Communications Biology最新文献

Normative modeling provides a principled framework for quantifying individual deviations from typical brain development and is increasingly used to study heterogeneity in neuropsychiatric conditions. While widely applied to structural phenotypes, functional normative models remain underdeveloped. Here, we introduce MEGaNorm, a normative modeling framework for charting lifespan trajectories of resting-state magnetoencephalography (MEG) brain oscillations. Using a large, multi-site dataset comprising 1846 individuals aged 6-88 and spanning three MEG systems, we model relative oscillatory power in canonical frequency bands using hierarchical Bayesian regression, accounting for age, sex, and site effects. To support interpretation at multiple scales, we introduce Neuro-Oscillo Charts, visual tools that summarize normative trajectories at the population level and quantify individual-level deviations, enabling personalized assessment of functional brain dynamics. Applying this framework to a Parkinson's disease cohort (n = 160), we demonstrate that normative deviation scores reveal disease-related abnormalities and identify a continuum of patients in the theta-beta deviation space. This work establishes a multi-site normative reference for resting-state MEG oscillations (3-40 Hz) across a broad age range, enabling population-level characterization and individualized benchmarking. All models and tools are openly available and designed for federated, continual adaptation as new data become available, providing a methodological foundation toward precision neuropsychiatry.

Selective fetal growth restriction (sFGR) in monochorionic diamniotic twins (MCDA) reflects placental dysfunction, but trophoblast adaptation mechanisms remain unclear. Using single-cell RNA sequencing on placental tissues from three paired sFGR, we demonstrate that villous cytotrophoblasts (VCT) in growth-restricted placentas undergo a transition from VCT_TP63, which expresses barrier-associated TP63/SOX6 and maintains cytoskeletal integrity, to VCT_LDHA, a metabolically reprogrammed phenotype marked by LDHA/YY1/RELA activation. Trajectory analysis shows diminished syncytial precursors, suggesting impaired fusion capacity. Immune profiling identifies depleted TREM2+ Hofbauer macrophages and expanded interferon-responsive natural killer (NK) cells. Cell-cell interaction mapping demonstrates enhanced Interferon Gamma (IFNG)-Interferon Gamma Receptor 1 (IFNGR1)-Signal Transducer and Activator of Transcription 1 (STAT1) signaling between VCT_LDHA and immune cells, alongside weakened VCT_TP63-stromal crosstalk. This study defines a maladaptive triad of metabolic stress, inflammation, and structural disintegration in sFGR, contributing to sFGR pathogenesis.

Tea, derived from the leaves of Camellia sinensis, is a globally consumed beverage with considerable nutritional and economic value. Specific cultivars exhibit a striking purple leaf coloration due to anthocyanin accumulation, yet the molecular mechanisms governing this trait remain incompletely understood. In this study, we identified a sense-intronic long non-coding RNA, Cs_lncRNA.18443.6, that is co-expressed with CsUFGT (UDP-glucose: flavonoid 3-O-glucosyltransferase) and is predicted to act in cis on this gene. Together with the transcription factor CsMYB12, these components form a hypothesized three-tier regulatory module that contributes to anthocyanin accumulation in purple tea leaves. CsUFGT emerges as a potential regulatory hub in anthocyanin biosynthesis. Weighted gene co-expression network analysis (WGCNA), combined with the construction of a competing endogenous RNA network construction reveals Cs_lncRNA.18443.6 as a cis-acting lncRNA associated with CsUFGT expression. This association was supported by RNA fluorescence in situ hybridization (FISH), transient expression assays in transgenic tobacco, and RT-qPCR analysis. Dual-luciferase reporter assays provided preliminary evidence that Cs_lncRNA.18443.6 influences CsUFGT transcription by affecting CsMYB12-dependent promoter activation. These findings uncover a previously uncharacterized lncRNA association with anthocyanin biosynthesis and offer new hypotheses and provide candidate targets for the molecular breeding of anthocyanin-enriched tea cultivars.

Cholestatic liver disease (CLD) is characterized by disrupted bile acid (BA) homeostasis and excessive accumulation of toxic bile acids in the liver. While both genetic and acquired factors are known to contribute to its pathogenesis, the full spectrum of underlying pathological mechanisms remains incompletely understood, and treatment options are limited. Cardiotrophin-like cytokine factor 1 (CLCF1), a CNTFR ligand, plays a pivotal role in energy metabolic homeostasis, yet its role in cholestasis remains unclear. Here, we show that hepatic CLCF1 expression is markedly upregulated in cholestatic patients and mouse models (all mice used in this study were male). Hepatocyte-specific Cntfr deletion exacerbates DDC-induced cholestasis and fibrosis, whereas AAV-mediated hepatic Clcf1 overexpression attenuates cholestatic liver injury and fibrosis in both Abcb4 knockout (Mdr2^-/-) and DDC-fed mice. Mechanistically, CLCF1 suppresses BA synthesis enzymes independently of hepatic FXR-SHP signaling, and selectively enriches FXR-agonistic BAs (e.g., LCA) in the gut, activating the intestinal FXR-FGF15 axis. Gut-restricted FXR antagonism partially reverses CLCF1-mediated hepatoprotection, underscoring the gut-liver axis as a critical effector. Furthermore, CLCF1 remodels the microbiota to favor Firmicutes, enhancing BA excretion. Altogether, our data demonstrate that CLCF1 mitigates CLD through suppressing BA synthesis and enhancing BA excretion. CLCF1 may represent a promising therapeutic avenue for cholestasis.

Blanchability, the ease of seed coat removal after roasting, is a critical post-harvest trait in groundnut (Arachis hypogaea L.) that directly influences processing efficiency and product quality. Despite its economic value, limited genetic understanding restricts breeding efforts for customized blanchability in groundnut. Here, we integrate whole-genome resequencing of 184 diverse groundnut genotypes with multi-season phenotyping to dissect the haplotype-level genomic architecture of blanchability. Genome-wide association studies identify 26 significant single-nucleotide polymorphism-trait associations across multiple chromosomes, six of which are further validated using KASP markers, with two successfully validating the expected allelic effects across breeding lines and genotypes. Haplo-pheno analyses identify distinct subspecies-specific signatures for the major associations on chromosomes Ah01, Ah05, Ah06, and Ah17. Superior high-blanchability haplotypes (Ah01HapBL4, Ah05HapBL3, Ah06HapBL5, Ah06HapBL10, and Ah17HapBL6) are predominantly found in the fastigiata subspecies from South Asia and South America. In contrast, the low-blanchability haplotypes (Ah01HapBL2, Ah05HapBL6, Ah06HapBL3, Ah17HapBL2) are enriched in the hypogaea subspecies, mainly from Africa. These contrasting haplotypes offer the flexibility to achieve either high or low blanchability tailored to specific end-use applications. The availability of diagnostic markers and donor genotypes harboring multiple favorable haplotypes provides immediate tools for haplotype-based breeding. Collectively, this study introduces blanchability as a novel, customizable breeding target and establishes a translational framework to enhance the processing quality and industrial value of groundnut through haplotype-based breeding.

The nematode Ditylenchus destructor comprises multiple haplotypes with distinct host preferences, while the genetic basis remains unclear. We generate three genomes (Haplotypes A, B, and C) using hybrid assembly and conduct comparative analysis with two published Haplotype A genomes. Integrating haplotype-resolved phylogeny, whole-genome alignments, functional annotation, orthogroup profiling, and secretome analysis shows Haplotypes B and C are more similar to each other than to Haplotype A. We identify several key genomic differences that may underlie host adaptation: Haplotype A features expanded chemosensory GPCR repertoires and GH31 glycoside hydrolases. Haplotype B possesses an abundance of cytochrome P450 domain proteins and secretory pectate lyases. Haplotype C harbors more genes encoding NADPH reductases, oxidoreductases, ABC transporters, secreted animal haem peroxidases, C-type lectins, and Astacins. We propose that these genomic variations facilitate the nematode's adaptation to different host plants. Collectively, our findings establish a genomic framework for understanding host adaptation in D. destructor.

Perinatal failure in the growth hormone (GH)-insulin-like growth factor-1 (IGF-1) axis causes impaired body growth and central and autonomous neurodevelopmental disorders. However, whether a primary neurodevelopmental disorder causes organ misinnervation as a contributing factor in growth retardation is elusive. To interrogate this, here we generated a late embryonic neural-specific cdc20 homolog 1 (Cdh1) knockout mouse model, which exhibited a primary delay in early postnatal brain development. These mice displayed an intact GH-releasing hormone (GHRH)-GH-hepatic GH receptor (GHR) pathway despite a body growth retardation that could be reversed by IGF-1 administration in the early postnatal life. Mechanistically, liver sympathetic misinnervation impaired signal transducers and activators of transcription 5 (STAT5) phosphorylation, required for liver IGF-1 biosynthesis and release. We also report decreased blood levels of IGF-1 in a patient harboring a pathogenic mutation in Cdh1 that causes neurodevelopmental and growth delay. Taken together, these findings demonstrate that a primary neurodevelopmental defect disrupts sympathetic hepatic innervation, leading to a GH-independent growth retardation, thus establishing a positive feedback loop that propagates the disease presentation.

The soil bacterium Pseudomonas putida injects toxic proteins into neighbouring competitors, including resilient phytopathogens, using the Type VI secretion system (T6SS). The secretion of toxins endows P. putida with a significant fitness advantage, allowing this biocontrol agent to thrive in plant-related polymicrobial environments and prevent phytopathogen infections. Despite its agricultural significance, the toxin repertoire of P. putida, particularly those secreted via the K2- and K3-T6SSs, remains poorly understood. We present a comprehensive molecular study of Tke5, a potent toxin encoded within the K3-T6SS, which represents the initial biophysical and functional analysis of the BTH_I2691 family. Our data demonstrate that Tke5 is a pore-forming toxin that disrupts bacterial membranes through selective ion transport, inducing membrane depolarisation and cell death. Tke5 is neutralised by Tki5 in the inner membrane of Gram-negative bacteria. Unlike detergent-like pore-forming toxins, Tke5 preserves overall membrane integrity, avoiding large, non-specific disruptions. This mechanism offers a powerful approach to targeting resilient phytopathogens. This study reveals a previously undescribed mode of action within a widespread yet understudied toxin family. Our findings highlight the potential of P. putida as a biocontrol agent, offering alternatives to chemical pesticides by exploiting novel toxin mechanisms, crucial for developing effective strategies to combat plant pathogens.

Certain human mutations in the mitochondrial aldehyde dehydrogenase 4A1 (ALDH4A1) lead to a severe, paediatric form of epilepsy and developmental abnormalities, yet the precise molecular mechanism leading to the clinical phenotypes remains unexplained. ALDH4A1 metabolizes glutamic-γ-semialdehyde (GSA). Mutations in ALDH4A1, which lead to inactive enzyme variants, cause GSA to accumulate and vitamin B6 inactivation. Patients with severe ALDH4A1 deficiency have paediatric epilepsy and are resistant to prescribed therapies. We develop knock-in cell culture and mouse models of the S352L variant to help characterize this human pathology. The knock-in models show that ALDH4A1 is necessary for clearing a non-canonical substrate, 4-hydroxynonenal (4-HNE), without becoming inactivated, like the main clearance mechanism of 4-HNE, ALDH2, and that ALDH4A1 deficiency alters transcriptional profiles in genes that regulate brain development, including LGI1 and FOXB1. Protein levels, including those in the proline metabolic pathway (e.g., spermine synthase), are also downregulated in both S352L iPSCs and the brains of S352L homozygous mice. This work identifies additional metabolic and transcriptional pathways regulated by ALDH4A1, and potential pathways that can be targeted to treat patients with ALDH4A1 deficiency.

At dawn, we experience a shift from slumber to sentience following neurophysiological transitions, termed as sleep inertia (SI). Although resting-state fMRI studies have discovered brain reorganizations during SI, the neural basis underlying impaired alertness in SI remains unclear. We conduct simultaneous EEG-fMRI recordings on 26 adults with repeated measures of pre-sleep, nocturnal sleep and consecutive post-sleep awakenings. Using the psychomotor vigilance task (PVT) to probe tonic alertness, we discover that cingulo-opercular network (CON) activation, inclusive of thalamus, troughs upon awakening, and increments along with the post-sleep awake duration. The dynamic recovery of thalamus activity during SI depends on prior sleep architecture and the awake duration, mediating the PVT performances on awakening. Although CON connectivity remains stable, the connectivity changes between thalamus and frontoparietal network (FPN) are associated with changes of thalamic activation and PVT performances during SI. Collectively, thalamic activity and its coupling with the FPN support the restoration of tonic alertness during SI, providing a concise framework for the neural mechanisms underlying cognitive recovery upon awakening.