Oncogenic Kras induces spatiotemporally specific tissue deformation through converting pulsatile into sustained ERK activation.

Tissue regeneration and maintenance rely on coordinated stem cell behaviours. This orchestration can be impaired by oncogenic mutations leading to cancer. However, it is largely unclear how oncogenes perturb stem cells' orchestration to disrupt tissue. Here we used intravital imaging to investigate the mechanisms by which oncogenic Kras mutation causes tissue disruption in the hair follicle. Through longitudinally tracking hair follicles in live mice, we found that KrasG12D, a mutation that can lead to squamous cell carcinoma, induces epithelial tissue deformation in a spatiotemporally specific manner, linked with abnormal cell division and migration. Using a reporter mouse capture real-time ERK signal dynamics at the single-cell level, we discovered that KrasG12D, but not a closely related mutation HrasG12V, converts ERK signal in stem cells from pulsatile to sustained. Finally, we demonstrated that interrupting sustained ERK signal reverts KrasG12D-induced tissue deformation through modulating specific features of cell migration and division.

UPLC-Q-TOF/MS analysis of chemical components of single decoction and combined decoction of Qige decoction reveals the differences between various preparation processes.

The aim of this work was to explore the differences between various pharmaceutical processes in combined solutions of a single decoction (QGHBY) and a combined decoction (QGHJY) of Qi-Ge decoction from the perspective of chemical composition changes, so as to further guide the clinical application of drugs. A combined solution of a single decoction and a combined decoction of Astragali Radix, Puerariae Lobatae Radix and Citri Reticulatae Chachiensis Pericarpium was prepared with the same technological parameters. The chemical components of the two were detected and identified based on UPLC-Q-TOF/MS, and the different components were determined by principal component analysis. Eighty-eight compounds were identified in the pharmaceutical solution of Qi-Ge decoction. Principal component analysis revealed 11 different components of QGHBY and QGHJY with the conditions of Variable Importance in Projection (VIP) ≥ 1, fold change ≥ 2 and p < 0.05, among which hesperidin, hesperitin, isosinensetin, sinensetin and 5-demethylnobiletin were the components of Citri Reticulatae Chachiensis Pericarpium. The levels of these 11 different components in QGHJY were higher than those of QGHBY. The combined decoction is beneficial for the dissolution of flavonoids and other chemical components, and there is a significant difference in the content of chemical components between modern herbal concentrate granules and traditional decoctions.

Comparative analysis and evaluation of wild and cultivated Radix Fici Simplicissimae using an UHPLC-Q-Orbitrap mass spectrometry-based metabolomics approach.

Radix Fici Simplicissimae (RFS) is widely studied, and is in demand for its value in medicines and food products, with increased scientific focus on its cultivation and breeding. We used ultra-high-performance liquid chromatography quadrupole-orbitrap mass spectrometry-based metabolomics to elucidate the similarities and differences in phytochemical compositions of wild Radix Fici Simplicissimae (WRFS) and cultivated Radix Fici Simplicissimae (CRFS). Untargeted metabolomic analysis was performed with multivariate statistical analysis and heat maps to identify the differences. Eighty one compounds were identified from WRFS and CRFS samples. Principal component analysis and orthogonal partial least squares discrimination analysis indicated that mass spectrometry could effectively distinguish WRFS from CRFS. Among these, 17 potential biomarkers with high metabolic contents could distinguish between the two varieties, including seven phenylpropanoids, three flavonoids, one flavonol, one alkaloid, one glycoside, and four organic acids. Notably, psoralen, apigenin, and bergapten, essential metabolites that play a substantial pharmacological role in RFS, are upregulated in WRFS. WRFS and CRFS are rich in phytochemicals and are similar in terms of the compounds they contain. These findings highlight the effects of different growth environments and drug varieties on secondary metabolite compositions and provide support for targeted breeding for improved CRFS varieties.

The art of observation: bridging science and art to see the unexpected.

Observation is the heart of research, but it can be challenging to observe deeply and go beyond expected observations. Here, we describe activities designed for scientists to enhance their observational skills by engaging with art. In collaboration with an art gallery at our university, our lab practiced observing representational paintings in a systematic way, separating the act of observation from interpretation. Applying this skill to our microscopy images allowed us to access information in the data that may otherwise have been overlooked. In addition, these activities highlighted the power of collecting observations from multiple observers before generating interpretations, as well as the value of discussing the creative and emotional aspects of data collection and interpretation. We provide concrete examples of how we will incorporate these skills into our research processes, as well as details that other groups can use to engage in similar art-based training activities to enhance their own observational skills.

Organ function is preserved despite reorganization of niche architecture in the hair follicle.

The ability of stem cells to build and replenish tissues depends on support from their niche. Although niche architecture varies across organs, its functional importance is unclear. During hair follicle growth, multipotent epithelial progenitors build hair via crosstalk with their remodeling fibroblast niche, the dermal papilla, providing a powerful model to functionally interrogate niche architecture. Through mouse intravital imaging, we show that dermal papilla fibroblasts remodel individually and collectively to form a morphologically polarized, structurally robust niche. Asymmetric TGF-ß signaling precedes morphological niche polarity, and loss of TGF-ß signaling in dermal papilla fibroblasts leads them to progressively lose their stereotypic architecture, instead surrounding the epithelium. The reorganized niche induces the redistribution of multipotent progenitors but nevertheless supports their proliferation and differentiation. However, the differentiated lineages and hairs produced by progenitors are shorter. Overall, our results reveal that niche architecture optimizes organ efficiency but is not absolutely essential for organ function.

PAM variants were associated with type 2 diabetes mellitus risk in the Chinese population.

This study aimed to assess the association between PAM single-nucleotide polymorphisms (SNPs) and T2DM risk in the Chinese population. We performed the genotype of PAM SNPs using Agena MassARRAY in 1002 subjects. The effect of PAM polymorphisms on T2DM occurrence was evaluated by logistic regression analysis. False-positive report probability (FPRP) was utilized to assess the noteworthiness of the significant results. This study showed that PAM rs406761, rs17154889, and rs6889592 were related to an increased risk of T2DM. The similar results were also in subjects with ≤ 60 years. Rs2431320 and rs406761 were related to an increased risk of T2DM in males, and rs6889592 was only found to be associated with T2DM risk in females. Rs2431320 and rs406761 increased T2DM risk in people with BMI > 24, and rs6889592 and rs26431 significantly correlated with T2DM risk in people with BMI ≤ 24. By comparing patients with no retinopathy with controls, the correlation between PAM rs406761 and rs17154889 and T2DM risk was observed. The significant association between T2DM risk and PAM SNPs was remarkable by FPRP values. PAM SNPs were correlated with T2DM risk in the Chinese population, illustrating the importance of PAM SNPs in the pathogenesis of T2DM.

Numerical Studies on Cellulose Hydrolysis in Organic-Liquid-Solid Phase Systems with a Liquid Membrane Catalysis Model.

The catalytic hydrolysis of cellulose to produce 5-hydroxymethylfurfural (HMF) is a powerful means of biomass resources. The current efficient hydrolysis of cellulose to obtain HMF is dominated by multiphase reaction systems. However, there is still a lack of studies on the synergistic mechanisms and component transport between the various processes of cellulose hydrolysis in a complex multiphase system. In this paper, a liquid membrane catalytic model was developed to simulate the hydrolysis of cellulose and its further reactions, including the adsorption of the liquid membrane on cellulose particles, the consumption of cellulose solid particles, the complex chemical reactions in the liquid membrane, and the transfer of HMF at the phase interface. The simulations show the synergistic effect between cellulose hydrolysis and multiphase mass transfer. We defined an indicator () to characterize the sensitivity of HMF yield to the initial liquid membrane thickness at different reaction stages. decreased gradually when the glucose conversion increased from 0 to 80%, and increased with the thickening of the initial liquid membrane thickness. It was shown that the thickening of the initial liquid membrane thickness promoted the HMF yield under the same glucose conversion. In summary, our results reveal the mechanism of the interaction between multiple physicochemical processes of the cellulose liquid membrane reaction system.

Specifically Formed Corona on Silica Nanoparticles Enhances Transforming Growth Factor ß1 Activity in Triggering Lung Fibrosis.

A corona is a layer of macromolecules formed on a nanoparticle surface in vivo. It can substantially change the biological identity of nanomaterials and possibly trigger adverse responses from the body tissues. Dissecting the role of the corona in the development of a particular disease may provide profound insights for understanding toxicity of nanomaterials in general. In our present study, we explored the capability of different silica nanoparticles (SiNPs) to induce silicosis in the mouse lung and analyzed the composition of coronas formed on these particles. We found that SiNPs of certain size and surface chemistry could specifically recruit transforming growth factor ß1 (TGF-ß1) into their corona, which subsequently induces the development of lung fibrosis. Once embedded into the corona on SiNPs, TGF-ß1 was remarkably more stable than in its free form, and its fibrosis-triggering activity was significantly prolonged. Our study meaningfully demonstrates that a specific corona component on a certain nanoparticle could initiate a particular pathogenic process in a clinically relevant disease model. Our findings may shed light on the understanding of molecular mechanisms of human health risks correlated with exposure to small-scale substances.