L. John Gagliardi


self portrait

Professor Emeritus, Physics
Rutgers University


l.gagliardi@rutgers.edu

Selected Biophysics Research



L J Gagliardi and D H Shain, Biophysical Mechanism for Zinc as an Anticancer Agent, Medical Hypotheses 144 (2020) 110273.

L J Gagliardi and D H Shain, Electrostatic Contributions to Carcinogenesis , Open Journal of Biophysics, vol. 10, 27-45 (2020).

L J Gagliardi and D H Shain, Electrostatic Mechanism for Depolymerization-Based Poleward Force Generation at Kinetochores , Open Journal of Biophysics, vol. 9, 198-203 (2019).

L J Gagliardi and D H Shain, Emergent Mitotic Chromosome Motions from a Changing Intracellular pH , Open Journal of Biophysics, vol. 8, No.1, 9-21 (2018).

L J Gagliardi and D H Shain, Electrostatic forces drive poleward chromosome motions at kinetochores , Cell Division 2016, 11:14.

L J Gagliardi and D H Shain, Intracellular pH as an Electrostatic Regulator of the Spindle Assembly Checkpoint , Medical Res. Archives, vol. 2, No. 7, 12--18 November, 2015.

L J Gagliardi and D H Shain, Polar Electrostatic Forces Drive Poleward Chromosome Motions , Cell Division 2014, 9:5.

L J Gagliardi and D H Shain, Chromosome Congression Explained by Nanoscale Electrostatics , Theoretical Biology and Medical Modelling 2014, 11:12.

L J Gagliardi and D H Shain, Is Intracellular pH a Clock for Mitosis?, Theoretical Biology and Medical Modelling 2013, 10:8.

L J Gagliardi, "Electrostatic Forces and Mitosis", NCI Sponsored Workshop: Electromagnetic Properties of Cells as a Window into Cancer, Arizona State University, March 19-21, 2012 (Invited).

D H Shain and L J Gagliardi, Can Molecular Cell Biology Explain Chromosome Motions?, Theoretical Biology and Medical Modelling 2011, 8:15.

Review Article: L J Gagliardi, Continuum Electrostatics in Cell Biology, NeuroQuantology, vol. 8, No. 3, 416-429 (2010).

Book: L J Gagliardi, Electrostatic Considerations in Mitosis. Bloomington, IN: iUniverse Publishing (2009).

L J Gagliardi, Electrostatic Considerations in Nuclear Envelope Breakdown and Reassembly, Journal of Electrostatics, vol. 64, 843-849 (2006).

L J Gagliardi, Electrostatic Force Generation in Chromosome Motions During Mitosis, Journal of Electrostatics, vol. 63, 309-327 (2005).

L J Gagliardi, "Does Nanoscale Electrostatics Move Chromosomes During Mitosis?", 45th Annual Meeting of the American Society for Cell Biology, San Francisco, CA, December 10-14, 2005.

L J Gagliardi, "Electrical Force in Mitosis", NSF Sponsored Workshop: On the Role of Theory in Biological Physics and Materials, Fiesta Inn Resort, Tempe, AZ, May 15-18, 2004 (Invited).

L J Gagliardi, "Electrostatic Force in Prometaphase, Metaphase, and Anaphase-A Chromosome Motions", International Symposium on Endogenous Physical Fields in Biology, Prague, Czech Republic, July 1-3, 2002 (Invited).

L J Gagliardi, Electrostatic Force in Prometaphase, Metaphase, and Anaphase-A Chromosome Motions, Physical Review E, vol. 66, 011901 (2002).




Comments on Mitotic Chromosome Motions

In spite of a series of ingenious experiments over the last 40 years, the causes for most of the mitotic motions remains unclear. The current paradigm in molecular biology requires that specific molecules, and/or molecular geometries, for force generation be identified. However, it is possible to account for mitotic motions in terms of experimentally known bound cellular electric charge distributions on molecules interacting over nanometer distances. This is the approach that has been taken in the series of papers listed here.

The known charge in mitotic chromosome motions resides at kinetochores, centrosomes, at the free ends of microtubules, and on chromosome arms. In 2002 Physical Review E and 2005 Journal of Electrostatics papers (see above listing), I argued that indirect experimental evidence indicates that pole-facing "plates" of kinetochores manifest positive charge that interacts with negative charge at and near the plus ends of microtubules to generate force for poleward chromosome movements. Subsequently, experiments have implicated positively charged molecules in kinetochores in establishing a dynamic coupling to negatively charged microtubule free ends for force generation during mitosis [Miller SA et al., Curr. Biol. 2008;18:1785].

Given positive charge at kinetochores, and negative charge at and near the free plus ends of microtubules, it is possible to derive the magnitude of the maximum (tension) force per microtubule for poleward chromosome motions that falls within the experimental range [Gagliardi LJ and Shain DH, Cell Div. 2016; 11:14; Gagliardi LJ and Shain DH, Open J. Biophys., vol.9, 198-203 (2019)].

In the above-mentioned Phys. Rev. E and J. Electrostat. papers I also proposed that indirect experimental evidence is consistent with negative charge on centrosomes. Experimental measurements have confirmed this [Hormeno S. et al., Biophys. J. 2009; 97:1022]. Experimental verification of net negative charge on centrosomes is consistent with positive charge on free minus microtubule ends for polar force generation. Positive charge on microtubule minus free ends is supported by large scale computer calculations on microtubules [Baker NA et al., Proc. Natl. Acad. Sci. 2001; 98:10037]. A calculation of the polar electrostatic poleward force per microtubule that falls within the experimental range has been carried out [Gagliardi LJ and Shain DH, Cell Div. 2014; 9:5].

Models in the current literature primarily attempt to address one or two mitotic motions, most often involving poleward force generation at kinetochores. Critical experiments involving the "slip-clutch" mechanism [Rieder CL and Salmon ED, J. Cell Biol. 1994; 124:223; Maiato H et al., J. Cell Sci. 2004; 117:5461], the effect of calcium ion concentration on anaphase-A chromosome motion [Zhang DH, Callaham DA, Hepler PK, J. Cell Biol. 1990; 111:171], antipoleward force production for chromosome congression [Gagliardi LJ and Shain DH, Theor. Biol. Med. Model. 2014, 11:12], and polar generation of poleward force for chromosome motions are not consistently addressed by these models. In the above listed papers, interactions between known bound molecular charge distributions can account for these observations.

Regarding molecular motor contributions to mitotic motions, it is generally thought that molecular motors are likely involved in the sliding microtubule sidewall "capture" motion of chromatid pairs. The case for molecular motors as the cause for post-attachment chromosome motions at kinetochores is considerably less convincing.

Identifying the motive force is central to explaining post-attachment chromosome motions during mitosis. Presently, there is no consensus on what it is. I have proposed a minimal assumptions model for post-attachment chromosome movements based on the dynamic instability of microtubules and nanoscale electrostatics. Given the electrical properties of (tubulin and) microtubules, and charge distributions on kinetochores, centrosomes and chromosome arms, as well as the pH-dependent dynamics of microtubules [Gagliardi LJ and Shain DH, Theor. Biol. Med. Model. 2013,10:8], it is possible to account for post-attachment prometaphase, metaphase, and anaphase-A chromosome motions within a model that also addresses the timing of these motions.