Nanomechanical mapping helps explain differences in outcomes of eye microsurgery: A comparative study of macular pathologies.

Many ocular diseases are associated with an alteration of the mechanical and the material properties of the eye. These mechanically-related diseases include macular hole and pucker, two ocular conditions due to the presence of abnormal physical tractions acting on the retina. A complete relief of these tractions can be obtained through a challenging microsurgical procedure, which requires the mechanical peeling of the internal limiting membrane of the retina (ILM). In this paper, we provide the first comparative study of the nanoscale morphological and mechanical properties of the ILM in macular hole and macular pucker. Our nanoscale elastic measurements unveil a different bio-mechanical response of the ILM in the two pathologies, which correlates well to significant differences occurring during microsurgery. The results here presented pave the way to the development of novel dedicated microsurgical protocols based on the material ILM properties in macular hole or pucker. Moreover, they contribute to clarify why, despite a common aetiology, a patient might develop one disease or the other, an issue which is still debated in literature.

Dynamic structural determinants underlie the neurotoxicity of the N-terminal tau 26-44 peptide in Alzheimer's disease and other human tauopathies.

The intrinsically disordered tau protein plays a pivotal role in the pathogenesis of Alzheimer's disease (AD) and other human tauopathies. Abnormal post-translational modifications of tau, such as truncation, are causally involved in the onset/development of these neurodegenerative diseases. In this context, the AD-relevant N-terminal fragment mapping between 26 and 44 amino acids of protein (tau26-44) is interesting, being endowed with potent neurotoxic effects in vitro and in vivo. However, the understanding of the mechanism(s) of tau26-44 toxicity is a challenging task because, similarly to the full-length tau, it does not have a unique 3D structure but exists as dynamic ensemble of conformations. Here we use Atomic Force Spectroscopy, Small Angle X-ray Scattering and Molecular Dynamics simulation to gather structural and functional information on the tau26-44. We highlight the presence, the type and the location of its temporary secondary structures and we unveil the occurrence of relevant transient tertiary conformations that could contribute to tau26-44 toxicity. Data are compared with those obtained on the biologically-inactive, reverse-sequence (tau44-26 peptide) which has the same mass, charge, aminoacidic composition as well as the same overall unfolded character of tau26-44.

A novel method for post-mortem interval estimation based on tissue nano-mechanics.

Forensic estimation of post-mortem interval relies on different methods, most of which, however, have practical limitations or provide insufficient results, still lacking a gold standard method. In order to better understand the phenomenon of rigor mortis and its applicability to the post-mortem interval estimation, we decided to use atomic force microscopy, a tool often employed to measure mechanical properties of adherent cells. Thus, we surgically removed skeletal muscle samples of three forensic cases from 0 to 120 h post-mortem and quantitatively evaluate two parameters: the Young's modulus (E), which gives information about the sample stiffness, and the hysteresis (H), which estimates the contribution of viscous forces. Despite being a preliminary study, the obtained results show that the temporal behavior of E well correlates with the expected evolution of rigor mortis between 0 and 48 h post-mortem, and then monotonically decreases over time. Unfortunately, it is strongly affected by inter-individual variability. However, we found that H provides measurable data along a time-dependent curve back to the starting point, and these data measured on different subjects collapse onto a single master curve, getting rid of the inter-individual variability. Although a larger sampling should be performed to improve the result reliability, this finding is strongly suggestive that the evaluation of rigor mortis should involve the measure of the nanoscale dissipative behavior of muscular tissues.

Nanoscale mechanics of brain abscess: An atomic force microscopy study.

Mechanical stimuli are a fundamental player in the pathophysiology of the brain influencing its physiological development and contributing to the onset and progression of many diseases. In some pathological states, the involvement of mechanical and physical stimuli might be extremely subtle; in others, it is more evident and particularly relevant. Among the latter pathologies, one of the most serious life-threatening condition is the brain abscess (BA), a focal infection localized in the brain parenchyma, which causes large brain mechanical deformations, giving rise to a wide range of neurological impairments. In this paper, we present the first nano-mechanical characterization of surgically removed human brain abscess tissues by means of atomic force microscopy (AFM) in the spectroscopy mode. Consistently with previous histological findings, we modeled the brain abscess as a multilayered structure, composed of three main layers: the cerebritis layer, the collagen capsule, and the internal inflammatory border. We probed the viscoelastic behavior of each layer separately through the measure of the apparent Young's modulus (E), that gives information about the sample stiffness, and the AFM hysteresis (H), that estimates the contribution of viscous and dissipative forces. Our experimental findings provide a full mechanical characterization of the abscess, showing an average E of (94 ±â€¯5) kPa and H of 0.37 ±â€¯0.01 for the cerebritis layer, an average E = (1.04 ±â€¯0.05) MPa and H = 0.10 ±â€¯0.01 for the collagen capsule and an average E = (9.8 ±â€¯0.4) kPa and H = 0.57 ±â€¯0.01 for the internal border. The results here presented have the potential to contribute to the development of novel surgical instruments dedicated to the treatment of the pathology and to stimulate the implementation of novel constitutive mechanical models for the estimation of brain compression and damage during BA progression.

Nano-mechanical signature of brain tumours.

Glioblastoma (GBM) and meningothelial meningioma (MM) are the most frequent malignant and benign brain lesions, respectively. Mechanical cues play a major role in the progression of both malignancies that is modulated by the occurrence of aberrant physical interactions between neoplastic cells and the extracellular matrix (ECM). Here we investigate the nano-mechanical properties of human GBM and MM tissues by atomic force microscopy. Our measures unveil the mechanical fingerprint of the main hallmark features of both lesions, such as necrosis in GBM and dural infiltration in MM. These findings have the potential to positively impact on the development of novel AFM-based diagnostic methods to assess the tumour grade. Most importantly, they provide a quantitative description of the tumour-induced mechanical modifications in the brain ECM, thus being of potential help in the search for novel ECM targets for brain tumours and especially for GBM that, despite years of intense research, has still very limited therapeutic options.

Changes in cellular mechanical properties during onset or progression of colorectal cancer.

Colorectal cancer (CRC) development represents a multistep process starting with specific mutations that affect proto-oncogenes and tumour suppressor genes. These mutations confer a selective growth advantage to colonic epithelial cells that form first dysplastic crypts, and then malignant tumours and metastases. All these steps are accompanied by deep mechanical changes at the cellular and the tissue level. A growing consensus is emerging that such modifications are not merely a by-product of the malignant progression, but they could play a relevant role in the cancer onset and accelerate its progression. In this review, we focus on recent studies investigating the role of the biomechanical signals in the initiation and the development of CRC. We show that mechanical cues might contribute to early phases of the tumour initiation by controlling the Wnt pathway, one of most important regulators of cell proliferation in various systems. We highlight how physical stimuli may be involved in the differentiation of non-invasive cells into metastatic variants and how metastatic cells modify their mechanical properties, both stiffness and adhesion, to survive the mechanical stress associated with intravasation, circulation and extravasation. A deep comprehension of these mechanical modifications may help scientist to define novel molecular targets for the cure of CRC.