Biology subjects

Kimmel, G.

Publications and source records attributed to Kimmel, G..

3 recordsLinked to original sources

bioRxiv2026

Klp61f and ncd function as an accelerator and brake to regulate myonuclear spacing

One of the first genes identified to regulate the spacing of nuclei in the multinucleated myofiber was Kinesin-1. However, the mechanism by which Kinesin-1 or other kinesins regulate myonuclear spacing is not known. Critically, the myofiber lacks centrosomes, and the many myonuclei act as the primary microtubule organizing centers of the cell. Because of this unique re-structuring, we hypothesized that the kinesins that drive centrosomes apart during mitotic spindle elongation may play a similar role in spacing myonuclei. We found that the bipolar Kinesin-5 (Klp61f) and the (-)-end directed Kinesin-14 (ncd) were both necessary for myonuclear spacing at different times, with both being necessary during embryogenesis, but only ncd being necessary in the fully differentiated myofiber. To investigate the shared mechanisms during embryogenesis, we used live-imaging and found that, similar to the mitotic spindle, Klp61f acts as an accelerator for myonuclear movement, whereas ncd acts as a brake contrary to this movement. To investigate these mechanisms and test the hypothesis that this is dependent on microtubule-sliding, we used super-resolution microscopy to visualize and quantify the microtubule network in animals with disrupted Klp61f or ncd. We found that in both cases, there was a decrease in the amount of microtubule overlap between neighboring myonuclei. Furthermore, we found that disrupting ncd led to severe changes in microtubule network organization, supporting our hypotheses that microtubule-sliding is necessary to space myonuclei, and that ncd likely functions through a unique mechanism in the differentiated myofiber to maintain myonuclear spacing. Together, our data supports a model where myonuclear spacing is regulated by a counteracting force generated by different kinesins during embryonic development. Furthermore, one kinesin, ncd, is repurposed in the differentiated myofiber to dynamically crosslink microtubules, a function necessary to anchor nuclei in place. Thus, kinesin motors regulate myonuclear spacing across developmental time by leveraging opposing forces through diverse mechanisms.

cell biology↗

bioRxiv2021

Spatial Clustering of CD68+ Tumor Associated Macrophages with Tumor Cells is Associated with Worse Overall Survival in Metastatic Clear Cell Renal Cell Carcinoma

Immune infiltration is typically quantified using cellular density, not accounting for cellular clustering. Tumor-associated macrophages (TAM) activate oncogenic signaling through paracrine interactions with tumor cells, which may be better reflected by local cellular clustering than global density metrics. Using multiplex immunohistochemistry and digital pathologic analysis we quantified cellular density and cellular clustering for myeloid cell markers in 129 regions of interest from 55 samples from 35 patients with metastatic ccRCC. CD68+ cells were found to be clustered with tumor cells and dispersed from stromal cells, while CD163+ and CD206+ cells were found to be clustered with stromal cells and dispersed from tumor cells. CD68+ density was not associated with OS, while high tumor/CD68+ cell clustering was associated with significantly worse OS. These novel findings would not have been identified if immune infiltrate was assessed using cellular density alone, highlighting the importance of including spatial analysis in studies of immune cell infiltration of tumors. SIGNIFICANCEIncreased clustering of CD68+ TAMs and tumor cells was associated with worse overall survival for patients with metastatic ccRCC. This effect would not have been identified if immune infiltrate was assessed using cell density alone, highlighting the importance of including spatial analysis in studies of immune cell infiltration of tumors.

cancer biology↗

bioRxiv2018

Extinction times in diffusive public good population dynamics

The co-evolutionary dynamics of competing populations can be strongly affected by frequency-dependent selection and population structure in space. As co-evolving populations grow into a spatial domain, their initial spatial arrangement, as well as their growth rate differences determine the dynamics. Here, we are interested in the dynamics of producers and free-rider co-evolution in the context of an ecological public good that is produced by a sub-population but evokes growth benefits to all individuals. We consider the spatial growth dynamics in one, two and three dimensions by modeling producer cell, free-rider cell and public good densities in space, driven by birth, death and diffusion. Typically, one population goes extinct. We find that uncorrelated initial spatial structures do not influence the time to extinction in comparison to the well-mixed system. We derive a slow manifold solution in order to estimate the time to extinction of either free-riders or producers. For invading populations, i.e. for populations that are initially highly segregated, we observe a traveling wave, whose speed can be calculated to improve the extinction time estimate by a simple superposition of the two times. Our results show that local effects of spatial dynamics evolve independently of the dynamics of the mean populations. Our considerations provide quantitative predictions for the transient dynamics of cooperative traits under pressure of extinction, and a potential experiment to derive elusive details of the fitness function of an ecological public goods game through extinction time observations.\n\nAuthor SummaryEcological public goods (PG) relationships emerge in growing cellular populations, for example between bacteria and cancer cells. We study the eco-evolutionary dynamics of a PG in populations that grow in space. In our model, public good-producer cells and free-rider cells can grow according to their own birth and death rates. Co-evolution occurs due to public good-driven surplus in the intrinsic growth rates and a cost to producers. A net growth rate benefit to free-riders leads to the well-known tragedy of the commons in which producers go extinct. What is often omitted from discussions is the time scale on which this extinction can occur, especially in spatial populations. We derive analytical estimates of the time to extinction in different spatial settings, and identify spatial scenarios in which extinction takes long enough such that the tragedy of the commons never occurs within the lifetime of the populations. Using numerical simulations we analyze the deviations from analytical predictions. Our results have direct implications for inferring ecological public good game properties from in vitro and in vivo experimental observations.

ecology↗