Lawes M et al. (2020) Neurotoxicology "Metal-induced neurotoxicity in a RAGE-expressing C. elegans model."

Iroegbu JD, Aschner M, Ijomone OM, Pinkas A, Lawes M, Frohlich BA

[Neurotoxicology, 2020]

Environmental and occupational metal exposure poses serious global concerns. Metal exposure have severally been associated with neurotoxicity and brain damage. Furthermore, receptor for advanced glycation end products (RAGE) is also implicated in neurological disorders, particularly those with altered glucose metabolism. Here, we examine potential compounding effect of metal exposure and RAGE expression on dopamine (DA) and serotonin (SER) neurons in C. elegans. In addition, we evaluate the effect of RAGE expression on DA and SER neurons in hyperglycemic conditions. Newly generated RAGE-expressing C. elegans tagged with green fluorescent proteins (GFP) in DAergic and SERergic neurons were treated with cadmium (Cd) or manganese (Mn). Additionally, the RAGE-expressing worms were also exposed to high glucose conditions. Results showed metals induced neurodegeneration both in the presence and absence of RAGE expression, but the manner of degeneration differed between Cd and Mn treated nematodes. Furthermore, RAGE-expressing worms showed significant neurodegeneration in both DAergic and SERergic neurons. Our results indicate co-occurrence of metal exposure and RAGE expression can induce neurodegeneration. Additionally, we show that RAGE expression can exacerbate hyperglycemic induced neurodegeneration.

Arata Y et al. (2014) Front Physiol "Power law relationship between cell cycle duration and cell volume in the early embryonic development of Caenorhabditis elegans."

Takagi H, Sawa H, Sako Y, Arata Y

[Front Physiol, 2014]

Cell size is a critical factor for cell cycle regulation. In Xenopus embryos after midblastula transition (MBT), the cell cycle duration elongates in a power law relationship with the cell radius squared. This correlation has been explained by the model that cell surface area is a candidate to determine cell cycle duration. However, it remains unknown whether this second power law is conserved in other animal embryos. Here, we found that the relationship between cell cycle duration and cell size in Caenorhabditis elegans embryos exhibited a power law distribution. Interestingly, the powers of the time-size relationship could be grouped into at least three classes: highly size-correlated, moderately size-correlated, and potentially a size-non-correlated class according to C. elegans founder cell lineages (1.2, 0.81, and <0.39 in radius, respectively). Thus, the power law relationship is conserved in Xenopus and C. elegans, while the absolute powers in C. elegans were different from that in Xenopus. Furthermore, we found that the volume ratio between the nucleus and cell exhibited a power law relationship in the size-correlated classes. The power of the volume relationship was closest to that of the time-size relationship in the highly size-correlated class. This correlation raised the possibility that the time-size relationship, at least in the highly size-correlated class, is explained by the volume ratio of nuclear size and cell size. Thus, our quantitative measurements shed a light on the possibility that early embryonic C. elegans cell cycle duration is coordinated with cell size as a result of geometric constraints between intracellular structures.

Wypijewska A et al. (2012) Biochemistry "7-methylguanosine diphosphate (m(7)GDP) is not hydrolyzed but strongly bound by decapping scavenger (DcpS) enzymes and potently inhibits their activity."

Wypijewska A, Darzynkiewicz E, Davis RE, Jemielity J, Bojarska E, Lukaszewicz M, Stepinski J

[Biochemistry, 2012]

Decapping scavenger (DcpS) enzymes catalyze the cleavage of a residual cap structure following 3' 5' mRNA decay. Some previous studies suggested that both m(7)GpppG and m(7)GDP were substrates for DcpS hydrolysis. Herein, we show that mononucleoside diphosphates, m(7)GDP (7-methylguanosine diphosphate) and m(3)(2,2,7)GDP (2,2,7-trimethylguanosine diphosphate), resulting from mRNA decapping by the Dcp1/2 complex in the 5' 3' mRNA decay, are not degraded by recombinant DcpS proteins (human, nematode, and yeast). Furthermore, whereas mononucleoside diphosphates (m(7)GDP and m(3)(2,2,7)GDP) are not hydrolyzed by DcpS, mononucleoside triphosphates (m(7)GTP and m(3)(2,2,7)GTP) are, demonstrating the importance of a triphosphate chain for DcpS hydrolytic activity. m(7)GTP and m(3)(2,2,7)GTP are cleaved at a slower rate than their corresponding dinucleotides (m(7)GpppG and m(3)(2,2,7)GpppG, respectively), indicating an involvement of the second nucleoside for efficient DcpS-mediated digestion. Although DcpS enzymes cannot hydrolyze m(7)GDP, they have a high binding affinity for m(7)GDP and m(7)GDP potently inhibits DcpS hydrolysis of m(7)GpppG, suggesting that m(7)GDP may function as an efficient DcpS inhibitor. Our data have important implications for the regulatory role of m(7)GDP in mRNA metabolic pathways due to its possible interactions with different cap-binding proteins, such as DcpS or eIF4E.

Yadav A et al. (2015) Chaos "Origin and implications of zero degeneracy in networks spectra."

Yadav A, Jalan S

[Chaos, 2015]

The spectra of many real world networks exhibit properties which are different from those of random networks generated using various models. One such property is the existence of a very high degeneracy at the zero eigenvalue. In this work, we provide all the possible reasons behind the occurrence of the zero degeneracy in the network spectra, namely, the complete and partial duplications, as well as their implications. The power-law degree sequence and the preferential attachment are the properties which enhances the occurrence of such duplications and hence leading to the zero degeneracy. A comparison of the zero degeneracy in protein-protein interaction networks of six different species and in their corresponding model networks indicates importance of the degree sequences and the power-law exponent for the occurrence of zero degeneracy.

Dames SA et al. (1997) International C. elegans Meeting "Mortality Kinetics of Large Populations of C. elegans"

Johnson TE, Dames SA

[International C. elegans Meeting, 1997]

We are currently examining multiple aspects of C. elegans mortality. Previous research using both heterogenous and homogenous genetic populations (180,000 total animals) has demonstrated that C. elegans exhibits an age-specific (post reproductive) mortality increase predicted by the Gompertz Law. Originally proposed in 1825 as an empirical model for human aging, the Gompertz Law states that as population increases in age, mortality rates increase exponentially. Recent studies using large populations (up to 1,000,000 animals) of C. capitata (medfly) and D. melanogaster indicate that the Gompertz Law may not accurately predict mortality rates of these exceedingly large populations. These populations display an initial Gompertz-like mortality rate until very late in life when the last few of the surviving animal's mortality rates appear to level off. Human census data has also introduced concerns as to the ability of the Gompertz Law to predict the mortality rates in contemporary human populations (which appear to level off at age 85). We have assessed the mortality kinetics of >500,000 genotypically identical "wild type" C. elegans hermaphrodites in a standard environment. The results are indicative of a two-stage Gompertz-like mortality rate. We will be performing multiple mortality kinetics experiments using large populations (>100,000) of the long-lived strain age-1 to determine how this mutation affects mortality kinetics. In future experiments, we intend to alter environmental conditions (population density, food resources, temperature) to obtain differences in the overall mortality kinetics of C. elegans. We are especially interested in how the overall "wild type" mortality rate function is influenced by these limiting conditions. Experiments will be performed with a variety of strains (including males) to observe if the general C. elegans mortality function is altered by genotype. This may prove useful in predicting the mortality rates of large heterogenic populations (such as humans).

O'Connell EM et al. (2015) J Infect Dis "Targeting Filarial Abl-like Kinases: Orally Available, Food and Drug Administration-Approved Tyrosine Kinase Inhibitors Are Microfilaricidal and Macrofilaricidal."

Nutman TB, O'Connell EM, Bennuru S, Steel C, Dolan MA

[J Infect Dis, 2015]

BACKGROUND: Elimination of onchocerciasis and lymphatic filariasis is targeted for 2020. Given the coincident Loa loa infections in Central Africa and the potential for drug resistance development, the need for new microfilaricides and macrofilaricides has never been greater. With the genomes of L. loa, Onchocerca volvulus, Wuchereria bancrofti, and Brugia malayi available, new drug targets have been identified. METHODS: The effects of the tyrosine kinase inhibitors imatinib, nilotinib, and dasatinib on B. malayi adult males, adult females, L3 larvae, and microfilariae were assessed using a wide dose range (0-100 M) in vitro. RESULTS: For microfilariae, median inhibitory concentrations (IC50 values) on day 6 were 6.06 M for imatinib, 3.72 M for dasatinib, and 81.35 M for nilotinib; for L3 larvae, 11.27 M, 13.64 M, and 70.98 M, respectively; for adult males, 41.6 M, 3.87 M, and 68.22 M, respectively; and for adult females, 42.89 M, 9.8 M, and >100 M, respectively. Three-dimensional modeling suggests how these tyrosine kinase inhibitors bind and inhibit filarial protein activity. CONCLUSIONS: Given the safety of imatinib in humans, plans are underway for pilot clinical trials to assess its efficacy in patients with filarial infections.

Dames SA et al. (1996) West Coast Worm Meeting "MORTALITY KINETICS IN C. ELEGANS: THE MILLION WORM PROJECT."

Dames SA, Duhon SA, Johnson TE, Tedesco PM

[West Coast Worm Meeting, 1996]

Predicting the mortality rates of large populations is of significant economic importance. In the United States, over 20 percent of the population will be 65 years of age or older. Estimates off as little as one or two percent could have suboptimal economic implications by 2020. Using C. elegans and its obvious advantages in expense and speed will be useful in predicting the mortality kinetics of large populations. We are currently examining multiple aspects of C. elegans mortality. Previous research using both heterogenous and homogenous genetic populations (180,000 total animals) has demonstrated that C. elegans exhibits an age-specific (post reproductive) mortality increase predicted by the Gompertz Law. Originally proposed in 1825 as an empirical model for human aging, the Gompertz Law states that as population increases in age, mortality rates increase exponentially, and can be represented mathematically as: m(t) = Aeat Where "m(t)" is the mortality rate at time "t"; "A" is the mortality rate at reproductive maturity; and "a" is the Gompertz exponent which describes the rate of accelera- tion of age specific mortality with chronological age. Recent studies using large populations (up to 1,000,000 animals) of C. capitata (medfly) and D. melanogaster indicate that the Gompertz Law may not accurately predict mortality rates of these exceedingly large populations. These populations display an initial Gompertz-like mortality rate until very late in life when the last few of the surviving animal's mortality rates appear to level off. Human census data has also introduced concerns as to the ability of the Gompertz Law to predict the mortality rates in contemporary human populations (which appear to level off at age 85). We are in the process of determining the mortality rate of at least 1,000,000 genotypically identical animals in order to look for late stage alterations in mortality rates. We intend to alter environmental conditions (population density, food resources, temperature) to obtain differences in the overall mortality kinetics of C. elegans. We are especially interested in how the overall "wild type" mortality rate function is influenced by these conditions. Experiments will be performed with a variety of strains (including males) to observe if the general C. elegans mortality function is altered by genotype. This may prove useful in predicting the mortality rates of large heterogenic populations (such as humans).

Arata Y et al. (2022) Sci Rep "Insulin signaling shapes fractal scaling of C. elegans behavior."

Sako Y, Arata Y, Shiga I, Jurica P, Kimura H, Kiyono K, Ikeda Y

[Sci Rep, 2022]

Fractal scaling in animal behavioral activity, where similar temporal patterns appear repeatedly over a series of magnifications among time scales, governs the complex behavior of various animal species and, in humans, can be altered by neurodegenerative diseases and aging. However, the mechanism underlying fractal scaling remains unknown. Here, we cultured C. elegans in a microfluidic device for 3days and analyzed temporal patterns of C. elegans activity by fractal analyses. The residence-time distribution of C. elegans behaviors shared a common feature with those of human and mice. Specifically, the residence-time power-law distribution of the active state changed to an exponential-like decline at a longer time scale, whereas the inactive state followed a power-law distribution. An exponential-like decline appeared with nutrient supply in wild-type animals, whereas this decline disappeared in insulin-signaling-defective daf-2 and daf-16 mutants. The absolute value of the power-law exponent of the inactive state distribution increased with nutrient supply in wild-type animals, whereas the value decreased in daf-2 and daf-16 mutants. We conclude that insulin signaling differentially affects mechanisms that determine the residence time in active and inactive states in C. elegans behavior. In humans, diabetes mellitus, which is caused by defects in insulin signaling, is associated with mood disorders that affect daily behavioral activities. We hypothesize that comorbid behavioral defects in patients with diabetes may be attributed to altered fractal scaling of human behavior.

Tiraihi A et al. (2011) Theor Biol Med Model "Self-organization of developing embryo using scale-invariant approach."

Tiraihi T, Tiraihi M, Tiraihi A

[Theor Biol Med Model, 2011]

BACKGROUND: Self-organization is a fundamental feature of living organisms at all hierarchical levels from molecule to organ. It has also been documented in developing embryos. METHODS: In this study, a scale-invariant power law (SIPL) method has been used to study self-organization in developing embryos. The SIPL coefficient was calculated using a centro-axial skew symmetrical matrix (CSSM) generated by entering the components of the Cartesian coordinates; for each component, one CSSM was generated. A basic square matrix (BSM) was constructed and the determinant was calculated in order to estimate the SIPL coefficient. This was applied to developing C. elegans during early stages of embryogenesis. The power law property of the method was evaluated using the straight line and Koch curve and the results were consistent with fractal dimensions (fd). Diffusion-limited aggregation (DLA) was used to validate the SIPL method. RESULTS AND CONCLUSION: The fractal dimensions of both the straight line and Koch curve showed consistency with the SIPL coefficients, which indicated the power law behavior of the SIPL method. The results showed that the ABp sublineage had a higher SIPL coefficient than EMS, indicating that ABp is more organized than EMS. The fd determined using DLA was higher in ABp than in EMS and its value was consistent with type 1 cluster formation, while that in EMS was consistent with type 2.

Ciftci K (2018) Network "Synaptic noise facilitates the emergence of self-organized criticality in the Caenorhabditis elegans neuronal network."

Ciftci K

[Network, 2018]

Avalanches with power-law distributed size parameters have been observed in neuronal networks. This observation might be a manifestation of self-organized criticality (SOC). Yet, the physiological mechanisms of this behaviour are currently unknown. Describing synaptic noise as transmission failures mainly originating from the probabilistic nature of neurotransmitter release, this study investigates the potential of this noise as a mechanism for driving the functional architecture of the neuronal networks towards SOC. To this end, a simple finite state neuron model, with activity dependent and synapse specific failure probabilities, was built based on the known anatomical connectivity data of the nematode Ceanorhabditis elegans. Beginning from random values, it was observed that synaptic noise levels picked out a set of synapses and consequently an active subnetwork that generates power-law distributed neuronal avalanches. The findings of this study bring up the possibility that synaptic failures might be a component of physiological processes underlying SOC in neuronal networks.