scholarly journals Biophysics and biofluid dynamics of primary cilia: evidence for and against the flow-sensing function

2017 ◽  
Vol 313 (3) ◽  
pp. F706-F720 ◽  
Author(s):  
Subhra Nag ◽  
Andrew Resnick
Keyword(s):  
Primary Cilia ◽  
Mechanical Response ◽  
Hydrodynamic Drag ◽  
Essential Information ◽  
Biofluid Dynamics ◽  
Flow Sensing ◽  
Experimental Approaches ◽  
Relevant Work ◽  
Cell Signaling Pathways

Primary cilia have been called “the forgotten organelle” for over 20 yr. As cilia now have their own journal and several books devoted to their study, perhaps it is time to reconsider the moniker “forgotten organelle.” In fact, during the drafting of this review, 12 relevant publications have been issued; we therefore apologize in advance for any relevant work we inadvertently omitted. What purpose is yet another ciliary review? The primary goal of this review is to specifically examine the evidence for and against the hypothesized flow-sensing function of primary cilia expressed by differentiated epithelia within a kidney tubule, bringing together differing disciplines and their respective conceptual and experimental approaches. We will show that understanding the biophysics/biomechanics of primary cilia provides essential information for understanding any potential role of ciliary function in disease. We will summarize experimental and mathematical models used to characterize renal fluid flow and incident force on primary cilia and to characterize the mechanical response of cilia to an externally applied force and discuss possible ciliary-mediated cell signaling pathways triggered by flow. Throughout, we stress the importance of separating the effects of fluid shear and stretch from the action of hydrodynamic drag.

scholarly journals Discerning the role of mechanosensors in regulating proximal tubule function

2016 ◽  
Vol 310 (1) ◽  
pp. F1-F5 ◽  
Author(s):  
Venkatesan Raghavan ◽  
Ora A. Weisz
Keyword(s):  
Shear Stress ◽  
Proximal Tubule ◽  
Primary Cilia ◽  
The Body ◽  
Flow Sensors ◽  
Body Experience ◽  
Flow Sensing ◽  
Axial Shear ◽  
Stretch Activated Channels

All cells in the body experience external mechanical forces such as shear stress and stretch. These forces are sensed by specialized structures in the cell known as mechanosensors. Cells lining the proximal tubule (PT) of the kidney are continuously exposed to variations in flow rates of the glomerular ultrafiltrate, which manifest as changes in axial shear stress and radial stretch. Studies suggest that these cells respond acutely to variations in flow by modulating their ion transport and endocytic functions to maintain glomerulotubular balance. Conceptually, changes in the axial shear stress in the PT could be sensed by three known structures, namely, the microvilli, the glycocalyx, and primary cilia. The orthogonal component of the force produced by flow exhibits as radial stretch and can cause expansion of the tubule. Forces of stretch are transduced by integrins, by stretch-activated channels, and by cell-cell contacts. This review summarizes our current understanding of flow sensing in PT epithelia, discusses challenges in dissecting the role of individual flow sensors in the mechanosensitive responses, and identifies potential areas of opportunity for new study.

scholarly journals Inhibition Effect of Chloroquine and Integrin-Linked Kinase Knockdown on Translation in Melanoma Cells

2021 ◽  
Vol 22 (7) ◽  
pp. 3682
Author(s):  
Dorota Gil ◽  
Piotr Laidler ◽  
Marta Zarzycka ◽  
Joanna Dulińska-Litewka
Keyword(s):  
Signaling Pathways ◽  
Melanoma Cell ◽  
Melanoma Cells ◽  
Antitumor Effects ◽  
Regulatory Pathways ◽  
Scratch Wound ◽  
Integrin Linked Kinase ◽  
And Migration ◽  
Cell Signaling Pathways

The twofold role of autophagy in cancer is often the therapeutic target. Numerous regulatory pathways are shared between autophagy and other molecular processes needed in tumorigenesis, such as translation or survival signaling. Thus, we have assumed that ILK knockdown should promote autophagy, and used together with chloroquine, an autophagy inhibitor, it could generate a better anticancer effect by dysregulation of common signaling pathways. Expression at the protein level was analyzed using Western Blot; siRNA transfection was done for ILK. Analysis of cell signaling pathways was monitored with phospho-specific antibodies. Melanoma cell proliferation was assessed with the crystal violet test, and migration was evaluated by scratch wound healing assays. Autophagy was monitored by the accumulation of its marker, LC3-II. Our data show that ILK knockdown by siRNA suppresses melanoma cell growth by inducing autophagy through AMPK activation, and simultaneously initiates apoptosis. We demonstrated that combinatorial treatment of melanoma cells with CQ and siILK has a stronger antitumor effect than monotherapy with either of these. It generates the synergistic antitumor effects by the decrease of translation of both global and oncogenic proteins synthesis. In our work, we point to the crosstalk between translation and autophagy regulation.

The Role of Mechanical Tension in Neurons

2010 ◽  
Vol 1274 ◽  
Author(s):  
Taher Saif ◽  
Jagannathan Rajagopalan ◽  
Alireza Tofangchi
Keyword(s):  
Mechanical Response ◽  
Mechanical Forces ◽  
Active Tension ◽  
Mechanical Tension ◽  
Deformation Response ◽  
Linear Force ◽  
Tension Regulation ◽  
Over Time

AbstractWe used high resolution micromechanical force sensors to study the in vivo mechanical response of embryonic Drosophila neurons. Our experiments show that Drosophila axons have a rest tension of a few nN and respond to mechanical forces in a manner characteristic of viscoelastic solids. In response to fast externally applied stretch they show a linear force-deformation response and when the applied stretch is held constant the force in the axons relaxes to a steady state value over time. More importantly, when the tension in the axons is suddenly reduced by releasing the external force the neurons actively restore the tension, sometimes close to their resting value. Along with the recent findings of Siechen et al (Proc. Natl. Acad. Sci. USA 106, 12611 (2009)) showing a link between mechanical tension and synaptic plasticity, our observation of active tension regulation in neurons suggest an important role for mechanical forces in the functioning of neurons in vivo.

scholarly journals Lights and Shadows in the Genetics of Syndromic and Non-Syndromic Hearing Loss in the Italian Population

Genes ◽  
2020 ◽  
Vol 11 (11) ◽  
pp. 1237
Author(s):  
Anna Morgan ◽  
Stefania Lenarduzzi ◽  
Beatrice Spedicati ◽  
Elisabetta Cattaruzzi ◽  
Flora Maria Murru ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Disease Genes ◽  
Italian Population ◽  
Essential Information ◽  
Whole Exome ◽  
Relevant Role ◽  
Multiplex Ligation Probe Amplification ◽  
Syndromic Hearing Loss

Hearing loss (HL), both syndromic (SHL) and non-syndromic (NSHL), is the most common sensory disorder, affecting ~460 million people worldwide. More than 50% of the congenital/childhood cases are attributable to genetic causes, highlighting the importance of genetic testing in this class of disorders. Here we applied a multi-step strategy for the molecular diagnosis of HL in 125 patients, which included: (1) an accurate clinical evaluation, (2) the analysis of GJB2, GJB6, and MT-RNR1 genes, (3) the evaluation STRC-CATSPER2 and OTOA deletions via Multiplex Ligation Probe Amplification (MLPA), (4) Whole Exome Sequencing (WES) in patients negative to steps 2 and 3. Our approach led to the characterization of 50% of the NSHL cases, confirming both the relevant role of the GJB2 (20% of cases) and STRC deletions (6% of cases), and the high genetic heterogeneity of NSHL. Moreover, due to the genetic findings, 4% of apparent NSHL patients have been re-diagnosed as SHL. Finally, WES characterized 86% of SHL patients, supporting the role of already know disease-genes. Overall, our approach proved to be efficient in identifying the molecular cause of HL, providing essential information for the patients’ future management.

scholarly journals Mechanics of tubular helical assemblies: ensemble response to axial compression and extension

2021 ◽  
Author(s):  
Jacopo Quaglierini ◽  
Alessandro Lucantonio ◽  
Antonio DeSimone
Keyword(s):  
Boundary Conditions ◽  
Elastic Properties ◽  
Central Region ◽  
Mechanical Response ◽  
Different Boundary Conditions ◽  
Kirchhoff Rods ◽  
Model Versus ◽  
The Individual ◽  
Opposite Chirality

Abstract Nature and technology often adopt structures that can be described as tubular helical assemblies. However, the role and mechanisms of these structures remain elusive. In this paper, we study the mechanical response under compression and extension of a tubular assembly composed of 8 helical Kirchhoff rods, arranged in pairs with opposite chirality and connected by pin joints, both analytically and numerically. We first focus on compression and find that, whereas a single helical rod would buckle, the rods of the assembly deform coherently as stable helical shapes wound around a common axis. Moreover, we investigate the response of the assembly under different boundary conditions, highlighting the emergence of a central region where rods remain circular helices. Secondly, we study the effects of different hypotheses on the elastic properties of rods, i.e., stress-free rods when straight versus when circular helices, Kirchhoff’s rod model versus Sadowsky’s ribbon model. Summing up, our findings highlight the key role of mutual interactions in generating a stable ensemble response that preserves the helical shape of the individual rods, as well as some interesting features, and they shed some light on the reasons why helical shapes in tubular assemblies are so common and persistent in nature and technology. Graphic Abstract We study the mechanical response under compression/extension of an assembly composed of 8 helical rods, pin-jointed and arranged in pairs with opposite chirality. In compression we find that, whereas a single rod buckles (a), the rods of the assembly deform as stable helical shapes (b). We investigate the effect of different boundary conditions and elastic properties on the mechanical response, and find that the deformed geometries exhibit a common central region where rods remain circular helices. Our findings highlight the key role of mutual interactions in the ensemble response and shed some light on the reasons why tubular helical assemblies are so common and persistent.

scholarly journals Centrin2 regulates CP110 removal in primary cilium formation

2015 ◽  
Vol 208 (6) ◽  
pp. 693-701 ◽  
Author(s):  
Suzanna L. Prosser ◽  
Ciaran G. Morrison
Keyword(s):  
Calcium Binding ◽  
Primary Cilia ◽  
Reverse Genetics ◽  
Cell Types ◽  
Serum Starvation ◽  
Basal Bodies ◽  
Cilium Formation ◽  
Cellular Quiescence ◽  
Retinal Pigmented Epithelial Cells

Primary cilia are antenna-like sensory microtubule structures that extend from basal bodies, plasma membrane–docked mother centrioles. Cellular quiescence potentiates ciliogenesis, but the regulation of basal body formation is not fully understood. We used reverse genetics to test the role of the small calcium-binding protein, centrin2, in ciliogenesis. Primary cilia arise in most cell types but have not been described in lymphocytes. We show here that serum starvation of transformed, cultured B and T cells caused primary ciliogenesis. Efficient ciliogenesis in chicken DT40 B lymphocytes required centrin2. We disrupted CETN2 in human retinal pigmented epithelial cells, and despite having intact centrioles, they were unable to make cilia upon serum starvation, showing abnormal localization of distal appendage proteins and failing to remove the ciliation inhibitor CP110. Knockdown of CP110 rescued ciliation in CETN2-deficient cells. Thus, centrin2 regulates primary ciliogenesis through controlling CP110 levels.

scholarly journals Notes from the Editors

2014 ◽  
Vol 108 (2) ◽  
pp. iii-ix
Keyword(s):  
Basic Research ◽  
Decision Makers ◽  
The Other ◽  
Good Effect ◽  
Scholarly Journals ◽  
Other Hand ◽  
Relevant Work

We introduce this issue with a thought. There has been much made of the need for our discipline to be “policy relevant,” and much ridicule has been directed at the Review recently that comments how little the Review offers that is relevant for decision makers. But what does it mean to be policy relevant? Generally, scholarly journals publish the best in basic research, which hopefully can be used by those in positions of authority to good effect. This often means that there are no catchy titles, nor opinion-editorial pieces that are so often portrayed as the model of policy relevant work. In our view, the role of the Review is to expand knowledge on important scholarly questions, not only to publish work that is currently popular or somehow ordained as useful by pundits. There is certainly a place for such work, but not in the pages of the Review. On the other hand, we as the editors of the Review understand the need to make the Review accessible to as broad an audience as possible, and we have made great efforts to do just that.

Virtual trabecular bone models and their mechanical response

2008 ◽  
Vol 222 (8) ◽  
pp. 1185-1195 ◽  
Author(s):  
F E Donaldson ◽  
P Pankaj ◽  
A H Law ◽  
A H Simpson
Keyword(s):  
Finite Element ◽  
Trabecular Bone ◽  
Mechanical Behaviour ◽  
Mechanical Response ◽  
Elastic Response ◽  
Anatomical Site ◽  
Virtual Samples ◽  
Micro Level ◽  
Architectural Characteristics

The study of the mechanical behaviour of trabecular bone has extensively employed micro-level finite element (μFE) models generated from images of real bone samples. It is now recognized that the key determinants of the mechanical behaviour of bone are related to its micro-architecture. The key indices of micro-architecture, in turn, depend on factors such as age, anatomical site, sex, and degree of osteoporosis. In practice, it is difficult to acquire sufficient samples that encompass these variations. In this preliminary study, a method of generating virtual finite element (FE) samples of trabecular bone is considered. Virtual samples, calibrated to satisfy some of the key micro-architectural characteristics, are generated computationally. The apparent level elastic and post-elastic mechanical behaviour of the generated samples is examined: the elastic mechanical response of these samples is found to compare well with natural trabecular bone studies conducted by previous investigators; the post-elastic response of virtual samples shows that material non-linearities have a much greater effect in comparison with geometrical non-linearity for the bone densities considered. Similar behaviour has been reported by previous studies conducted on real trabecular bone. It is concluded that virtual modelling presents a potentially valuable tool in the study of the mechanical behaviour of trabecular bone and the role of its micro-architecture.

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