Anthelmintic drug actions in resistant and susceptible C. elegans revealed by electrophysiological recordings in a multichannel microfluidic device

doi:10.1016/j.ijpddr.2018.10.003

. 2018 Dec;8(3):607-628.

doi: 10.1016/j.ijpddr.2018.10.003. Epub 2018 Oct 30.

Anthelmintic drug actions in resistant and susceptible C. elegans revealed by electrophysiological recordings in a multichannel microfluidic device

Janis C Weeks¹, Kristin J Robinson², Shawn R Lockery³, William M Roberts⁴

Affiliations

¹ Institute of Neuroscience, University of Oregon, 1254 University of Oregon, Eugene, OR, 97403-1254, USA. Electronic address: jweeks@uoregon.edu.
² Institute of Neuroscience, University of Oregon, 1254 University of Oregon, Eugene, OR, 97403-1254, USA. Electronic address: kristinr@uoneuro.uoregon.edu.
³ Institute of Neuroscience, University of Oregon, 1254 University of Oregon, Eugene, OR, 97403-1254, USA. Electronic address: shawn@uoregon.edu.
⁴ Institute of Neuroscience, University of Oregon, 1254 University of Oregon, Eugene, OR, 97403-1254, USA. Electronic address: billr@uoregon.edu.

PMID: 30503202
PMCID: PMC6287544
DOI: 10.1016/j.ijpddr.2018.10.003

Anthelmintic drug actions in resistant and susceptible C. elegans revealed by electrophysiological recordings in a multichannel microfluidic device

Janis C Weeks et al. Int J Parasitol Drugs Drug Resist. 2018 Dec.

. 2018 Dec;8(3):607-628.

doi: 10.1016/j.ijpddr.2018.10.003. Epub 2018 Oct 30.

Authors

Janis C Weeks¹, Kristin J Robinson², Shawn R Lockery³, William M Roberts⁴

Affiliations

¹ Institute of Neuroscience, University of Oregon, 1254 University of Oregon, Eugene, OR, 97403-1254, USA. Electronic address: jweeks@uoregon.edu.
² Institute of Neuroscience, University of Oregon, 1254 University of Oregon, Eugene, OR, 97403-1254, USA. Electronic address: kristinr@uoneuro.uoregon.edu.
³ Institute of Neuroscience, University of Oregon, 1254 University of Oregon, Eugene, OR, 97403-1254, USA. Electronic address: shawn@uoregon.edu.
⁴ Institute of Neuroscience, University of Oregon, 1254 University of Oregon, Eugene, OR, 97403-1254, USA. Electronic address: billr@uoregon.edu.

PMID: 30503202
PMCID: PMC6287544
DOI: 10.1016/j.ijpddr.2018.10.003

Abstract

Many anthelmintic drugs used to treat parasitic nematode infections target proteins that regulate electrical activity of neurons and muscles: ion channels (ICs) and neurotransmitter receptors (NTRs). Perturbation of IC/NTR function disrupts worm behavior and can lead to paralysis, starvation, immune attack and expulsion. Limitations of current anthelmintics include a limited spectrum of activity across species and the threat of drug resistance, highlighting the need for new drugs for human and veterinary medicine. Although ICs/NTRs are valuable anthelmintic targets, electrophysiological recordings are not commonly included in drug development pipelines. We designed a medium-throughput platform for recording electropharyngeograms (EPGs)-the electrical signals emitted by muscles and neurons of the pharynx during pharyngeal pumping (feeding)-in Caenorhabditis elegans and parasitic nematodes. The current study in C. elegans expands previous work in several ways. Detecting anthelmintic bioactivity in drugs, compounds or natural products requires robust, sustained pharyngeal pumping under baseline conditions. We generated concentration-response curves for stimulating pumping by perfusing 8-channel microfluidic devices (chips) with the neuromodulator serotonin, or with E. coli bacteria (C. elegans' food in the laboratory). Worm orientation in the chip (head-first vs. tail-first) affected the response to E. coli but not to serotonin. Using a panel of anthelmintics-ivermectin, levamisole and piperazine-targeting different ICs/NTRs, we determined the effects of concentration and treatment duration on EPG activity, and successfully distinguished control (N2) and drug-resistant worms (avr-14; avr-15; glc-1, unc-38 and unc-49). EPG recordings detected anthelmintic activity of drugs that target ICs/NTRs located in the pharynx as well as at extra-pharyngeal sites. A bus-8 mutant with enhanced permeability was more sensitive than controls to drug treatment. These results provide a useful framework for investigators who would like to more easily incorporate electrophysiology as a routine component of their anthelmintic research workflow.

Keywords: Anthelmintic drug; C. elegans; Drug screening; Electrophysiology; Microfluidics; Pharyngeal pumping.

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Figures

**Fig. 1**
Microfluidic EPG recording device (chip). A. In this image (modified from Weeks et al., 2016b; https://creativecommons.org/licenses/by/4.0/), microchannels were filled with a red dye to aid visualization. *C. elegans* were loaded into the input port (filled arrow) and distributed via a branching network of channels into 8 recording modules, each with a distal (blue) electrode wire. A hollow metal electrode (not shown) inserted into the input port delivered perfusate and served as a common electrical reference. Solutions flowed past worms and exited to waste reservoirs (*, waste reservoirs for recording module 1). Open arrow indicates expanded region shown in B. B. Recording modules were modified from an earlier design by adding bilateral side channels parallel to the worm channel to enhance access of perfused solutions to worms. Feature height in the PDMS layer of the chip was measured relative to the glass substrate. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

**Fig. 2**
Stimulation of pharyngeal pumping by 5HT. A. Experimental protocol for most experiments. Worms were perfused with a control solution for 30 min, followed by switching the perfusate to a test solution and recording for 60 min more. B. Representative example of 5HT-stimulated EPG activity. Simultaneous EPG recordings from seven N2 worms (numbered 1 to 7) in one chip: each trace from a different worm. Baseline pumping in M9 was followed by switching (vertical bar masks electrical artifact) to 10 mM 5HT in M9. Pumping increased rapidly and EPG amplitude increased over time (insets show pumps from worm 1; E, excitatory spike, R, relaxation spike). Worms 1, 5 and 6 were head-first in worm traps while the others were tail-first. C. Effect of 5HT on pump frequency and amplitude. Switch to 10 mM 5HT occurred at the vertical dotted line, with the electrical artifact blanked. Time-series data were extracted using custom software (see Section 2.6) and plotted as mean pump frequency (solid line) and amplitude (dashed line; peak-to-peak from E spike to R spike) (shading depicts S.E.M. in all Figures; n = 19 worms). D. IPI probability density histogram for worms in 10 mM 5HT, during t = 30–60 min post-switch (same worms as C). The mode of the distribution is marked (arrow; 225 ms, or 4.44 Hz). E. Steady-state pump frequency increased with 5HT concentration. Worms were perfused for 60 min with 5HT to achieve steady-state pump frequency, which was measured for the next 30 min (t = 60–90 min). Plot shows mean ± S.E.M. (n = 19–23 worms/group) pump frequency for different 5HT concentrations, fitted using the Hill equation (maximum frequency, 5.08 Hz; C_1/2, 1.15 mM; Hill coefficient, 0.86). Some error bars are smaller than the symbols.

**Fig. 3**
Stimulation of pharyngeal pumping by *E. coli* OP50. A. Representative example of simultaneous EPG recordings from seven N2 worms (numbered 1 to 7) in one chip; each trace from a different worm. Baseline activity recorded in M9 was followed by switching (vertical bar masks electrical artifact) to OP50 (O.D.₆₀₀ = 4) in M9; the switch marked the termination of a 2-h period of food deprivation. Pumping increased and occurred in irregular bouts. Worms 1 and 5 were head-first in worm traps while the others were tail-first. B. Time course of pumping stimulation by OP50. Perfusate switch occurred at the vertical dotted line, with the electrical artifact blanked. Lines show mean pump frequency in worms perfused with OP50 at O.D.₆₀₀ values between 0 (blank control) to 5 (n = 19–33 worms/group). Concentrations are denoted by color (see key). C. Concentration-response curves for rapid and sustained responses to OP50. Plots show mean pump frequency measured from t = 2–7 min (open circles and dashed line; rapid response) or t = 30–60 min (filled circles and solid line; sustained response) following the switch to OP50. The lowest OP50 concentration tested (O.D.₆₀₀ = 1) evoked nearly half-maximal pump frequencies, which implies that C_1/2 ≅ 1 mM for both rapid and sustained responses, but more data would be required to accurately constrain C_1/2 and the Hill coefficient. The smooth curves in Fig. 3C, which are best fits to the Hill equation calculated assuming a Hill coefficient = 5, show saturating values of 3.37 Hz and 2.55 Hz for rapid and sustained responses, respectively. D. Effect of OP50 on pump frequency and amplitude. Data from worms perfused with OP50 between O.D.₆₀₀ = 2–5 were combined and plotted as mean pump frequency (solid line) and peak-to-peak amplitude (dashed line; n = 90 worms). Switch to OP50 occurred at the vertical dotted line, with the electrical artifact blanked. E. IPI probability density histogram for worms perfused with OP50 between O.D.₆₀₀ = 2–5, from t = 30–60 min (n = 90 worms). The mode of the distribution is marked (arrow; 205 ms, or 4.89 Hz). Plots in panels **B-E** are from the same groups of worms. Some error bars are smaller than the symbols. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

**Fig. 4**
*avr-14*; *avr-15*; *glc-1* (IVM-resistant) worms are less sensitive to IVM than N2s. A. Representative EPG recordings from individual worms, all perfused with M9-5HT during the baseline period. Vertical bar masks electrical artifact when the perfusate was switched. i, ii, N2 and *avr-14*; *avr-15*; *glc-1* worms switched to M9-5HT (controls); **iii**, iv, N2 and *avr-14*; *avr-15*; *glc-1* worms switched to 3 μM IVM in M9-5HT. IVM inhibited pumping more strongly in N2 than *avr-14*; *avr-15*; *glc-1*. **B, C.** Pump frequency plotted against time for N2 (B) and *avr-14*; *avr-15*; *glc-1* (C) worms switched at t = 0 min to different concentrations of IVM (mean ± S.E.M.; n = 14–35 worms/group). The key in B applies to all panels; IVM concentration is denoted by color and genotype by line type (solid, N2; dashed, *avr-14*; *avr-15*; *glc-1*). Perfusate switch occurred at the vertical dotted line, with the electrical artifact blanked. IVM caused concentration-dependent inhibition of pumping in both strains. D. Same data as in B and C, displayed together after normalizing pump frequency to its mean value between t = −12 to −2 min within each worm, to correct for different baseline frequencies (see Section 2.6). Pump frequency plots were right-shifted (arrows) in *avr-14*; *avr-15*; *glc-1* relative to N2 worms at each IVM concentration, indicating resistance. E. Same data, plotted as the cumulative fraction (CF) of pumps occurring over time after perfusate switch at t = 0 min, for each strain and IVM concentration. Dotted line denotes CF₅₀, the intercept at which statistical comparisons were made. CF₅₀ median values were (N2, *avr-14*; *avr-15*; *glc-1*, respectively, in minutes): 0 μM IVM, 30.8, 29.5; 0.1 μM IVM, 29.6, 26.0; 1 μM IVM, 15.0, 21.2; 3 μM IVM, 4.3, 10.9; and 10 μM IVM, 3.0, 6.0. Arrows denote rightward shifts of CF plots in *avr-14*; *avr-15*; *glc-1* vs. N2 worms. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

**Fig. 5**
Inter-pump interval (IPI) and pump duration data for three anthelmintic drugs. A. IPI probability density histograms from N2 worms during t = 0–60 min for i. IVM, **ii.** LEV and **iii.** PPZ (same data as Fig. 4, Fig. 7, Fig. 9, respectively). Drug concentrations are given in keys. Control data are from Fig. 4. B. Plot of pump duration (interval from E to R spike) during t = −15 to 60 min for same three drugs; see key. Perfusate switch occurred at the vertical dotted line, with the electrical artifact blanked. Data are shown for a representative, intermediate concentration of each drug at which pumping continued for the entire 60-min post-switch period. All data are from N2 worms (solid lines) except for *unc-38 (*LEV-resistant; dashed line), included for comparison. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

**Fig. 6**
*bus-8* (disrupted cuticle and epidermis) worms are more sensitive to IVM than N2s. Chips used for both strains were pre-treated with Pluronic F-127 to facilitate loading *bus-8* worms, which adhere to PDMS (see Section 2.5). A. Representative EPG recordings from individual worms, all perfused with M9-5HT during the baseline period. i, ii, N2 and *bus-8* worms switched to M9-5HT (controls); **iii**, iv, N2 and *bus-8* worms switched to 3 μM IVM in M9-5HT. IVM inhibited pumping more rapidly in *bus-8* than in N2 worms. B. Normalized pump frequency (see Section 2.6) plotted against time for N2 and *bus-8* worms switched to 3 μM IVM (mean ± S.E.M.; n = 18–29 worms/group). The key in B applies to B and C. Arrow denotes leftward shift of pump frequency plot for *bus-8* compared to N2 worms, indicating increased sensitivity to IVM. C. Same data as B, plotted as the cumulative fraction (CF) of pumps occurring over time after perfusate switch at t = 0 min. Dotted line denotes CF₅₀, the intercept at which statistical comparisons were made. CF₅₀ median values were (N2, *bus-8*, respectively, in minutes): 0 μM IVM, 30.1, 29.3; 3 μM IVM, 7.7, 4.2. Arrow denotes leftward shift of CF plot in *bus-8* relative to N2s.

**Fig. 7**
*unc-38* (LEV-resistant) worms are less sensitive to LEV than N2s. A. Representative EPG recordings from individual worms, all perfused with M9-5HT during the baseline period. i, ii, N2 and *unc-38* worms switched to M9-5HT (controls); **iii**, iv, N2 and *unc-38* worms switched to 1 mM LEV in M9-5HT. LEV inhibited pumping more strongly in N2 than in *unc-38*. **B, C.** Pump frequency plotted over time for N2 (B) and *unc-38* (C) worms switched at t = 0 min to different concentrations of LEV (mean ± S.E.M., n = 16–32 worms/group). In all panels, concentrations are denoted by color and genotype by line type (solid, N2; dashed, *unc-38*). Perfusate switch occurred at the vertical dotted line, with the electrical artifact blanked. LEV caused concentration-dependent inhibition of pumping in both strains. D. Same data as in B and C, displayed together after normalizing pump frequency. N2s showed an early phase of inhibition compared to *unc-38* worms; arrows denote reduced inhibition in *unc-38* compared to N2 worms at 0.3, 1 and 3 mM LEV. E. Same data, fitted to the Hill equation for post-switch interval t = 0–15 min (“rapid” inhibition; teal lines) and t = 45–60 min (“sustained” inhibition; pink lines). Dashed line denotes EC₅₀ (LEV concentration at which pump frequency was reduced by half). EC₅₀ values (mean ± S.E.M.) for LEV were: N2 rapid, 0.46 ± 0.06 μM; N2 sustained, 1.00 ± 0.12 μM; *unc-38* rapid, 1.38 ± 0.15 μM; *unc-38* sustained, 1.14 ± 0.07 μM. Statistical comparisons are provided in Section 3.6. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

**Fig. 8**
LEV-induced paralysis expels worm through worm trap. Trace shows a representative EPG recording from an N2 worm; vertical bar marks perfusate switch from M9-5HT to 10 mM LEV in M9-5HT. During baseline, the EPG signal was of normal amplitude (inset) (in this example, baseline pumping had gaps). Following the switch to LEV, EPG signal amplitude increased (inset), followed by loss of the signal (red arrow) when the worm was expelled from the chip's recording module into the waste reservoir. All traces are shown at the same vertical scale. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

**Fig. 9**
*unc-49* (PPZ-resistant) worms are less sensitive to PPZ than N2s. A. Representative EPG recordings from individual worms, all perfused with M9-5HT during the baseline period. i, ii, N2 and *unc-49* worms switched to M9-5HT (controls); **iii**, iv, N2 and *unc-49* worms switched to 100 mM PPZ in M9-5HT. PPZ inhibited pumping more strongly in N2 than *unc-49* worms. **B, C.** Pump frequency plotted over time for N2 (B) and *unc-49* (C) worms switched at t = 0 min to different concentrations of PPZ (mean ± S.E.M., n = 17–29 worms/group). In all panels, concentrations are denoted by color and genotype by line type (solid, N2; dashed, *unc-49*). Perfusate switch occurred at the vertical dotted line, with the electrical artifact blanked. D. Same data as in B and C, displayed together after normalizing pump frequency. PPZ caused concentration-dependent inhibition of pumping in both strains; arrows denote reduced inhibition in *unc-49* compared to N2 worms at 40 and 100 mM PPZ. E. Same data, plotted as the cumulative fraction (CF) of pumps occurring over time after perfusate switch at t = 0 min, for each genotype and PPZ concentration. Dotted line denotes CF₅₀, the intercept at which statistical comparisons were made between groups. CF₅₀ median values were (N2, *unc-49*, respectively, in minutes): 0 mM PPZ, 30.4, 30.7; 10 mM PPZ, 30.1, 30.1; 40 mM PPZ, 28.4, 29.9; and 100 mM PPZ, 22.3, 29.3. Arrows denote same difference between strains as in D. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

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References

1. Abongwa M., Buxton S.K., Courtot E., Charvet C.L., Neveu C., McCoy C.J., Verma S., Robertson A.P., Martin R.J. Pharmacological profile of Ascaris suum ACR‐16, a new homomeric nicotinic acetylcholine receptor widely distributed in Ascaris tissues. Br. J. Pharmacol. 2016;173:2463–2477. doi: 10.1111/bph.13524. - DOI - PMC - PubMed
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1. Ardeshiri R., Mulcahy B., Zhen M., Rezai P. A hybrid microfluidic device for on-demand orientation and multidirectional imaging of C. elegans organs and neurons. Biomicrofluidics. 2016;10:064111. doi: 10.1063/1.4971157. - DOI - PMC - PubMed
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[1] Abongwa M., Buxton S.K., Courtot E., Charvet C.L., Neveu C., McCoy C.J., Verma S., Robertson A.P., Martin R.J. Pharmacological profile of Ascaris suum ACR‐16, a new homomeric nicotinic acetylcholine receptor widely distributed in Ascaris tissues. Br. J. Pharmacol. 2016;173:2463–2477. doi: 10.1111/bph.13524. - DOI - PMC - PubMed

[2] Abongwa M., Buxton S.K., Courtot E., Charvet C.L., Neveu C., McCoy C.J., Verma S., Robertson A.P., Martin R.J. Pharmacological profile of Ascaris suum ACR‐16, a new homomeric nicotinic acetylcholine receptor widely distributed in Ascaris tissues. Br. J. Pharmacol. 2016;173:2463–2477. doi: 10.1111/bph.13524. - DOI - PMC - PubMed

[3] Ardelli B.F., Stitt L.E., Tompkins J.B., Prichard R.K. A comparison of the effects of ivermectin and moxidectin on the nematode Caenorhabditis elegans. Vet. Parasitol. 2009;165:96–108. doi: 10.1016/j.vetpar.2009.06.043. - DOI - PubMed

[4] Ardelli B.F., Stitt L.E., Tompkins J.B., Prichard R.K. A comparison of the effects of ivermectin and moxidectin on the nematode Caenorhabditis elegans. Vet. Parasitol. 2009;165:96–108. doi: 10.1016/j.vetpar.2009.06.043. - DOI - PubMed

[5] Ardeshiri R., Mulcahy B., Zhen M., Rezai P. A hybrid microfluidic device for on-demand orientation and multidirectional imaging of C. elegans organs and neurons. Biomicrofluidics. 2016;10:064111. doi: 10.1063/1.4971157. - DOI - PMC - PubMed

[6] Ardeshiri R., Mulcahy B., Zhen M., Rezai P. A hybrid microfluidic device for on-demand orientation and multidirectional imaging of C. elegans organs and neurons. Biomicrofluidics. 2016;10:064111. doi: 10.1063/1.4971157. - DOI - PMC - PubMed

[7] Aubry G., Lu H. Droplet array for screening acute behaviour response to chemicals in Caenorhabditis elegans. Lab a Chip. 2017;17:4303–4311. doi: 10.1039/c7lc00945c. - DOI - PubMed

[8] Aubry G., Lu H. Droplet array for screening acute behaviour response to chemicals in Caenorhabditis elegans. Lab a Chip. 2017;17:4303–4311. doi: 10.1039/c7lc00945c. - DOI - PubMed

[9] Avery L. Motor neuron M3 controls pharyngeal muscle relaxation timing in Caenorhabditis elegans. J. Exp. Biol. 1993;175:283–297. - PubMed

[10] Avery L. Motor neuron M3 controls pharyngeal muscle relaxation timing in Caenorhabditis elegans. J. Exp. Biol. 1993;175:283–297. - PubMed

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Anthelmintic drug actions in resistant and susceptible C. elegans revealed by electrophysiological recordings in a multichannel microfluidic device

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Anthelmintic drug actions in resistant and susceptible C. elegans revealed by electrophysiological recordings in a multichannel microfluidic device

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