BMC Biology最新文献

Background: Cyclic peptides, known for their high binding affinity and low toxicity, show potential as innovative drugs for targeting "undruggable" proteins. However, their therapeutic efficacy is often hindered by poor membrane permeability. Over the past decade, the FDA has approved an average of one macrocyclic peptide drug per year, with romidepsin being the only one targeting an intracellular site. Biological experiments to measure permeability are time-consuming and labor-intensive. Rapid assessment of cyclic peptide permeability is crucial for their development.

Results: In this work, we proposed a novel deep learning model, dubbed as MultiCycPermea, for predicting cyclic peptide permeability. MultiCycPermea extracts features from both the image information (2D structural information) and sequence information (1D structural information) of cyclic peptides. Additionally, we proposed a substructure-constrained feature alignment module to align the two types of features. MultiCycPermea has made a leap in predictive accuracy. In the in-distribution setting of the CycPeptMPDB dataset, MultiCycPermea reduced the mean squared error (MSE) by approximately 44.83% compared to the latest model Multi_CycGT (0.29 vs 0.16). By leveraging visual analysis tools, MultiCycPermea can reveal the relationship between peptide modification structures and membrane permeability, providing insights to improve the membrane permeability of cyclic peptides.

Conclusions: MultiCycPermea provides an effective tool that accurately predicts the permeability of cyclic peptides, offering valuable insights for improving the membrane permeability of cyclic peptides. This work paves a new path for the application of artificial intelligence in assisting the design of membrane-permeable cyclic peptides.

Mechanical stimulation, including wind exposure, is a common environmental factor for plants and can significantly impact plant phenotype, development, and growth. Most responses to external mechanical stimulation are defined by the term thigmomorphogenesis. While these morphogenetic changes in growth and development may not be immediately apparent, their end-results can be substantial. Although mostly studied in dicotyledonous plants, recently monocot grasses, particularly cereal crops, have received more attention. This review summarizes current knowledge on mechanical stimulation in plants, particularly focusing on the molecular, physiological, and phenological responses in cereals, and explores practical applications to sustainably improve the resilience of agricultural crops.

Background: Relaxins are a family of peptides that regulate reproductive physiology in vertebrates. Evidence that this is an evolutionarily ancient role of relaxins has been provided by the discovery of two relaxin-like gonad-stimulating peptides (RGP1 and RGP2) that trigger spawning in starfish. The main aim of this study was to identify the receptor(s) that mediate(s) the effects of RGP1 and RGP2 in starfish.

Results: Here we show that RGP1 and RGP2 belong to a family of peptides that include vertebrate relaxins, Drosophila insulin-like peptide 8 (Dilp8), and other relaxin-like peptides in several protostome taxa. An ortholog of the human relaxin receptors RXFP1 and RXFP2 and the Drosophila receptor LGR3 was identified in starfish (RXFP/LGR3). In Drosophila, but not in humans and other vertebrates, there is a paralog of LGR3 known as LGR4, and here an LGR4-type receptor was also identified in starfish. In vitro pharmacological experiments revealed that both RGP1 and RGP2 act as ligands for RXFP/LGR3 in the starfish Acanthaster cf. solaris and Asterias rubens, but neither peptide acts as a ligand for LGR4 in these species.

Conclusions: Discovery of the RXFP/LGR3-type receptor for RGP1 and RGP2 in starfish provides a new insight into the evolution of relaxin-type signaling as a regulator of reproductive processes. Furthermore, our findings indicate that RXFP/LGR3-type receptors have been lost in several phyla, including urochordates, mollusks, bryozoans, platyhelminthes, and nematodes.

The discovery of diverse molecular mechanisms of regulated cell death has opened new avenues for cancer therapy. Ferroptosis, a unique form of cell death driven by iron-catalyzed peroxidation of membrane phospholipids, holds particular promise for targeting resistant cancer types. This review critically examines current literature on ferroptosis, focusing on its defining features and therapeutic potential. We discuss how molecular profiling of tumors and liquid biopsies can generate extensive multi-omics datasets, which can be leveraged through machine learning-based analytical approaches for patient stratification. Addressing these challenges is essential for advancing the clinical integration of ferroptosis-driven treatments in cancer care.

Background: Thermotolerance is a critical trait for yeasts employed in industrial settings, and the utilization of unconventional yeasts has gained notable attention in recent years. However, the mechanisms underlying thermotolerance in unconventional yeasts, particularly Pichia spp., remain insufficiently elucidated.

Results: This study focuses on the thermotolerance of a non-traditional yeast strain Pichia kudriavzevii LC375240, renowned for its remarkable thermotolerance. Through transcriptomic analysis of both short-term and long-term heat shock exposures, we uncovered an intricate regulatory response in P. kudriavzevii. During long-term heat treatment, the yeast exhibited elevated expression of genes involved in the tricarboxylic acid (TCA) cycle and suppressed expression of genes in the pentose phosphate pathway (PPP). Additionally, long-term heat treatment led to an upregulation of heat shock proteins (HSPs) and an increase in trehalose, glutathione (GSH), and superoxide dismutase (SOD) levels, along with a reduction in the intracellular NADPH/NADP⁺ ratio and pyruvate content. These changes collectively contribute to the thermotolerance of P. kudriavzevii. CRISPR-Cas9-mediated knockout experiments further highlighted the critical roles of HSPs, antioxidases, and the trehalose metabolic pathway in the yeast's response to high temperatures.

Conclusions: Taken together, this study demonstrates that P. kudriavzevii adapts to thermal stress through a combination of enhanced TCA cycle, reduced PPP, increased HSPs, trehalose, GSH, and SOD levels. These findings provide a comprehensive understanding of the molecular mechanisms underlying thermotolerance in P. kudriavzevii.

Background: The rhythmic mating behavior of insects has been extensively documented, yet the regulation of this behavior through sex pheromone sensing olfactory genes affected by the clock genes in the rhythm pathway remains unclear.

Results: In this study, we investigated the impact of circadian rhythm on female recognition of male rectal Bacillus-produced sex pheromone in B. dorsolis. Behavioral and electrophysiological assays revealed a peak in both mating behavior and response to sex pheromones in the evening in females. Comparative transcriptome analysis of female heads demonstrated rhythmic expression of the Timeless gene-Tim and odorant binding protein gene-Pbp5, with the highest expression levels occurring in the evening. Protein structural modeling, tissue expression patterns, RNAi treatment, and physiological/behavioral studies supported Pbp5 as a sex pheromone binding protein whose expression is affected by Tim. Furthermore, manipulation of the female circadian rhythm resulted in increased morning mating activity, accompanied by consistent peak expression of Tim and Pbp5 during this time period. These findings provide evidence that insect mating behavior can be modulated by clock genes through their effects on sex pheromone sensing processes.

Conclusions: Our results also contribute to a better understanding of the molecular mechanisms underlying rhythmic insect mating behavior.

Background: Sex chromosome (SC) evolution is a longstanding topic of focus in evolutionary biology. Teleosts often exhibit rapid turnover of SCs and sex-determining (SD) genes, alongside a diverse range of SC differentiation mechanisms.

Results: On the basis of new chromosome-scale assemblies of three Silurus species (S. microdorsalis, S. glanis, and S. lanzhouensis) and two outgroup species (Pterocryptis cochinchinensis and Kryptopterus bicirrhis), along with our previous assemblies of S. meridionalis and S. asotus, we traced the evolution of SC in the Silurus genus (Siluriformes), following the fate of the known SD gene amhr2y. Phylogenetic analysis showed that amhr2y occurred at least before the divergence of Pterocryptis, Kryptopterus, and Silurus and lost in P. cochinchinensis and K. bicirrhis. Chr24 has become the SC in the ancestor of five Silurus species due to the duplication-and-translocation of amhr2 mediated by LTR transposon. Then, a proto Y was formed and maintained with a shared 60 kb male-specific region of the Y chromosome (MSY) by transposable elements (TEs) expansion and gene gathering. Due to the continuous TEs accumulation, genes other than amhr2y in MSYs have degenerated or been lost, while non-recombinant regions continue to expend, forming MSYs of different sizes in different Silurus species (from 320 to 550 kb). Two turnover events, one homologous (from the left arm to the right arm of Chr24) and one nonhomologous (from Chr24 to Chr5), occurring among five Silurus species were possibly mediated by hAT and Helitron transposons.

Conclusions: Our results on the dynamic evolutionary trajectory of SD gene amhr2y, MSYs, and SCs in Silurus catfish indicated the variability and diversity of fish SCs and confirmed that frequent turnover is an important way to maintain the homology and low differentiation of fish SCs.

Background: BMP signaling is responsible for the second body axis patterning in Bilateria and in the bilaterally symmetric members of the bilaterian sister clade Cnidaria-corals and sea anemones. However, medusozoan cnidarians (jellyfish, hydroids) are radially symmetric, and yet their genomes contain BMP signaling components. This evolutionary conservation suggests that BMP signaling must have other functions not related to axial patterning, which keeps BMP signaling components under selective pressure.

Results: To find out what these functions might be, we generated a detailed whole-body atlas of BMP activity in the sea anemone Nematostella. In the adult polyp, we discover an unexpected diversity of domains with BMP signaling activity, which is especially prominent in the head, as well as across the neuro-muscular and reproductive parts of the gastrodermis. In accordance, analysis of two medusozoan species, the true jellyfish Aurelia and the box jellyfish Tripedalia, revealed similarly broad and diverse BMP activity.

Conclusions: Our study reveals multiple, distinct domains of BMP signaling in Anthozoa and Medusozoa, supporting the versatile nature of the BMP pathway across Cnidaria. Most prominently, BMP signaling appears to be involved in tentacle formation, neuronal development, and gameto- or gonadogenesis.

Background: When a species changes its host preference, it often requires modifications in its sensory systems. Many of these changes remain largely uninvestigated in the global fruit pest Drosophila suzukii (also known as spotted wing Drosophila, SWD). This species, which shares a last common ancestor with the model organism D. melanogaster-a species that prefers overripe fruits- ~ 15 million years ago, has shifted its preference from overripe to ripe, soft-skinned fruits, causing significant damage to fruit industries worldwide.

Results: Here, we functionally characterized the coeloconic sensilla in D. suzukii and compared their responses to those of its close relatives, D. biarmipes and D. melanogaster. We find that D. suzukii's responses are grouped into four functional types. These responses are consistent across sexes and reproductive status. The odorant receptor co-receptor Orco is required for certain responses. Comparative analysis across these species revealed evolutionary changes in physiological and behavioral responses to specific odorants, such as acetic acid, a key indicator of microbial fermentation, and phenylacetaldehyde, an aromatic compound found in a diverse range of fruits. Phenylacetaldehyde produced lower electrophysiological responses in D. suzukii compared to D. melanogaster and elicited strong attraction in D. suzukii but not in any of the other tested species.

Conclusions: The olfactory changes identified in this study likely play a significant role in the novel behavior of D. suzukii. This work also identifies phenylacetaldehyde as a potent attractant for D. suzukii, which can be used to develop targeted management strategies to mitigate the serious impact of this pest.

Background: Proteolysis targeting chimera (PROTAC), a novel drug discovery strategy, utilizes the ubiquitin-proteasome system to degrade target proteins in cells. While Western blotting, mass spectrometry, and Lumit Immunoassay have been instrumental in determining protein levels, the rapid screening of PROTACs continues to pose challenges, necessitating the development of alternative methodologies.

Results: We herein reported an alternative high-throughput method for screening PROTACs using a dual-reporter system expressing a Renilla luciferase (RLUC)-fused target protein and enhanced green fluorescent protein (EGFP). EGFP served as an internal reference and RLUC as an indicated target protein degradation. Rapid measurement of EGFP or RLUC light signals was achieved using a fluorescence/luminescence plate-based reader in the endpoint mode. The feasibility of the screening model was tested using ARV110, a clinical trial-stage PROTAC targeting the androgen receptor (AR). In EGFP/RLUC-tAR-expressing modal cells treated with varying concentrations of ARV110, normalized RLUC luminescence decreased dose-dependently, as confirmed via western blotting detection of AR expression. Then the platform was used to practically screen Sirtuin 2 (SIRT2) degraders from a small group of PROTACs that we built. Normalized RLUC luminescence changes in model cells expressing EGFP/RLUC-SIRT2 reflected the degradation efficiencies of PROTACs. Compounds 128 and 129 exhibited the highest degradation efficacies, leading to dose-dependent degradation of endogenous SIRT2 protein in the MCF-7 cell line and inducing cell growth arrest.

Conclusions: The dual-reporter system using both fluorescence and chemiluminescence was successfully constructed. Using this method, we identified effective candidate PROTACs against SIRT2. The dual-reporter system may accelerate drug discovery during PROTAC development.