Biology Open最新文献

The B16 murine melanoma cell lines are considered the gold standard for testing melanoma immunotherapies due to low treatment success rates. However, the clinical relevance of these models has been questioned due to a mutational landscape void of driver mutations typically seen in human melanomas and a tendency to form necrotic cores at high tumor volumes. Creating the YUMM1.7 line addressed these limitations by providing an additional contextually consistent model with a more clinically relevant genetic background. The combined use of both models can generate stronger studies in melanoma immunology and immunotherapy. However, to date, there have been no direct functional comparisons of the characteristics of these two models to inform the design of such studies. To address this, we conducted a series of functional experiments to characterize the kinetics of tumor growth, chemotherapeutic sensitivity, and immunogenicity of these models. We found that the B16F0 model had faster intrinsic tumor growth rates, was more susceptible to lysis by tumor-specific CD8+ T cells, and secreted higher levels of the angiogenic factors VEGF and Ang2. Meanwhile, the YUMM1.7 model was more sensitive to chemotherapeutic treatment, secreted higher levels of chemokines CCL2, CXCL1, and CX3CL1, and showed higher infiltration of lymphocyte and myeloid subsets at the same tumor size. Overall, YUMM1.7 model may be better suited for in vivo studies of mechanisms that require a wider observation window and intervention than the B16F0 model, such as immune response. However, angiogenesis and immunotherapy studies may benefit from a more in-depth comparative analyses of both models.

Potato (Solanum tuberosum L.) is a global crop with a vital role in food security and economic significance in many countries. Potato virus Y (PVY) is one of its major viral threats, causing severe yield and quality losses when not controlled properly. PVY spreads primarily through aphids and infected tubers, and current management relies on insecticides and protective oils. Novel detection methods are needed to identify infected plants accurately at an early stage of plant development, thus reducing pesticide use. Trained honeybees (Apis mellifera L.) can detect specific volatiles emitted by plants infected by viruses like PVY. Using associative conditioning and the proboscis extension reflex, we tested the capacity of harnessed worker bees to distinguish PVY-infected and healthy potato leaves as a first step towards field application. As a whole, the results were impeded by low response levels and no significant result was obtained. However, we were able to show the capability of honeybees to learn and differentiate between two conditioned stimuli (healthy potato leaves versus clean air). Our findings therefore suggest that honeybees, as a globally accessible resource, have the potential to be used as a cost-effective solution in crop health monitoring, with further investigation and protocol refinement needed to achieve accurate PVY detection in agricultural settings.

Reactivation of transposable elements (TEs) in somatic tissues, particularly of LINE-1, is associated with disease by causing gene mutations and DNA damage. Previous work has shown that the PIWI pathway is crucial for TE suppression in the germline. However, the status and function of this pathway is not well characterized in differentiated somatic cells and there is a lack of consensus on the role of the pathway in somatic tumorigenesis. To shed light on this conundrum, we examined the PIWI pathway in colon cancer through combining bioinformatic analyses and cell-based assays. Shifted weighted annotation network (SWAN) analysis revealed that the pathway experiences significant allelic losses in colon cancer and that PIWIL2, the main catalytic component of the pathway responsible for TE silencing, experiences the highest percent deletions. PIWIL2 is downregulated in colon tumors of advanced stage, nodal metastasis, and in certain subtypes, correlating with poor survival, while it is also downregulated in ulcerative colitis, an inflammatory bowel disease that predisposes to colon cancer. PIWIL2 depletion in colon epithelial Caco2 cells leads to increased anchorage-independent growth, decreased levels of TE-targeting non-canonical piRNAs, increased LINE-1 levels and activity, and in DNA damage, altogether highlighting a tumor-suppressing role of PIWIL2 in the colon.

Results of recent research show that bats perform flights with continual altitude changes rather than flying at a constant altitude. However, the current state of knowledge suggests that the reason for these altitude changes is not known, and it is stated in the literature that further study is necessary in order to understand this behaviour. The goal of this paper is to provide an explanation by showing that flights with continual altitude changes constitute a fuel-saving flight mode in bats. The descents in the altitude changes - which were analysed using flight measurement data - show a power support by flapping the wings to yield a powered glide. Accordingly, this flight mode may be termed powered-gliding/climbing flight. Corresponding to the described flight characteristics, powered-gliding/climbing flight can be seen as an extension of flap-gliding flight, which is a flight mode known in the research on animal flight. This paper shows that the powered glide enables a decrease in aerodynamic drag, as well as an explanation of the underlying physical mechanism. I also developed a flight mechanics model of powered/gliding climbing flight in bats. Results based on this model show that fuel consumption can be reduced. Thus, a substantial fuel saving can be achieved when compared with the best flight at constant altitude, which is classically considered as the flight mode requiring the lowest fuel consumption.

Loss of structural habitat complexity associated with habitat degradation in marine systems may expose early life stages of fishes to harsh environmental conditions. Specifically, loss of coral cover means less suitable refuge is available for some reef fish species to lay their eggs, exposing them to pervasive stressors such as ultraviolet radiation (UVR). Here, using laboratory experiments, we exposed embryos of the clownfish Amphiprion ocellaris for 2 h daily to two UVR levels reflective of their depth at settlement; high UVR (280 µW m-2), reflective of shallow depths, and low UVR (80 µW m-2), reflective of deeper depths over their embryonic period, and then measured changes in mass, yolk sac volume, DNA damage, and survival. Despite being exposed to ecologically relevant levels of UV radiation, there was 100% mortality before hatching and inflated yolk sacs in both high and low UVR-treated animals. Exposure to UVR also resulted in DNA damage, albeit only in high UVR treatments. It is evident from our results that the protection that the reef can offer from UVR is critical for the survival of clownfish. Our results also underscore the need for future work to consider this often-neglected stressor and the role of adequate refuge for the healthy development of early-life stages of reef organisms.

The thalamic dorsolateral geniculate nucleus (dLGN) receives visual input from the retina via the optic nerve, and projects to the cortical visual area, where eye-derived signals are elaborated. The transcription factors SOX2 and NR2F1 are directly involved in the differentiation of dLGN neurons, based on mouse work and patient mutations leading to vision defects. However, whether they regulate each other, or control common targets is still unclear. By RNA-seq analysis of neonatal dLGN from thalamo-specific Sox2 and Nr2f1 mouse mutants, we found a striking overlap of deregulated genes. Among them, Vgf, encoding a cytokine transported along thalamic-cortical axons is strongly downregulated in both mutants. Direct SOX2 binding to some of these genes was confirmed by CUT&RUN, which identified a SOX2 chromatin-binding pattern characteristic of the dLGN. Collectively, our genetic and molecular analyses on the SOX2 and NR2F1-coregulated genes contribute to our understanding of the gene regulatory network driving the differentiation and connectivity of thalamic neurons, and the vision impairments caused by mutations in these genes.

Glutathione S transferase pi-1 (GSTP1) is a detoxification enzyme essential for oxidative homeostasis. In cancer, GSTP1 has been implicated in tumorigenicity, cell cycle progression, and chemoresistance. While GSTP1 depletion has been associated with decreased cancer growth in various models, the mechanism remains poorly understood. This study investigates GSTP1 as a therapeutic target for pancreatic ductal adenocarcinoma (PDAC) using inducible knockdown models. We demonstrate that GSTP1 loss disrupts redox balance, impairs cell survival, and induces metabolic adaptations. Multiomics analysis characterized the global impact of inducible GSTP1 knockdown on the transcriptome and proteome of PDAC cells, identifying 550 differentially expressed genes and 62 proteins. Notably, 43 of these showed consistent regulation at both the mRNA and protein levels. We identify dysregulation of key stress response proteins, including dimethylarginine dimethylaminohydrolase 1 (DDAH1), involved in nitric oxide metabolism, and protein disulfide isomerase A6 (PDIA6), which maintains protein homeostasis. The interplay between GSTP1, DDAH1 and PDIA6 highlights the complexity of redox regulation in pancreatic cancer and suggests that targeting GSTP1 may offer a new therapeutic approach for PDAC.

Zebrafish is a valuable model for antiangiogenic drug testing. We hypothesized that the efficacy of antiangiogenic compounds might vary in hypoxic tissue environments compared to normal tissue. To explore this, we established a chemically induced zebrafish model using DMOG, which inhibits prolyl hydroxylases, and a genetic model by knocking out vhl gene via CRISPR/Cas9 to activate hypoxia signaling. In wild-type larvae, the antiangiogenic drug sorafenib inhibited blood vessel growth. However, in the DMOG model and vhl-/- model, no inhibition occurred in sub-intestinal vessel (SIV) upon sorafenib treatment. Also, gene expression analysis showed that the DMOG induced hypoxia had 20-fold increase in phd3 expression, a marker for hypoxia signaling activation, which rose to 65-fold and 280-fold with sorafenib treatment at the concentration 0.1 μM and 0.2 μM, respectively. In the vhl-/- model phd3 expression was found to be increased to 220-fold and reaching up to 400-fold with sorafenib treatment. This increased activation of hypoxia signaling elevated the proangiogenic factors like vegfaa, vegfab and vegfd, which might have protected the SIV region from sorafenib treatment in hypoxic models. This confirms that the hypoxia zebrafish models gained resistance against chemotherapeutic drugs by increasing the cellular hypoxia levels. Thus, our zebrafish model for hypoxia provides evidence that the efficacy of chemotherapy for cancer significantly depends on hypoxic microenvironment.

Diversin is a vertebrate homolog of the core planar cell polarity (PCP) protein Diego. Here we studied the function of Diversin in Xenopus embryo morphogenesis and its subcellular localization at different locations in superficial ectoderm cells. Depletion of Diversin in the neuroectoderm inhibited apical domain size and neural tube closure and disrupted the polarized localization of endogenous Vangl2, another PCP protein. Whereas Diversin puncta were randomly distributed in early ectoderm, they acquired planar polarity in the neuroectoderm in a stage- and position-specific manner. We find that Diversin is accumulated at the cell junctions adjacent to apically constricting cells at the Xenopus neural plate border and the gastrula blastopore lip. Moreover, Diversin cytoplasmic puncta redistributed in the direction of the pulling forces from the cells with constricting apical domains, suggesting a mechanosensitive process. PCP complexes of Dishevelled (Dvl2) and Diversin or the mechanosensitive adaptor ADIP exhibited planar polarity in the neural plate and the wound edge and promoted wound healing. We propose that Diversin- and Dvl2-containing PCP complexes control morphogenesis in a tension-dependent manner.