Conserved Signaling Pathway Research Articles

A collection of split-Gal4 drivers targeting conserved signaling ligands in Drosophila.

Communication between cells in metazoan organisms is mediated by a remarkably small number of highly conserved signaling pathways. Given the relatively small number of signaling pathways, the existence of multiple related ligands for many of these pathways is thought to represent a key evolutionary innovation for encoding complexity into cell-cell signaling. Relatedly, crosstalk and other interactions between pathways is another critical feature which allows a modest number pathways to ultimately generate an enormously diverse range of outcomes. It would thus be useful to have genetic tools to identify and manipulate not only those cells which express a given signaling ligand, but also those cells that specifically co-express pairs of signaling ligands. Here, we present a collection of split-Gal4 knock-in lines targeting many of the ligands for highly conserved signaling pathways in Drosophila (Notch, Hedgehog, FGF, EGF, TGF β , JAK/STAT, JNK, and PVR). We demonstrate that these lines faithfully recapitulate the endogenous expression pattern of their targets, and that they can be used to specifically identify the cells and tissues that co-express pairs of signaling ligands. As a proof of principle, we demonstrate that the 4th chromosome TGF β ligands myoglianin and maverick are broadly co-expressed in muscles and other tissues of both larva and adults, and that the JAK/STAT ligands upd2 and upd3 are partially co-expressed from cells of the midgut following gut damage. Together with our previously collection of split-Gal4 lines targeting the seven Wnt ligands, this resource allows Drosophila researchers to identify and genetically manipulate cells that specifically express pairs of conserved ligands from nearly all the major intercellular signaling pathways.

Drosophila melanogaster as an Alternative Model to Higher Organisms for In Vivo Lung Research.

COPD and asthma are lung diseases that cause considerable burden to more than 800 million people worldwide. As both lung diseases are so far incurable, it is mandatory to understand the mechanisms underlying disease development and progression for developing novel therapeutic approaches. Exposures to environmental cues such as cigarette smoke in earliest life are known to increase disease risks in the individual's own future. To explore the pathomechanisms leading to later airway disease, mammalian models are instrumental. However, such in vivo experiments are time-consuming and burdensome for the animals, which applies in particular to transgenerational studies. Along this line, the fruit fly Drosophila melanogaster comes with several advantages for research in this field. The short lifespan facilitates transgenerational studies. A high number of evolutionary conserved signaling pathways, together with a large toolbox for tissue-specific gene modification, has the potential to identify novel target genes involved in disease development. A well-defined airway microbiome could help to untangle interactions between disease development and microbiome composition. In the following article, Drosophila melanogaster is therefore presented and discussed as an alternative in vivo model to investigate airway diseases that can complement and/or replace models in higher organisms.

Antagonistic insulin-like signaling influencing glucose regulation in C. elegans

The insulin/ IGF-signaling (IIS) is an evolutionary conserved signaling pathway within eukaryotic organisms that regulates glucose metabolism and cell division. The nematode, C. elegans is an excellent model for exploring IIS as they have 40 insulin-like peptides that act on a single receptor, DAF-2. We aim to explore the relationships between IIS and glucose metabolism, focusing on the antagonistic insulin-like peptide, INS-17 and its influence over FDGT-1 (facilitated glucose transporter 1). FDGT-1 is expressed throughout the nematode, including the basolateral membrane of intestinal cells and where it is theorized to export glucose to the surrounding somatic cells rather than absorb it from the intestinal tract. We hypothesize that IIS controls transcription of FDGT-1 and antagonistic peptides should lead to a decrease in FDGT-1 transcription, resulting in the increased lifespan and increased fat accumulation observed in daf-2(lf) loss of function and ins-17(oe) over expressing strains. In this study, survival assays are used to assess the impact which high-glucose content has on lifespan, along with Oil Red O (ORO) lipid staining to visualize lipid accumulation amongst conditions and protein quantification of FDGT-1:GFP to evaluate FDGT-1 protein levels. Our findings are consistent with the idea of low insulin signaling leading to extended lifespan as daf-2(lf) lived significantly longer than WT in both 0% and 2% glucose conditions and ins-17(oe) living significantly longer than wildtype in 2% glucose conditions. The ORO lipid staining revealed that high glucose conditions and low insulin signaling result in lipid accumulation within the nematode. Using the fdgt-1:gfp strain, we were able to determine an increase in the FDGT-1 in the presence of glucose, suggesting FDGT-1 expression is influenced by glucose. These findings aim to further our understanding of IIS regulating glucose uptake and metabolism, along with the significance of the FDGT-1 glucose transporter.

Role of osteokines in atherosclerosis.

Despite their diverse physiologies and roles, the heart, skeletal muscles, and smooth muscles all derive from a common embryonic source as bones. Moreover, bone tissue, skeletal and smooth muscles, and the heart share conserved signaling pathways. The maintenance of skeletal health is precisely regulated by osteocytes, osteoblasts, and osteoclasts through coordinated secretion of bone-derived factors known as osteokines. Increasing evidence suggests the involvement of osteokines in regulating atherosclerotic vascular disease. Therefore, this review aims to examine the evidence for the role of osteokines in atherosclerosis development and progression comprehensively. Specifically discussed are extensively studied osteokines in atherosclerosis such as osteocalcin, osteopontin, osteoprotegerin, and fibroblast growth factor 23. Additionally, we highlighted the effects of exercise on modulating these key regulators derived from bone tissue metabolism. We believe that gaining an enhanced understanding of how osteocalcin contributes to the process of atherosclerosis will enable us to develop targeted and comprehensive therapeutic strategies against diseases associated with its progression.

The Vps21 signalling pathway regulates white-opaque switching and mating in Candida albicans

ABSTRACT Candida albicans is able to switch between two epigenetic cell types, namely white and opaque. Multiple conserved signalling pathways control the switch between white and opaque cell types in response to environmental changes. Here, we report the regulatory roles of the endosomal Rab family GTPase Vps21 and associated key components of the Vps21 signalling pathway in white-opaque switching and mating in C. albicans. Deletion of VPS21 promoted a switch from the white to the opaque phenotype in the presence of N-acetyl-glucosamine (GlcNAc). Consistently, inactivation of the guanine nucleotide exchange factor of Vps21 (Vps9) and downstream components in the Vps21 pathway (Vps3, Vac1, and Pep12) had similar promoting effects on phenotypic switching. The mating efficiency of opaque cells is much higher than that of white cells under standard laboratory culture conditions. However, compared to the wildtype strain, the vps21/vps21, vps9/vps9, vps3/vps3, vac1/vac1, and pep12/pep12 mutant strains exhibited dramatically reduced mating efficiencies. Quantitative RT-PCR assays demonstrated that inactivation of the Vps21 signalling pathway led to downregulation of pheromone expression and mating response pathway associated genes. Taken together, our findings indicate that the conserved Vps21 signalling pathway plays critical roles in the regulation of cell-type switching and mating in C. albicans.

Host JAK-STAT activity is a target of parasitoid wasp virulence strategies.

Innate immune responses that allow hosts to survive infection depend on the action of multiple conserved signaling pathways. Pathogens and parasites in turn have evolved virulence factors to target these immune signaling pathways in an attempt to overcome host immunity. Consequently, the interactions between host immune molecules and pathogen virulence factors play an important role in determining the outcome of an infection. The immune responses of Drosophila melanogaster provide a valuable model to understand immune signaling and host-pathogen interactions. Flies are commonly infected by parasitoid wasps and mount a coordinated cellular immune response following infection. This response is characterized by the production of specialized blood cells called lamellocytes that form a tight capsule around wasp eggs in the host hemocoel. The conserved JAK-STAT signaling pathway has been implicated in lamellocyte proliferation and is required for successful encapsulation of wasp eggs. Here we show that activity of Stat92E, the D. melanogaster STAT ortholog, is induced in immune tissues following parasitoid infection. Virulent wasp species are able to suppress Stat92E activity during infection, suggesting they target JAK-STAT pathway activation as a virulence strategy. Furthermore, two wasp species (Leptopilina guineaensis and Ganaspis xanthopoda) suppress phenotypes associated with a gain-of-function mutation in hopscotch, the D. melanogaster JAK ortholog, indicating that they inhibit the activity of the core signaling components of the JAK-STAT pathway. Our data suggest that parasitoid wasp virulence factors block JAK-STAT signaling to overcome fly immune defenses.

Pseudogenization of NK3 homeobox 2 (Nkx3.2) in monotremes provides insight into unique gastric anatomy and physiology.

The enzymatic breakdown and regulation of food passage through the vertebrate antral stomach and pyloric sphincter (antropyloric region) is a trait conserved over 450 million years. Development of the structures involved is underpinned by a highly conserved signalling pathway involving the hedgehog, bone morphogenetic protein and Wingless/Int-1 (Wnt) protein families. Monotremes are one of the few vertebrate lineages where acid-based digestion has been lost, and this is consistent with the lack of genes for hydrochloric acid secretion and gastric enzymes in the genomes of the platypus (Ornithorhynchus anatinus) and short-beaked echidna (Tachyglossus aculeatus) . Furthermore, these species feature unique gastric phenotypes, both with truncated and aglandular antral stomachs and the platypus with no pylorus. Here, we explore the genetic underpinning of monotreme gastric phenotypes, investigating genes important in antropyloric development using the newest monotreme genomes (mOrnAna1.pri.v4 and mTacAcu1) together with RNA-seq data. We found that the pathway constituents are generally conserved, but surprisingly, NK3 homeobox 2 (Nkx3.2) was pseudogenized in both platypus and echidna. We speculate that the unique sequence evolution of Grem1 and Bmp4 sequences in the echidna lineage may correlate with their pyloric-like restriction and that the convergent loss of gastric acid and stomach size genotypes and phenotypes in teleost and monotreme lineages may be a result of eco-evolutionary dynamics. These findings reflect the effects of gene loss on phenotypic evolution and further elucidate the genetic control of monotreme stomach anatomy and physiology.

Characterization of heat, salt, acid, alkaline, and antibiotic stress response in soil isolate Bacillus subtilis strain PSK.A2.

Microbes play an essential role in soil fertility by replenishing the nutrients; they encounter various biotic and abiotic stresses disrupting their cellular homeostasis, which expedites activating a conserved signaling pathway for transient over-expression of heat shock proteins (HSPs). In the present study, a versatile soil bacterium Bacillus subtilis strain PSK.A2 was isolated and characterized. Further, the isolated bacterium was exposed with several stresses, viz., heat, salt, acid, alkaline, and antibiotics. Stress-attributed cellular morphological modifications such as swelling, shrinkage, and clump formation were observed under the scanning electron microscope. The comparative protein expression pattern was studied by SDS-PAGE, relative protein stabilization was assessed by protein aggregation assay, and relative survival was mapped by single spot dilution and colony-counting method under control, stressed, lethal, and stressed lethal conditions of the isolate. The findings demonstrated that bacterial stress tolerance was maintained via the activation of various HSPs of molecular weight ranging from 17 to 115 kD to respective stimuli. The treatment of subinhibitory dose of antibiotics not interfering protein synthesis (amoxicillin and ciprofloxacin) resulted in the expression of eight HSPs of molecular weight ranging from 18 to 71 kD. The pre-treatment of short stress dosage showed endured overall tolerance of bacterium to lethal conditions, as evidenced by moderately enhanced total soluble intracellular protein content, better protein stabilization, comparatively over-expressed HSPs, and relatively enhanced cell survival. These findings hold an opportunity for developing novel approaches towards enhancing microbial resilience in a variety of conditions, including industrial bioprocessing, environmental remediation, and infectious disease management.

Diverse Fgfr1 signaling pathways and endocytic trafficking regulate mesoderm development.

The fibroblast growth factor (FGF) pathway is a conserved signaling pathway required for embryonic development. Activated FGF receptor 1 (FGFR1) drives multiple intracellular signaling cascade pathways, including ERK/MAPK and PI3K/AKT, collectively termed canonical signaling. However, unlike Fgfr1-null embryos, embryos containing hypomorphic mutations in Fgfr1 lacking the ability to activate canonical downstream signals are still able to develop to birth but exhibit severe defects in all mesodermal-derived tissues. The introduction of an additional signaling mutation further reduces the activity of Fgfr1, leading to earlier lethality, reduced somitogenesis, and more severe changes in transcriptional outputs. Genes involved in migration, ECM interaction, and phosphoinositol signaling were significantly downregulated, proteomic analysis identified changes in interactions with endocytic pathway components, and cells expressing mutant receptors show changes in endocytic trafficking. Together, we identified processes regulating early mesoderm development by mechanisms involving both canonical and noncanonical Fgfr1 pathways, including direct interaction with cell adhesion components and endocytic regulation.

Hippo and PI5P4K signaling intersect to control the transcriptional activation of YAP.

Phosphoinositides are essential signaling molecules. The PI5P4K family of phosphoinositide kinases and their substrates and products, PI5P and PI4,5P2, respectively, are emerging as intracellular metabolic and stress sensors. We performed an unbiased screen to investigate the signals that these kinases relay and the specific upstream regulators controlling this signaling node. We found that the core Hippo pathway kinases MST1/2 phosphorylated PI5P4Ks and inhibited their signaling in vitro and in cells. We further showed that PI5P4K activity regulated several Hippo- and YAP-related phenotypes, specifically decreasing the interaction between the key Hippo proteins MOB1 and LATS and stimulating the YAP-mediated genetic program governing epithelial-to-mesenchymal transition. Mechanistically, we showed that PI5P interacted with MOB1 and enhanced its interaction with LATS, thereby providing a signaling connection between the Hippo pathway and PI5P4Ks. These findings reveal how these two important evolutionarily conserved signaling pathways are integrated to regulate metazoan development and human disease.

Gonadal Transcriptome Sequencing Analysis Reveals the Candidate Sex-Related Genes and Signaling Pathways in the East Asian Common Octopus, Octopus sinensis.

The East Asian common octopus (Octopus sinensis) is an economically important species among cephalopods. This species exhibits a strict dioecious and allogamous reproductive strategy, along with a phenotypic sexual dimorphism, where the third right arm differentiates into hectocotylus in males. However, our understanding of the molecular mechanisms that underlie sex determination and differentiation in this species remains limited. In the present study, we surveyed gene-expression profiles in the immature male and female gonads of O. sinensis based on the RNA-seq, and a total of 47.83 Gb of high-quality data were generated. Compared with the testis, we identified 8302 differentially expressed genes (DEGs) in the ovary, of which 4459 genes were up-regulated and 3843 genes were down-regulated. Based on the GO enrichment, many GO terms related to sex differentiation were identified, such as sex differentiation (GO: 0007548), sexual reproduction (GO: 0019953) and male sex differentiation (GO: 0046661). A KEGG classification analysis identified three conserved signaling pathways that related to sex differentiation, including the Wnt signaling pathway, TGF-β signaling pathway and Notch signaling pathway. Additionally, 21 sex-related DEGs were selected, of which 13 DEGs were male-biased, including Dmrt1, Foxn5, Foxj1, Sox30, etc., and 8 DEGs were female-biased, including Sox14, Nanos3, β-tubulin, Suh, etc. Ten DEGs were used to verify the expression patterns in the testis and ovary using the RT-qPCR method, and the results showed that the expression level shown by RT-qPCR was consistent with that from the RNA-seq, which confirmed the reliability of the transcriptome data. The results presented in this study will not only contribute to our understanding of sex-formation mechanisms in O. sinensis but also provide the foundational information for further investigating the molecular mechanisms that underline its gonadal development and facilitate the sustainable development of octopus artificial breeding.

The Mms22-Rtt107 axis dampens the DNA damage checkpoint by reducing the stability of the Rad9 checkpoint mediator.

The DNA damage checkpoint is a highly conserved signaling pathway induced by genotoxin exposure or endogenous genome stress. It alters many cellular processes such as arresting the cell cycle progression and increasing DNA repair capacities. However, cells can downregulate the checkpoint after prolonged stress exposure to allow continued growth and alternative repair. Strategies that can dampen the DNA damage checkpoint are not well understood. Here, we report that budding yeast employs a pathway composed of the scaffold protein Rtt107, its binding partner Mms22, and an Mms22-associated ubiquitin ligase complex to downregulate the DNA damage checkpoint. Mechanistically, this pathway promotes the proteasomal degradation of a key checkpoint factor, Rad9. Furthermore, Rtt107 binding to Mms22 helps to enrich the ubiquitin ligase complex on chromatin and target the chromatin-bound form of Rad9. Finally, we provide evidence that the Rtt107-Mms22 axis operates in parallel with the Rtt107-Slx4 axis, which displaces Rad9 from chromatin. We thus propose that Rtt107 enables a bifurcated "anti-Rad9" strategy to optimally downregulate the DNA damage checkpoint.

StMAPKK5 responds to heat stress by regulating potato growth, photosynthesis, and antioxidant defenses.

As a conserved signaling pathway, mitogen-activated protein kinase (MAPK) cascade regulates cellular signaling in response to abiotic stress. High temperature may contribute to a significant decrease in economic yield. However, research into the expression patterns of StMAPKK family genes under high temperature is limited and lacks experimental validation regarding their role in supporting potato plant growth. To trigger heat stress responses, potato plants were grown at 35°C. qRT-PCR was conducted to analyze the expression pattern of StMAPKK family genes in potato plants. Plant with StMAPKK5 loss-of-function and gain-of-function were developed. Potato growth and morphological features were assessed through measures of plant height, dry weight, and fresh weight. The antioxidant ability of StMAPKK5 was indicated by antioxidant enzyme activity and H2O2 content. Cell membrane integrity and permeability were suggested by relative electrical conductivity (REC), and contents of MDA and proline. Photosynthetic capacity was next determined. Further, mRNA expression of heat stress-responsive genes and antioxidant enzyme genes was examined. In reaction to heat stress, the expression profiles of StMAPKK family genes were changed. The StMAPKK5 protein is located to the nucleus, cytoplasm and cytomembrane, playing a role in controlling the height and weight of potato plants under heat stress conditions. StMAPKK5 over-expression promoted photosynthesis and maintained cell membrane integrity, while inhibited transpiration and stomatal conductance under heat stress. Overexpression of StMAPKK5 triggered biochemical defenses in potato plant against heat stress, modulating the levels of H2O2, MDA and proline, as well as the antioxidant activities of CAT, SOD and POD. Overexpression of StMAPKK5 elicited genetic responses in potato plants to heat stress, affecting heat stress-responsive genes and genes encoding antioxidant enzymes. StMAPKK5 can improve the resilience of potato plants to heat stress-induced damage, offering a promising approach for engineering potatoes with enhanced adaptability to challenging heat stress conditions.

The interplay between hippo signaling and mitochondrial metabolism: Implications for cellular homeostasis and disease.

Mitochondria are the membrane-bound organelles producing energy for cellular metabolic processes. They orchestrate diverse cell signaling cascades regulating cellular homeostasis. This functional versatility may be attributed to their ability to regulate mitochondrial dynamics, biogenesis, and apoptosis. The Hippo pathway, a conserved signaling pathway, regulates various cellular processes, including mitochondrial functions. Through its effectors YAP and TAZ, the Hippo pathway regulates transcription factors and creates a seriatim process that mediates cellular metabolism, mitochondrial dynamics, and survival. Mitochondrial dynamics also potentially regulates Hippo signaling activation, indicating a bidirectional relationship between the two. This review outlines the interplay between the Hippo signaling components and the multifaceted role of mitochondria in cellular homeostasis under physiological and pathological conditions.

Genetically modified Wnt signaling data analysed using machine learning

Signaling pathways are vital for the development of organisms, orchestrating a plethora of biological processes. Pathways failing to function properly can cause numerous disorders, including neurodegenerative diseases and malignant tumors. Only a handful of highly conserved signaling pathways are able to specify cell fates during development. Wnt signaling is one of those and it is known to be involved in development, tissue maintenance and homeostasis. Wnt signalling’s importance is underlined by its conserved presence in almost all mammalian organisms. Mis-regulation of Wnt signaling can result in numerous diseases. We used previously published Rna-seq datasets, deriving from gene edited Hek293T cell lines. Those cells lines lack major components of the Wnt signalling pathway. Here, we are combining machine learning together with traditional statistical analysis methods, in order to analyze the RNA-seq data, but also to compare the robustness of machine learning versus traditional statistical analysis methods. In addition, enrichment analysis based both on machine learning and statistical analysis, is been introduced. Finally, we reveal numerous genes, which are potentially linked to diseases for the first time, utilizing our A.I. analysis.

Reduced insulin/IGF-1 signalling upregulates two anti-viral immune pathways, decreases viral load and increases survival under viral infection in C. elegans.

Reduced insulin/IGF-1 signalling (rIIS) improves survival across diverse taxa and there is a growing interest in its role in regulating immune function. Whilst rIIS can improve anti-bacterial resistance, the consequences for anti-viral immunity are yet to be systematically examined. Here, we show that rIIS in adult Caenorhabditis elegans increases the expression of key genes in two different anti-viral immunity pathways, whilst reducing viral load in old age, increasing survival and reducing rate-of-senescence under infection by naturally occurring positive-sense single-stranded RNA Orsay virus. We found that both drh-1 in the anti-viral RNA interference (RNAi) pathway and cde-1 in the terminal uridylation-based degradation of viral RNA pathway were upregulated in early adulthood under rIIS and increased anti-viral resistance was not associated with reproductive costs. Remarkably, rIIS increased anti-viral gene expression only in infected worms, potentially to curb the costs of constitutively upregulated immunity. RNA viruses are found across taxa from plants to mammals and we demonstrate a novel role for rIIS in regulating resistance to viral infection. We therefore highlight this evolutionarily conserved signalling pathway as a promising therapeutic target to improve anti-viral immunity.

Research progress of traditional Chinese medicine intervention for ulcerative colitis based on Notch1 signaling pathway

Ulcerative colitis(UC) is one of the common gastrointestinal diseases worldwide. In recent years, the incidence of UC has been continuously increasing, seriously threatening the health of people globally. It thus has become an urgent problem that needs to be addressed. There is research evidence that intestinal mucosal barrier dysfunction, including changes in intestinal stem cell secretion lineage, mucosal layer damage, disruption of cell junctions, overactive immune function, and imbalanced gut microbiota, is an important pathogenic factor and molecular basis of UC. The Notch signaling pathway is a highly conserved signaling pathway in eukaryotes during evolution, which transmits signals through cell connections between adjacent cells, affecting a series of processes such as cell proliferation, differentiation, development, migration, and apoptosis. Therefore, the Notch signaling pathway can regulate intestinal stem cells, CD4~+T cells, innate lymphoid cells(ILCs), macrophages(MØ), and intestinal microbiota and thus affect the chemical, physical, immune, and biological mucosal barriers of the intestinal mucosa. Its function is extensive and unique, different from those signaling pathways that mainly focus on anti-inflammatory and antioxidant stress. It can explain the therapeutic effects of traditional Chinese medicine from different perspectives. This article reviewed the role of the Notch1 signaling pathway in the pathogenesis of UC and the relevant literature on the targeted prevention and treatment of UC with traditional Chinese medicine, so as to provide new targets and theoretical support for further research on the effective prevention and treatment of UC.

Abstract 2837: Conservation of JAK-STAT signaling in canine lymphocytes responding to human IL-6, IL-7, and IL-1 alpha

Abstract Dogs share physiological similarities with humans, positioning them as valuable models for studying the efficacy and safety of drugs and their underlying mechanisms of action. The JAK-STAT pathway, a highly conserved signaling pathway across species, including humans and dogs, presents an opportunity to investigate the therapeutic potential of cytokines that utilize this pathway. In this study, we aimed to evaluate the functional activity of three canine cytokines on canine cells. To assess stimulation of the JAK/STAT pathway, we used a flow cytometry assay that measures phospho-STAT in activated canine or human lymphocytes in whole blood specimens. Testing of commercially available human and canine IL-6 proteins revealed that canine lymphocytes respond poorly to most canine IL-6 products, whereas all recombinant human IL-6 products stimulated STAT phosphorylation in canine lymphocytes, despite sharing low sequence similarity with canine IL-6. In human T cells, both canine IL-6 and human IL-6 stimulated STAT phosphorylation, demonstrating biological activity from the canine IL-6 products. Several JAK inhibitors inhibited cytokine-induced STAT phosphorylation in both canine and human CD4 T-cells, consistent with JAK inhibition, but targeting the IL-6 receptor with tocilizumab only blocked IL-6-induced STAT phosphorylation in human but not canine CD4 T-cells in whole blood. These findings demonstrate the potential of our assay system to assess cross-species cytokine reactivity, determine if JAK/STAT inhibitors used clinically might be useful in treating inflammatory conditions in dogs, and identify novel canine-specific inhibitors. Additionally, we explored the induction of IL-8 by human and canine IL-1 alpha in IL-1 alpha sensitive human cells. Human IL-1 alpha failed to stimulate a canine IL-1 alpha sensitive cell line, suggesting species-specific differences in IL-1 alpha activity. Furthermore, we discovered that canine IL-7 and human IL-7 are species-specific. In summary, this proof-of-concept study highlights the capability to assess the activation of STATs and pathway inhibition by JAK inhibitors in canine whole blood using flow cytometry. We confirmed that human IL-6 stimulates JAK/STAT signaling in canine CD4 T-cells. Our results also revealed significant differences in species cross-reactivity of human IL-6, IL-7, and IL-1 alpha, underscoring the importance of species-specific investigations. Leveraging the similarities and differences between canine and human cytokines targeting the JAK-STAT pathway can enhance drug development efforts and contribute to the advancement of safer and more effective therapies for both humans and pet dogs with similar diseases. This study was funded by NCI Contract No. 75N91019D00024. Citation Format: King Leung Fung, Melissa L. Breiner, James B. Mitchell, Ralph E. Parchment. Conservation of JAK-STAT signaling in canine lymphocytes responding to human IL-6, IL-7, and IL-1 alpha [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2837.

Hippo pathway in non-small cell lung cancer: mechanisms, potential targets, and biomarkers.

Lung cancer is the primary contributor to cancer-related deaths globally, and non-small cell lung cancer (NSCLC) constitutes around 85% of all lung cancer cases. Recently, the emergence of targeted therapy and immunotherapy revolutionized the treatment of NSCLC and greatly improved patients' survival. However, drug resistance is inevitable, and extensive research has demonstrated that the Hippo pathway plays a crucial role in the development of drug resistance in NSCLC. The Hippo pathway is a highly conserved signaling pathway that is essential for various biological processes, including organ development, maintenance of epithelial balance, tissue regeneration, wound healing, and immune regulation. This pathway exerts its effects through two key transcription factors, namely Yes-associated protein (YAP) and transcriptional co-activator PDZ-binding motif (TAZ). They regulate gene expression by interacting with the transcriptional-enhanced associate domain (TEAD) family. In recent years, this pathway has been extensively studied in NSCLC. The review summarizes a comprehensive overview of the involvement of this pathway in NSCLC, and discusses the mechanisms of drug resistance, potential targets, and biomarkers associated with this pathway in NSCLC.

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.