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Soil-transmitted parasitic nematodes infect over one billion people and cause devastating morbidity worldwide. Many of these parasites have infective larvae that locate hosts using thermal cues. Here, we identify the thermosensory neurons of the human threadworm Strongyloides stercoralis and show that they display unique functional adaptations that enable the precise encoding of temperatures up to human body temperature. We demonstrate that experience-dependent thermal plasticity regulates the dynamic range of these neurons while preserving their ability to encode host-relevant temperatures. We describe a novel behavior in which infective larvae spontaneously reverse attraction to heat sources at sub-body temperatures and show that this behavior is mediated by rapid adaptation of the thermosensory neurons. Finally, we identify thermoreceptors that confer parasite-specific sensitivity to body heat. Our results pinpoint the parasite-specific neural adaptations that enable parasitic nematodes to target humans and provide the foundation for drug development to prevent human infection.

Temperature is a universal cue and regulates many essential processes ranging from enzymatic reactions to species migration. Due to the profound impact of temperature on physiology and behavior, animals and humans have evolved sophisticated mechanisms to detect temperature changes. Studies from animal models, such as mouse, Drosophila, and C. elegans, have revealed many exciting principles of thermosensation. For example, conserved molecular thermosensors, including thermosensitive channels and receptors, act as the initial detectors of temperature changes across taxa. Additionally, thermosensory neurons and circuits in different species appear to adopt similar logic to transduce and process temperature information. Here, we present the current understanding of thermosensation at the molecular and cellular levels. We also discuss the fundamental coding strategies of thermosensation at the circuit level. A thorough understanding of thermosensation not only provides key insights into sensory biology but also builds a foundation for developing better treatments for various sensory disorders.

Corollary discharge allows organisms to discriminate external sensory inputs from self-generated cues. However, the underlying synaptic and molecular mechanisms are not well understood. A new study has identified a tyraminergic corollary discharge signal that extrasynaptically modulates chemosensory neurons in Caenorhabditis elegans.

Age-related mobility decline is often associated with negative physical and psychological outcomes, such as frailty, in the elderly population. In C. elegans, during the early stage of the aging process, a progressive deficit of synaptic exocytosis in the motor neurons results in a functional decline at the neuromuscular junctions, which eventually leads to degeneration of both neurons and muscles. This age-dependent functional decline can be ameliorated by pharmacological interventions, such as arecoline, a muscarinic AChR agonist known to promote synaptic exocytosis at the neuromuscular junctions. In this study, we found that a short-term treatment of arecoline during the early stage of aging, when the NMJ functional decline begins, not only slows muscle tissue aging, but also extends lifespan in C. elegans. We have also demonstrated that arecoline acts on the GAR-2/PLCβ pathway in the motor neurons to increases longevity. Together, our findings suggest that synaptic transmission in aging motor neurons may serve as a potential target for pharmacological interventions to promote both health span and lifespan, when applied at the early stage aging. Impact statement The functional decline of motor activity is a common feature in almost all aging animals that leads to frailty, loss of independence, injury, and even death in the elderly population. Thus, understanding the molecular mechanism that drives the initial stage of this functional decline and developing strategies to increase human healthspan and even lifespan by targeting this process would be of great interests to the field. In this study, we found that by precisely targeting the motor neurons to potentiate its synaptic releases either genetically or pharmacologically, we can not only delay the functional aging at NMJs but also slow the rate of aging at the organismal level. Most importantly, we have demonstrated that a critical window of time, that is the early stage of NMJs functional decline, is required for the beneficial effects. A short-term treatment within this time period is sufficient to extend the animals’ lifespan.

SUMMARYTemperature information is precisely processed in the nervous system. While progress has been made in identifying molecular thermosensors in the periphery, the neural circuits that process temperature information in the central nervous system remain unknown. Here we have identified an essential node in the neural circuitry for innocuous cool sensations. We found that a population of excitatory interneurons co-expressing Calbindin1 and Lbx1 (Calb1Lbx1) in the dorsal horn of the spinal cord is activated by innocuous cool temperatures. Genetic ablation or silencing of spinal Calb1Lbx1 neurons causes loss of innocuous cool but not noxious cold sensations. Further Brainbow labeling with expansion microscopy and electrophysiology showed that a small cluster of spinal Calb1Lbx1 interneurons in lamina I and the outer layer of lamina II represents the cooling-transmission neurons. These neurons receive monosynaptic connections from TRPM8+ primary sensory neurons and amplify the activity of cool-sensitive spinoparabrachial projection neurons. Our findings reveal a microcircuit in the dorsal spinal cord that specifically transmits innocuous cool sensations.

Molecular glue degraders have emerged as a powerful class of small-molecule therapeutics, as demonstrated by the clinical successes of thalidomide analogs in the treatment of hematological malignancies. These small molecules act by recruiting ubiquitin ligases to disease-relevant proteins, resulting in neosubstrate ubiquitination and degradation. To date, only a small number of ubiquitin ligase - neosubstrate interactions have been exploited by molecular glue degraders, limiting the targeting scope of this therapeutic modality. Covalent chemistry, which confers high binding affinity and the ability of targeting shallow binding sites, can expand the addressable protein interfaces for molecular glue degraders. In this study, we identified a new class of BRD4 covalent molecular glue degraders (GNE-0011, TMX-4137, MMH-252, MMH-272) by derivatizing electrophiles on the solvent-facing side of a non-degradative BRD4 inhibitor, JQ1. These degraders recruit the ubiquitin ligase CUL4DCAF16 to BRD4 via a novel, trans-labeling mechanism we term “template-assisted covalent modification.” These covalent small molecules have only weak reactivity to DCAF16 in the absence of BRD4. However, BRD4 binding allows its BD2 domain, in complex with DCAF16, to serve as a structural template to boost the covalent modification of these degraders to DCAF16. This leads to efficient BRD4-degrader-DCAF16 ternary complex formation and subsequent BRD4 degradation. We solved the cryo-electron microscopy structure of the DDB1-DCAF16 ligase complex bound to BRD4(BD2) and MMH-272, demonstrating that DCAF16 and BRD4(BD2) have pre-existing structural complementarity which optimally orients the reactive moiety of MMH-272 for DCAF16 covalent modification. We performed systematic mutagenesis screens of both DCAF16 and BRD4(BD2) to characterize the drug-induced interaction, discovering that Cys58 of DCAF16 is modified by covalent warheads and is critical for the activity of these degraders, and that His437 of BRD4(BD2) and its adjacent residues are important for a stable interaction with DCAF16. Analysis of a chemical series revealed that the covalent reactivity of these small molecules is required for degradation, and that the degree of reactivity can tune the potency and specificity of the degraders. Our work highlights a new class of BRD4 molecular glue degraders that are enabled by the template-assisted covalent modification of DCAF16. The templated reactivity is likely to exist in other covalent small molecules that engage complementary protein interfaces, and this trans-labeling mechanism can be exploited to develop covalent drugs with more precisely controlled reactivity. Moreover, our findings demonstrate that the decoration of solvent-exposed electrophiles to protein-binding small molecules has great potential to enable discovery and optimization of novel molecular glue degraders. Citation Format: Yen-Der Li, Michelle W. Ma, Muhammad Murtaza Hassan, Kedar Puvar, Mingxing Teng, Brittany Sandoval, Ryan Lumpkin, Scott B. Ficarro, Michelle Y. Wang, Shawn Xu, Brian J. Groendyke, Logan H. Sigua, Isidoro Tavares, Charles Zou, Jonathan M. Tsai, Paul M. Park, Hojong Yoon, Radosław P. Nowak, Jarrod A. Marto, Jun Qi, Katherine A. Donovan, Mikołaj Słabicki, Nathanael S. Gray, Eric S. Fischer, Benjamin L. Ebert. Template-assisted covalent modification of DCAF16 enables BRD4 molecular glue degraders [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3424.

GABA, a prominent inhibitory neurotransmitter, is best known to regulate neuronal functions in the nervous system. However, much less is known about the role of GABA signaling in other physiological processes. Interestingly, recent work showed that GABA signaling can regulate life span via a metabotropic GABABreceptor in Caenorhabditis elegans. However, the role of other types of GABA receptors in life span has not been clearly defined. It is also unclear whether GABA signaling regulates health span. Here, using C. elegans as a model, we systematically interrogated the role of various GABA receptors in both life span and health span. We find that mutations in four different GABA receptors extend health span by promoting resistance to stress and pathogen infection and that two such receptor mutants also show extended life span. Different GABA receptors engage distinct transcriptional factors to regulate life span and health span, and even the same receptor regulates life span and health span via different transcription factors. Our results uncover a novel, profound role of GABA signaling in aging in C. elegans, which is mediated by different GABA receptors coupled to distinct downstream effectors.

The role of food nutrients in mediating the positive effect of dietary restriction (DR) on longevity has been extensively characterized, but how non-nutrient food components regulate lifespan is not well understood. Here, we show that food-associated odors shorten the lifespan of Caenorhabditis elegans under DR but not those fed ad libitum, revealing a specific effect of food odors on DR-mediated longevity. Food odors act on a neural circuit comprising the sensory neurons ADF and CEP, and the interneuron RIC. This olfactory circuit signals the gut to suppress DR-mediated longevity via octopamine, the mammalian homolog of norepinephrine, by regulating the energy sensor AMP-activated protein kinase (AMPK) through a Gq-phospholipase Cβ-CaMKK-dependent mechanism. In mouse primary cells, we find that norepinephrine signaling regulates AMPK through a similar mechanism. Our results identify a brain–gut axis that regulates DR-mediated longevity by relaying olfactory information about food abundance from the brain to the gut. The authors found that the olfactory perception of food abundance can regulate the impact of dietary restriction on longevity in Caenorhabditis elegans. They show that food odors act on olfactory circuitry that signals the gut via octopamine to suppress dietary restriction-induced longevity.

Bardet-Biedl syndrome (BBS) is a genetic disorder that affects primary cilia. BBSome, a protein complex composed of eight BBS proteins, regulates the structure and function of cilia, and its malfunction causes BBS in humans. Here, we report a cilia-independent function of BBSome. To identify genes that regulate the C. elegans photoreceptor protein LITE-1 in ciliated ASH photosensory neurons, we performed a genetic screen and isolated bbs mutants. Functional analysis revealed that BBSome regulates LITE-1 protein stability independently of cilia. Through another round of genetic screening, we found that this cilia-independent function of BBSome is mediated by DLK-MAPK signaling, which acts downstream of BBSome to control LITE-1 stability via Rab5-mediated endocytosis. BBSome exerts its function by regulating the expression of DLK. BBSome also regulates the expression of LZK, a mammalian DLK in human cells. These studies identify a cilia-independent function of BBSome and uncover DLK as an evolutionarily conserved BBSome effector.

The eyeless C. elegans exhibits robust phototaxis behavior in response to short-wavelength light, particularly UV light. C. elegans senses light through LITE-1, a unique photoreceptor protein that belongs to the invertebrate taste receptor family. However, it remains unclear how LITE-1 is regulated. Here, we performed a forward genetic screen for genes that when mutated suppress LITE-1 function. One group of lite-1 suppressors are the genes required for producing the two primary antioxidants thioredoxin and glutathione, suggesting that oxidization of LITE-1 inhibits its function. Indeed, the oxidant hydrogen peroxide (H2O2) suppresses phototaxis behavior and inhibits the photoresponse in photoreceptor neurons, whereas other sensory behaviors are relatively less vulnerable to H2O2. Conversely, antioxidants can rescue the phenotype of lite-1 suppressor mutants and promote the photoresponse. As UV light illumination generates H2O2, we propose that upon light activation of LITE-1, light-produced H2O2 then deactivates LITE-1 to terminate the photoresponse, while antioxidants may promote LITE-1’s recovery from its inactive state. Our studies provide a potential mechanism by which H2O2 and antioxidants act synergistically to regulate photosensation in C. elegans., Author summary The nematode C. elegans possesses a unique photoreceptor protein, LITE-1, which mediates a light-avoidance behavior upon light exposure. C. elegans avoids short-wavelength light, particularly UV light, providing a potential mechanism by which worms escape from the dangerous UV rays in the sunlight. However, it is not clear how LITE-1 is regulated. Here, we performed a genetic screen to identify genes regulating LITE-1. We uncovered six genes that when mutated suppress LITE-1 function. All these genes are involved in regenerating cellular antioxidants that function to clear reactive oxygen species, particularly hydrogen peroxide (H2O2), suggesting that the function of LITE-1 is vulnerable to H2O2. Indeed, we show that H2O2 exposure inhibits LITE-1 function, while antioxidants promote it. Notably, other sensory functions are relatively less sensitive to H2O2. As UV light illumination is known to generate H2O2 within the cell, this provides a potential mechanism to turn off LITE-1. Our results uncover a potential mechanism of LITE-1 regulation, where antioxidants and oxidants act to promote and suppress LITE-1 function, respectively.

How neural circuits drive behavior is a central question in neuroscience. Proper execution of motor behavior requires the precise coordination of many neurons. Within a motor circuit, individual neurons tend to play discrete roles by promoting or suppressing motor output. How exactly neurons function in specific roles to fine tune motor output is not well understood. In C. elegans, the interneuron RIM plays important yet complex roles in locomotion behavior. Here, we show that RIM both promotes and suppresses distinct features of locomotion behavior to fine tune motor output. This dual function is achieved via the excitation and inhibition of the same motor circuit by electrical and chemical neurotransmission, respectively. Additionally, this bi-directional regulation contributes to motor adaptation in animals placed in novel environments. Our findings reveal that individual neurons within a neural circuit may act in opposing ways to regulate circuit dynamics to fine tune behavioral output.

Age-related mobility decline is often associated with negative physical and psychological outcomes, such as frailty, in the elderly population. In C. elegans, during the early stage of the aging process, a progressive deficit of synaptic exocytosis in the motor neurons results in a functional decline at the neuromuscular junctions, which eventually leads to degeneration of both neurons and muscles. This age-dependent functional decline can be ameliorated by pharmacological interventions, such as arecoline, a muscarinic AChR agonist known to promote synaptic exocytosis at the neuromuscular junctions. In this study, we found that a short-term treatment of arecoline during the early stage of aging, when the NMJ functional decline begins, not only slows muscle tissue aging, but also extends lifespan in C. elegans. We have also demonstrated that arecoline acts on the GAR-2/PLCβ pathway in the motor neurons to increases longevity. Together, our findings suggest that synaptic transmission in aging motor neurons may serve as a potential target for pharmacological interventions to promote both health span and lifespan, when applied at the early stage aging. IMPACT STATEMENT: The functional decline of motor activity is a common feature in almost all aging animals that leads to frailty, loss of independence, injury, and even death in the elderly population. Thus, understanding the molecular mechanism that drives the initial stage of this functional decline and developing strategies to increase human healthspan and even lifespan by targeting this process would be of great interests to the field. In this study, we found that by precisely targeting the motor neurons to potentiate its synaptic releases either genetically or pharmacologically, we can not only delay the functional aging at NMJs but also slow the rate of aging at the organismal level. Most importantly, we have demonstrated that a critical window of time, that is the early stage of NMJs functional decline, is required for the beneficial effects. A short-term treatment within this time period is sufficient to extend the animals’ lifespan.

Bardet-Biedl Syndrome (BBS) is a genetic disorder affecting primary cilia. BBSome, a protein complex composed of eight BBS proteins, regulates the structure and function of cilia in diverse organisms, and its malfunction causes BBS in humans. Here, we report a new function of BBSome inC. elegans. In a forward genetic screen for genes regulating the light sensitivity of the ciliated ASH sensory neurons, we isolatedbbsmutants, indicating that BBSome regulates ASH photosensitivity. Surprisingly, cilia are not required for ASH neurons to sense light, suggesting that BBSome regulates ASH photosensitivity independently of cilia. Interestingly, the light-sensing receptor LITE-1, which mediates photosensation, is a non-ciliary protein in ASH neurons. LITE-1 in ASH neurons becomes unstable inbbsmutants in an age-dependent manner, indicating that BBSome regulates the stability of LITE-1 in these neurons. These results identify a cilium-independent function of BBSome in regulating a non-ciliary protein in ciliated cells.

This study examines the relationship between tax avoidance and asymmetric cost behavior. This relationship arises due to direct economic benefits of cash savings from tax avoidance. On one hand, cash savings from tax avoidance may prompt managers to retain excess resources when activity goes down. On the other hand, tax avoidance may alleviate managers’ concerns about adjustment costs due to cost reductions in sales downturns. Using a large sample spanning the 1993-2013 period, we document a significantly negative relationship between tax avoidance, proxied by cash effective tax rate, and asymmetric cost behavior. The result suggests that asymmetric cost behavior is less pronounced when tax avoidance is higher. We further find that this relationship varies with firms’ business strategies, cash flow volatility, and tax fees paid to the auditor. This study advances the understanding of accounting researchers on the relationship between tax avoidance and managers’ resource adjustment decisions.

Beige adipocytes have recently been shown to regulate energy dissipation when activated and help organisms defend against hypothermia and obesity. Prior reports indicate that beige-like adipocytes exist in adult humans and that they may present novel opportunities to curb the global epidemic in obesity and metabolic illnesses. In an effort to identify unique features of activated beige adipocytes, we found that expression of the cholinergic receptor nicotinic alpha 2 subunit (Chrna2) was induced in subcutaneous fat during the activation of these cells and that acetylcholine-producing immune cells within this tissue regulated this signaling pathway via paracrine mechanisms. CHRNA2 functioned selectively in uncoupling protein 1 (Ucp1)-positive beige adipocytes, increasing thermogenesis through a cAMP- and protein kinase A-dependent pathway. Furthermore, this signaling via CHRNA2 was conserved and present in human subcutaneous adipocytes. Inactivation of Chrna2 in mice compromised the cold-induced thermogenic response selectively in subcutaneous fat and exacerbated high-fat diet-induced obesity and associated metabolic disorders, indicating that even partial loss of beige fat regulation in vivo had detrimental consequences. Our results reveal a beige-selective immune-adipose interaction mediated through CHRNA2 and identify a novel function of nicotinic acetylcholine receptors in energy metabolism. These findings may lead to identification of therapeutic targets to counteract human obesity.

Tissue–tissue communications are integral to organismal aging, orchestrating a body-wide aging process. The brain plays a key role in this process by detecting and processing signals from the environment and then communicating them to distal tissues such as the gut to regulate longevity. How this is achieved, however, is poorly understood. Here, using Caenorhabditis elegans as a model, we identified two distinct neuroendocrine signaling circuits by which the worm nervous system senses cool and warm environmental temperatures through cool- and warm-sensitive neurons and then signals the gut to extend and shorten life span, respectively. The prolongevity “cool” circuit uses the small neurotransmitters glutamate and serotonin, whereas the anti-longevity “warm” circuit is mediated by insulin-like neuropeptides. Both types of neuroendocrine signals converge on the gut through their cognate receptors to differentially regulate the transcription factor DAF-16/FOXO, leading to opposing outcomes in longevity. Our study illustrates how the brain detects and processes environmental signals to bidirectionally regulate longevity by signaling the gut.

Body temperature control is essential for survival. In mammals, thermoregulation is mediated by the preoptic area of anterior hypothalamus (POA), with ~30% of its neurons sensitive to brain temperature change. It is still unknown whether and how these temperature-sensitive neurons are involved in thermoregulation, because for eight decades they can only be identified via electrophysiological recording. By combining single-cell RNA-seq with whole-cell patch-clamp recordings, we identified Ptgds as a genetic marker for temperature-sensitive POA neurons. We then demonstrated these neruons’ role in thermoregulation via chemogenetics. Given that Ptgds encodes the enzyme that synthesizes prostaglandin D2 (PGD(2)), we further explored its role in thermoregulation. Our study revealed that rising temperature of POA alters the activity of Ptgds-expressing neurons so as to increase PGD(2) production. PGD(2) activates its receptor DP1 and excites downstream neurons in the ventral medial preoptic area (vMPO) that mediates body temperature decrease – a negative feedback loop for thermoregulation.

SUMMARY Unlike olfaction, taste, touch, vision, and proprioception, which are widespread across animal phyla, hearing is found only in vertebrates and some arthropods. The vast majority of invertebrate species are thus considered insensitive to sound. Here, we challenge this conventional view by showing that the earless nematode C. elegans senses airborne sound at frequencies reaching the kHz range. Sound vibrates C. elegans skin, which acts as a pressure-to-displacement transducer similar to vertebrate eardrum, activates sound-sensitive FLP/PVD neurons attached to the skin, and evokes phonotaxis behavior. We identified two nAChRs that transduce sound signals independently of ACh, revealing an unexpected function of nAChRs in mechanosensation. Thus, the ability to sense airborne sound is not restricted to vertebrates and arthropods as previously thought, and might have evolved multiple times independently in the animal kingdom, suggesting convergent evolution. Our studies also demonstrate that animals without ears may not be presumed to be sound insensitive., In brief Hearing is thought to exist only in vertebrates and some arthropods, but not other animal phyla. Here, Xu and colleagues report that the earless nematode C. elegans senses airborne sound and engages in phonotaxis. Thus, hearing might have evolved multiple times independently in the animal kingdom, suggesting convergent evolution.

Upon exposure to harmful microorganisms, hosts engage in protective molecular and behavioral immune responses, both of which are ultimately regulated by the nervous system. Using the nematode Caenorhabditis elegans, we show that ingestion of Enterococcus faecalis leads to a fast pathogen avoidance behavior that results in aversive learning. We have identified multiple sensory mechanisms involved in the regulation of avoidance of E. faecalis. The G-protein coupled receptor NPR-1-dependent oxygen-sensing pathway opposes this avoidance behavior, while an ASE neuron-dependent pathway and an AWB and AWC neuron-dependent pathway are directly required for avoidance. Colonization of the anterior part of the intestine by E. faecalis leads to AWB and AWC mediated olfactory aversive learning. Finally, two transient receptor potential melastatin (TRPM) channels, GON-2 and GTL-2, mediate this newly described rapid pathogen avoidance. These results suggest a mechanism by which TRPM channels may sense the intestinal distension caused by bacterial colonization to elicit pathogen avoidance and aversive learning by detecting changes in host physiology.

In 1963, Sidney Brenner wrote a proposal to Max Perutz on tackling the next ‘big questions’ in molecular biology. Beginning with the postulate that simple organisms have many of the features that c...

GABA, a prominent inhibitory neurotransmitter, is best known to regulate neuronal functions in the nervous system. However, much less is known about the role of GABA signaling in other physiological processes. Interestingly, recent work showed that GABA signaling can regulate life span via a metabotropic GABA(B) receptor in Caenorhabditis elegans. However, the role of other types of GABA receptors in life span has not been clearly defined. It is also unclear whether GABA signaling regulates health span. Here, using C. elegans as a model, we systematically interrogated the role of various GABA receptors in both life span and health span. We find that mutations in four different GABA receptors extend health span by promoting resistance to stress and pathogen infection and that two such receptor mutants also show extended life span. Different GABA receptors engage distinct transcriptional factors to regulate life span and health span, and even the same receptor regulates life span and health span via different transcription factors. Our results uncover a novel, profound role of GABA signaling in aging in C. elegans, which is mediated by different GABA receptors coupled to distinct downstream effectors.

Summary Reactive α-dicarbonyls (α-DCs), like methylglyoxal (MGO), accumulate with age and have been implicated in aging and various age-associated pathologies, such as diabetic complications and neurodegenerative disorders like Alzheimer's and Parkinson's diseases. Evolutionarily conserved glyoxalases are responsible for α-DC detoxification; however, their core biochemical regulation has remained unclear. We have established a Caenorhabditis elegans model, based on an impaired glyoxalase ( glod - 4 / GLO1 ), to broadly study α-DC-related stress. We show that, in comparison to wild-type (N2, Bristol), glod - 4 animals rapidly exhibit several pathogenic phenotypes, including hyperesthesia, neuronal damage, reduced motility, and early mortality. We further demonstrate TRPA-1/TRPA1 as a sensor for α-DCs, conserved between worms and mammals. Moreover, TRPA-1 activates SKN-1/Nrf via calcium-modulated kinase signaling, ultimately regulating the glutathione-dependent (GLO1) and co-factor-independent (DJ1) glyoxalases to detoxify α-DCs. Interestingly, this pathway is in stark contrast to the TRPA-1 activation and the ensuing calcium flux implicated in cold sensation in C. elegans , whereby DAF-16/FOXO gets activated via complementary kinase signaling. Finally, a phenotypic drug screen using C. elegans identified podocarpic acid as a novel activator of TRPA1 that rescues α-DC-induced pathologies in C. elegans and mammalian cells. Our work thus identifies TRPA1 as a bona fide drug target for the amelioration of α-DC stress, which represents a viable option to address aging-related pathologies in diabetes and neurodegenerative diseases.

Noxious pH triggers pungent taste and nocifensive behavior. While the mechanisms underlying acidic pH sensation have been extensively characterized, little is known about how animals sense alkaline pH in the environment. TMC genes encode a family of evolutionarily conserved membrane proteins whose functions are largely unknown. Here, we characterize C. elegans TMC-1, which was suggested to form a Na(+)-sensitive channel mediating salt chemosensation. Interestingly, we find that TMC-1 is required for worms to avoid noxious alkaline environment. Alkaline pH evokes an inward current in nociceptive neurons, which is primarily mediated by TMC-1 and to a lesser extent by the TRP channel OSM-9. However, unlike OSM-9, which is sensitive to both acidic and alkaline pH, TMC-1 is only required for alkali-activated current, revealing a specificity for alkaline sensation. Ectopic expression of TMC-1 confers alkaline sensitivity to alkali-insensitive cells. Our results identify an unexpected role for TMCs in alkaline sensation and nociception.

Aging is the greatest risk factor for a number of neurodegenerative diseases, such as Alzheimer's and Parkinson's disease. Furthermore, normal aging is associated with a decline in sensory, motor, and cognitive functions. Emerging evidence suggests that synapse alterations, rather than neuronal cell death, are the causes of neuronal dysfunctions in normal aging and in early stages of neurodegenerative diseases. However, little is known about the mechanisms underlying age-related synaptic decline. Here, we uncover a surprising role of the anterograde molecular motor UNC-104/KIF1A as a key regulator of neural circuit deterioration in aging C. elegans. Through analyses of synapse protein localization, synaptic transmission, and animal behaviors, we find that reduced function of UNC-104 accelerates motor circuit dysfunction with age, whereas upregulation of UNC-104 significantly improves motor function at advanced ages and also mildly extends lifespan. In addition, UNC-104-overexpressing animals outperform wild-type controls in associative learning and memory tests. Further genetic analyses suggest that UNC-104 functions downstream of the DAF-2-signaling pathway and is regulated by the FOXO transcription factor DAF-16, which contributes to the effects of DAF-2 in neuronal aging. Together, our cellular, electrophysiological, and behavioral analyses highlight the importance of axonal transport in the maintenance of synaptic structural integrity and function during aging and raise the possibility of targeting kinesins to slow age-related neural circuit dysfunction.

Insulin signaling has been suggested to modulate nicotine dependence, but the underlying genetic evidence has been lacking. Here, we used the nematode, Caenorhabditis elegans, to investigate whether genetic alterations in the insulin signaling pathway affect behavioral responses to nicotine. For this, we challenged drug-naive C. elegans with an acute dose of nicotine (100 μmol/l) while recording changes in their locomotion speed. Although nicotine treatment stimulated locomotion speed in wild-type C. elegans, the same treatment reduced locomotion speed in mutants defective in insulin signaling. This phenotype could be suppressed by mutations in daf-16, a gene encoding a FOXO transcription factor that acts downstream of insulin signaling. Our data suggest that insulin signaling genes, daf-2, age-1, pdk-1, akt-1, and akt-2, modulate behavioral responses to nicotine in C. elegans, indicating a genetic link between nicotine behavior and insulin signaling.

We examine the relation between tax aggressiveness and firm value. Using a tax enforcement change in Taiwan that limits firms’ abilities to pursue aggressive tax strategies, we document that the relation between tax aggressiveness and firm value becomes more negative after the regulatory change. Further analyses reveal that the negative change is more pronounced for firms that are more likely to be targeted by the stricter tax enforcement. In addition, we do not find strong evidence on the impact of corporate governance in moderating the main relation. Our results seem to be consistent with the argument that potential increases in regulatory costs may outweigh the benefit of the stricter tax enforcement in constraining insiders’ income diversion, intensifying the conflict between aggressive tax positions and shareholder wealth in our research setting.

Summary Maintaining energy homeostasis upon environmental challenges, such as cold or excess calorie intake, is essential to the fitness and survival of mammals. Drug discovery efforts targeting β-adrenergic signaling have not been fruitful after decades of intensive research. We recently identified a new beige fat regulatory pathway mediated via the nicotinic acetylcholine receptor subunit CHRNA2. Here, we generated fat-specific Chrna2 KO mice and observed thermogenic defects in cold and metabolic dysfunction upon dietary challenges caused by adipocyte-autonomous regulation in vivo. We found that CHRNA2 signaling is activated after acute high fat diet feeding and this effect is manifested through both UCP1- and creatine-mediated mechanisms. Furthermore, our data suggested that CHRNA2 signaling may activate glycolytic beige fat, a subpopulation of beige adipocytes mediated by GABPα emerging in the absence of β-adrenergic signaling. These findings reveal the biological significance of the CHRNA2 pathway in beige fat biogenesis and energy homeostasis.