Modelling Nuclear Morphology and Shape Transformation: A Review

As one of the most important cellular compartments, the nucleus contains genetic materials and separates them from the cytoplasm with the nuclear envelope (NE), a thin membrane that is susceptible to deformations caused by intracellular forces. Interestingly, accumulating evidence has also indicated that the morphology change of NE is tightly related to nuclear mechanotransduction and the pathogenesis of diseases such as cancer and Hutchinson–Gilford Progeria Syndrome. Theoretically, with the help of well-designed experiments, significant progress has been made in understanding the physical mechanisms behind nuclear shape transformation in different cellular processes as well as its biological implications. Here, we review different continuum-level (i.e., energy minimization, boundary integral and finite element-based) approaches that have been developed to predict the morphology and shape change of the cell nucleus. Essential gradients, relative advantages and limitations of each model will be discussed in detail, with the hope of sparking a greater research interest in this important topic in the future.

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Altered Nuclear Functions in Progeroid Syndromes: a Paradigm for Aging Research

The Scientific World JOURNAL ◽

10.1100/tsw.2009.159 ◽

2009 ◽

Vol 9 ◽

pp. 1449-1462 ◽

Cited By ~ 3

Author(s):

Baomin Li ◽

Sonali Jog ◽

Jose Candelario ◽

Sita Reddy ◽

Lucio Comai

Keyword(s):

Werner Syndrome ◽

Accelerated Aging ◽

Natural Aging ◽

Aging Research ◽

Cellular Processes ◽

Functional Connections ◽

Age Related ◽

Progeroid Syndromes ◽

Progeria Syndrome ◽

Hutchinson Gilford Progeria Syndrome

Syndromes of accelerated aging could provide an entry point for identifying and dissecting the cellular pathways that are involved in the development of age-related pathologies in the general population. However, their usefulness for aging research has been controversial, as it has been argued that these diseases do not faithfully reflect the process of natural aging. Here we review recent findings on the molecular basis of two progeroid diseases, Werner syndrome (WS) and Hutchinson-Gilford progeria syndrome (HGPS), and highlight functional connections to cellular processes that may contribute to normal aging.

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Faculty Opinions recommendation of Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1013669.191606 ◽

2003 ◽

Author(s):

Anne Bowcock

Keyword(s):

De Novo ◽

Point Mutations ◽

Lamin A ◽

Progeria Syndrome ◽

Hutchinson Gilford Progeria Syndrome

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Faculty Opinions recommendation of A lamin A protein isoform overexpressed in Hutchinson-Gilford progeria syndrome interferes with mitosis in progeria and normal cells.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1086874.539808 ◽

2007 ◽

Author(s):

Yosef Gruenbaum

Keyword(s):

Lamin A ◽

Normal Cells ◽

Protein Isoform ◽

Progeria Syndrome ◽

Hutchinson Gilford Progeria Syndrome

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Faculty Opinions recommendation of Treatment with a farnesyltransferase inhibitor improves survival in mice with a Hutchinson-Gilford progeria syndrome mutation.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1097392.553443 ◽

2007 ◽

Author(s):

Channing Der

Keyword(s):

Farnesyltransferase Inhibitor ◽

Progeria Syndrome ◽

Hutchinson Gilford Progeria Syndrome

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Targeting DNA Repair and Chromatin Crosstalk in Cancer Therapy

Cancers ◽

10.3390/cancers13030381 ◽

2021 ◽

Vol 13 (3) ◽

pp. 381

Author(s):

Danielle P. Johnson ◽

Mahesh B. Chandrasekharan ◽

Marie Dutreix ◽

Srividya Bhaskara

Keyword(s):

Dna Repair ◽

Cancer Therapy ◽

Therapeutic Intervention ◽

Synthetic Lethality ◽

Checkpoint Proteins ◽

Cellular Processes ◽

Repair Pathways ◽

Made In

Aberrant DNA repair pathways that underlie developmental diseases and cancers are potential targets for therapeutic intervention. Targeting DNA repair signal effectors, modulators and checkpoint proteins, and utilizing the synthetic lethality phenomena has led to seminal discoveries. Efforts to efficiently translate the basic findings to the clinic are currently underway. Chromatin modulation is an integral part of DNA repair cascades and an emerging field of investigation. Here, we discuss some of the key advancements made in DNA repair-based therapeutics and what is known regarding crosstalk between chromatin and repair pathways during various cellular processes, with an emphasis on cancer.

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High-Throughput Screen Detects Calcium Signaling Dysfunction in Hutchinson-Gilford Progeria Syndrome

International Journal of Molecular Sciences ◽

10.3390/ijms22147327 ◽

2021 ◽

Vol 22 (14) ◽

pp. 7327

Author(s):

Juan A. Fafián-Labora ◽

Miriam Morente-López ◽

Fco. Javier de Toro ◽

María C. Arufe

Keyword(s):

Calcium Signaling ◽

Rare Disease ◽

Cell Lines ◽

Healthy Aging ◽

Accelerated Aging ◽

Cytosolic Calcium ◽

Calcium Handling ◽

Therapeutic Window ◽

Progeria Syndrome ◽

Hutchinson Gilford Progeria Syndrome

Hutchinson–Gilford progeria syndrome (HGPS) is a deadly childhood disorder, which is considered a very rare disease. It is caused by an autosomal dominant mutation on the LMNA gene, and it is characterized by accelerated aging. Human cell lines from HGPS patients and healthy parental controls were studied in parallel using next-generation sequencing (NGS) to unravel new non-previously altered molecular pathways. Nine hundred and eleven transcripts were differentially expressed when comparing healthy versus HGPS cell lines from a total of 21,872 transcripts; ITPR1, ITPR3, CACNA2D1, and CAMK2N1 stood out among them due to their links with calcium signaling, and these were validated by Western blot analysis. It was observed that the basal concentration of intracellular Ca2+ was statistically higher in HGPS cell lines compared to healthy ones. The relationship between genes involved in Ca2+ signaling and mitochondria-associated membranes (MAM) was demonstrated through cytosolic calcium handling by means of an automated fluorescent plate reading system (FlexStation 3, Molecular Devices), and apoptosis and mitochondrial ROS production were examined by means of flow cytometry analysis. Altogether, our data suggest that the Ca2+ signaling pathway is altered in HGPS at least in part due to the overproduction of reactive oxygen species (ROS). Our results unravel a new therapeutic window for the treatment of this rare disease and open new strategies to study pathologies involving both accelerated and healthy aging.

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Shape Sensitivity Formulation for Axisymmetric Thermal Conducting Solids

Proceedings of the Institution of Mechanical Engineers Part C Journal of Mechanical Engineering Science ◽

10.1243/pime_proc_1993_207_118_02 ◽

1993 ◽

Vol 207 (3) ◽

pp. 209-216 ◽

Cited By ~ 7

Author(s):

Boo Youn Lee

Keyword(s):

Shape Change ◽

Direct Method ◽

Design Sensitivity ◽

Boundary Integral ◽

Singular Boundary ◽

Concept Design ◽

Shape Sensitivity ◽

Material Derivative ◽

Thermal Conducting ◽

Thermal Diffuser

A direct differentiation method is presented for the shape design sensitivity analysis of axisymmetric thermal conducting solids. Based purely on the standard boundary integral equation (BIE) formulation, a new BIE is derived using the material derivative concept. Design derivatives in terms of shape change are directly calculated by solving the derived BIE. The present direct method has a computational advantage over the adjoint variable method, in the sense that it avoids the problem of solving for the adjoint system with the singular boundary condition. Numerical accuracy of the method is studied through three examples. The sensitivities by the present method are compared with analytic sensitivities for two problems of a hollow cylinder and a hollow sphere, and are then compared with those by finite differences for a thermal diffuser problem. As a practical application to numerical optimization, an optimal shape of the thermal diffuser to minimize the weight under a prescribed constraint is found by use of an optimization routine.

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