Biology subjects

Levin, M.

Publications and source records attributed to Levin, M..

7 recordsLinked to original sources

bioRxiv2026

Membrane voltage and connexin expression work together to enhance tumor growth and metastasis in cancer

There is strong evidence of tumors manipulating their resting membrane potential (Vmem). While most fully-differentiated cells have a Vmem of roughly -70mV, tumor cells are generally depolarized, with Vmem {approx}-30mV, which more closely resembles the Vmem of stem cells. This is often believed to serve the purpose of accelerating the cell cycle and hence advantaging tumor proliferation. But when the tumor becomes invasive, its cells sometimes revert to a hyperpolarized Vmem with no obvious reason why. Separately, it is well accepted that solid tumors that are not yet invasive greatly underexpress connexins relative to healthy tissue; connexins, for our purpose, form gap junctions (GJs), small connecting tubes between nearby cells. Tumors that are invasive, by contrast, overexpress connexins. There is very little explanation for the paradox that connexins are first underexpressed and then overexpressed. However, it has long been known that Vmem electrically gates GJs; specifically, that homotypic GJs conduct best when the two cells they connect have a similar Vmem. Our in-silico model results explain this phenomenon, showing that when considered together, tumors' electrical and connexin-expression behaviors form a unified and effective strategy to control communication between the tumor and its healthy neighbor cells. This has implications for the emerging field of cancer bioelectrics, potentially leading to more precisely-targeted therapies.

cancer biology↗

bioRxiv2026

Living multicellular systems induce decodable spatial patterns in bacterial collectives

Living systems continuously modify their environments through chemical, mechanical, metabolic and bioelectrical activity. Whether a presence of a multicellular system can be encoded into the emergent spatial organization of another living collective in a distributed and decodable way is unknown. Here we show that motile Bacillus subtilis populations reorganize their spatial and ionic collective states in response to nearby Xenopus embryos and Xenobots. The bacteria in a liquid culture formed autonomous motility-dependent patterns that were redirected by living targets into attraction halos, which tracked target position at a distance. Extracellular levels of potassium amplified attraction, altered local potassium dynamics, and coupled target presence to global pattern complexity. Self-supervised machine learning further identified distributed bacterial spatial signatures predictive of Xenopus embryo vs. Xenobot presence at a distance from the target. Together, these findings suggest that bacterial collectives can encode information about the state of other biota in their environment, revealing a previously unrecognized form of inter-kingdom interaction between living morphogenetic systems.

systems biology↗

bioRxiv2018

PCF11 connects alternative polyadenylation to formation and spontaneous regression of neuroblastoma

Diversification at the transcriptome 3end is an important and evolutionarily conserved layer of gene regulation associated with differentiation and dedifferentiation processes. However the underlying mechanisms and functional consequences are poorly defined. Here, we identify extensive transcriptome-3end-alterations in neuroblastoma, a tumour entity with a paucity of recurrent somatic mutations and an unusually high frequency of spontaneous regression. Utilising extensive RNAi-screening we reveal the landscape and drivers of transcriptome-3end-diversification, discovering PCF11 as critical regulator, directing alternative polyadenylation (APA) of hundreds of transcripts including a differentiation RNA-operon. PCF11 shapes inputs converging on WNT-signalling, and governs cell cycle, proliferation, apoptosis and neurodifferentiation. Postnatal PCF11 down-regulation induces a neurodifferentiation program, and low-level PCF11 in neuroblastoma associates with favourable outcome and spontaneous tumour regression. Our findings document a critical role for APA in tumourigenesis and describe a novel mechanism for cell fate reprogramming in neuroblastoma with important clinical implications. An interactive data repository of transcriptome-wide APA covering >170 RNAis, and an APA-network map with regulatory hubs is provided.

developmental biology↗

bioRxiv2018

Estimating parasite load dynamics to reveal novel resistance mechanisms to human malaria

Improved methods are needed to identify host mechanisms which directly protect against human infectious diseases in order to develop better vaccines and therapeutics1,2. Pathogen load determines the outcome of many infections3, and is a consequence of pathogen multiplication rate, duration of the infection, and inhibition or killing of pathogen by the host (resistance). If these determinants of pathogen load could be quantified then their mechanistic correlates might be determined. In humans the timing of infection is rarely known and treatment cannot usually be withheld to monitor serial changes in pathogen load and host response. Here we present an approach to overcome this and identify potential mechanisms of resistance which control parasite load in Plasmodium falciparum malaria. Using a mathematical model of longitudinal infection dynamics for orientation, we made individualized estimates of parasite multiplication and growth inhibition in Gambian children at presentation with acute malaria and used whole blood RNA-sequencing to identify their correlates. We identified novel roles for secreted proteases cathepsin G and matrix metallopeptidase 9 (MMP9) as direct effector molecules which inhibit P. falciparum growth. Cathepsin G acts on the erythrocyte membrane, cleaving surface receptors required for parasite invasion, whilst MMP9 acts on the parasite. In contrast, the type 1 interferon response and expression of CXCL10 (IFN-{gamma}-inducible protein of 10 kDa, IP-10) were detrimental to control of parasite growth. Natural variation in iron status and plasma levels of complement factor H were determinants of parasite multiplication rate. Our findings demonstrate the importance of accounting for the dynamic interaction between host and pathogen when seeking to identify correlates of protection, and reveal novel mechanisms controlling parasite growth in humans. This approach could be extended to identify additional mechanistic correlates of natural- and vaccine-induced immunity to malaria and other infections.

systems biology↗

bioRxiv2018

Cellular Migration May Exhibit Intrinsic Left-Right Asymmetries: A meta-analysis

The intracellular model of embryonic left-right (LR) asymmetry proposes that body laterality originates from intrinsic chiral properties of individual cells, and several recent studies identified consistent chirality in the behavior of cells in vitro. Here, we explored one prediction of the intrinsic asymmetry model: that LR asymmetries would be present in a wide range of mammalian cells, manifesting in the form of LR-biased migration toward an attractant. We mined data from published papers on galvanotaxis and chemotaxis and quantitatively analyzed the migration trajectories of adult somatic cells, stem cells, and cancer cells to determine whether they display significant consistent LR biases in their movements toward migration targets. We found that several cell types exhibited LR biases during galvanotaxis and chemotaxis, and that treatments inhibiting cytoskeletal remodeling or targeting ion channel activity both abolished these LR biases. While we cannot conclusively rule out the existence of subtle biasing cues in the apparatus of some of the studies, the analysis of this dataset suggests specific assays and cell types for further investigation into the chiral aspects of intrinsic cell behavior.\n\nFundingThis work was funded by the American Heart Association Established Investigator grant 0740088N and NIH grants R01-GM077425 (to ML) and NRSA grant 1F32GM087107 (to LNV). M.L. is also supported by the G. Harold and Leila Y. Mathers Charitable Foundation.

cell biology↗

bioRxiv2017

Effects of Ivermectin exposure on regeneration of D. dorotocephala planaria

The ability of cells to communicate is essential during pattern formation, as they make decisions that drive growth and form. One mode of cellular signaling is via bioelectrical properties determined by the activity of ion channels. Several studies have shown a role for bioelectric signaling in planarian regeneration, but these have focused on D. japonica and S. mediterranea. It is not known how the alterations of ion channel activity would affect regeneration in other species of planaria. Here, we tested the effect of ivermectin (IVM), a chloride channel opener drug commonly used to combat heart worms, on regeneration in a new species of planaria: D. dorotocephala. Exposure to IVM during regeneration resulted in patterning abnormalities, such as bifurcated tails with partial heads, as well as delayed regeneration. By testing the effect of drugs that target resting potential on regenerative repair in novel model species, additional insight is gained on the comparative roles of ionic signaling across taxa.

developmental biology↗

bioRxiv2017

Integrated pathogen load and dual transcriptome analysis of systemic host-pathogen interactions in severe malaria

The pathogenesis of severe Plasmodium falciparum malaria is incompletely understood. Since the pathogenic stage of the parasite is restricted to blood, dual RNA-sequencing of host and parasite transcripts in blood can reveal their interactions at a systemic scale. Here we identify human and parasite gene expression associated with severe disease features in Gambian children. Differences in parasite load explained up to 99% of differential expression of human genes but only a third of the differential expression of parasite genes. Co-expression analyses showed a remarkable co-regulation of host and parasite genes controlling translation, and host granulopoiesis genes uniquely co-regulated and differentially expressed in severe malaria. Our results indicate that high parasite load is the proximal stimulus for severe P. falciparum malaria, that there is an unappreciated role for many parasite genes in determining virulence, and hint at a molecular arms-race between host and parasite to synthesise protein products.

systems biology↗