Reciprocal modulation of 5-HT and octopamine regulates pumping via feedforward and feedback circuits in C. elegans.

Feeding is vital for animal survival and is tightly regulated by the endocrine and nervous systems. To study the mechanisms of humoral regulation of feeding behavior, we investigated serotonin (5-HT) and octopamine (OA) signaling in Caenorhabditis elegans, which uses pharyngeal pumping to ingest bacteria into the gut. We reveal that a cross-modulation mechanism between 5-HT and OA, which convey feeding and fasting signals, respectively, mainly functions in regulating the pumping and secretion of both neuromodulators via ADF/RIC/SIA feedforward neurocircuit (consisting of ADF, RIC, and SIA neurons) and ADF/RIC/AWB/ADF feedback neurocircuit (consisting of ADF, RIC, AWB, and ADF neurons) under conditions of food supply and food deprivation, respectively. Food supply stimulates food-sensing ADFs to release more 5-HT, which augments pumping via inhibiting OA secretion by RIC interneurons and, thus, alleviates pumping suppression by OA-activated SIA interneurons/motoneurons. In contrast, nutrient deprivation stimulates RICs to secrete OA, which suppresses pumping via activating SIAs and maintains basal pumping and 5-HT production activity through excitation of ADFs relayed by AWB sensory neurons. Notably, the feedforward and feedback circuits employ distinct modalities of neurosignal integration, namely, disinhibition and disexcitation, respectively.

Human papillomavirus-Inequalities in disease prevention and the impact on racial, ethnic, sexual, and gender minorities.

HPV, a sexually transmitted viral infection, is the etiological agent of significant dermatologic disease including benign anogenital warts and invasive cancers. Sexual and gender minority individuals are particularly vulnerable to HPV-associated disease due to reduced vaccination rates in these cohorts, low awareness of HPV, lack of provider recommendation, and inadequate consensus guidelines on screening and prevention in these individuals. A targeted approach is needed with regards to vaccination in all children -especially those from racial, ethnic, sexual, and gender minorities; provider recommendation, especially from pediatric dermatologists, is crucial. Effort must also be made to use transgender and non-binary affirming language as dividing vaccination programs by anatomic sex and sexuality reinforces problematic notions of gender identity and sexuality, isolating the most vulnerable.

Mechano-gated channels in C. elegans.

Mechanosensation such as touch, hearing and proprioception, is functionally regulated by mechano-gated ion channels through the process of transduction. Mechano-gated channels are a subtype of gated ion channels engaged in converting mechanical stimuli to chemical or electrical signals thereby modulating sensation. To date, a few families of mechano-gated channels (DEG/ENaC, TRPN, K2P, TMC and Piezo) have been identified in eukaryotes. Using a tractable genetic model organism Caenorhabditis elegans, the molecular mechanism of mechanosensation have been the focus of much research to comprehend the process of mechanotransduction. Comprising of almost all metazoans classes of ion channels, transporters and receptors, C. elegans is a powerful genetic model to explore mechanosensitive behaviors such as touch sensation and proprioception. The nematode relies primarily on its sensory abilities to survive in its natural environment. Genetic screening, calcium imaging and electrophysiological analysis have established that ENaC proteins and TRPN channel (TRP-4 protein) can characterize mechano-gated channels in C. elegans. A recent study reported that TMCs are likely the pore-forming subunit of a mechano-gated channel in C. elegans. Nevertheless, it still remains unclear whether Piezo as well as other candidate proteins can form mechano-gated channels in C. elegans.

Off-label use of dupilumab for pediatric patients with atopic dermatitis: A multicenter retrospective review.

BACKGROUND: Atopic dermatitis (AD) is a common, chronic type 2 inflammatory skin disease, typically starting in infancy, with increased risk for subsequent extracutaneous atopic morbidities. Dupilumab is the first biologic agent targeting type 2 inflammation approved by the U.S. Food and Drug Administration (USFDA); it was licensed in 2017 for adults with moderate to severe AD and 2 years later for adolescents. Systemic treatment for pediatric AD remains a significant unmet medical need. OBJECTIVE: To analyze off-label use of dupilumab in children with AD. METHODS: Multicenter retrospective review that evaluated children who were prescribed dupilumab for moderate to severe AD. RESULTS: One hundred eleven of 124 patients (89.5%) gained access to dupilumab after a mean of 9 weeks. The dosing range was 4 to 15.5 mg/kg for the loading dose and 2.0 to 15.3 mg/kg every other week for maintenance. The range was widest for 6- to 11-year-olds and was related to use of either full or half of adult dosing. Associated morbidities, treatment response, and adverse events were comparable to those in previous adolescent and adult trials. LIMITATIONS: The retrospective design of the study limited uniform data collection. CONCLUSION: Access to dupilumab was achievable for the majority of children after a mean 9-week delay because of insurance payment denial. This review supports dupilumab response and tolerability in children. Optimal dosing for patients younger than 12 years has not been defined. Availability of the drug in 2 different concentrations is an important safety issue.

Dermatopathologist assessment of "pathologist-to-dermatologist" communication for dermatopathology services.

BACKGROUND: While patients are the ultimate beneficiaries of pathology services, pathologist to clinician communication is an essential component of excellent patient care. OBJECTIVE: To survey dermatologists on how well pathologists communicate with them and to assess which aspects of pathologists' communication skills are deemed most significant to dermatologists, stratified by practice type. METHODS: A survey-based instrument was developed and sent to dermatologists through various email listservs. Of the approximately 400 potential Association of Professors of Dermatology respondents, 64 returned the survey questionnaire (response rate 16%). Of the 79 state and regional dermatologic societies, seven agreed to distribute the survey on their listservs (response rate 9%). RESULTS: Surveyed dermatologists believe that the pathologists with whom they work are meeting expectations in the areas of diagnostic accuracy, communicating pertinent information in a timely fashion, integrating written pathology reports into the electronic medical record, and making a clinically meaningful histopathologic interpretation. Discussion of cost of ancillary testing is an area of improvement. University affiliated dermatologists are more likely to use electronic medical records as their predominant mode of communication compared to community dermatologists with and without academic affiliations. Community dermatologists are more likely to use faxed written pathology reports as their predominant mode of communication. CONCLUSION: Physician-to-physician communication is a key component of effective patient care. When it comes to dermatopathology services, dermatologists appear overall satisfied with the indicators examined, however, potential opportunities for improvement exist.

Improving nonattendance rates among pediatric patients with Medicaid or private insurance.

BACKGROUND: Access to dermatologists is low among Medicaid-insured patients. Higher clinic nonattendance among Medicaid-insured patients might affect provider decisions to accept these patients. OBJECTIVE: To determine the effect of different scheduling policies on the attendance among children seen at a pediatric dermatology clinic. METHODS: In this retrospective review, we compared nonattendance among children for 3 different scheduling policies implemented over 3 consecutive years. The scheduling policies used were a first-available open scheduling policy, a 2-week in advance scheduling policy, and a 4-week in advance scheduling policy. Subset analyses were performed by clinic location and insurance type. RESULTS: The interval between scheduling and appointment date was directly related to nonattendance rates; rates were higher for Medicaid-insured than privately insured patients. Open scheduling was associated with a 37% nonattendance rate for Medicaid-insured patients and 18% nonattendance rate for privately insured patients. A 4-week in advance scheduling policy significantly decreased the nonattendance rate to 19% among Medicaid-insured and 7% among privately insured patients. A 2-week in advance policy further decreased the nonattendance rate to 11% among Medicaid-insured patients and 4% among privately insured patients. LIMITATIONS: This is a retrospective study, and same-day cancellations were not tracked. CONCLUSION: Decreasing the time interval between scheduling and appointment dates can significantly decrease nonattendance. This strategy might help dermatologists incorporate more Medicaid-insured patients into their practices.

Do Patterns of Reconstruction Choices After Mohs Surgery Vary by Specialty? A Pilot Study of Mohs Surgeons and Facial Plastic Surgeons.

BACKGROUND: Differences in approach to repair a specified defect after Mohs micrographic surgery (MMS) between specialties have not been previously examined. OBJECTIVE: To assess the difference in frequency of which reconstruction repairs are selected after MMS, among Mohs surgeons and facial plastic surgeons (FPS), and evaluate whether the level of satisfaction with the final repair outcome differed between specialties. MATERIALS AND METHODS: The study was approved by the Saint Louis University Institutional Review Board. A link to the survey was distributed to members of American College of Mohs Surgery (ACMS) and American Academy of Facial Plastic and Reconstructive Surgery (AAFPRS), between January and May 2016. RESULTS: The reconstructive procedure selected most often ("top choice") was not significantly different between Mohs surgeons and FPS for the majority of the images. There was no material difference in how dermatologists and FPS rate the aesthetic outcome of the 3 presented closure types, with the exception of one closure type-nose with graft. CONCLUSION: Mohs surgeons were found to more likely cluster around a single preference for their reconstruction technique compared with FPS, in which a higher percentage of surgeons also selected other options.

Phasic/tonic glial GABA differentially transduce for olfactory adaptation and neuronal aging.

Phasic (fast) and tonic (sustained) inhibition of γ-aminobutyric acid (GABA) are fundamental for regulating day-to-day activities, neuronal excitability, and plasticity. However, the mechanisms and physiological functions of glial GABA transductions remain poorly understood. Here, we report that the AMsh glia in Caenorhabditis elegans exhibit both phasic and tonic GABAergic signaling, which distinctively regulate olfactory adaptation and neuronal aging. Through genetic screening, we find that GABA permeates through bestrophin-9/-13/-14 anion channels from AMsh glia, which primarily activate the metabolic GABAB receptor GBB-1 in the neighboring ASH sensory neurons. This tonic action of glial GABA regulates the age-associated changes of ASH neurons and olfactory responses via a conserved signaling pathway, inducing neuroprotection. In addition, the calcium-evoked, vesicular glial GABA release acts upon the ionotropic GABAA receptor LGC-38 in ASH neurons to regulate olfactory adaptation. These findings underscore the fundamental significance of glial GABA in maintaining healthy aging and neuronal stability.

Nematode homologs of the sour taste receptor Otopetrin1 are evolutionarily conserved acid-sensitive proton channels.

Numerous taste receptors and related molecules have been identified in vertebrates and invertebrates. Otopetrin1 has recently been identified as mammalian sour taste receptor which is essential for acid sensation. However, whether other Otopetrin proteins are involved in PH-sensing remains unknown. In C. elegans, there are eight otopetrin homologous genes but their expression patterns and functions have not been reported so far. Through heterologous expression in HEK293T cells, we found that ceOTOP1a can be activated by acid in NMDG+ solution without conventional cations, which generated inward currents and can be blocked by zinc ions. Moreover, we found that Otopetrin channels are widely expressed in numerous tissues, especially in sensory neurons in the nematode. These results suggest that the biophysical characteristics of the Otopetrin channels in nematodes are generally conserved. However, a series of single gene mutations of otopetrins, which were constructed by CRISPR-Cas9 method, did not affect either calcium responses in ASH polymodal sensory neurons to acid stimulation or acid avoidance behaviors, suggesting that Otopetrin channels might have diverse functions among species. This study reveals that nematode Otopetrins are evolutionarily conserved acid-sensitive proton channels, and provides a framework for further revealing the function and mechanisms of Otopetrin channels in both invertebrates and vertebrates.

Inhibition of melanogenesis by 3-(1'-methyltetrahydropyridinyl)-2,4-6-trihydroxy acetophenone via suppressing the activity of cAMP response element-binding protein (CREB) and nuclear exclusion of CREB-regulated transcription coactivator 1 (CRTC1).

Exposure to Ultraviolet radiation or α-melanocyte-stimulating hormone (α-MSH) stimulates the Cyclic Adenosine Monophosphate/Protein Kinase A signalling pathway, which leads to the synthesis and deposition of melanin granules in the epidermis. Skin pigmentation is the major physiological defence against inimical effects of sunlight. However, excessive melanin production and accumulation can cause various skin hyperpigmentation disorders. The present study involved the identification of 3-(1'-methyltetrahydropyridinyl)-2,4-6-trihydroxy acetophenone (IIIM-8) as an inhibitor of melanogenesis, IIIM-8 significantly inhibited pigment production both in vitro and in vivo without incurring any cytotoxicity in Human Adult Epidermal Melanocytes (HAEM). IIIM-8 repressed melanin synthesis and secretion both at basal levels and in α-MSH stimulated cultured HAEM cells by decreasing the levels of Cyclic Adenosine Monophosphate (cAMP) and inhibiting the phosphorylation of cAMP response element-binding (CREB) protein, coupled with restoring the phosphorylation of CREB-regulated transcription coactivator 1 (CRTC1) and its nuclear exclusion in HAEM cells. This impeding effect correlates with diminished expression of master melanogenic proteins including microphthalmia-associated transcription factor (MITF), Tyrosinase (TYR), Tyrosinase related protein 1 (TRP1), and Tyrosinase related protein 2 (TRP2). Additionally, topical application of IIIM-8 induced tail depigmentation in C57BL/6J mice. Furthermore, IIIM-8 efficiently mitigated the effect of ultraviolet-B radiation on melanin synthesis in the auricles of C57BL/6J mice. This study demonstrates that IIIM-8 is an active anti-melanogenic agent against ultraviolet radiation-induced melanogenesis and other hyperpigmentation disorders.

TRPM2 as a conserved gatekeeper determines the vulnerability of DA neurons by mediating ROS sensing and calcium dyshomeostasis.

Different dopaminergic (DA) neuronal subgroups exhibit distinct vulnerability to stress, while the underlying mechanisms are elusive. Here we report that the transient receptor potential melastatin 2 (TRPM2) channel is preferentially expressed in vulnerable DA neuronal subgroups, which correlates positively with aging in Parkinson's Disease (PD) patients. Overexpression of human TRPM2 in the DA neurons of C. elegans resulted in selective death of ADE but not CEP neurons in aged worms. Mechanistically, TRPM2 activation mediates FZO-1/CED-9-dependent mitochondrial hyperfusion and mitochondrial permeability transition (MPT), leading to ADE death. In mice, TRPM2 knockout reduced vulnerable substantia nigra pars compacta (SNc) DA neuronal death induced by stress. Moreover, the TRPM2-mediated vulnerable DA neuronal death pathway is conserved from C. elegans to toxin-treated mice model and PD patient iPSC-derived DA neurons. The vulnerable SNc DA neuronal loss is the major symptom and cause of PD, and therefore the TRPM2-mediated pathway serves as a promising therapeutic target against PD.

Kir2.1 channel: Macrophage plasticity in tumor microenvironment.

Diverse ion channels have dysregulated functional expression in the tumor microenvironment (TME). In this issue of Cell Metabolism, Chen et al. reveal that high intratumoral K+ ions restrict the plasticity of tumor-associated macrophages (TAMs). Inhibition of the Kir2.1 potassium channel induced metabolic reprogramming and repolarization of pro-tumor M2-TAMs to tumoricidal M1-like states.

Protocol for glial Ca2+ imaging in C. elegans following chemical, mechanical, or optogenetic stimulation.

Caenorhabditis elegans is an exceptionally transparent model to analyze calcium (Ca2+) signals, but available protocols for neuronal Ca2+ imaging may not be suitable for studying glial cells. Here, we present a detailed protocol for glial Ca2+ imaging in C. elegans following three different approaches including chemical, mechanical, and optogenetic stimulation. We also provide the details for imaging analysis using Image-J. For complete details on the use and execution of this protocol, please refer to Duan et al. (2020).

The Voltage-Gated Calcium Channel EGL-19 Acts on Glia to Drive Olfactory Adaptation.

Calcium channelopathies have been strongly linked to cardiovascular, muscular, neurological and psychiatric disorders. The voltage-gated calcium channels (VGCC) are vital transducers of membrane potential changes to facilitate the dynamics of calcium ions and release of neurotransmitter. Whether these channels function in the glial cell to mediate calcium variations and regulate behavioral outputs, is poorly understood. Our results showed that odorant and mechanical stimuli evoked robust calcium increases in the amphid sheath (AMsh) glia from C. elegans, which were largely dependent on the L-Type VGCC EGL-19. Moreover, EGL-19 modulates the morphologies of both ASH sensory neurons and AMsh glia. Tissue-specific knock-down of EGL-19 in AMsh glia regulated sensory adaptability of ASH neurons and promoted olfactory adaptation. Our results reveal a novel role of glial L-Type VGCC EGL-19 on olfaction, lead to improved understanding of the functions of VGCCs in sensory transduction.

Mechanosensation: Alpha-7 nAChR transduces sound signals in earless C. elegans.

How do organisms without specialized auditory systems perceive and transduce sound? In this issue of Neuron, Iliff et al. (2021) investigate the functional mechanism of airborne sound sensation in Caenorhabditis elegans and highlight the crucial role of alpha-7 nicotinic acetylcholine receptor subunits in mechanotransduction.

Polymodal Functionality of C. elegans OLL Neurons in Mechanosensation and Thermosensation.

Sensory modalities are important for survival but the molecular mechanisms remain challenging due to the polymodal functionality of sensory neurons. Here, we report the C. elegans outer labial lateral (OLL) sensilla sensory neurons respond to touch and cold. Mechanosensation of OLL neurons resulted in cell-autonomous mechanically-evoked Ca2+ transients and rapidly-adapting mechanoreceptor currents with a very short latency. Mechanotransduction of OLL neurons might be carried by a novel Na+ conductance channel, which is insensitive to amiloride. The bona fide mechano-gated Na+-selective degenerin/epithelial Na+ channels, TRP-4, TMC, and Piezo proteins are not involved in this mechanosensation. Interestingly, OLL neurons also mediated cold but not warm responses in a cell-autonomous manner. We further showed that the cold response of OLL neurons is not mediated by the cold receptor TRPA-1 or the temperature-sensitive glutamate receptor GLR-3. Thus, we propose the polymodal functionality of OLL neurons in mechanosensation and cold sensation.

Case Report: Leprosy and Psoriasis: A Rare Coexistence.

Leprosy presents with erythematous or pigmented patches, plaques, and nodules with loss of sensation and nerve thickening. Psoriasis presents as sharply demarcated erythematous plaques with overlying silvery scales. The controversial relationship between both has existed since biblical times when psoriasis was considered to be a form of leprosy. Records of leprosy patients have depicted a rarity of the coexistence of psoriasis, leading to a hypothesis that both rarely develop in the same patient. We report a rare coexistence of both diseases.

Molecular Crux of Hair Cell Mechanotransduction Machinery.

Although 62 years have elapsed since the first report of hereditary deafness in a mouse strain, the molecular mechanism of hair cell mechanotransduction remains elusive. Three recent studies present crucial insights into the molecular crux of hair cell mechanotransduction machinery.