14 research outputs found
Mammary epithelium‐specific inactivation of V‐ATPase reduces stiffness of extracellular matrix and enhances metastasis of breast cancer
Extracellular matrix (ECM) critically impacts tumor progression and is influenced by both cancer and host tissue cells. While our understanding of cancer cell ECM remodeling is widespread, the importance of host tissue ECM, which provides initial congenial environment for primary tumor formation, is partly understood. Here, we report a novel role of epithelial cell‐associated vacuolar ATPase ‘a2’ isoform (a2V) in regulating breast tissue ECM stiffness to control metastasis. Using a mammary gland‐specific a2V‐knockout model, we show that in the absence of a2V, breast tumors exhibit atypically soft tumor phenotype, less tumor rigidity, and necrotic tumor microenvironment. These tumors contain a decreased number of cancer cells at primary tumor site, but showed extensive metastases compared to control. Nanomechanical evaluation of normal breast tissues revealed a decrease in stiffness and collagen content in ECM of a2V‐deleted breast tissues. Mechanistically, inhibition of a2V expression caused dispersed Golgi morphology with relocation of glycosyltransferase enzymes to early endosomes in mammary epithelial cells. This resulted in defective glycosylation of ECM proteins and production of compromised ECM that further influenced tumor metastasis. Clinically, in patients with cancer, low a2V expression levels in normal breast tissue correlated with lymph node metastasis. Thus, using a new knockout mouse model, we have identified a2V expression in epithelial cells as a key requirement for proper ECM formation in breast tissue and its expression levels can significantly modulate breast tumor dissemination. Evaluation of a2V expression in normal breast tissues can help in identifying patients with high risk of developing metastases
Soluble state high resolution atomic force microscopy study of Alzheimer’s β-amyloid oligomers
We report here the direct observation of high resolution structures of assemblies of Alzheimer β-amyloid oligomers and monomers using liquid atomic force microscopy (AFM). Visualization of nanoscale features of Aβ oligomers (also known as ADDLs) was carried out in tapping mode AFM in F12 solution. Our results indicate that ADDL preparations exist in solution primarily as a mixture of monomeric peptides and higher molecular mass oligomers. Our study clearly reveals that the size and shape of these oligomer aggregates exhibit a pronounced dependence on concentration. These studies show that wet AFM enables direct assessment of oligomers in physiological fluids and suggests that this method may be developed to visualize Aβ oligomers from human fluids
Out-of-Plane Mechanical Properties of 2D Hybrid Organic–Inorganic Perovskites by Nanoindentation
Two-dimensional
(2D) layered hybrid organic–inorganic perovskites
(HOIPs) have demonstrated improved stability and promising photovoltaic
performance. The mechanical properties of such functional materials
are both fundamentally and practically important to achieve both high
performance and mechanically stable (flexible) devices. Here, we report
the mechanical properties of a series of 2D layered lead iodide HOIPs
and investigate the role of structural subunits (e.g., variation of
the length of the organic spacer molecules, R and the number of inorganic
layers, <i>n</i>) in the mechanical properties. Although
2D HOIPs have much lower nominal elastic modulus and hardness than
3D HOIPs, larger <i>n</i> number and shorter R lead to stiffer
materials. Density functional theory simulations showed a trend similar
to the experimental results. We compared these findings with other
2D layered crystals and shed light on routes to further tune the out-of-plane
mechanical properties of 2D layered HOIPs
Micromachined Chip Scale Thermal Sensor for Thermal Imaging
The
lateral resolution of scanning thermal microscopy (SThM) has
hitherto never approached that of mainstream atomic force microscopy,
mainly due to poor performance of the thermal sensor. Herein, we report
a nanomechanical system-based thermal sensor (thermocouple) that enables
high lateral resolution that is often required in nanoscale thermal
characterization in a wide range of applications. This thermocouple-based
probe technology delivers excellent lateral resolution (∼20
nm), extended high-temperature measurements >700 °C without
cantilever
bending, and thermal sensitivity (∼0.04 °C). The origin
of significantly improved figures-of-merit lies in the probe design
that consists of a hollow silicon tip integrated with a vertically
oriented thermocouple sensor at the apex (low thermal mass) which
interacts with the sample through a metallic nanowire (50 nm diameter),
thereby achieving high lateral resolution. The efficacy of this approach
to SThM is demonstrated by imaging embedded metallic nanostructures
in silica core–shell, metal nanostructures coated with polymer
films, and metal–polymer interconnect structures. The nanoscale
pitch and extremely small thermal mass of the probe promise significant
improvements over existing methods and wide range of applications
in several fields including semiconductor industry, biomedical imaging,
and data storage
Energy landscapes and functions of supramolecular systems.
By means of two supramolecular systems--peptide amphiphiles engaged in hydrogen-bonded β-sheets, and chromophore amphiphiles driven to assemble by π-orbital overlaps--we show that the minima in the energy landscapes of supramolecular systems are defined by electrostatic repulsion and the ability of the dominant attractive forces to trap molecules in thermodynamically unfavourable configurations. These competing interactions can be selectively switched on and off, with the order of doing so determining the position of the final product in the energy landscape. Within the same energy landscape, the peptide-amphiphile system forms a thermodynamically favoured product characterized by long bundled fibres that promote biological cell adhesion and survival, and a metastable product characterized by short monodisperse fibres that interfere with adhesion and can lead to cell death. Our findings suggest that, in supramolecular systems, functions and energy landscapes are linked, superseding the more traditional connection between molecular design and function
Elucidating Molecular Mass and Shape of a Neurotoxic Aβ Oligomer
Alzheimer's
disease (AD), the most prevalent type of dementia,
has been associated with the accumulation of amyloid β oligomers
(AβOs) in the central nervous system. AβOs vary widely
in size, ranging from dimers to larger than 100 kDa. Evidence indicates
that not all oligomers are toxic, and there is yet no consensus on
the size of the actual toxic oligomer. Here we used NU4, a conformation-dependent
anti-AβO monoclonal antibody, to investigate size and shape
of a toxic AβO assembly. By using size-exclusion chromatography
and immuno-based detection, we isolated an AβO-NU4 complex amenable
for biochemical and morphological studies. The apparent molecular
mass of the NU4-targeted oligomer was 80 kDa. Atomic force microscopy
imaging of the AβO-NU4 complex showed a size distribution centered
at 5.37 nm, an increment of 1.5 nm compared to the size of AβOs
(3.85 nm). This increment was compatible with the size of NU4 (1.3
nm), suggesting a 1:1 oligomer to NU4 ratio. NU4-reactive oligomers
extracted from AD human brain concentrated in a molecular mass range
similar to that found for in vitro prepared oligomers, supporting
the relevance of the species herein studied. These results represent
an important step toward understanding the connection between AβO
size and toxicity
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Structured silicon for revealing transient and integrated signal transductions in microbial systems
Bacterial response to transient physical stress is critical to their homeostasis and survival in the dynamic natural environment. Because of the lack of biophysical tools capable of delivering precise and localized physical perturbations to a bacterial community, the underlying mechanism of microbial signal transduction has remained unexplored. Here, we developed multiscale and structured silicon (Si) materials as nongenetic optical transducers capable of modulating the activities of both single bacterial cells and biofilms at high spatiotemporal resolution. Upon optical stimulation, we capture a previously unidentified form of rapid, photothermal gradient–dependent, intercellular calcium signaling within the biofilm. We also found an unexpected coupling between calcium dynamics and biofilm mechanics, which could be of importance for biofilm resistance. Our results suggest that functional integration of Si materials and bacteria, and associated control of signal transduction, may lead to hybrid living matter toward future synthetic biology and adaptable materials