Head, Brian P. et al. (2013) International Worm Meeting "Whole genome expression analysis of C. elegans upon recovery from Salmonella enterica infection."

Head, Brian P., Aballay, Alejandro

[International Worm Meeting, 2013]

C. elegans are capable of mounting an immune response to a variety of pathogens. In the last decade, several major steps in the C. elegans innate immune response have been dissected including: 1) host surveillance pathways detect a pathogen and/or loss of homeostasis, 2) various intracellular signaling modules are activated in distinct cell types, and 3) immune effector molecules are produced at the site of infection (primarily the intestinal and hypodermal epithelia). Moreover, stress response pathways are activated to cope with cellular damage from both host immune effectors and pathogen-derived molecules. Much less is known about the physiology of the animal during recovery from an infection. Thus, we are utilizing the C. elegans-pathogen model to study recovery from infection by Salmonella enterica. After generating a "mild" Salmonella infection in the worm, we alleviate this infection by a combination of antibiotic treatment plus a change in food source. We demonstrate that "recovered" worms have a reduced bacterial burden and enhanced survival. To better understand the transcriptional response during recovery, we have utilized whole genome microarray technology. A variety of expected and novel gene clusters are altered during recovery. Representative genes from several clusters and other interesting candidates were confirmed by qRT-PCR. We are in the process of testing these genes for effects on recovery using standard reverse genetic techniques.

Head, Brian et al. (2015) International Worm Meeting "The role of GATA and other cell-autonomous transcription factors in mediating C. elegans recovery from acute pathogenic infection."

Head, Brian, Aballay, Alejandro

[International Worm Meeting, 2015]

The host response to acute microbial infection is complex but, at a broad level, involves sensing the pathogen, tolerating pathogen- and host-induced damage, reducing pathogen burden, and, finally, restoring homeostasis. This final phase is critical because if the host cannot restore physiological homeostasis, long-term problems can arise. In humans, these problems manifest in a multitude of disorders including recurrent pathogenic infection, inflammatory bowel diseases (IBDs), and gastritis/duodenitis.We are utilizing a C. elegans acute infection model to study recovery - the final restorative phase in the host response to acute microbial challenge. Our acute infection protocol consists of a short exposure to an intestinal pathogen - either Salmonella enterica or Pseudomonas aeruginosa - followed by antibiotic treatment and a change in food source. In previously published work, we demonstrated that "recovered" animals have a reduced bacterial burden and enhanced survival (similar to unchallenged animals). We also determined that the conserved GATA transcription factor ELT-2 acts in a cell-autonomous manner in the intestine to control the expression of genes that are important for recovery. This transcriptional output consists of genes involved in xenobiotic detoxification, redox regulation, and cellular homeostasis. We are continuining to define the network of cell-autonomous transcription factors (DAF-16, SKN-1) and non-cell autonomous signaling pathways (neuronal circuits) that shape gene expression patterns during recovery. Our recent results will be presented.

Brian Head et al. (2005) International Worm Meeting "Identification of Drp-1 Interacting Proteins"

Alexander M van der Bliek, Brian Head

[International Worm Meeting, 2005]

Mitochondrial division is essential for the development and survival of multicellular organisms. It is necessary for cell growth, homeostasis of energy production, and proper distribution of mitochondria during mitosis. Furthermore, experiments in mammalian tissue culture and C. elegans have shown that mitochondrial division plays a central role in programmed cell death, or apoptosis (Frank et al., 2001; Jagasia et al., 2005). Identification of the fundamental players Drp-1, Mdv-1, and Fis-1 has been useful in extending our basic knowledge concerning this essential process. However, it is certain that these components do not comprise an exhaustive list of mitochondrial division proteins. In the lab, we are using a combined biochemical/genetic approach in C. elegans to identify new components of the mitochondrial division apparatus. Biochemical purifications of TAP-tagged Drp-1, a GTPase that acts at mitochondrial division sites, will allow for the identification of Drp-1 binding partners. These proteins may be regulators of division or they may be novel components of the division complex. We are also conducting open-ended screens for enhancers of Drp-1 loss of function and using feeding RNAi to reveal genetic interaction with selected proteins.

Brian P Head et al. (2004) West Coast Worm Meeting "Identification of Novel Mitochondrial Division Proteins"

Alexander M van der Bliek, Brian P Head

[West Coast Worm Meeting, 2004]

Mitochondrial division is essential for the survival of eukaryotic organisms. It is necessary for cell growth, homeostasis of energy production, and proper distribution of mitochondria during mitosis. Furthermore, experiments in mammalian tissue culture have shown that mitochondrial division has a role in programmed cell death, or apoptosis (Frank, 2001). Identification of the fundamental players - Drp-1, Mdv-1, and Fis-1 - has been useful in extending our basic knowledge concerning this essential process. However, it is certain that these components do not comprise an exhaustive list of mitochondrial division proteins. In the lab, we are using a combined genetic/biochemical approach in C. elegans to identify new components of the mitochondrial division apparatus. Biochemical purifications of TAP-tagged Drp-1, a GTPase that acts at mitochondrial division sites, will allow for the identification of binding partners that also act in division. Erp-1, a protein identified by homology to components of the endocytic pit, is unlike Drp-1 because its' role in division is still hotly contested. In order to shed light on the true function of this highly conserved protein, we will purify Erp-1 using the TAP-tag system. Genetically, we will identify Drp-1 alleles and Drp-1 interacting proteins using various enhancer and lethal screens. Finally, in collaboration with other lab members, we are attempting to determine the role that phospholipids play in regulating mitochondrial division.

Shingai R et al. (2013) Front Behav Neurosci "Evaluation of Head Movement Periodicity and Irregularity during Locomotion of Caenorhabditis elegans."

Furudate M, Iwasaki Y, Shingai R, Hoshi K

[Front Behav Neurosci, 2013]

Caenorhabditis elegans is suitable for studying the nervous system, which controls behavior. C. elegans shows sinusoidal locomotion on an agar plate. The head moves not only sinusoidally but also more complexly, which reflects regulation of the head muscles by the nervous system. The head movement becomes more irregular with senescence. To date, the head movement complexity has not been quantitatively analyzed. We propose two simple methods for evaluation of the head movement regularity on an agar plate using image analysis. The methods calculate metrics that are a measure of how the head end movement is correlated with body movement. In the first method, the length along the trace of the head end on the agar plate between adjacent intersecting points of the head trace and the quasi-midline of the head trace, which was made by sliding an averaging window of 1/2 the body wavelength, was obtained. Histograms of the lengths showed periodic movement of the head and deviation from it. In the second method, the intersections between the trace of the head end and the trace of the 5 (near the pharynx) or 50% (the mid-body) point from the head end in the centerline length of the worm image were marked. The length of the head trace between adjacent intersections was measured, and a histogram of the lengths was produced. The histogram for the 5% point showed deviation of the head end movement from the movement near the pharynx. The histogram for the 50% point showed deviation of the head movement from the sinusoidal movement of the body center. Application of these methods to wild type and several mutant strains enabled evaluation of their head movement periodicity and irregularity, and revealed a difference in the age-dependence of head movement irregularity between the strains. A set of five parameters obtained from the histograms reliably identifies differences in head movement between strains.

Shen Y et al. (2016) Elife "An extrasynaptic GABAergic signal modulates a pattern of forward movement in Caenorhabditis elegans."

Qin Y, Kawano T, Liu H, Zhong C, Samuel AD, Wu M, Xu T, Harris G, Zhang Y, Shen Y, Wen Q

[Elife, 2016]

As a common neurotransmitter in the nervous system, -aminobutyric acid (GABA) modulates locomotory patterns in both vertebrates and invertebrates. However, the signaling mechanisms underlying the behavioral effects of GABAergic modulation are not completely understood. Here, we demonstrate that a GABAergic signal in C. elegans modulates the amplitude of undulatory head bending through extrasynaptic neurotransmission and conserved metabotropic receptors. We show that the GABAergic RME head motor neurons generate undulatory activity patterns that correlate with head bending and the activity of RME causally links with head bending amplitude. The undulatory activity of RME is regulated by a pair of cholinergic head motor neurons SMD, which facilitate head bending, and inhibits SMD to limit head bending. The extrasynaptic neurotransmission between SMD and RME provides a gain control system to set head bending amplitude to a value correlated with optimal efficiency of forward movement.

Ouellette MH et al. (2018) eNeuro "A Gate-and-Switch Model for Head Orientation Behaviors in Caenorhabditis elegans."

Desrochers MJ, Gheta I, Ouellette MH, Ramos R, Hendricks M

[eNeuro, 2018]

The nervous system seamlessly integrates perception and action. This ability is essential for stable representation of and appropriate responses to the external environment. How the sensorimotor integration underlying this ability occurs at the level of individual neurons is of keen interest. In <i>Caenorhabditis elegans</i>, RIA interneurons receive input from sensory pathways and have reciprocal connections with head motor neurons. RIA simultaneously encodes both head orientation and sensory stimuli, which may allow it to integrate these two signals to detect the spatial distribution of stimuli across head sweeps and generate directional head responses. Here, we show that blocking synaptic release from RIA disrupts head orientation behaviors in response to unilaterally presented stimuli. We found that sensory encoding in RIA is gated according to head orientation. This dependence on head orientation is independent of motor encoding in RIA, suggesting a second, posture-dependent pathway upstream of RIA. This gating mechanism may allow RIA to selectively attend to stimuli that are asymmetric across head sweeps. Attractive odor removal during head bends triggers rapid head withdrawal in the opposite direction. Unlike sensory encoding, this directional response is dependent on motor inputs to and synaptic output from RIA. Together, these results suggest that RIA is part of a sensorimotor pathway that is dynamically regulated according to head orientation at two levels: the first is a gate that filters sensory representations in RIA, and the second is a switch that routes RIA synaptic output to dorsal or ventral head motor neurons.

Zhang H et al. (2022) BMC Bioinformatics "Automated recognition and analysis of head thrashes behavior in C. elegans."

Zhang H, Chen W, Gao S

[BMC Bioinformatics, 2022]

BACKGROUND: Locomotive behaviors are a rapid evaluation indicator reflecting whether the nervous system of worms is damaged, and has been proved to be sensitive to chemical toxicity. In many toxicological studies, C. elegans head thrashes is a key indicator of locomotive behaviors to measure the vitality of worms. In previous studies, the number of head thrashes was manually counted, which is time-consuming and labor-intensive. RESULTS: This paper presents an automatic recognition and counting method for head thrashes behavior of worms from experimental videos. First, the image processing algorithm is designed for worm morphology features calculation, mean gray values of head and tail are used to locate the head of worm accurately. Next, the worm skeleton is extracted and divided into equal parts. The angle formulas are used to calculate the bending angle of the head of worm. Finally, the number of head thrashes is counted according to the bending angle of the head in each frame. The robustness of the proposed algorithm is evaluated by comparing the counting results of the manual counting. It is proved that the proposed algorithm can recognize the occurrence of head thrashes of C. elegans of different strains. In addition, the difference of the head thrashes behavior of different worm strains is analyzed, it is proved that the relationship between worm head thrashes behavior and lifespan. CONCLUSIONS: A new method is proposed to automatically count the number of head thrashes of worms. This algorithm makes it possible to count the number of head thrashes from the worm videos collected by the automatic tracking system. The proposed algorithm will play an important role in toxicological research and worm vitality research. The code is freely available at https://github.com/hthana/HTC .

Singh VK et al. (2015) Eur J Med Chem "Synthesis, molecular docking and Brugia malayi thymidylate kinase (BmTMK) enzyme inhibition study of novel derivatives of [6]-shogaol."

Narender T, Doharey PK, Singh VK, Rathaur S, Siddiqi MI, Saxena JK, Kumar V

[Eur J Med Chem, 2015]

[6]-Shogaol (1) was isolated from Zingiber officinale. Twelve novel compounds have been synthesized and evaluated for their Brugia malayi thymidylate kinase (BmTMK) inhibition activity, which plays important role for the DNA synthesis in parasite. [6]-Shogaol (1) and shogaol with thymine head group (2), 5-bromouracil head group (3), adenine head group (4) and 2-amino-3-methylpyridine head group (5) showed potential inhibitory effect on BmTMK activity. Further molecular docking studies were carried out to explore the putative binding mode of compounds 1-5.

Chen X et al. (2015) Mol Neurodegener "Erratum to: Ethosuximide ameliorates neurodegenerative disease phenotypes by modulating DAF-16/FOXO target gene expression."

McCue HV, Chen X, Morgan A, Kashyap SS, Barclay JW, Kraemer BC, Burgoyne RD, Wong SQ

[Mol Neurodegener, 2015]

The original version of this article [1] unfortunately contained a mistake. The author list contained a spelling error for the author Hannah V. McCue. The original article has been corrected for this error. The corrected author list is given below:Xi Chen, Hannah V. McCue, Shi Quan Wong, Sudhanva S. Kashyap, Brian C. Kraemer, Jeff W. Barclay, Robert D. Burgoyne and Alan Morgan