Feeding state-dependent regulation of developmental plasticity via CaMKI and neuroendocrine signaling

Information about nutrient availability is assessed via largely unknown mechanisms to drive developmental decisions, including the choice of Caenorhabditis elegans larvae to enter into the reproductive cycle or the dauer stage. In this study, we show that CMK-1 CaMKI regulates the dauer decision as a function of feeding state. CMK-1 acts cell-autonomously in the ASI, and non cell-autonomously in the AWC, sensory neurons to regulate expression of the growth promoting daf-7 TGF-β and daf-28 insulin-like peptide (ILP) genes, respectively. Feeding state regulates dynamic subcellular localization of CMK-1, and CMK-1-dependent expression of anti-dauer ILP genes, in AWC. A food-regulated balance between anti-dauer ILP signals from AWC and pro-dauer signals regulates neuroendocrine signaling and dauer entry; disruption of this balance in cmk-1 mutants drives inappropriate dauer formation under well-fed conditions. These results identify mechanisms by which nutrient information is integrated in a small neuronal network to modulate neuroendocrine signaling and developmental plasticity. © Neal et al.1

페로몬 감각 각인의 기초가 되는 회로 메커니즘연구

Experiences during early development can influence neuronal functions and modu-late adult behaviors. However, the molecular mechanisms underlying the long-term be-havioral effects of these early experiences are not fully understood. The C. elegans ascr#3 pheromone triggers avoidance behavior in adult hermaphrodites. Here, I show that hermaphrodites that are briefly exposed to ascr#3 immediately af-ter birth exhibit increased ascr#3-specific avoidance as adults indicating that ascr#3-experienced animals form a long lasting memory or imprint of this early ascr#3 exposure. ascr#3 imprinting is mediated by increased synaptic activity between the ascr#3-sensing ADL neurons and their post-synaptic SMB motor neuron partners via increased expression of the odr-2 GPI-linked signaling and avr-14 glutamate-gated chloride channel genes in the SMB neurons. My study suggests that the memory for early ascr#3 experience is imprinted via al-teration of a single synaptic connection, that in turn shapes experience-dependent plastici-ty in adult ascr#3 responses. ⓒ 2017 DGISTopenⅠ. Introduction 1-- 1.1 Neuroconnectome 1-- 1.2 Synaptic plasticity 1-- 1.3 Studying of C. elegans as a model system 2-- 1.4 C. elegans pheromones 3-- 1.5 Early pheromone-experienced study of C. elegans 4-- II. Experimental Method & Materials 5-- 2.1 Experimental Model and Subject Details 5-- 2.2 Method Details 5-- 2.2.1 Generation of C. elegans transgenic lines 5-- 2.2.2 Pheromone imprinting 6-- 2.2.3 Post-dauer assay 7-- 2.2.4 Behavioral assay 7-- 2.2.5 In vivo calcium imaging 8-- 2.2.6 Levamizole treatment 8-- 2.2.7 Heat shock treatment 9-- 2.3 Quantification and Statistical Analysis 9-- 2.3.1 Representative images 9-- 2.3.2 GFP quantification 9-- 2.3.3 Statistical tests 10-- III. Result 11-- 3.1 Adult C. elegans transiently exposed to ascr#3 during larval stages ex-hibits increased acsr#3 pheromone avoidance 11-- 3.1.1 Pheromone imprinting assay of naive and pre-exposed worms 11-- 3.1.2 Optimal ascr#3 concentration of pre-exposure effect 13-- 3.1.3 Early ascr#3 experience of males 14-- 3.2 The memory for ascr#3 is acquired during the L1 larval stage 14-- 3.2.1 ascr#3 imprinting is L1 specific 14-- 3.2.2 The critical time for imprinting of L1 stage 15-- 3.2.3 ascr#3 imprinting is pheromone specific 16-- 4.1 odr-2 Acts in the SMB neurons to increase ascr#3 avoidance in ascr#3-imprinted animals 20-- 4.1.1 Candidate gene search 20-- 4.1.2 odr-2 recue study 22-- 4.1.3 SMB sensory/inter/motor neurons 24-- 4.1.4 Association of SMB and Imprining 25-- 4.2 ascr#3-induced responses in the ADL chemosensory neurons are unal-tered in ascr#3 imprinted worms 25-- 4.2.1 ADL Ca²⁺ Imaging 25-- 4.2.2 ADL Ca²⁺ Imaging in odr-2 27-- 4.2.3 AIB, AVD, AVA Ca²⁺ imaging 27-- 4.3 SMB mediates increased ascr#3 avoidance in ascr#3 imprinted ani-mals 30-- 4.3.1 SMB Ca²⁺ Imaging 30-- 4.3.2 Levamisole-treated SMB Ca²⁺ Imaging 31-- 4.3.3 ADLp::TeTx-treated SMB Ca²⁺ Imaging 32-- 4.3.4 SMB Ca²⁺ Imaging in odr-2 34-- 4.4 Upregulation of odr-2 expression in SMB of ascr#3-imprinted L1 lar-vae is sufficient for ascr#3 imprinting 34-- 4.4.1 GFP quantification of naive and imprinted C. elegans 34-- 4.4.2 Heatshock study of non-imprinted animals 35-- 4.4.3 avr-14 study 36-- IV. Discussion 38-- V. Conclusion 40본 논문은 전체 게놈이 최초로 알려졌으며 유일무이한 개체수준의 뉴로커넥톰이 구축된 예쁜꼬마선충을 모델시스템으로 연구를 진행하였다. 이전 연구들은 각 신경들의 구조와 기능에 대한 미시적 수준에 머물러, 뉴로커넥톰의 역할과 기능에 관한 거시적 수준에서의 연구는 미약한 실정이었다. 본 논문은 세계최초로 페로몬에 대한 ‘각인’이라는 장기기억 현상을 발견하였다. 먼저 이러한 행동가소성을 야기하는 원인 유전자를 찾아 신경세포 수준에서의 접근법을 모색 하였고, 그 후 분자생물학 및 유전학적 방법을 기반으로 관련 신경회로의 작동원리를 규명하여 스마트 뉴로커넥톰을 구축하는데 일조하였다. 따라서 본 논문은 뉴로커넥톰의 작동원리 규명, 향후 뇌신경계 기능 구현, 다양한 신경정신 질환의 원인 규명 및 치료로의 활용에 획기적 단서를 제공할 것이다.DoctordCollectio

Environmental Pyrethroid Exposure and Cognitive Dysfunction in U.S. Older Adults: The NHANES 2001–2002

Pyrethroid compounds are widely used in household insecticides and agricultural pesticides. Recent studies, however, report that pyrethroid exposures affect neurobehavioral function in animals and may be associated with adverse neurocognitive development in children. This study aimed to examine the association between pyrethroid exposure and cognitive dysfunction in older adults using a well-defined general population. We analyzed data from 336 individuals, aged 60–84 years, who participated in the National Health and Nutrition Examination Survey 2001–2002. We used urinary 3-phenoxybenzoic acid (3-PBA) concentration as a biomarker of pyrethroid exposures and assessed cognitive function with the digit–symbol coding test. The geometric means (±geometric standard errors) of creatinine-uncorrected and corrected urinary 3-PBA were 0.30 (±0.87) μg/L and 0.36 (±0.89) μg/g. After adjusting for sociodemographic factors, higher 3-PBA concentrations (> vs. ≤0.30 μg/g creatinine (median)) were associated with lower scores of cognitive function (−3.83 95% confidence interval: −7.11, −0.54). Significance was persistent after additionally adjusting for physical activity and smoking pack-year (−3.76 95% CI: −7.16, −0.36) and further adjusting for BMI and presence of hypertension and diabetes (−3.82 95% CI: −6.92, −0.71). Our findings suggest that pyrethroid exposure is associated with cognitive dysfunction in older adults

Targeting FAK/PYK2 with SJP1602 for Anti-Tumor Activity in Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) presents significant challenges due to its aggressive nature and limited treatment options. Focal adhesion kinase (FAK) has emerged as a critical factor promoting tumor growth and metastasis in TNBC. Despite encouraging results from preclinical and early clinical trials with various FAK inhibitors, none have yet achieved clinical success in TNBC treatment. This study investigates the therapeutic potential of a novel dual inhibitor of FAK and PYK2, named SJP1602, for TNBC. In vitro experiments demonstrate that SJP1602 effectively inhibits FAK and PYK2 activities, showing potent effects on both kinases. SJP1602 shows concentration-dependent inhibition of cell growth, migration, invasion, and 3D spheroid formation in TNBC cell lines, surpassing the efficacy of other FAK inhibitors. Pharmacokinetic studies in rats indicate favorable bioavailability and sustained plasma concentrations of SJP1602, supporting its potential as a therapeutic agent. Furthermore, in TNBC xenograft models, SJP1602 exhibits significant dose-dependent inhibition of tumor growth. These promising results emphasize the potential of SJP1602 as a potent dual inhibitor of FAK and PYK2, deserving further investigation in clinical trials for TNBC treatment

Ultrafast van der Waals diode using graphene quantum capacitance and Fermi-level depinning

Graphene, with superior electrical tunabilities, has arisen as a multifunctional insertion layer in vertically stacked devices. Although the role of graphene inserted in metal-semiconductor junctions has been well investigated in quasi-static charge transport regime, the implication of graphene insertion at ultrahigh frequencies has rarely been considered. Here, we demonstrate the diode operation of vertical Pt/n-MoSe2/graphene/Au assemblies at ~200-GHz cutoff frequency (fC). The electric charge modulation by the inserted graphene becomes essentially frozen above a few GHz frequencies due to graphene quantum capacitance-induced delay, so that the Ohmic graphene/MoSe2 junction may be transformed to a pinning-free Schottky junction. Our diodes exhibit much lower total capacitance than devices without graphene insertion, deriving an order of magnitude higher fC, which clearly demonstrates the merit of graphene at high frequencies.11Nsciescopu

Early Pheromone Experience Modifies a Synaptic Activity to Influence Adult Pheromone Responses of C. elegans

Experiences during early development can influence neuronal functions and modulate adult behaviors [1, 2]. However, the molecular mechanisms underlying the long-term behavioral effects of these early experiences are not fully understood. The C. elegans ascr#3 (asc-ΔC9; C9) pheromone triggers avoidance behavior in adult hermaphrodites [3–7]. Here, we show that hermaphrodites that are briefly exposed to ascr#3 immediately after birth exhibit increased ascr#3-specific avoidance as adults, indicating that ascr#3-experienced animals form a long-lasting memory or imprint of this early ascr#3 exposure [8]. ascr#3 imprinting is mediated by increased synaptic activity between the ascr#3-sensing ADL neurons and their post-synaptic SMB motor neuron partners via increased expression of the odr-2 glycosylated phosphatidylinositol (GPI)-linked signaling gene in the SMB neurons. Our study suggests that the memory for early ascr#3 experience is imprinted via alteration of activity of a single synaptic connection, which in turn shapes experience-dependent plasticity in adult ascr#3 responses. Hong et al. show that early pheromone experience in C. elegans hermaphrodites is imprinted via alteration of activity of a single synaptic connection and, in turn, modulates behavioral responses to the pheromone as adults. © 2017 Elsevier Ltd1