Communications Biology最新文献

Lysine malonylation (Kmal) is a novel post-translational modification (PTM) implicated in numerous biological processes. Our recent study finds that human sperm proteins are modified by Kmal, but the functional significance of Kmal in human sperm remains unclear. The present study shows that Kmal primarily occurs in human sperm tail proteins with molecular weights ranging from 15 to 250 kDa. Similar to somatic cells, Kmal is derived from malonyl-CoA, with acyltransferase P300 and sirtuin 5 (SIRT5) potentially acting as the writer and eraser, respectively, for Kmal in human sperm. The Kmal level in asthenozoospermic sperm is significantly higher than that in normozoospermic sperm and exhibits a negative correlation with progressive motility. Elevated Kmal levels in asthenozoospermic sperm are associated with reduced sperm SIRT5 and ATP levels, as well as inhibited glycolysis. Furthermore, the induction of sperm Kmal by sodium malonate significantly diminishes the motility and penetration ability of normozoospermic samples by reducing sperm [Ca²⁺]i, ATP, and cAMP levels, and by suppressing glycolysis and PKA activity. Our findings elucidate the regulatory function of Kmal in human sperm motility and its association with asthenozoospermia, thereby offering insights for the diagnosis and treatment of idiopathic male infertility.

Neurogenic bladder (NB) is a lower urinary tract dysfunction caused by lesions in the nervous system that regulate urine storage and micturition. Fibrosis is considered the basic pathological alteration of NB, whereas the underlying mechanism remains unclear. Here, we find that Wnt11 is significantly up-regulated in the rat fibrotic bladders induced by bilateral pelvic nerve injury (BPNI) and spinal cord injury (SCI) and promotes bladder fibroblasts (BFs)-to-myofibroblasts transition and smooth muscle cells (SMCs) phenotypic transformation. Selective inhibition or gene silencing of Wnt11 in vivo and in vitro attenuates BFs and SMCs activation, and mitigates the development of NB fibrosis. Mechanistically, Wnt11 specifically binds to Vangl2 receptor to activate downstream JNK/c-JUN signaling via the membrane recruitment of DVL2. Further research shows that Wnt11 signaling interacts with transforming growth factor beta 1 (TGF-β1)/Smad-dependent pathway through the binding of membrane receptors (Vangl2 and TβR1) and the crosstalk of nuclear transcription factors. These findings uncover the regulatory mechanism and may provide a new therapeutic strategy for NB fibrosis.

Growing evidence shows that sleep can be enhanced in a non-invasive, drug-free manner through sensory stimulation. While modalities such as auditory and vestibular stimulation effectively increase sleep, the cognitive and cellular consequences of such enhancement remain unclear. Here, we investigated the effects of vestibular stimulation via rocking on sleep architecture, motor learning, cortical gene expression, and synaptic organization in the motor cortex. Eleven consecutive days of rocking enhanced sleep in mice, increasing both sleep duration and consolidation. These improvements were accompanied by greater motor learning performance, and the degree of learning enhancement positively correlated with total sleep amount. At the molecular level, improved learning was associated with transcriptional changes in genes involved in glutamatergic signalling and synaptic plasticity, alongside an increased density of excitatory synapses in the motor cortex. Together, these findings demonstrate that sleep enhancement via rocking facilitates learning by promoting neuroplastic mechanisms in the motor cortex.

Spatial transcriptomics is an emerging technology that can analyze gene expression profiles of tissues while preserving spatial location information. To restore cell type proportions from mixed gene expression data, here we present DANST, a deconvolution framework based on deep domain adversarial neural networks. By integrating single-cell RNA sequencing (scRNA-seq) with inferred spatial coordinates, we construct pseudo-spatial data. DANST utilizes a variational autoencoder to learn refined feature representations and introduces a domain adversarial architecture to align feature distributions between pseudo and real data, enabling accurate label transfer. Benchmarking on human and mouse datasets shows that DANST achieves superior deconvolution accuracy compared with existing methods. These findings highlight its effectiveness for tumor microenvironment analysis and potential clinical utility.

The evolutionary processes contributing to plant biodiversity in the tropics are a matter of active discussion, as there are remaining questions about lineages' diversification patterns and adaptations after migration from the tropics to the subtropics. Here, we investigate these issues using the epiphytic orchids Dendrobium section Dendrobium. We reconstructed the spatio-temporal dynamics of this group based on whole plastome and nrITS data, analyzed macroevolutionary patterns, explored adaptive traits of subtropical lineages and predicted their distribution over time. We found that D. sect. Dendrobium originated in the Asian tropics in the middle Miocene and independently dispersed into the Asian subtropics at least four times since the early Pliocene. The net diversification rate decreased continuously due to temperature decline in the Asian tropics, while the net diversification rate of subtropical lineages increased with niche and trait rates rising. Smaller stem and leaf sizes of D. sect. Dendrobium were morphological adaptations in the Asian subtropics, and were mainly related to temperature seasonality. Importantly, the northern distribution limits of D. sect. Dendrobium mostly overlapped with the Asian subtropical evergreen broad-leaved forests since the Pliocene. This study represents an important case for understanding plant adaptations as they move out of the tropics.

Lanthanum (La), the second most produced rare earth element, is detected in various environmental and human samples. Epidemiological studies have reported a strong association between La exposure and liver injury. However, the effects of early La exposure on liver development and underlying mechanisms remain limited. Here, we evaluate the hepatotoxicity of LaCl₃ at environmentally relevant concentrations using zebrafish larvae. Embryonic LaCl₃ exposure causes concentration-dependent hepatic steatosis, which cannot be reversed after exposure cessation. Metabolomic profiling reveals that very-low-density lipoprotein (VLDL) and its multiple downstream metabolites are consistently downregulated upon LaCl₃ treatment, together with increased triglycerides (TG) level, indicating impaired TG-VLDL biosynthesis. In addition, transcriptomics suggest that genes related to the PPARα signaling pathway are significantly downregulated, especially those involved in TG-VLDL biosynthesis (mttp and all apob subtypes). Further studies show that LaCl₃ can inhibit the transcriptional regulatory activity of PPARα. The upregulation of the PPARα signaling pathway corresponding genes of ppara, mttp, and apob effectively rescues LaCl₃-induced liver impairments. Subsequently, a subcellular localization assay finds that increased ApoB degradation in the endoplasmic reticulum contributes to LaCl₃-triggered lipid droplet accumulation. Overall, our findings fill critical research gaps regarding LaCl₃-induced hepatotoxicity and provide important evidence for the environmental risk assessment of La.

Human working memory is supported by a broadly distributed set of brain networks. Content-specific networks communicate with a domain-general, supramodal network that is recruited regardless of the type of content. Here, we contrasted visual and auditory working memory tasks to examine interactions between the supramodal network and two content-specific networks. Functional connectivity among visual-biased, auditory-biased, and supramodal working memory networks was assayed by collecting task and resting-state fMRI data from 24 human participants (age 18-43; 11 men and 13 women). At rest, as found previously, the supramodal network exhibited stronger functional connectivity with the visual-biased network than with the auditory-biased network. This asymmetry raises questions about how networks communicate to support robust performance across modalities. However, during auditory task performance, dynamic changes increased auditory network connectivity with supramodal and visual-biased frontal regions, while decreasing connectivity from posterior visual areas to supramodal and frontal visual regions. In contrast, the visual task produced weak changes. Across individuals, auditory working memory precision correlated with the strength of auditory network connectivity changes, while no such brain-behavior link was observed for visual working memory. These results demonstrate an asymmetry in working memory network organization and reveal that dynamic reorganization accompanies performance of working memory tasks.

Adult hippocampal neurogenesis, crucial for maintaining neural homeostasis, is integral to neurodegeneration. We previously identified Miro2 as a key regulator of mitochondrial dynamics and survival in hippocampal neural stem cells with potential relevance to Alzheimer's disease. Here, using TurboID-based proximity labeling, we explore Miro2's interaction networks and identify sixty-six unique interactors specific to hippocampal neural stem cells. Functional enrichment analysis reveals that these proteins are crucial for mitochondrial organization, transport, and neurodegeneration. CISD1 emerges as a significant interaction partner. Knockdown of Miro2 and CISD1 impairs mitochondrial trafficking in adult hippocampal stem cells, disrupted stem cell differentiation with increased cytotoxicity. Rescue experiments partially reverse cell death, and both Miro2 and CISD1 show increased expression and interaction during differentiation. These findings suggest the Miro2-CISD1 axis as a critical regulator of mitochondrial remodeling and neurogenesis, providing a framework for future studies on how mitochondrial dynamics contribute to neurodegenerative disease mechanisms.

Mediator complex (MED) is an important auxiliary factor in the RNA polymerase II transcription apparatus, and MED13 is a subunit in the CDK8-kinase module of the complex. Currently, extensive clinical evidence has implicated its involvement in the pathogenesis of neurodevelopmental disorders (NDDs). However, the mechanism by which dysfunction of MED13 contributes to NDDs remains poorly understood. Here, we specifically knocked down Med13 expression in cortical neurons using in-utero electroporation to examine its function in cortical development and utilized mass spectrum to explore the downstream molecules involved in cortical development. We found that silencing Med13 in cortical neurons impaired its radial migration and contralateral projection as well as dendritic complexity in mice. Differential protein analysis of human neuroblastoma cells (SH-SY5Y) with MED13 deletion revealed a large number of dysregulated proteins, including PLXNA4. Notably, the impaired radial migration and callosal projection, but not dendritic complexity, were largely restored by overexpression of PlxnA4 in Med13 knock-down neurons. Collectively, our findings establish that Med13 regulates cortical neuronal radial migration and callosal projection at least in part through PlxnA4, shedding light on the molecular mechanisms underlying the pathogenesis of MED13-associated NDDs.

The NF-κB pathway plays a critical role in mediating the innate immune response downstream of activated immune receptors such as the TNFαR. Activation of this pathway is induced by several ubiquitin ligases (e.g., cIAP, TRAFs, NEMO, β-TrCP, KPC1), including Nedd4-1. Nedd4-1 comprises a C2-WW(4)-HECT domain architecture. We recently characterized a primate-specific splice isoform of Nedd4-1, Nedd4-1(NE), in which the C2 domain is replaced by a large N-terminally Extended (NE) region. Using miniTurbo BioID, we identified here several components of the NF-κB pathway in complex with Nedd4-1(NE) (but not with the canonical Nedd4-1), including IKKα/β and p105-NF-κB1. We further show that (i) Nedd4-1(NE) ubiquitinates and promotes degradation of IKKβ, therefore inhibiting phosphorylation and promoting stability of its substrate, the inhibitory IκBα; (ii) active Nedd4-1(NE) binds and destabilizes NF-κB1, an interaction that is dependent upon Nedd4-1(NE)-mediated KPC1 ubiquitination. Furthermore, KPC1 promotes translocation of NF-κB1 to late endosomal membranes, where Nedd4-1(NE) resides, to facilitate the Nedd4-1(NE): NF-κB1 interaction. Consequently, Nedd4-1(NE)-mediated regulation of both IKKβ and NF-κB1 suppresses NF-κB1 nuclear translocation and activation of its target genes; and (iii) Nedd4-1(NE) (but not canonical Nedd4-1) mRNA expression is increased upon prolonged TNFα treatment of cells. This work uncovered an E3 ubiquitin ligase that suppresses the NF-κB1 pathway to ensure termination of this pro-inflammatory signaling pathway in primates via a negative feedback mechanism; Such an additional layer of immune regulation has important implications for understanding inflammatory homeostasis and its dysregulation in human disease.