BMC Biology最新文献

Background: The retrovirus-derived Rtl1 gene is integral to skeletal muscle development. However, the underlying mechanisms and functional roles of Rtl1 in skeletal muscle growth remain unclear.

Results: We generated conditional overexpression of Rtl1 in mice via synonymous mutations that silence seven miRNA target sites, thereby efficiently abolishing miRNA-mediated inhibition in vivo. This conditional, specific overexpression of synonymous mutated Rtl1 (mRtl1) in the diaphragm muscles of mice foetuses resulted in aberrant embryonic diaphragm muscle development, adversely affecting both diaphragmatic and pulmonary development. This modification ultimately culminated in severe respiratory distress, leading to postnatal mortality. Subsequently, the conditional overexpression of mRtl1 in the tibialis anterior muscle of adult mice resulted in inflammation and hypertrophy. Furthermore, the overexpression of mRtl1 in cultured myotubes activated the TLR7/8-NFκB and Jak-STAT3 signalling pathways, resulting in hypertrophy and inflammation.

Conclusions: These findings suggest that the overexpression of Rtl1 may contribute to skeletal muscle hypertrophy and induce inflammation in murine models. Consequently, the precise regulation of Rtl1 expression is essential for maintaining skeletal muscle function.

Background: Protein aggregation is indicative of the loss of proteostasis associated with neurodegenerative diseases, including Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD). Proteins like Fused in sarcoma (FUS) and Tar DNA-binding protein 43 (TDP-43) accumulate and aggregate in the cytosol of neurons in ALS/FTD. Yet, it remains unclear how ageing affects FUS and TDP-43 aggregation, and how these aggregates in turn influence neurodegeneration in ALS/FTD. In addition, mistranslation can reduce longevity, challenge proteostasis, and modulate protein aggregation. To investigate how ageing and mistranslation modulate FUS and TDP-43 aggregation and toxicity, we enlist tractable and reliable yeast models.

Results: Using optimized low-expression FUS and TDP-43 yeast models, we demonstrate that chronological ageing antagonizes proteostasis, the steady state levels and solubility of molecular chaperones, and aggregation of FUS and TDP-43. In addition, mistranslation caused by tRNA variants further antagonize FUS and TDP-43 aggregation and synergize to exacerbate FUS and TDP-43 cytotoxicity.

Conclusions: Our work provides new insights into factors that uncouple FUS and TDP-43 aggregation from toxicity and support a rather protective role for FUS and TDP-43 aggregates in promoting longevity.

Background: The formation of the Han Chinese is deeply rooted in the Neolithic cultures of the Yellow River basin, particularly the pivotal Longshan cultural sphere which bridged prehistoric societies and early dynastic civilization. However, the genetic impact of Longshan-era populations on subsequent historical groups remains largely unexplored due to a critical lack of ancient genomic data from this key transitional period. This gap hinders a clear understanding of how early cultural integration in the heartland shaped the genetic structure of later Chinese populations.

Results: This study reports 28 newly sequenced ancient human genomes from the Han Dynasty Xujiacundong and Zhouhe archaeological sites in Shandong Province, which are integrated with previously published regional datasets to investigate the genetic legacy of Neolithic Longshan populations in the formation of Han Chinese ancestry. Our analyses reveal pronounced genetic differentiation between Longshan populations from the Central Plain and lower Yellow River basin during the Late Neolithic period. Most individuals from the Xujiacundong site exhibit mixed ancestry, predominantly derived from Central Plain Longshan-related ancestry (93.8%) with a minor contribution from southeastern coastal China-related ancestry (6.2%). In contrast, all individuals from the Zhouhe site exhibit genetic homogeneity with Central Plain Longshan-related ancestry. These results indicate substantial genetic heterogeneity within the lower Yellow River basin during the Han Dynasty. Moreover, we found a high degree of genetic homogeneity between ancient Han Dynasty populations and modern Han Chinese from Shandong. Admixture modeling and f-statistics further demonstrate that Longshan-related ancestries-particularly those associated with the Central Plain-played a dominant role in shaping the genetic structure of historical populations across a wide geographic range, including the Upper Yellow River, the West Liao River Basin, and Southwest China, etc. CONCLUSIONS: These findings underscore the profound and pervasive genetic influence of the Central Plain Longshan populations on surrounding regions, driving the demographic expansion and genetic homogenization of the Han Chinese. This interplay of population movements and cultural diffusion highlights the central role of Longshan-era demic expansion in shaping the genetic landscape and cohesion of the Han people.

Background: G protein-coupled receptors (GPCRs) can signal in the absence of agonists through constitutive activity. This activity can be enhanced by mutations, resulting in receptors known as constitutively active mutants (CAMs). Such receptors are implicated in various physiological and pathophysiological conditions, and also offer significant therapeutic potential. However, the molecular basis of their constitutive activity remains unknown.

Results: To investigate how CAMs affect receptor activation, we employed enhanced sampling simulations to study the dopamine D2 receptor (D2R), a key target in central nervous system therapies. Free energy landscape analyses revealed that CAMs promote a conformational shift favoring an active state similar to the agonist-bound receptor. To then identify novel CAMs, we developed a comprehensive strategy combining structural comparison, in-silico residue scanning, and free energy calculations, validated by luminescence-complementation-based assays. Applied to D2R, this approach uncovered a new single-point CAM, D2R-I48^1.46W, which was functionally validated. Further investigation revealed that this mutation activates allosteric communication pathways primarily involving transmembrane helix 5, particularly Ser194^5.43, underscoring its role in transmitting activation signals to the intracellular domain.

Conclusions: This study elucidates how CAMs reshape the activation landscape of D2R and establishes a broadly applicable computational-experimental framework for discovering constitutively active GPCR variants. These CAMs provide valuable ligand-independent models for probing receptor activation mechanisms at structural, cellular, and physiological levels.

Background: Synaptic organization is central for proper transmission of neural information. Studies in invertebrates and mammalian cortices show that synapses are clustered along neurite extensions, an organization that promotes key functional roles.

Results: Here we studied how these synaptic clusters emerge during the development of a nervous system. Leveraging the available C. elegans connectomes that span all larval developmental stages, we show that clustered synapses are formed at the early stages of the neural network development and that their occurrence further increases throughout development. These synaptic clusters significantly constitute small neural circuits that endow the network with important functional roles, such as feedback between mutually synapsing neurons and information transfer in mutually regulated neurons. Moreover, clustered synapses emerge early on during the development of the head motor system, where they facilitate the crucial 3D head swings. Finally, the synaptic clusters within these key neural circuits are maintained throughout all developmental stages and are robustly found across different individuals, further accentuating their central functional roles in neural networks.

Conclusions: Clustered synaptic structures emerge early on during the development of the neural network and are consistently observed among individuals. They appear significantly in motor circuits, possibly contributing to their function.

Background: Plasticity is crucial for environmental adaptation in animals, yet its role in life cycle evolution remains poorly understood. Anurans exhibit a biphasic life cycle, with tadpole and frog following distinct evolutionary trajectories. The non-obligate cave-dwelling frog Oreolalax rhodostigmatus exemplifies this phenomenon: its tadpoles have well adapted to caves, while frogs depend on outside resources. Stage-dependent adaptive plasticity may explain this paradoxical life cycle, predicting that environmental responsiveness declines after metamorphic climax and that early-stage plasticity facilitates adaptations to resource-limited cave environments.

Results: We examined transcriptional plasticity of O. rhodostigmatus by comparing cave- and outside-dwelling tadpoles from the same population across four organs (liver, tail, skin, and hindlimb) at ten developmental stages, spanning pre-metamorphosis to metamorphic climax. Organ transcriptomes reflected both developmental and environmental effects. As predicted, transcriptional responses to environmental conditions in the liver, skin, and tail declined markedly after the onset of metamorphic climax, while the frog-specific organ, hindlimb, showed the weakest environmental responsiveness. Prior to the metamorphic climax, cave-dwelling individuals showed upregulation of fundamental cellular processes (e.g., RNA and protein synthesis) while downregulation of immune-related processes, consistent with a resource-allocation strategy in resource-limited environments. Moreover, increased expression of genes involved in bile biosynthesis and xenobiotic metabolism in the liver suggests enhanced nutrient absorption and utilization, while upregulation of glucagon- and insulin-resistance-related genes in the tail indicates improved tolerance to starvation.

Conclusions: Our findings support the hypothesis that stage-dependent plasticity explains the evolution of non-obligate cave-dwelling in anurans, highlighting the potential role of plasticity in shaping animal lifestyle evolution.

Background: The Caenorhabditis elegans-Escherichia coli system is advantageous for studying host-microbe interactions at the single-gene level. By screening with this system, we identified that the deletion of cpxR, an E. coli transcription factor for the envelope stress response, delays C. elegans development. This finding led us to investigate how this gene regulates host development.

Results: We identified that E. coli ΔcpxR induced C. elegans developmental delay and activated the C. elegans mitochondrial unfolded protein response pathway through reactive oxygen species. It is widely accepted that the Cpx system is important for bacterial pathogenesis, and activating CpxR is regarded as an antimicrobial strategy. Moreover, we discovered that ΔcpxR cultured in LB medium, not cultured in M9 minimal medium, delayed C. elegans development, and the L-histidine-related metabolism of ΔcpxR contributed mostly to the difference. The metabolic fluctuations of commensal bacteria reveal that, rather than the activation of the E. coli Cpx response, the dynamic response of the E. coli Cpx system really contributes to C. elegans development. Furthermore, as the concentration of N-acetylcysteine increased, the phenotype of C. elegans fed ΔcpxR transitioned from developmental delay to survival resistance. The dynamic response is also indicated in the process in which commensal E. coli improves the stress tolerance of the host C. elegans to N-acetylcysteine.

Conclusions: Our results illustrate that environmental factors can shape the regulation of the E. coli Cpx response to C. elegans, providing new evidence for why Cpx-mediated virulence phenotypes are inconsistent among gram-negative species in different ecological niches.

Background: Drosophila melanogaster has been a valuable model for dissecting the molecular architecture of innate immunity. However, the family Drosophilidae encompasses over 4000 species, spanning deep evolutionary divergences and diverse ecologies. Here, we use immune challenge with the Gram-negative pathogen Providencia rettgeri to investigate the conservation and evolution of immune responses in three non-model drosophilid species that diverged from D. melanogaster over 45 million years ago-Hirtodrosophila cameraria, H. confusa, and Scaptodrosophila deflexa.

Results: We find that all three species retain a core set of immune signaling and recognition genes, but exhibit substantial variation in effector gene content and inducibility. In particular, Scaptodrosophila deflexa lacks orthologs of multiple antimicrobial peptides (AMPs) known from D. melanogaster, including DptA, AttA, and AttC, and shows little transcriptional response to bacterial challenge with Providencia rettgeri. In contrast, both of the Hirtodrosophila species exhibit substantial transcriptional responses, including strong induction of canonical Imd pathway genes. Microbiome profiling of our samples revealed higher Providencia abundance in H. cameraria, and high levels of the defensive symbiont Spiroplasma in S. deflexa-potentially explaining differences in infection outcome. Our combined annotation and expression analysis of these species also allowed us to identify 20 novel AMP-like candidates, many with structural features like known AMPs.

Conclusions: Our study demonstrates the feasibility of functional immune analyses in non-model Drosophila species and reveals striking lineage-specific differences in immune gene repertoire and expression. These findings highlight the importance of non-model, wild-derived samples for uncovering novel immune effectors and understanding evolutionary forces shaping insect immunity.

Background: Hexadecanamide (HEX) has been recognized for its significant anti-inflammatory properties. However, its specific role and underlying mechanisms in the context of colitis remain poorly understood.

Results: Herein, we first determined the effect of oral HEX on DSS-induced colitis in mice. Our results showed that HEX alleviated DSS-induced colitis in mice, which was related to the improvement of intestinal barrier integrity and the reduction of colonic inflammatory responses. Interestingly, HEX suppressed the initiation of DSS-induced ferroptosis. In detail, HEX inhibited autophagy and ferritinophagy, which subsequently blocked lipid peroxidation. 16S rRNA sequencing revealed that HEX intervention regulated the gut microbial composition, characterized by an increased relative abundance of Actinobacteriota and Patescibacteria and a decreased the relative abundance of Firmicutes. To validate these findings, fecal microbiota transplantation (FMT) was performed in DSS-treated mice. The microbiota derived from HEX-treated mice exhibited greater efficacy in alleviating colitis compared to that from control-treated mice, as evidenced by prominent anti-inflammatory effects and colonic barrier repair, and consistent alterations in the gut microbial community, which were further confirmed by FMT.

Conclusions: Overall, our findings suggest that HEX markedly ameliorates DSS-induced colitis by limiting inflammation, improving barrier integrity and regulating gut microbial composition. These results highlight the critical role of HEX in maintaining intestinal homeostasis and suggest its potential as a novel preventive and therapeutic strategy.

Background: RNA interference (RNAi), a naturally occurring gene silencing mechanism found in almost all eukaryotic organisms, has proven to be an adaptable and powerful tool in therapeutics, bioengineering, and agriculture. Differential responses to RNAi, however, are a key limiting factor, in which cellular uptake of exogenous dsRNA in target organisms remains poorly understood.

Results: Here, to fill this knowledge gap, we integrated omics tools with phenotypic assays to characterize dsRNA uptake mechanisms across tissues in the migratory locust, Locusta migratoria (Orthoptera). Our findings clearly demonstrate that cellular uptake of dsRNA is tissue-dependent, involving multiple cell membrane receptors and pathways. In hemocytes, uptake is rapid and mediated by clathrin-mediated endocytosis and macropinocytosis. Epidermal cells utilize clathrin- and caveolin-mediated endocytosis, while midgut cells employ caveolin-mediated endocytosis and Sid-like channel transport. Comparatively, clathrin-mediated endocytosis appears to be the most conserved mechanism across insects, including the red flour beetle, Tribolium castaneum (Coleoptera), and the Asian corn borer, Ostrinia furnacalis (Lepidoptera).

Conclusions: Taken together, dsRNA enters the cells of different tissue types through diverse pathways. This systematic and comprehensive study not only advances our understanding of the cellular uptake of extracellular dsRNA and the resultant differential sensitivity to RNAi in insects, but also facilitates the ongoing integration of this species-specific biotechnology into sustainable integrated pest management practices.