Communications Biology最新文献

Despite much promise in overcoming drug-resistant infections, clinical studies of bacteriophage antibacterial therapy have failed to show durable effectiveness. Although lysogeny plays an important role in bacterial physiology, its significance in diverse microbiomes remains unclear. Here, we tested the following hypotheses: 1) urinary microbiome phage populations switch to a higher relative proportion of temperate phages, and 2) the activity of the phage recombination machinery (integration/excision/transposition) is higher during human urinary tract infections (UTIs) than in non-infected urinary tracts. Using human urine, model organisms, mass spectrometry, gene expression analysis, and the phage phenotype prediction model BACPHLIP, the results corroborated our hypotheses at the functional protein and gene levels. From a human health perspective, these data suggest that temperate phages may facilitate bacterial infections rather than function as protective agents. These findings support the use of lysogenic phages as therapeutic Trojan Horses.

How and to what extent mosquito-virus interaction is influenced by climate change is a complex question of ecological and epidemiological relevance. We worked at the intersection between thermal biology and vector immunology and studied shifts in tolerance and resistance to the cell fusing agent virus (CFAV), a prominent component of the mosquito virome known to contribute to shaping mosquito vector competence, in warm-acclimated and warm-evolved Aedes albopictus mosquitoes. We show that the length of the thermal challenge influences the outcome of the infection with warm-evolved mosquitoes being more tolerant to CFAV infection, while warm-acclimated mosquitoes being more resistant and suffering from extensive fitness costs. These results highlight the importance of considering fluctuations in vector immunity in relation to the length of a thermal challenge to understand natural variation in vector response to viruses and frame realistic transmission models.

Enzalutamide is a potent second-generation antiandrogen commonly used to treat hormone-sensitive and castration-resistant prostate cancer (CRPC) patients. While initially effective, the disease almost always develops resistance. Given that many enzalutamide-resistant tumors lack specific somatic mutations, there is strong evidence that epigenetic factors can cause enzalutamide resistance. To explore how resistance arises, we systematically test all epigenetic modifiers in several models of castration-resistant and enzalutamide-resistant prostate cancer with a custom epigenetic CRISPR library. From this, we identify and validate SMARCC2, a core component of the SWI/SNF complex, that is selectivity essential in enzalutamide-resistant models. We show that the chromatin occupancy of SMARCC2 and BRG1 is expanded in enzalutamide resistance at regions that overlap with CRPC-associated transcription factors that are accessible in CRPC clinical samples. Overall, our study reveals a regulatory role for SMARCC2 in enzalutamide-resistant prostate cancer and supports the feasibility of targeting the SWI/SNF complex in late-stage PCa.

The cuticle is a polymeric membrane covering all plant aerial organs of primary origin. It regulates water loss and defends against environmental stressors and pathogens. Despite its significance, understanding of the micro-mechanical properties of the cuticle (cuticular membrane; CM) remains limited. In this study, non-invasive Brillouin light scattering (BLS) spectroscopy was applied to probe the micro-mechanics of native CM, dewaxed CM (DCM), and isolated cutin matrix (CU) of mature apple fruit. The BLS signal arises from the photon interaction with thermally induced pressure waves and allows for imaging with mechanical contrast. The derived loss tangent showed significant differences with wax extraction from the CM and further with carbohydrate extraction from the DCM, consistent with tensile test results. Spatial heterogeneity between anticlinal and periclinal regions was observed by BLS microscopy of CM and DCM, but not in CU. The key conclusions are: (1) BLS is sensitive to micro-mechanical variations, particularly the strain-stiffening effect of the cutin framework, offering insights into the CM's micro-mechanical behavior and underlying chemical structures; (2) CM and DCM exhibit spatial micro-mechanical heterogeneity between periclinal and anticlinal regions.

Phosphodiesterase 4D interacting protein (PDE4DIP) is a Golgi/centrosome-associated protein that plays critical roles in the regulation of microtubule dynamics and maintenance of the Golgi structure. However, its biological role in human cancer remains largely unknown. In this study, we showed that PDE4DIP is overexpressed in human non-small cell lung cancer (NSCLC) tissues and that upregulated PDE4DIP expression is associated with poor prognosis in patients with lung cancer. We demonstrated that PDE4DIP knockdown inhibits NSCLC cell proliferation in vitro and tumorigenicity in vivo. We further demonstrated that PDE4DIP knockdown triggers apoptosis and cell cycle arrest in NSCLC cells by activating the Protein kinase A (PKA) /CREB signalling pathway. PDE4DIP coordinates with A-kinase anchoring proteins 9 (AKAP9) to enhance the Golgi localization and stability of PKA RIIα. Depletion of PDE4DIP mislocalizes PKA RIIα from the Golgi and leads to its degradation, thereby compromising its negative regulatory effect on PKA signalling. Overall, our findings provide novel insights into the roles of the PDE4DIP-AKAP9 complex in regulating PKA signalling and NSCLC growth and highlight PDE4DIP as a promising therapeutic target for NSCLC.

Peptide-based drugs often fail in clinical trials due to their toxicity or hemolytic activity against red blood cells (RBCs). Existing methods predict hemolytic peptides but not the concentration (HC₅₀) required to lyse 50% of RBCs. This study develops classification and regression models to identify and quantify hemolytic activity. These models train on 1926 peptides with experimentally determined HC₅₀ against mammalian RBCs. Analysis indicates that hydrophobic and positively charged residues were associated with higher hemolytic activity. Among classification models, including machine learning (ML), quantum ML, and protein language models, a hybrid model combining random forest (RF) and a motif-based approach achieves the highest area under the receiver operating characteristic curve (AUROC) of 0.921. Regression models achieve a Pearson correlation coefficient (R) of 0.739 and a coefficient of determination (R²) of 0.543. These models outperform existing methods and are implemented in HemoPI2, a web-based platform and standalone software for designing peptides with desired HC₅₀ values ( http://webs.iiitd.edu.in/raghava/hemopi2/ ).

The understanding of selective forces driving the compartmentalization of microbiota in plants remains limited. In this study, we performed a phenotypic characterization of bacterial endophytes isolated from the medicinal plant Origanum heracleoticum, together with the determination of the antibiotic resistance profiles and the antagonistic interactions of communities within and across different plant organs. Results revealed organ-related differences in the metabolic capabilities of bacteria, with those associated with stems displaying the highest metabolic activity for carbon sources. Contrarily, the patterns of antibiotic resistance appeared closely aligned with the taxonomical classification of the endophytes. The presence of antagonistic interactions, likely spurred by resource limitations, favor bacteria exhibiting greater metabolic plasticity. In conclusion, this research advances our comprehension of the intricate dynamics between plants and their associated microbiota, indicating that its composition is mainly influenced by forces contributing to the selection of distinct functions and phenotypic traits.

A cognitive map is an internal model of the world's causal structure, crucial for adaptive behaviors. The orbitofrontal cortex (OFC) is central node to decision-making and cognitive map representation. However, it remains unclear how the medial OFC (mOFC) and lateral OFC (lOFC) contribute to the formation of cognitive maps in humans. By performing a multi-step sequential task and multivariate analyses of functional magnetic resonance imaging (fMRI) data, we found that the mOFC and lOFC play complementary but dissociable roles in this process. Specifically, the mOFC represents all hidden task state components. The lOFC and dorsolateral prefrontal cortex (dlPFC) encode abstract rules governing structure knowledge across task states. Furthermore, the two orbitofrontal subregions are functionally connected to share state-hidden information for constructing a representation of the task structure. Collectively, these findings provide an account that can increase our understanding of how the brain constructs abstract cognitive maps in a task-relevant space.

Human induced pluripotent stem cell (iPSC)-derived lung organoids, engineered to carry targeted genes, offer a robust platform for investigating mechanistic insights in lung research. Although lentiviral vectors (LVVs) are highly effective for stable expression due to their integrative properties, achieving efficient transduction in human iPSC-derived lung organoids poses a significant technical challenge, likely due to the complex structure of these organoids. In this study, we optimized a method to enhance LVV transduction efficiency by physically disrupting the organoids to increase surface area, followed by spinoculation to apply shear force during cell dissociation. This approach, combined with the use of an optimized culture medium, significantly improved transduction efficiency. The success of this method was validated at both the gene and protein levels using single-cell RNA sequencing (scRNA-seq) and various cellular and molecular assays. Our optimized transduction protocol may provide a valuable tool for investigating specific cellular and molecular mechanisms in development and disease models using human iPSCs-derived lung organoids.