Tiraihi A et al. (2007) Biosystems "Early onset of regionalization in EMS lineage of C. elegans embryo: a quantitative study."

Tiraihi A, Tiraihi T

[Biosystems, 2007]

Early localization of C. elegans founder cell descendents in certain regions of embryo has been documented. The purpose of this investigation is to evaluate the onset of ABp and EMS descendent cell regionalization in the embryo using the random motility coefficient as a quantitative parameter. The forward migration index (FMI) was also calculated in order to evaluate the chemotatic biases of ABp-dc and EMS-dc during regionalization. The results showed that the random motility coefficient declined as the cells tended to regionalize. The mean squared displacement (MSD) versus time plot showed a non-linear model which indicated non-random cell movement. FMI showed progressive increase as the cells tended to regionalized, and it was significantly higher in EMS-dc than ABp-dc, moreover the chemotatic biases were higher in EMS-dc than ABp-dc. The circular plots showed that the statistical differences between the two lineages were significant, while ABp-dc showed significant differences in xy, xz and yz planes; EMS derived cells showed no significant differences except in yz planes. The conclusion of this study is that the onset of early regionalization occurs in EMS-dc sooner than in ABp-dc.

Kim YG et al. (2018) Front Microbiol "Herring Oil and Omega Fatty Acids Inhibit Staphylococcus aureus Biofilm Formation and Virulence."

Raorane CJ, Park JG, Lee JH, Oh ST, Kim YG, Lee J

[Front Microbiol, 2018]

<i>Staphylococcus aureus</i> is notorious for its ability to become resistant to antibiotics and biofilms play a critical role in antibiotic tolerance. <i>S. aureus</i> is also capable of secreting several exotoxins associated with the pathogenesis of sepsis and pneumonia. Thus, the objectives of the study were to examine <i>S. aureus</i> biofilm formation <i>in vitro</i>, and the effects of herring oil and its main components, omega fatty acids [<i>cis</i>-4,7,10,13,16,19-docosahexaenoic acid (DHA) and <i>cis</i>-5,8,11,14,17-eicosapentaenoic acid (EPA)], on virulence factor production and transcriptional changes in <i>S. aureus</i>. Herring oil decreased biofilm formation by two <i>S. aureus</i> strains. GC-MS analysis revealed the presence of several polyunsaturated fatty acids in herring oil, and of these, two omega-3 fatty acids, DHA and EPA, significantly inhibited <i>S. aureus</i> biofilm formation. In addition, herring oil, DHA, and EPA at 20 g/ml significantly decreased the hemolytic effect of <i>S. aureus</i> on human red blood cells, and when pre-treated to <i>S. aureus</i>, the bacterium was more easily killed by human whole blood. Transcriptional analysis showed that herring oil, DHA, and EPA repressed the expression of the -hemolysin <i>hla</i> gene. Furthermore, in a <i>Caenorhabditis elegans</i> nematode model, all three prolonged nematode survival in the presence of <i>S. aureus</i>. These findings suggest that herring oil, DHA, and EPA are potentially useful for controlling persistent <i>S. aureus</i> infection.

Zhong F et al. (2011) Genes Dev "Disruption of telomerase trafficking by TCAB1 mutation causes dyskeratosis congenita."

Alter BP, Artandi SE, Shkreli M, Jessop L, Zhong F, Giri N, Savage SA, Chen R, Myers T

[Genes Dev, 2011]

Dyskeratosis congenita (DC) is a genetic disorder of defective tissue maintenance and cancer predisposition caused by short telomeres and impaired stem cell function. Telomerase mutations are thought to precipitate DC by reducing either the catalytic activity or the overall levels of the telomerase complex. However, the underlying genetic mutations and the mechanisms of telomere shortening remain unknown for as many as 50% of DC patients, who lack mutations in genes controlling telomere homeostasis. Here, we show that disruption of telomerase trafficking accounts for unknown cases of DC. We identify DC patients with missense mutations in TCAB1, a telomerase holoenzyme protein that facilitates trafficking of telomerase to Cajal bodies. Compound heterozygous mutations in TCAB1 disrupt telomerase localization to Cajal bodies, resulting in misdirection of telomerase RNA to nucleoli, which prevents telomerase from elongating telomeres. Our findings establish telomerase mislocalization as a novel cause of DC, and suggest that telomerase trafficking defects may contribute more broadly to the pathogenesis of telomere-related disease.

Sharma R et al. (2014) Genes Dev "Differential spatial and structural organization of the X chromosome underlies dosage compensation in C. elegans."

Kind J, Vaillant C, Meister P, Jost D, Askjaer P, Sharma R, Gomez-Saldivar G, van Steensel B

[Genes Dev, 2014]

The adjustment of X-linked gene expression to the X chromosome copy number (dosage compensation [DC]) has been widely studied as a model of chromosome-wide gene regulation. In Caenorhabditis elegans, DC is achieved by twofold down-regulation of gene expression from both Xs in hermaphrodites. We show that in males, the single X chromosome interacts with nuclear pore proteins, while in hermaphrodites, the DC complex (DCC) impairs this interaction and alters X localization. Our results put forward a structural model of DC in which X-specific sequences locate the X chromosome in transcriptionally active domains in males, while the DCC prevents this in hermaphrodites.

Rezai P et al. (2011) Biomicrofluidics "Effect of pulse direct current signals on electrotactic movement of nematodes Caenorhabditis elegans and Caenorhabditis briggsae."

Selvaganapathy PR, Gupta BP, Salam S, Rezai P

[Biomicrofluidics, 2011]

The nematodes (worms) Caenorhabditiselegans and Caenorhabditisbriggsae are well-known model organisms to study the basis of animal development and behaviour. Their sinusoidal pattern of movement is highly stereotypic and serves as a tool to monitor defects in neurons and muscles that control movement. Until recently, a simple yet robust method to initiate movement response on-demand did not exist. We have found that the electrical stimulation in a microfluidic channel, using constant DC electric field, induces movement (termed electrotaxis) that is instantaneous, precise, sensitive, and fully penetrant. We have further characterized this behaviour and, in this paper, demonstrate that electrotaxis can also be induced using a pulse DC electric signal. Worms responded to pulse DC signals with as low as 30% duty cycle by moving towards the negative electrode at the same speed as constant DC fields (average speed of C. elegans=296+/-43m/s and C. briggsae=356+/-20m/s, for both constant and pulse DC electric fields with various frequencies). C. briggsae was found to be more sensitive to electric signals compared to C. elegans. We also investigated the turning response of worms to a change in the direction of constant and pulse DC signals. The response for constant DC signal was found to be instantaneous and similar for most worms. However, in the case of pulse DC signal, alterations in duty cycle affected the turning response time as well as the number of responding worms. Our findings show that pulse DC method allows quantitative measurement of response behaviour of worms and suggest that it could be used as a tool to study the neuronal basis of such a behaviour that is not observed under constant DC conditions.

Semnani RT et al. (2008) J Immunol "Induction of TRAIL- and TNF-alpha-dependent apoptosis in human monocyte-derived dendritic cells by microfilariae of Brugia malayi."

Skinner JA, Venugopal PG, Chien D, Mahapatra L, Chaussabel D, Meylan F, Dorward DW, Nutman TB, Semnani RT, Siegel RM

[J Immunol, 2008]

Dysregulation of professional APC has been postulated as a major mechanism underlying Ag-specific T cell hyporesponsiveness in patients with patent filarial infection. To address the nature of this dysregulation, dendritic cells (DC) and macrophages generated from elutriated monocytes were exposed to live microfilariae (mf), the parasite stage that circulates in blood and is responsible for most immune dysregulation in filarial infections. DC exposed to mf for 24-96 h showed a marked increase in cell death and caspase-positive cells compared with unexposed DC, whereas mf exposure did not induce apoptosis in macrophages. Interestingly, 48-h exposure of DC to mf induced mRNA expression of the proapoptotic gene TRAIL and both mRNA and protein expression of TNF-alpha. mAb to TRAIL-R2, TNF-R1, or TNF-alpha partially reversed mf-induced cell death in DC, as did knocking down the receptor for TRAIL-R2 using small interfering RNA. The mf also induced gene expression of BH3-interacting domain death agonist and protein expression of cytochrome c in DC; mf-induced cleavage of BH3-interacting domain death agonist could be shown to induce release of cytochrome c, leading to activation of caspase 9. Our data suggest that mf induce DC apoptosis in a TRAIL- and TNF-alpha-dependent fashion.

Galimov ER et al. (2018) Cell Rep "Coupling of Rigor Mortis and Intestinal Necrosis during C.elegans Organismal Death."

Pincus Z, Gems D, Poole SE, Galimov ER, Benedetto A, Pryor RE

[Cell Rep, 2018]

Organismal death is a process of systemic collapse whose mechanisms are less well understood than those of cell death. We previously reported that death in C.elegans is accompanied by a calcium-propagated wave of intestinal necrosis, marked by a wave of blue autofluorescence (death fluorescence). Here, we describe another feature of organismal death, a wave of body wall muscle contraction, or death contraction (DC). This phenomenon is accompanied by a wave of intramuscular Ca²⁺release and, subsequently, of intestinal necrosis. Correlation of directions of the DC and intestinal necrosis waves implies coupling of these death processes. Long-lived insulin/IGF-1-signaling mutants show reduced DC and delayed intestinal necrosis, suggesting possible resistance to organismal death. DC resembles mammalian rigor mortis, a postmortem necrosis-related process in which Ca²⁺influx promotes muscle hyper-contraction. In contrast to mammals, DC is an early rather than a late event in C.elegans organismal death. VIDEO ABSTRACT.

Kim J et al. (2022) Elife "Condensin DC loads and spreads from recruitment sites to create loop-anchored TADs in C. elegans."

Morao AK, Street LA, Kim J, Winterkorn LH, Albritton SE, Ercan S, Ragipani B, Zhang B, Jimenez DS, Kramer M

[Elife, 2022]

Condensins are molecular motors that compact DNA via linear translocation. In Caenorhabditis elegans, the X-chromosome harbors a specialized condensin that participates in dosage compensation (DC). Condensin DC is recruited to and spreads from a small number of recruitment elements on the X-chromosome (rex) and is required for the formation of topologically associating domains (TADs). We take advantage of autosomes that are largely devoid of condensin DC and TADs to address how rex sites and condensin DC give rise to the formation of TADs. When an autosome and X-chromosome are physically fused, despite the spreading of condensin DC into the autosome, no TAD was created. Insertion of a strong rex on the X-chromosome results in the TAD boundary formation regardless of sequence orientation. When the same rex is inserted on an autosome, despite condensin DC recruitment, there was no spreading or features of a TAD. On the other hand, when a 'super rex' composed of six rex sites or three separate rex sites are inserted on an autosome, recruitment and spreading of condensin DC led to the formation of TADs. Therefore, recruitment to and spreading from rex sites are necessary and sufficient for recapitulating loop-anchored TADs observed on the X-chromosome. Together our data suggest a model in which rex sites are both loading sites and bidirectional barriers for condensin DC, a one-sided loop-extruder with movable inactive anchor.

Semnani RT et al. (2003) J Immunol "Brugia malayi microfilariae induce cell death in human dendritic cells, inhibit their ability to make IL-12 and IL-10, and reduce their capacity to activate CD4+ T cells."

Sabzevari H, Kubofcik J, Gilden JK, Zhou J, Nutman TB, Semnani RT, Liu AY

[J Immunol, 2003]

Parasite Ag-specific T cell unresponsiveness and diminished IFN-gamma production are immunologic hallmarks of patent infection with lymph-dwelling filarial nematodes. Although this diminished responsiveness is directed primarily against the intravascular microfilarial (MF) parasite stage and mediated in part by reduced APC function, the mechanisms involved are not fully understood. In this report, we demonstrate that human dendritic cells (DC) exposed to live MF up-regulate both the cell surface and gene expression of CD54 (ICAM-1). Moreover, live MF result in a 3-fold increase in DC death compared with MF-unexposed DC, primarily due to apoptosis. Notably, microarray and real-time RT-PCR data indicate that live MF concurrently up-regulate mRNA expression of proinflammatory molecules such as IL-8, RANTES, IL-1alpha, TNF-alpha, and IL-beta in DC, the presence of which is also detected at the protein level, while inhibiting the production of IL-12 (p40 and p70) and IL-10. Soluble excretory-secretory products from live MF diminished IL-12 and IL-10 production and induced DC death, although to a lesser degree. Moreover, exposure of DC to live MF resulted in a decrease in the ability of DC to promote CD4(+) T cell production of IFN-gamma and IL-5. Our findings clearly suggest that the interaction between live MF and DC is complex but contributes to the hyporesponsiveness and parasite persistence associated with the MF(+) state in the infected human. These data further suggest that MF induce an orchestrated response in APC that leads to a diminished capacity to function appropriately, which in turn has significant consequences for CD4(+) T cells.

Das M et al. (2024) Nat Genet "Condensin I folds the Caenorhabditis elegans genome."

Annan A, Dakhovnik A, Gitchev T, Das M, Campos J, Statzer C, Semple JI, Volodkina V, Haemmerli A, Scotton J, Mozziconacci J, Meister P, Ewald CY

[Nat Genet, 2024]

The structural maintenance of chromosome (SMC) complexes-cohesin and condensins-are crucial for chromosome separation and compaction during cell division. During the interphase, mammalian cohesins additionally fold the genome into loops and domains. Here we show that, in Caenorhabditis elegans, a species with holocentric chromosomes, condensin I is the primary, long-range loop extruder. The loss of condensin I and its X-specific variant, condensin I^DC, leads to genome-wide decompaction, chromosome mixing and disappearance of X-specific topologically associating domains, while reinforcing fine-scale epigenomic compartments. In addition, condensin I/I^DC inactivation led to the upregulation of X-linked genes and unveiled nuclear bodies grouping together binding sites for the X-targeting loading complex of condensin I^DC. C. elegans condensin I/I^DC thus uniquely organizes holocentric interphase chromosomes, akin to cohesin in mammals, as well as regulates X-chromosome gene expression.