John CM et al. (2007) EMBO J "The Caenorhabditis elegans septin complex is nonpolar."

Winkler FK, Steinmetz MO, John CM, Hite RK, Schlapfer D, Fitzgerald DJ, Faty M, Weirich CS, Walz T, Kroschewski R, Jawhari H, Barral Y

[EMBO J, 2007]

Septins are conserved GTPases that form heteromultimeric complexes and assemble into filaments that play a critical role in cell division and polarity. Results from budding and fission yeast indicate that septin complexes form around a tetrameric core. However, the molecular structure of the core and its influence on the polarity of septin complexes and filaments is poorly defined. The septin complex of the nematode Caenorhabditis elegans is formed entirely by the core septins UNC-59 and UNC-61. We show that UNC-59 and UNC-61 form a dimer of coiled-coil-mediated heterodimers. By electron microscopy, this heterotetramer appears as a linear arrangement of four densities representing the four septin subunits. Fusion of GFP to the N termini of UNC-59 and UNC-61 and subsequent electron microscopic visualization suggests that the sequence of septin subunits is UNC-59/UNC-61/UNC-61/UNC-59. Visualization of GFP extensions fused to the extremity of the C-terminal coiled coils indicates that these extend laterally from the heterotetrameric core. Together, our study establishes that the septin core complex is symmetric, and suggests that septins form nonpolar filaments.

Pu S et al. (2010) PLoS One "Expanding the landscape of chromatin modification (CM)-related functional domains and genes in human."

Pu S, Parkinson J, Turinsky AL, Xiong X, Vlasblom J, Wodak SJ, Zhang Z, On T, Emili A, Greenblatt J

[PLoS One, 2010]

Chromatin modification (CM) plays a key role in regulating transcription, DNA replication, repair and recombination. However, our knowledge of these processes in humans remains very limited. Here we use computational approaches to study proteins and functional domains involved in CM in humans. We analyze the abundance and the pair-wise domain-domain co-occurrences of 25 well-documented CM domains in 5 model organisms: yeast, worm, fly, mouse and human. Results show that domains involved in histone methylation, DNA methylation, and histone variants are remarkably expanded in metazoan, reflecting the increased demand for cell type-specific gene regulation. We find that CM domains tend to co-occur with a limited number of partner domains and are hence not promiscuous. This property is exploited to identify 47 potentially novel CM domains, including 24 DNA-binding domains, whose role in CM has received little attention so far. Lastly, we use a consensus Machine Learning approach to predict 379 novel CM genes (coding for 329 proteins) in humans based on domain compositions. Several of these predictions are supported by very recent experimental studies and others are slated for experimental verification. Identification of novel CM genes and domains in humans will aid our understanding of fundamental epigenetic processes that are important for stem cell differentiation and cancer biology. Information on all the candidate CM domains and genes reported here is publicly available.

Plenefisch JD et al. (1994) Worm Breeder's Gazette "Cloning mua-3: Some Observations on the New Molecular Era"

Hedgecock EM, Plenefisch JD

[Worm Breeder's Gazette, 1994]

Cloning mua-3: some observations on the new Molecular Era John Plenefisch and Edward Hedgecock, Dept. of Biology, Johns Hopkins University, Baltimore MD 21218

Rincon S et al. (2019) J Infect Dis "Disrupting Membrane Adaptation Restores In Vivo Efficacy of Antibiotics Against Multidrug-Resistant Enterococci and Potentiates Killing by Human Neutrophils."

Rios R, Dinh AQ, Rincon S, Arias CA, Miller WR, Singh KV, Khan A, Diaz L, Reyes J, Garsin DA, Cruz MR, Tran TT, Panesso D, Shamoo Y

[J Infect Dis, 2019]

Daptomycin resistance in enterococci is often mediated by the LiaFSR system that orchestrates the cell membrane (CM) stress response. Activation of LiaFSR through the response regulator LiaR generates major changes in CM function and architecture (membrane adaptive response), permitting the organism to survive the antibiotic attack. Here, using a laboratory strain of Enterococcus faecalis, we developed a novel Caenorhabditis elegans model of daptomycin therapy and showed that disrupting LiaR-mediated CM adaptation restores the in vivo activity of daptomycin. The LiaR effect was also seen in a clinical strain of DAP-resistant E. faecium using a murine model of peritonitis. Furthermore, alteration of the CM response increased the ability of human-PMNs to readily clear both E. faecalis and MDR-E. faecium. Our results provide proof-of-concept that targeting the CM adaptive response restore the in vivo activity of antibiotics, prevent resistance and enhance the ability of the innate immune system to kill infecting bacteria.

Parham C et al. (1994) Worm Breeder's Gazette "Tc4 and Tc5: What Makes Them Move and Why It Matters"

Collins JJ, Butze K, Parham C, Beinhorn J

[Worm Breeder's Gazette, 1994]

Tc4 and Tc5: what makes them move and why it matters Christi Parham, Kristie Butze, Joanna Beinhorn and John Collins. Dept. of Biochemistry and Molecular Biology, University of New Hampshire. Durham, NH 03824

On T et al. (2010) Proteins "The evolutionary landscape of the chromatin modification machinery reveals lineage specific gains, expansions, and losses."

Turinsky A, Emili A, Pu S, On T, Zhang Z, Greenblatt J, Gong Y, Wodak SJ, Xiong X, Parkinson J

[Proteins, 2010]

Model organisms such as yeast, fly, and worm have played a defining role in the study of many biological systems. A significant challenge remains in translating this information to humans. Of critical importance is the ability to differentiate those components where knowledge of function and interactions may be reliably inferred from those that represent lineage-specific innovations. To address this challenge, we use chromatin modification (CM) as a model system for exploring the evolutionary properties of their components in the context of their known functions and interactions. Collating previously identified components of CM from yeast, worm, fly, and human, we identified a "core" set of 50 CM genes displaying consistent orthologous relationships that likely retain their interactions and functions across taxa. In addition, we catalog many components that demonstrate lineage specific expansions and losses, highlighting much duplication within vertebrates that may reflect an expanded repertoire of regulatory mechanisms. Placed in the context of a high-quality protein-protein interaction network, we find, contrary to existing views of evolutionary modularity, that CM complex components display a mosaic of evolutionary histories: a core set of highly conserved genes, together with sets displaying lineage specific innovations. Although focused on CM, this study provides a template for differentiating those genes which are likely to retain their functions and interactions across species. As such, in addition to informing on the evolution of CM as a system, this study provides a set of comparative genomic approaches that can be generally applied to any biological systems.

Almeida CA et al. (1994) Worm Breeder's Gazette "Function of a Domain of the Myosin Heavy Chain Implicated in Familial Hypertrophic Cardiomyopathy"

Swift KE, Almeida CA, Collins JJ

[Worm Breeder's Gazette, 1994]

Function of a Domain of the Myosin Heavy Chain Implicated in Familial Hypertrophic Cardiomyopathy Craig A. Almeida, Kerry E. Swift and John J. Collins Department of Biochemistry and Molecular, University of New Hampshire, Durham, NH 03820

Chalfie M (1993) J Neurobiol "Touch receptor development and function in Caenorhabditis elegans."

Chalfie M

[J Neurobiol, 1993]

Mutations causing a touch-insensitive phenotype in the nematode Caenorhabditis elegans have been the basis of studies on the specification of neuronal cell fate, inherited neurodegeneration, and the molecular nature of mechanosensory transduction. (C) 1993 John Wiley & sons, Inc.

Khan A et al. (2019) Proc Natl Acad Sci U S A "Antimicrobial sensing coupled with cell membrane remodeling mediates antibiotic resistance and virulence in Enterococcus faecalis."

Singh KV, Ton-That H, Rincon S, Rios R, Miller WR, Cruz MR, Nguyen AH, Davlieva M, Narechania A, Siegel SD, Khan A, Panesso D, Reyes J, Garsin DA, Arias CA, Shamoo Y, Diaz L, Tran TT, Planet PJ, Latorre M, Pemberton O

[Proc Natl Acad Sci U S A, 2019]

Bacteria have developed several evolutionary strategies to protect their cell membranes (CMs) from the attack of antibiotics and antimicrobial peptides (AMPs) produced by the innate immune system, including remodeling of phospholipid content and localization. Multidrug-resistant <i>Enterococcus faecalis,</i> an opportunistic human pathogen, evolves resistance to the lipopeptide daptomycin and AMPs by diverting the antibiotic away from critical septal targets using CM anionic phospholipid redistribution. The LiaFSR stress response system regulates this CM remodeling via the LiaR response regulator by a previously unknown mechanism. Here, we characterize a LiaR-regulated protein, LiaX, that senses daptomycin or AMPs and triggers protective CM remodeling. LiaX is surface exposed, and in daptomycin-resistant clinical strains, both LiaX and the N-terminal domain alone are released into the extracellular milieu. The N-terminal domain of LiaX binds daptomycin and AMPs (such as human LL-37) and functions as an extracellular sentinel that activates the cell envelope stress response. The C-terminal domain of LiaX plays a role in inhibiting the LiaFSR system, and when this domain is absent, it leads to activation of anionic phospholipid redistribution. Strains that exhibit LiaX-mediated CM remodeling and AMP resistance show enhanced virulence in the <i>Caenorhabditis elegans</i> model, an effect that is abolished in animals lacking an innate immune pathway crucial for producing AMPs. In conclusion, we report a mechanism of antibiotic and AMP resistance that couples bacterial stress sensing to major changes in CM architecture, ultimately also affecting host-pathogen interactions.

Pang S et al. (2010) Lab Chip "Implementation of a color-capable optofluidic microscope on a RGB CMOS color sensor chip substrate."

DeModena J, Pang S, Yang C, Wang YM, Cui X, Sternberg P

[Lab Chip, 2010]

We report the implementation of a color-capable on-chip lensless microscope system, termed color optofluidic microscope (color OFM), and demonstrate imaging of double stained Caenorhabditis elegans with lacZ gene expression at a light intensity about 10 mW/cm(2).