Efficacy and Safety of Topical Traditional Chinese Medicine Monotherapy in Persistent HPV Infection Among Males.

Objective: We studied the efficacy and safety of traditional Chinese medicine paiteling treatment of persistent human papillomavirus (HPV) infection in males. Methods: The study included 159 male patients with persistent HPV infection between January 2018 and July 2022, and categorized into the treatment group (n = 96) and control group (n = 63) based on the treatment. The treatment group was externally treated with paiteling diluent for 4 consecutive days and then stopped for 3 days. The total course of treatment was one month. The treatment group underwent a second test six months after treatment. The control group did not receive any therapy and underwent a second test in the seventh month. Results: 19 of the 159 patients were lost during the 6-month follow-up period, leaving 140 patients. The male HPV infection peaks between the ages of 26-35 years 73(52.14%), and its prevalence decrease with age. 84 (60.0%) were single type infections, and 22 (15.71%) had at least 3 types infections. There were 76 (54.29%) patients with the high-risk types, 34 (24.29%) with the low-risk types, and 30 (21.43%) with the mixed types. After 6 months, complete negative conversion rates and negative conversion rates were 74.7% and 90.8% in the treatment group respectively, compared to the control group (P < .01). A comparison of negative conversion rates among different types reveals that 16 type (89.5%) and 6 type (92.3%) had statistical differences, (P < .01) and (P < .05) respectively. Multivariate analysis revealed that the vaccine status of sexual partners was a protective factor (OR = 0.050-0.848) and multi-type infection was a risk factor (OR = 1.807-22.527) for the curative effect. Conclusion: Paiteling is convenient, safe, and effective for the treatment of persistent HPV infection in males.

Transcriptomics analysis of LINC02202/XBP1 axis in melanoma: Implications for drug targeting and PD-1 monoclonal antibody efficacy.

Malignant melanoma (MM) is a highly aggressive and deadly form of skin cancer, primarily caused by recurrence and metastasis. Therefore, it is crucial to investigate the regulatory mechanisms underlying melanoma recurrence and metastasis. Our study has identified a potential targeted regulatory relationship between LINC02202, miR-526b-3p and XBP1 in malignant melanoma. Through the regulation of the miR-526b-3p/XBP1 signalling pathway, LINC02202 may play a role in tumour progression and immune infiltration and inhibiting the expression of LINC02202 can increase the efficacy of immunotherapy for melanoma. Our findings shed light on the impact of LINC02202/XBP1 on the phenotype and function of malignant melanoma cells. Furthermore, this study provides a theoretical foundation for the development of novel immunotherapy strategies for malignant melanoma.

Repeat DNA methylation is modulated by adherens junction signaling.

Through its involvement in gene transcription and heterochromatin formation, DNA methylation regulates how cells interact with their environment. Nevertheless, the extracellular signaling cues that modulate the distribution of this central chromatin modification are largely unclear. DNA methylation is highly abundant at repetitive elements, but its investigation in live cells has been complicated by methodological challenges. Utilizing a CRISPR/dCas9 biosensor that reads DNA methylation of human α-satellite repeats in live cells, we here uncover a signaling pathway linking the chromatin and transcriptional state of repetitive elements to epithelial adherens junction integrity. Specifically, we find that in confluent breast epithelial cell monolayers, α-satellite repeat methylation is reduced by comparison to low density cultures. This is coupled with increased transcriptional activity at repeats. Through comprehensive perturbation experiments, we identify the junctional protein E-cadherin, which links to the actin cytoskeleton, as a central molecular player for signal relay into the nucleus. Furthermore, we find that this pathway is impaired in cancer cells that lack E-cadherin and are not contact-inhibited. This suggests that the molecular connection between cell density and repetitive element methylation could play a role in the maintenance of epithelial tissue homeostasis.

Learning Dynamics from Multicellular Graphs with Deep Neural Networks.

The inference of multicellular self-assembly is the central quest of understanding morphogenesis, including embryos, organoids, tumors, and many others. However, it has been tremendously difficult to identify structural features that can indicate multicellular dynamics. Here we propose to harness the predictive power of graph-based deep neural networks (GNN) to discover important graph features that can predict dynamics. To demonstrate, we apply a physically informed GNN (piGNN) to predict the motility of multi-cellular collectives from a snapshot of their positions both in experiments and simulations. We demonstrate that piGNN is capable of navigating through complex graph features of multicellular living systems, which otherwise can not be achieved by classical mechanistic models. With increasing amounts of multicellular data, we propose that collaborative efforts can be made to create a multicellular data bank (MDB) from which it is possible to construct a large multicellular graph model (LMGM) for general-purposed predictions of multicellular organization.

An interpenetrating-network theory of cytoplasm.

Under many physiological and pathological conditions such as division and migration, cells undergo dramatic deformations, under which their mechanical integrity is supported by cytoskeletal networks (i.e. intermediate filaments, F-actin, and microtubules). Recent observations of cytoplasmic microstructure indicate interpenetration among different cytoskeletal networks, and micromechanical experiments have shown evidence of complex characteristics in the mechanical response of the interpenetrating cytoplasmic networks of living cells, including viscoelastic, nonlinear stiffening, microdamage, and healing characteristics. However, a theoretical framework describing such a response is missing, and thus it is not clear how different cytoskeletal networks with distinct mechanical properties come together to build the overall complex mechanical features of cytoplasm. In this work, we address this gap by developing a finite-deformation continuum-mechanical theory with a multi-branch visco-hyperelastic constitutive relation coupled with phase-field damage and healing. The proposed interpenetrating-network model elucidates the coupling among interpenetrating cytoskeletal components, and the roles of finite elasticity, viscoelastic relaxation, damage, and healing in the experimentally-observed mechanical response of interpenetrating-network eukaryotic cytoplasm.

Local response and emerging nonlinear elastic length scale in biopolymer matrices.

Nonlinear stiffening is a ubiquitous property of major types of biopolymers that make up the extracellular matrices (ECM) including collagen, fibrin, and basement membrane. Within the ECM, many types of cells such as fibroblasts and cancer cells have a spindle-like shape that acts like two equal and opposite force monopoles, which anisotropically stretch their surroundings and locally stiffen the matrix. Here, we first use optical tweezers to study the nonlinear force-displacement response to localized monopole forces. We then propose an effective-probe scaling argument that a local point force application can induce a stiffened region in the matrix, which can be characterized by a nonlinear length scale R* that increases with the increasing force magnitude; the local nonlinear force-displacement response is a result of the nonlinear growth of this effective probe that linearly deforms an increasing portion of the surrounding matrix. Furthermore, we show that this emerging nonlinear length scale R* can be observed around living cells and can be perturbed by varying matrix concentration or inhibiting cell contractility.

Expression of vimentin alters cell mechanics, cell-cell adhesion, and gene expression profiles suggesting the induction of a hybrid EMT in human mammary epithelial cells.

Vimentin is a Type III intermediate filament (VIF) cytoskeletal protein that regulates the mechanical and migratory behavior of cells. Its expression is considered to be a marker for the epithelial to mesenchymal transition (EMT) that takes place in tumor metastasis. However, the molecular mechanisms regulated by the expression of vimentin in the EMT remain largely unexplored. We created MCF7 epithelial cell lines expressing vimentin from a cumate-inducible promoter to address this question. When vimentin expression was induced in these cells, extensive cytoplasmic VIF networks were assembled accompanied by changes in the organization of the endogenous keratin intermediate filament networks and disruption of desmosomes. Significant reductions in intercellular forces by the cells expressing VIFs were measured by quantitative monolayer traction force and stress microscopy. In contrast, laser trapping micro-rheology revealed that the cytoplasm of MCF7 cells expressing VIFs was stiffer than the uninduced cells. Vimentin expression activated transcription of genes involved in pathways responsible for cell migration and locomotion. Importantly, the EMT related transcription factor TWIST1 was upregulated only in wild type vimentin expressing cells and not in cells expressing a mutant non-polymerized form of vimentin, which only formed unit length filaments (ULF). Taken together, our results suggest that vimentin expression induces a hybrid EMT correlated with the upregulation of genes involved in cell migration.

Microbial redox coenzyme engineering and applications in biosynthesis.

Many biosynthetic processes, either in vivo or in vitro, involve redox reactions catalyzed by oxidoreductases - which depend on coenzymes as electron carriers. Redox balance is regulated mainly by coenzymes NAD(P)+ and NAD(P)H and is essential for biosynthesis. New techniques for the regulation and regeneration of coenzymes have recently advanced our understanding of, and demonstrated promising applications in, synthetic biology.

Configurational fingerprints of multicellular living systems.

Cells cooperate as groups to achieve structure and function at the tissue level, during which specific material characteristics emerge. Analogous to phase transitions in classical physics, transformations in the material characteristics of multicellular assemblies are essential for a variety of vital processes including morphogenesis, wound healing, and cancer. In this work, we develop configurational fingerprints of particulate and multicellular assemblies and extract volumetric and shear order parameters based on this fingerprint to quantify the system disorder. Theoretically, these two parameters form a complete and unique pair of signatures for the structural disorder of a multicellular system. The evolution of these two order parameters offers a robust and experimentally accessible way to map the phase transitions in expanding cell monolayers and during embryogenesis and invasion of epithelial spheroids.

Spatiotemporally Controlled Photoresponsive Hydrogels: Design and Predictive Modeling from Processing through Application.

Photoresponsive hydrogels (PRHs) are soft materials whose mechanical and chemical properties can be tuned spatially and temporally with relative ease. Both photo-crosslinkable and photodegradable hydrogels find utility in a range of biomedical applications that require tissue-like properties or programmable responses. Progress in engineering with PRHs is facilitated by the development of theoretical tools that enable optimization of their photochemistry, polymer matrices, nanofillers, and architecture. This review brings together models and design principles that enable key applications of PRHs in tissue engineering, drug delivery, and soft robotics, and highlights ongoing challenges in both modeling and application.