Molecular basis of conformational changes and mechanics of integrins.

Integrin, as a mechanotransducer, establishes the mechanical reciprocity between the extracellular matrix (ECM) and cells at integrin-mediated adhesion sites. This study used steered molecular dynamics (SMD) simulations to investigate the mechanical responses of integrin with and without 10th type III fibronectin (FnIII) binding for tensile, bending and torsional loading conditions. The ligand-binding integrin confirmed the integrin activation during equilibration and altered the integrin dynamics by changing the interface interaction between β-tail, hybrid and epidermal growth factor domains during initial tensile loading.

Interstitial fluid flow contributes to prostate cancer invasion and migration to bone; study conducted using a novel horizontal flow bioreactor.

Prostate cancer bone metastasis is the leading cause of cancer-related mortality in men in the United States, causing severe damage to skeletal tissue. The treatment of advanced-stage prostate cancer is always challenging due to limited drug treatment options, resulting in low survival rates. There is a scarcity of knowledge regarding the mechanisms associated with the effects of biomechanical cues by the interstitial fluid flow on prostate cancer cell growth and migration.

Nanoclays in medicine: a new frontier of an ancient medical practice.

Clays have been used as early as 2500 BC in human civilization for medicinal purposes. The ease of availability, biocompatibility, and versatility of these unique charged 2D structures abundantly available in nature have enabled the extensive applications of clays in human history. Recent advances in the use of clays in nanostructures and as components of polymer clay nanocomposites have exponentially expanded the use of clays in medicine.

Molecular and structural basis of actin filament severing by ADF/cofilin.

ADF/cofilin's cooperative binding to actin filament modifies the conformation and alignment of G-actin subunits locally, causing the filament to sever at "boundaries" formed among bare and ADF/cofilin-occupied regions. Analysis of the impact of the ADF/cofilin cluster boundary on the deformation behavior of actin filaments in a mechanically strained environment is critical for understanding the biophysics of their severing. The present investigation uses molecular dynamics simulations to generate atomic resolution models of bare, partially, and fully cofilin decorated actin filaments.

Label-free discrimination of tumorigenesis stages using in vitro prostate cancer bone metastasis model by Raman imaging.

Metastatic prostate cancer colonizes the bone to pave the way for bone metastasis, leading to skeletal complications associated with poor prognosis and morbidity. This study demonstrates the feasibility of Raman imaging to differentiate between cancer cells at different stages of tumorigenesis using a nanoclay-based three-dimensional (3D) bone mimetic in vitro model that mimics prostate cancer bone metastasis. A comprehensive study comparing the classification of as received prostate cancer cells in a two-dimensional (2D) model and cancer cells in a 3D bone mimetic environment was performed over various time intervals using principal component analysis (PCA).

A Coarse-Grained Model for the Mechanical Behavior of Na-Montmorillonite Clay.

Sodium montmorillonite (Na-MMT) is one of the most commonly found swelling clay minerals with diverse engineering and technological applications. The nanomechanical properties of this mineral have been extensively investigated computationally utilizing molecular dynamics (MD) simulations to portray the molecular-level changes at different environmental conditions. As the environmentally found Na-MMT clays are generally sized within hundreds of nanometers, all-atomistic (AA) MD simulations of clays within such size range are particularly challenging due to computational inefficiency.

Nanoarchitectonics of a Microsphere-Based Scaffold for Modeling Neurodevelopment and Neurological Disease.

Three-dimensional cellular constructs derived from pluripotent stem cells allow the study of neurodevelopment and neurological disease within a spatially organized model. However, the robustness and utility of three-dimensional models is impacted by tissue self-organization, size limitations, nutrient supply, and heterogeneity. In this work, we have utilized the principles of nanoarchitectonics to create a multifunctional polymer/bioceramic composite microsphere system for stem cell culture and differentiation in a chemically defined microenvironment.

Binding of SARS-COV-2 (COVID-19) and SARS-COV to human ACE2: Identifying binding sites and consequences on ACE2 stiffness.

The SARS-CoV-2 coronavirus (COVID-19) that is causing the massive global pandemic exhibits similar human cell invasion mechanism as the coronavirus SARS-CoV, which had significantly lower fatalities. The cell membrane protein Angiotensin-converting enzyme 2 (ACE2) is the initiation point for both the coronavirus infections in humans. Here, we model the molecular interactions and mechanical properties of ACE2 with both SARS-CoV and COVID-19 spike protein receptor-binding domains (RBD).

Differences in Interactions Within Viral Replication Complexes of SARS-CoV-2 (COVID-19) and SARS-CoV Coronaviruses Control RNA Replication Ability.

Unlabelled: COVID-19 has become a global pandemic caused by the SARS-CoV-2 coronavirus. SARS-CoV-2 shares many similarities with SARS coronavirus (SARS-CoV). A viral replication complex containing non-structural proteins (nsps) is the toolbox for RNA replication and transcription of both coronaviruses.

Nanostructured Biomaterials for Models of Bone Metastasis Cancer.

In recent years, tissue engineering approaches have attracted substantial attention owing to their ability to create physiologically relevant disease models that closely mimic conditions. Here, we review nanocomposite materials and scaffolds used for the design of models of cancer, including metastatic sites. We discuss the role of material properties in modulating cellular phenotype in 3D disease models.

Evaluation of quasi-static and dynamic nanomechanical properties of bone-metastatic breast cancer cells using a nanoclay cancer testbed.

In recent years, there has been increasing interest in investigating the mechanical properties of individual cells to delineate disease mechanisms. Reorganization of cytoskeleton facilitates the colonization of metastatic breast cancer at bone marrow space, leading to bone metastasis. Here, we report evaluation of mechanical properties of two breast cancer cells with different metastatic ability at the site of bone metastases, using quasi-static and dynamic nanoindentation methods.

Dissociation Mechanisms of G-actin Subunits Govern Deformation Response of Actin Filament.

Actin molecules are essential structural components of the cellular cytoskeleton. Here, we report a comprehensive analysis of F-actin's deformation behavior and highlight underlying mechanisms using steered molecular dynamics simulations (SMD). The investigation of F-actin was done under tension, compression, bending, and torsion.

Wnt/β-Catenin Signaling Pathway Regulates Osteogenesis for Breast Cancer Bone Metastasis: Experiments in an Nanoclay Scaffold Cancer Testbed.

Breast cancer shows a high affinity toward bone, causing bone-related complications, leading to a poor clinical prognosis. The Wnt/β-catenin signaling pathway has been well-documented for the bone regenerative process; however, the regulation of the Wnt/β-catenin pathway in breast cancer bone metastasis is poorly explored. Here, we report that the Wnt/β-catenin signaling pathway has a significant effect on osteogenesis during breast cancer bone metastasis.

Perfusion bioreactor enabled fluid-derived shear stress conditions for novel bone metastatic prostate cancer testbed.

Metastatic prostate cancer spreads preferentially to the bone, causing skeletal complications associated with significant morbidity and a poor prognosis, despite current therapeutic approaches. Hence, it is imperative to understand the complex metastatic cascade to develop therapeutic interventions for treating metastatic prostate cancer. Increasing evidence suggests the synergistic role of biochemical and biophysical cues in cancer progression at metastases.

Mechanobiological evaluation of prostate cancer metastasis to bone using an in vitro prostate cancer testbed.

Prostate cancer exhibits a propensity to metastasize to the bone, which often leads to fatality. Bone metastasis is characterized by complex biochemical, morphological, pathophysiological, and genetic changes to cancer cells as they colonize at bone sites. In this study, we report the evaluation of MDA PCa2b prostate cancer cells' nanomechanical properties during the mesenchymal-to-epithelial transition (MET) and during disease progression at the metastatic site.

Compression of Na-Montmorillonite Swelling Clay Interlayer Is Influenced by Fluid Polarity: A Steered Molecular Dynamics Study.

The compressive responses of an interlayer of the dry sodium-montmorillonite (Na-MMT) swelling clay as well as the clay intercalated with organic fluids of a wide range of dielectric constants from 110 (formamide) to 20 (acetone) are quantitatively evaluated using steered molecular dynamics simulations. Representative dry clay and clay with fluid (clay-fluid) molecular models are constructed, and the stress-strain relationships upon compression of these models are studied using constant force steered molecular dynamics (SMD) simulations. Our results show that the polarity of the fluids and the amount of the fluid molecules in the clay interlayer play a significant role in the interlayer spacing, interlayer volume, interlayer strain, interlayer modulus, nonbonded interactions, and conformation of the fluid molecules upon externally applied stresses.

Bone interface modulates drug resistance in breast cancer bone metastasis.

Metastatic breast cancer cells on arriving at bone site interact with the bone cells to influence their growth, proliferation, and chemoresistance. There are currently no effective therapeutics available in the clinic for bone metastases. Many existing anti-cancer therapeutics are ineffective at the metastatic bone site due to a lack of accurate models of breast cancer bone metastasis for drug screening.

Prostate Cancer Phenotype Influences Bone Mineralization at Metastasis: A Study Using an In Vitro Prostate Cancer Metastasis Testbed.

In this study, two types of prostate cancer cell lines, highly metastatic PC-3 and low metastatic MDA PCa 2b (PCa) were cultured on bone mimetic scaffolds to recapitulate metastasis to bone. A unique in vitro 3D tumor model that uses a sequential culture (SC) of human mesenchymal stem cells followed by seeding with cancer cells after bone formation was initiated to study the phenotype-specific interaction between prostate cancer cells and bone microenvironment. The PCa cells were observed to be less prolific and less metastatic, and to form multicellular tumoroids in the bone microenvironment, whereas PC-3 cells were more prolific and were highly metastatic, and did not form multicellular tumoroids in the bone microenvironment.

Tissue-engineered nanoclay-based 3D in vitro breast cancer model for studying breast cancer metastasis to bone.

Breast cancer (BrCa) preferentially spreads to bone and colonises within the bone marrow to cause bone metastases. To improve the outcome of patients with BrCa bone metastasis, we need to understand better the mechanisms underlying bone metastasis. Researchers have relied heavily upon in vivo xenografts due to limited availability of human bone metastasis samples.

Fourier transform infrared spectroscopy based spectral biomarkers of metastasized breast cancer progression.

Breast cancer is a global health issue and the second leading cause of cancer death in women. Breast cancer tends to migrate to bone and causes bone metastases which is ultimately the cause of death. Here, we report the use of FTIR to identify spectral biomarkers of cancer progression on 3D in vitro model of breast cancer bone metastasis.

In vitro design of mesenchymal to epithelial transition of prostate cancer metastasis using 3D nanoclay bone-mimetic scaffolds.

Nanocomposite scaffolds show extensive applications in regenerative medicine and have shown promise as in vitro analogues of human tissue that can be used for the study of diseases. The complex nature of cancer metastasis is recently investigated using several 3D scaffold models. Herein, we report a polymer-nanoclay-based in vitro tumour model that recapitulates early stage of prostate cancer (PCa) colonization during skeletal metastasis on bone mimetic scaffolds.

Cancer cell mechanics with altered cytoskeletal behavior and substrate effects: A 3D finite element modeling study.

A robust computational model of a cancer cell is presented using finite element modeling. The model accurately captures nuances of the various components of the cellular substructure. The role of degradation of cytoskeleton on overall elastic properties of the cancer cell is reported.

Probing electronic structure of biomineralized hydroxyapatite inside nanoclay galleries.

Hydroxyapatite, the most abundant mineral in the human body, is also an important component in design of biomaterials for bone tissue regeneration. Synthetic hydroxyapatite mineralized in the laboratory often does not exhibit the same biological and morphological properties of biogenic hydroxyapatite in human bone. A biomimetic hydroxyapatite structure is synthesized using biomineralization routes inside the clay galleries of montmorillonite clay.

Sequential culture on biomimetic nanoclay scaffolds forms three-dimensional tumoroids.

In recent times, the limitation of two-dimensional cultures and complexity of in vivo models has paved the way for the development of three-dimensional models for studying cancer. Here we report the development of a new tumor model using PCL/HAPClay scaffolds seeded with a sequential culture of human mesenchymal stem cells (hMSCs) followed by human prostate cancer cells (HPCCs). This nanocomposite system is used as a test-bed for studying cancer metastasis and efficacy of anti-cancer drugs using a polymersome delivery method.

Anisotropic properties of human cortical bone with osteogenesis imperfecta.

The heterogeneity of bone shape and size variation is modulated by genetic, mechanical, nutritional, and hormonal patterning throughout its lifetime. Microstructural changes across cross sections are a result of mechanistic optimization that results over the years of evolution while being based on universal, time-invariant ingredients and patterns. Here we report changes across anatomical sections of bone with osteogenesis imperfecta (OI) that undermines the work of evolution through genetic mutation.