Davis KC et al. (2016) J Physiol "A mechanism for sickness sleep: lessons from invertebrates."

Davis KC, Raizen DM

[J Physiol, 2016]

During health, animal sleep is regulated by an internal clock and by the duration of prior wakefulness. During sickness, sleep is regulated by cytokines released from either peripheral cells or from cells within the nervous system. These cytokines regulate central nervous system neurons to induce sleep. Recent research in the invertebrates Caenorhabditis elegans and Drosophila melanogaster has led to new insights into the mechanism of sleep during sickness. Sickness is triggered by exposure to environments such as infection, heat, or ultraviolet light irradiation, all of which cause cellular stress. Epidermal growth factor is released from stressed cells and signals to activate central neuroendocrine cell(s). These neuron(s) release neuropeptides including those containing an amidated arginine(R)-phenylalanine(F) motif at their C-termini (RFamide peptides). Importantly, mechanisms regulating sickness sleep are partially distinct from those regulating healthy sleep. We will here review key findings, which have elucidated the central neuroendocrine mechanism of sleep during sickness. Adaptive mechanisms employed in the control of sickness sleep may play a role in correcting cellular homeostasis after various insults. We speculate that these mechanisms may play a maladaptive role in human pathological conditions such as in the fatigue and anorexia associated with autoimmune diseases, with major depression, and with unexplained chronic fatigue. This article is protected by copyright. All rights reserved.

Davis KC et al. (2018) Sci Rep "Satiety behavior is regulated by ASI/ASH reciprocal antagonism."

Kim J, Choi YI, Davis KC, You YJ

[Sci Rep, 2018]

Appropriate decision-making is essential for ensuring survival; one such decision is whether to eat. Overall metabolic state and the safety of food are the two factors we examined using C. elegans to ask whether the metabolic state regulates neuronal activities and corresponding feeding behavior. We monitored the activity of sensory neurons that are activated by nutritious (or appetitive) stimuli (ASI) and aversive stimuli (ASH) in starved vs. well-fed worms during stimuli presentation. Starvation reduces ASH activity to aversive stimuli while increasing ASI activity to nutritious stimuli, showing the responsiveness of each neuron is modulated by overall metabolic state. When we monitored satiety quiescence behavior that reflects the overall metabolic state, ablation of ASI and ASH produce the opposite behavior, showing the two neurons interact to control the decision to eat or not. This circuit provides a simple approach to how neurons handle sensory conflict and reach a decision that is translated to behavior.

Chen, Lili et al. (2020) MicroPubl Biol

Wang, Ya, Chen, Lili, Gao, Shangbang

[MicroPubl Biol, 2020]

The action potential (AP) is the basic signaling unit in various crucial physiological processing, for instance, in neurotransmission, muscle contraction, and glandular secretion (Koch, 1990). The classic model animal, Caenorhabditis elegans (or C. elegans), with a simple and compact nervous system, conservatively employs the calcium-mediated all-or-none APs for odor response in AWA olfactory neurons (Liu et al., 2018), as well as for muscle contraction in either body wall muscles (Gao and Zhen, 2011; Liu et al., 2011) and pharyngeal muscles (Davis et al., 1999). Plateau potentials were also observed in ASE and RMD neurons (Goodman et al., 1998; Mellem et al., 2008; Lockery et al., 2009; Lockery and Goodman, 2009), though the underlying roles in specific behavior are still elusive. Either in neurons or in muscles, the action potential firing is dependent on the excitatory pre-synaptic vesicles release. The minimum number of the presynaptic vesicles to elicit a single action potential in C. elegans has not been reported before. Here, by the combination of optogenetics with in-vivo patch clamping technology, we demonstrated that at least approximately 37 excitatory acetylcholinergic vesicles are required for the initiation of an action potential at post-synaptic body wall muscles.

Preston S et al. (2017) FASEB J "Deguelin exerts potent nematocidal activity via the mitochondrial respiratory chain."

Sternberg PW, Ansell BRE, Andrews KT, Nowell C, Chang BCH, Hofmann A, Crawford S, Korhonen PK, Baell J, Gijs MAM, Fisher GM, Young ND, Preston S, Mouchiroud L, Gasser RB, Jabbar A, Auwerx J, Davis RA, McGee SL, Cornaglia M

[FASEB J, 2017]

As a result of limited classes of anthelmintics and an over-reliance on chemical control, there is a great need to discover new compounds to combat drug resistance in parasitic nematodes. Here, we show that deguelin, a plant-derived rotenoid, selectively and potently inhibits the motility and development of nematodes, which supports its potential as a lead candidate for drug development. Furthermore, we demonstrate that deguelin treatment significantly increases gene transcription that is associated with energy metabolism, particularly oxidative phosphorylation and mito-ribosomal protein production before inhibiting motility. Mitochondrial tracking confirmed enhanced oxidative phosphorylation. In accordance, real-time measurements of oxidative phosphorylation in response to deguelin treatment demonstrated an immediate decrease in oxygen consumption in both parasitic (Haemonchus contortus) and free-living (Caenorhabditis elegans) nematodes. Consequently, we hypothesize that deguelin is exerting its toxic effect on nematodes as a modulator of oxidative phosphorylation. This study highlights the dynamic biologic response of multicellular organisms to deguelin perturbation.-Preston, S., Korhonen, P. K., Mouchiroud, L., Cornaglia, M., McGee, S. L., Young, N. D., Davis, R. A., Crawford, S., Nowell, C., Ansell, B. R. E., Fisher, G. M., Andrews, K. T., Chang, B. C. H., Gijs, M. A. M., Sternberg, P. W., Auwerx, J., Baell, J., Hofmann, A., Jabbar, A., Gasser, R. B. Deguelin exerts potent nematocidal activity via the mitochondrial respiratory chain.

Blacque OE et al. (2006) Mol Biol Cell "The WD repeat-containing protein IFTA-1 is required for retrograde intraflagellar transport."

Scholey JM, Mah AK, Inglis PN, Leroux MR, Li C, Ou G, Esmail MA, Baillie DL, Blacque OE

[Mol Biol Cell, 2006]

Monitoring Editor: Trisha Davis The assembly and maintenance of cilia requires intraflagellar transport (IFT), a microtubule-dependent bidirectional motility of multisubunit protein complexes along ciliary axonemes. Defects in IFT and the functions of motile or sensory cilia are associated with numerous human ailments, including polycystic kidney disease and Bardet-Biedl syndrome (BBS). Here, we identify a novel Caenorhabditis elegans IFT gene, ifta-1 (IFT-Associated gene 1), which encodes a WD-repeat containing protein with strong homology to a mammalian protein of unknown function. Both the C. elegans and human IFTA-1 proteins localize to the base of cilia, and in C. elegans, IFTA-1 can be observed to undergo IFT. IFTA-1 is required for the function and assembly of cilia, since a C. elegans ifta-1 mutant displays chemosensory abnormalities and shortened cilia with prominent ciliary accumulations of core IFT machinery components that are indicative of retrograde transport defects. Analyses of C. elegans IFTA-1 localization/motility along bbs mutant cilia, where anterograde IFT assemblies are destabilised, and in a che-11 IFT gene mutant, demonstrate that IFTA-1 is closely associated with the IFT particle A subcomplex, which is implicated in retrograde IFT. Taken together, our data indicates that IFTA-1 is a novel IFT protein that is required for retrograde transport along ciliary axonemes.

Osman MA et al. (1998) J Cell Biol "Iqg1p, a yeast homologue of the mammalian IQGAPs, mediates cdc42p effects on the actin cytoskeleton."

Cerione RA, Osman MA

[J Cell Biol, 1998]

The Rho-type GTPase Cdc42p has been implicated in diverse cellular functions including cell shape, cell motility, and cytokinesis, all of which involve the reorganization of the actin cytoskeleton. Targets of Cdc42p that interface the actin cytoskeleton are likely candidates for mediating cellular activities. In this report, we identify and characterize a yeast homologue for the mammalian IQGAP, a cytoskeletal target for Cdc42p. The yeast IQGAP homologue, designated Iqg1p, displays a two-hybrid interaction with activated Cdc42p and coimmunoprecipitates with actin filaments. Deletion of IQG1 results in a temperature-sensitive lethality and causes aberrant morphologies including elongated and round multinucleated cells. This together with its localization at the mother-bud neck, suggest that Iqg1p promotes budding and cytokinesis. At restrictive temperatures, the vacuoles of the mutant cells enlarge and vesicles accumulate in the bud. Interestingly, Iqg1p shows two-hybrid interactions with the ankyrin repeat-containing protein, Akr1p (Kao, L.-R., J. Peterson, J. Ruiru, L. Bender, and A. Bender. 1996. Mol. Cell. Biol. 16:168-178), which inhibits pheromone signaling and appears to promote cytokinesis and/or trafficking. We also show two-hybrid interactions between Iqg1p and Afr1p, a septin-binding protein involved in projection formation (Konopka, J.B., C. DeMattei, and C. Davis. 1995. Mol. Cell. Biol. 15:723-730). We propose that Iqg1p acts as a scaffold to recruit and localize a protein complex involved in actin-based cellular functions and thus mediates the regulatory effects of Cdc42p on the actin cytoskeleton.

Espinosa F et al. (2001) J Gen Physiol "Dynamic interaction of S5 and S6 during voltage-controlled gating in a potassium channel."

Joho RH, Fleischhauer R, Espinosa F, McMahon A

[J Gen Physiol, 2001]

A gain-of-function mutation in the Caenorhabditis elegans exp-2 K+-channel gene is caused by a cysteine-to-tyrosine change (C480Y) in the sixth transmembrane segment of the channel (Davis, M.W, R. Fleisch-hauer, J.A. Dent, R.H.Joho, and L. Avery. 1999. Science. 286:2501-2504). In contrast to wild-type EXP-2 channels, homotetrameric C480Y mutant channels are open even at - 160 mV, explaining the lethality of the homozygous mutant. We modeled the structure of EXP-2 on the 3-D scaffold of the K+ channel KcsA. In the C480Y mutant, tyrosine 480 protrudes from S6 to near S5, suggesting that the bulky side chain may provide steric hindrance to the rotation of S6 that has been proposed to accompany the open-closed state transitions (Perozo, E., D.M. Cortes, and L.G. Cuello. 1999. Science. 285:73-78). We tested the hypothesis that only small side chains at position 480 allow the channel to close, but that bulky side chains trap the channel in the open state. Mutants with small side chain substitutions (Gly and Ser) behave like wild type; in contrast, bulky side chain substitutions (Trp, Phe, Leu, Ile, Val, and His) generate channels that conduct K+ ions at potentials as negative as - 120 mV. The side chain at position 480 in S6 in the pore model is close to and may interact With a conserved glycine (G421) in S5. Replacement of G421 with bulky side chains also leads to channels that are trapped in an active state, suggesting that S5 and S6 interact with each other during voltage-dependent open-closed state transitions, and that bulky side chains prevent the dynamic changes necessary for permanent channel closing. Single-channel recordings show that mutant channels open frequently at negative membrane potentials indicating that they fail to reach long-lasting, i.e., stable, closed states. Our data support a "two-gate model" with a pore gate responsible for the brief, voltage-independent openings and a separately located, voltage-activated gate (Liu, Y, and R.H.Joho. 1998. Pflugers Arch. 435: 654-661).

Qian Y et al. (2023) BMC Bioinformatics "MCL-DTI: using drug multimodal information and bi-directional cross-attention learning method for predicting drug-target interaction."

Zhang Q, Qian Y, Wu J, Li X

[BMC Bioinformatics, 2023]

BACKGROUND: Prediction of drug-target interaction (DTI) is an essential step for drug discovery and drug reposition. Traditional methods are mostly time-consuming and labor-intensive, and deep learning-based methods address these limitations and are applied to engineering. Most of the current deep learning methods employ representation learning of unimodal information such as SMILES sequences, molecular graphs, or molecular images of drugs. In addition, most methods focus on feature extraction from drug and target alone without fusion learning from drug-target interacting parties, which may lead to insufficient feature representation. MOTIVATION: In order to capture more comprehensive drug features, we utilize both molecular image and chemical features of drugs. The image of the drug mainly has the structural information and spatial features of the drug, while the chemical information includes its functions and properties, which can complement each other, making drug representation more effective and complete. Meanwhile, to enhance the interactive feature learning of drug and target, we introduce a bidirectional multi-head attention mechanism to improve the performance of DTI. RESULTS: To enhance feature learning between drugs and targets, we propose a novel model based on deep learning for DTI task called MCL-DTI which uses multimodal information of drug and learn the representation of drug-target interaction for drug-target prediction. In order to further explore a more comprehensive representation of drug features, this paper first exploits two multimodal information of drugs, molecular image and chemical text, to represent the drug. We also introduce to use bi-rectional multi-head corss attention (MCA) method to learn the interrelationships between drugs and targets. Thus, we build two decoders, which include an multi-head self attention (MSA) block and an MCA block, for cross-information learning. We use a decoder for the drug and target separately to obtain the interaction feature maps. Finally, we feed these feature maps generated by decoders into a fusion block for feature extraction and output the prediction results. CONCLUSIONS: MCL-DTI achieves the best results in all the three datasets: Human, C. elegans and Davis, including the balanced datasets and an unbalanced dataset. The results on the drug-drug interaction (DDI) task show that MCL-DTI has a strong generalization capability and can be easily applied to other tasks.