the liver, playing a pivotal role in maintaining homeostasis. The increased expression of tubulin beta-3 chain (TUBB3) is associated with the aggressiveness of various epithelial tumors. In this study, we investigate the role of TUBB3 in TAM of HCC and explore the mechanisms. TUBB3 is significantly augmented in HCC tissues, and the knockdown of TUBB3 in Kupffer cells (KCs) inhibits M2 polarization of TAM and hinders the HCC progression. In addition, TUBB3 knockdown enhances the efficacy of PD-1 immunotherapy in vivo. TUBB3 inhibits phosphatase and tensin homolog (PTEN)-induced serine-threonine protein kinase (AKT) phosphorylation, and activation of the AKT signaling reverses the inhibition of TAM-M2 polarization by knockdown of TUBB3 and promotes the malignant behavior of HCC cells. Deltex1 (DTX1) promotes TUBB3 ubiquitination, inducing the degradation of TUBB3. DTX1 overexpression suppresses the M2 polarization of TAM, which is overturned by TUBB3 overexpression. These findings provide the first evidence indicating that DTX1 mediates the ubiquitination of TUBB3 in KCs to block the AKT signaling and the M2 polarization of TAM in HCC.

Glioblastoma (GBM) is an aggressive brain cancer with a poor survival rate. Despite hundreds of clinical trials, there is no effective targeted therapy. Glioblastoma stem cells (GSCs) are an important GBM model system. In culture, these cells form spatial structures that share morphological aspects with their source tumors. We collected 17,000 phase-contrast images of 15 patient-derived GSC lines growing to confluence. We find that GSCs grow in characteristic multicellular patterns depending on their transcriptional state. Interpretable computer vision algorithms identified specific image features that predict transcriptional state across multiple cell confluency levels. This relationship will be useful in developing GSC screens where image features can be used to identify how GSC biology changes in response to perturbations simply by imaging cultured cells on plates.

Neuropsychiatric systemic lupus erythematosus (NPSLE) is a severe complication of systemic lupus erythematosus (SLE). Despite its high morbidity, the exact pathogenesis of NPSLE remains poorly understood, and effective therapeutic options remain unavailable. Here we show gut bacterium Lactobacillus reuteri (L. reuteri) and its metabolite indole-3-acetic acid (IAA) play key roles in the progression of NPSLE. L. reuteri and IAA induce behavioral deficits, microglial activation, pro-inflammatory cytokine secretion, neuronal loss, and blood brain barrier (BBB) disruption in female lupus-prone mice. Mechanistic studies show that IAA activates the aryl hydrocarbon receptor (AHR) and signal transducer and activator of transcription 3 (STAT3) signaling pathways in microglia, thereby upregulating inflammatory responses and exacerbating neuroinflammation. These findings suggest a critical role for gut-microbiota-metabolite-brain axis in NPSLE pathogenesis and provide insights into potential therapeutic targets.