Manipulation Of Signaling Research Articles

Tailored generation of insulin producing cells from canine mesenchymal stem cells derived from bone marrow and adipose tissue

The trend of regenerative therapy for diabetes in human and veterinary practices has conceptually been proven according to the Edmonton protocol and animal models. Establishing an alternative insulin-producing cell (IPC) resource for further clinical application is a challenging task. This study investigated IPC generation from two practical canine mesenchymal stem cells (cMSCs), canine bone marrow-derived MSCs (cBM-MSCs) and canine adipose-derived MSCs (cAD-MSCs). The results illustrated that cBM-MSCs and cAD-MSCs contain distinct pancreatic differentiation potential and require the tailor-made induction protocols. The effective generation of cBM-MSC-derived IPCs needs the integration of genetic and microenvironment manipulation using a hanging-drop culture of PDX1-transfected cBM-MSCs under a three-step pancreatic induction protocol. However, this protocol is resource- and time-consuming. Another study on cAD-MSC-derived IPC generation found that IPC colonies could be obtained by a low attachment culture under the three-step induction protocol. Further, Notch signaling inhibition during pancreatic endoderm/progenitor induction yielded IPC colonies through the trend of glucose-responsive C-peptide secretion. Thus, this study showed that IPCs could be obtained from cBM-MSCs and cAD-MSCs through different induction techniques. Also, further signaling manipulation studies should be conducted to maximize the protocol’s efficiency.

Topological states between inversion symmetric atomic insulators

One of the hallmarks of topological insulators is the correspondence between the value of its bulk topological invariant and the number of topologically protected edge modes observed in a finite-sized sample. This bulk-boundary correspondence has been well-tested for strong topological invariants, and forms the basis for all proposed technological applications of topology. Here, we report that a group of weak topological invariants, which depend only on the symmetries of the atomic lattice, also induces a particular type of bulk-boundary correspondence. It predicts the presence or absence of states localised at the interface between two inversion-symmetric band insulators with trivial values for their strong invariants, based on the space group representation of the bands on either side of the junction. We show that this corresponds with symmetry-based classifications of topological materials. The interface modes are protected by the combination of band topology and symmetry of the interface, and may be used for topological transport and signal manipulation in heterojunction-based devices.

Toll-Like Receptor-Based Strategies for Cancer Immunotherapy.

Toll-like receptors (TLRs) are expressed and play multiple functional roles in a variety of immune cell types involved in tumor immunity. There are plenty of data on the pharmacological targeting of TLR signaling using agonist molecules that boost the antitumor immune response. A recent body of research has also demonstrated promising strategies for improving the cell-based immunotherapy methods by inducing TLR signaling. These strategies include systemic administration of TLR antagonist along with immune cell transfer and also genetic engineering of the immune cells using TLR signaling components to improve the function of genetically engineered immune cells such as chimeric antigen receptor-modified T cells. Here, we explore the current status of the cancer immunotherapy approaches based on manipulation of TLR signaling to provide a perspective of the underlying rationales and potential clinical applications. Altogether, reviewed publications suggest that TLRs make a potential target for the immunotherapy of cancer.

Coherent Gate Operations in Hybrid Magnonics.

Electromagnonics-the hybridization of spin excitations and electromagnetic waves-has been recognized as a promising candidate for coherent information processing in recent years. Among its various implementations, the lack of available approaches for real-time manipulation on the system dynamics has become a common and urgent limitation. In this work, by introducing a fast and uniform modulation technique, we successfully demonstrate a series of benchmark coherent gate operations in hybrid magnonics, including semiclassical analogies of Landau-Zener transitions, Rabi oscillations, Ramsey interference, and controlled mode swap operations. Our approach lays the groundwork for dynamical manipulation of coherent signals in hybrid magnonics and can be generalized to a broad range of applications.

Nematode Signaling Molecules Are Extensively Metabolized by Animals, Plants, and Microorganisms.

Many bacterivorous and parasitic nematodes secrete signaling molecules called ascarosides that play a central role regulating their behavior and development. Combining stable-isotope labeling and mass spectrometry-based comparative metabolomics, here we show that ascarosides are taken up from the environment and metabolized by a wide range of phyla, including plants, fungi, bacteria, and mammals, as well as nematodes. In most tested eukaryotes and some bacteria, ascarosides are metabolized into derivatives with shortened fatty acid side chains, analogous to ascaroside biosynthesis in nematodes. In plants and C. elegans, labeled ascarosides were additionally integrated into larger, modular metabolites, and use of different ascaroside stereoisomers revealed the stereospecificity of their biosynthesis. The finding that nematodes extensively metabolize ascarosides taken up from the environment suggests that pheromone editing may play a role in conspecific and interspecific interactions. Moreover, our results indicate that plants, animals, and microorganisms may interact with associated nematodes via manipulation of ascaroside signaling.

Chemical control of receptor kinase signaling by rapamycin-induced dimerization

Membrane-localized leucine-rich repeat receptor kinases (LRR-RKs) sense diverse extracellular signals, and coordinate and specify cellular functions in plants. However, functional understanding and identification of the cellular signaling of most LRR-RKs remain a major challenge owing to their genetic redundancy, the lack of ligand information, and subtle phenotypes of LRR-RK overexpression. Here, we report an engineered rapamycin-inducible dimerization (RiD) receptor system that triggers a receptor-specific LRR-RK signaling independent of their cognate ligands or endogenous receptors. Using the RiD-receptors, we demonstrated that the rapamycin-mediated association of chimeric cytosolic kinase domains from the BRI1/BAK1 receptor/co-receptor, but not the BRI1/BRI1 or BAK1/BAK1 homodimer, is sufficient to activate downstream brassinosteroid signaling and physiological responses. Furthermore, we showed that the engineered RiD-FLS2/BAK1 could activate flagellin-22-mediated immune signaling and responses. Using the RiD system, we also identified the potential function of an unknown orphan receptor in immune signaling and revealed the differential activities of SERK co-receptors of LRR-RKs. Our results indicate that the RiD method can serve as a synthetic biology tool for precise temporal manipulation of LRR-RK signaling and for understanding LRR-RK biology.

IL-13Rα2 Regulates the IL-13/IFN-γ Balance during Innate Lymphoid Cell and Dendritic Cell Responses to Pox Viral Vector-Based Vaccination.

We have shown that manipulation of IL-13 and STAT6 signaling at the vaccination site can lead to different innate lymphoid cell (ILC)/dendritic cell (DC) recruitment, resulting in high avidity/poly-functional T cells and effective antibody differentiation. Here we show that permanent versus transient blockage of IL-13 and STAT6 at the vaccination site can lead to unique ILC-derived IL-13 and IFN-γ profiles, and differential IL-13Rα2, type I and II IL-4 receptor regulation on ILC. Specifically, STAT6−/− BALB/c mice given fowl pox virus (FPV) expressing HIV antigens induced elevated ST2/IL-33R+ ILC2-derived IL-13 and reduced NKp46+/− ILC1/ILC3-derived IFN-γ expression, whilst the opposite (reduced IL-13 and elevated IFN-γ expression) was observed during transient inhibition of STAT6 signaling in wild type BALB/c mice given FPV-HIV-IL-4R antagonist vaccination. Interestingly, disruption/inhibition of STAT6 signaling considerably impacted IL-13Rα2 expression by ST2/IL-33R+ ILC2 and NKp46− ILC1/ILC3, unlike direct IL-13 inhibition. Consistently with our previous findings, this further indicated that inhibition of STAT6 most likely promoted IL-13 regulation via IL-13Rα2. Moreover, the elevated ST2/IL-33R+ IL-13Rα2+ lung ILC2, 24 h post FPV-HIV-IL-4R antagonist vaccination was also suggestive of an autocrine regulation of ILC2-derived IL-13 and IL-13Rα2, under certain conditions. Knowing that IL-13 can modulate IFN-γ expression, the elevated expression of IFN-γR on lung ST2/IL-33R+ ILC2 provoked the notion that there could also be inter-regulation of lung ILC2-derived IL-13 and NKp46− ILC1/ILC3-derived IFN-γ via their respective receptors (IFN-γR and IL-13Rα2) at the lung mucosae early stages of vaccination. Intriguingly, under different IL-13 conditions differential regulation of IL-13/IL-13Rα2 on lung DC was also observed. Collectively these findings further substantiated that IL-13 is the master regulator of, not only DC, but also different ILC subsets at early stages of viral vector vaccination, and responsible for shaping the downstream adaptive immune outcomes. Thus, thoughtful selection of vaccine strategies/adjuvants that can manipulate IL-13Rα2, and STAT6 signaling at the ILC/DC level may prove useful in designing more efficacious vaccines against different/chronic pathogens.

Location Bias in cAMP Signaling and its effects on Parathyroid Hormone Receptor Biological Effectiveness

The parathyroid hormone (PTH) type 1 receptor (PTHR) is a class B G protein-coupled receptor (GPCR) that regulates mineral-ion, vitamin D, and bone homeostasis. PTH-induced activation of the PTHR results in both transient and sustained cAMP production, from the plasma membrane and endosomes, respectively; however, it is not clear whether the spatial (location) or temporal (duration) components of cAMP signaling result in distinct biological outcomes. To answer this question, we generated a location biased ligand via epimerization of a single amino acid in PTH (PTH7d). Here we show that PTH7d induces sustained cAMP responses exclusively from the plasma membrane that are very similar to those observed for PTH1-34 and a long-acting PTH analog (LA-PTH), two previously developed synthetic PTHR ligands that trigger sustained cAMP signaling from endosomes. PTH7d location bias occurs as a result of a unique active PTHR conformation that triggers sustained cAMP signaling exclusively from the plasma membrane due to impaired β-arrestin (βarr) coupling to the receptor. We further demonstrate the physiological importance of subcellular signaling location by the PTHR, as studies in mice show that sustained cAMP from endosomes is required for PTHR-mediated elevations in serum Ca2+ and active vitamin D levels. Additionally, assays in polarized epithelial cells reveal that endosomal cAMP signaling is a determinant for renal upregulation of the rate-limiting hydroxylase that catalyzes the formation of active vitamin D. Together, these results advance our understanding of how location of GPCR signaling can regulate particular biological functions and add new insights into drug design based upon spatiotemporal manipulation of GPCR signaling.

Memantine Alleviates Acute Lung Injury Via Inhibiting Macrophage Pyroptosis.

Acute lung injury (ALI) is caused by direct pulmonary insults and indirect systemic inflammatory responses that result from conditions such as sepsis and trauma. Alveolar macrophages are the main and critical leukocytes in the airspace, and through the synthesis and release of various inflammatory mediators critically influence the development of ALI following infection and non-infectious stimuli. There is increasing recognition that inflammation and cell death reciprocally affect each other, which forms an auto-amplification loop of these two factors, and in turn, exaggerates inflammation. Therefore, pharmacological manipulation of alveolar macrophage death signals may serve as a logical therapeutic strategy for ALI. In this study, we demonstrate that memantine, a N-methyl-D-aspartic acid receptor (NMDAR) antagonist, through suppressing Ca2+ influx and subsequent ASC oligomerization inhibits macrophage Nlrp3 inflammasome activation and pyroptosis, therefore, alleviates ALI in septic mice. This finding explores a novel application of memantine, an FDA already approved medication, in the treatment of ALI, which is currently lacking effective therapy.

ADCY2, ADCY5, and GRIA1 are the key genes of cAMP signaling pathway to participate in osteoporotic spinal fracture after the manipulation of Wnt signaling

IntroductionOsteoporotic spinal fracture, characterized by high morbidity and mortality, has become a health burden for the aging population. The inactivation of the Wnt signaling has been proved to promote osteoporotic fractures. Our study is to identify the key genes, miRNAs, and pathways that possibly lead to osteoporosis and osteoporotic spinal fracture after the aberrant activation or mutation of Wnt signaling pathway.Material and methodsImpute R package was used to screen out the differently expressed genes (DEGs) and differently expressed miRNAs in GEO datasets. STRING and Metascape were used to construct protein-protein interactions (PPI) network, gene ontology (GO) enrichment and pathway enrichment. The relative expression of ADCY2, ADCY5, and GRIA1 in bone tissues was measured by RT-qPCR.Results562 DEGs were screened out using Impute R package, and a PPI network involving the 562 DEGs was constructed using STRING and Metascape. GO enrichment and pathway enrichment showed that the 562 DEGs were associated with membrane protein-related signaling pathways. Then, 75 genes between the target genes of miR-18a-3p and 562 DEGs were overlapped using Venny 2.1.0. Finally, the cAMP signaling pathway was identified as the key pathway, whilst ADCY2, ADCY5, and GRIA1 were identified the key genes that possibly participate in osteoporotic spinal fracture after the manipulation of Wnt signaling pathway, which was further proved by their excessive downregulation in osteoporotic patients with spinal fracture.ConclusionsThe results demonstrated that ADCY2, ADCY5, and GRIA1 were the key genes to regulate the cAMP signaling pathway in osteoporotic spinal fracture after abnormal Wnt signaling.

Chemogenetic manipulation of astrocytic signaling in the basolateral amygdala reduces binge-like alcohol consumption in male mice.

Binge drinking is a common occurrence in the United States, but a high concentration of alcohol in the blood has been shown to have reinforcing and reciprocal effects on the neuroimmune system in both dependent and non-dependent scenarios. The first part of this study examined alcohol's effects on the astrocytic response in the central amygdala and basolateral amygdala (BLA) in a non-dependent model. C57BL/6J mice were given access to either ethanol, water, or sucrose during a "drinking in the dark" paradigm, and astrocyte number and astrogliosis were measured using immunohistochemistry. Results indicate that non-dependent consumption increased glial fibrillary acidic protein (GFAP) density but not the number of GFAP+ cells, suggesting that non-dependent ethanol is sufficient to elicit astrocyte activation. The second part of this study examined how astrocytes impacted behaviors and the neurochemistry related to alcohol using the chemogenetic tool, DREADDs (designer receptors exclusively activated by designer drugs). Transgenic GFAP-hM3Dq mice were administered clozapine N-oxide both peripherally, affecting the entire central nervous system (CNS), or directly into the BLA. In both instances, GFAP-Gq-signaling activation significantly reduced ethanol consumption and correlating blood ethanol concentrations. However, GFAP-Gq-DREADD activation throughout the CNS had more broad effects resulting in decreased locomotor activity and sucrose consumption. More targeted GFAP-Gq-signaling activation in the BLA only impacted ethanol consumption. Finally, a glutamate assay revealed that after GFAP-Gq-signaling activation glutamate concentrations in the amygdala were partially normalized to control levels. Altogether, these studies support the theory that astrocytes represent a viable target for alcohol use disorder therapies.

Stopping and Reversing Sound via Dynamic Dispersion Tuning in a Phononic Metamaterial

Slowing down, stopping, and reversing a signal is a core functionality for information processing. Here, we show that this functionality can be realized by tuning the dispersion of a periodic system through a dispersionless, or flat, band. Specifically, we propose a phononic metamaterial based on plate resonators, in which the phonon band dispersion can be modified from an acousticlike to an optical character by modulating a uniform prestress. The switch is enabled by the change in sign of an effective coupling between fundamental modes, which generically leads to a nearly dispersion-free band at the transition point. We demonstrate how adiabatic tuning of the band dispersion can immobilize and reverse the propagation of a sound pulse in simulations of a one-dimensional resonator chain. Our study relies on the basic principles of thin-plate elasticity independently of any specific material, making our results applicable across varied length scales and experimental platforms. More broadly, our approach could be replicated for signal manipulation in photonic metamaterials and electronic heterostructures.

Manipulation of EGFR-Induced Signaling for the Recruitment of Quiescent Neural Stem Cells in the Adult Mouse Forebrain.

The ventricular-subventricular zone (V-SVZ) is the principal neurogenic niche in the adult mammalian forebrain. Neural stem/progenitor cell (NSPC) activity within the V-SVZ is controlled by numerous of extrinsic factors, whose downstream effects on NSPC proliferation, survival and differentiation are transduced via a limited number of intracellular signaling pathways. Here, we investigated the relationship between age-related changes in NSPC output and activity of signaling pathways downstream of the epidermal growth factor receptor (EGFR), a major regulator of NSPC activity. Biochemical experiments indicated that age-related decline of NSPC activity in vivo is accompanied by selective deficits amongst various EGFR-induced signal pathways within the V-SVZ niche. Pharmacological loss-of-function signaling experiments with cultured NSPCs revealed both overlap and selectivity in the biological functions modulated by the EGFR-induced PI3K/AKT, MEK/ERK and mTOR signaling modules. Specifically, while all three modules promoted EGFR-mediated NSPC proliferation, only mTOR contributed to NSPC survival and only MEK/ERK repressed NSPC differentiation. Using a gain-of-function in vivo genetic approach, we electroporated a constitutively active EGFR construct into a subpopulation of quiescent, EGFR-negative neural stem cells (qNSCs); this ectopic activation of EGFR signaling enabled qNSCs to divide in 3-month-old early adult mice, but not in mice at middle-age or carrying familial Alzheimer disease mutations. Thus, (i) individual EGFR-induced signaling pathways have dissociable effects on NSPC proliferation, survival, and differentiation, (ii) activation of EGFR signaling is sufficient to stimulate qNSC cell cycle entry during early adulthood, and (iii) the proliferative effects of EGFR-induced signaling are dominantly overridden by anti-proliferative signals associated with aging and Alzheimer’s disease.

Circulator‐Free Brillouin Photonic Planar Circuit

AbstractOn‐chip stimulated Brillouin scattering (SBS) that results from enhanced light–sound interactions, has recently demonstrated great applicability and versatility for signal generation and manipulation. Progress toward realizing fully integrated Brillouin photonic circuits is promising; however, the control and routing of on‐chip optical waves requires non‐reciprocal elements such as circulators, which is challenging and adds complexity. Here, a circulator‐free Brillouin photonic planar waveguide circuit which eliminates the need for separate non‐reciprocal elements is demonstrated. Backward inter‐modal Brillouin scattering (BIBS) is used in a planar photonic integrated circuit, for the first time, to provide Brillouin processing capability in a multi‐modal waveguide, conveniently allowing for the separation of counter‐propagating pump and signal using passive integrated mode‐selective filters. Using an As2S3–Si hybrid multi‐modal photonic circuit, inter‐optical‐mode energy transfer with a Brillouin gain coefficient of 280 m−1W−1 is experimentally demonstrated, representing two orders of magnitude enhancement compared to conventional optical fibers. This on‐chip BIBS circuit allows for independent routing of pump and signal waves, showing resilience to the cross talk. The experimental demonstrations provide an important basis for achieving fully integrated Brillouin photonic circuits without requiring on‐chip circulators and fine spectral filtering, opening a new dimension for studying spatial‐dependent photon–phonon nonlinear dynamics.

From the Editor’s Desk...

From the Editor’s Desk...

Ciliary neuropeptidergic signaling dynamically regulates excitatory synapses in postnatal neocortical pyramidal neurons.

Primary cilia are compartmentalized sensory organelles present on the majority of neurons in the mammalian brain throughout adulthood. Recent evidence suggests that cilia regulate multiple aspects of neuronal development, including the maintenance of neuronal connectivity. However, whether ciliary signals can dynamically modulate postnatal circuit excitability is unknown. Here we show that acute cell-autonomous knockdown of ciliary signaling rapidly strengthens glutamatergic inputs onto cultured rat neocortical pyramidal neurons and increases spontaneous firing. This increased excitability occurs without changes to passive neuronal properties or intrinsic excitability. Further, the neuropeptide receptor somatostatin receptor 3 (SSTR3) is localized nearly exclusively to excitatory neuron cilia both in vivo and in culture, and pharmacological manipulation of SSTR3 signaling bidirectionally modulates excitatory synaptic inputs onto these neurons. Our results indicate that ciliary neuropeptidergic signaling dynamically modulates excitatory synapses and suggest that defects in this regulation may underlie a subset of behavioral and cognitive disorders associated with ciliopathies.

Exploiting Rational Assembly to Map Distinct Roles of Regulatory Cues during Autoimmune Therapy.

Autoimmune diseases like multiple sclerosis (MS), type 1 diabetes, and lupus occur when the immune system attacks host tissue. Immunotherapies that promote selective tolerance without suppressing normal immune function are of tremendous interest. Here, nanotechnology was used for rational assembly of peptides and modulatory immune cues into immune complexes. Complexes containing self-peptides and regulatory nucleic acids reverse established paralysis in a preclinical MS model. Importantly, mice responding to immunotherapy maintain healthy, antigen-specific B and T cell responses during a foreign antigen challenge. A therapeutic library isolating specific components reveals that regulatory nucleic acids suppress inflammatory genes in innate immune cells, while disease-matched peptide sequences control specificity of tolerance. Distinct gene expression profiles in cells and animals are associated with the immune signals administered in particulate and soluble forms, highlighting the impact of biophysical presentation of signals. This work provides insight into the rational manipulation of immune signaling to drive tolerance.

Regulation of ID4 In Vivo for Efficient Magnetothermal Therapy of Breast Cancer

AbstractMagnetic nanoparticles (MNPs) mediated magnetothermal therapy (MTT) has been proven as a promising modality for tumor treatment. However, the low therapeutic efficacy presents a major obstacle to its mass adoption. The Authors proposed to increase the therapeutic efficacy of MTT through the manipulation of magnetothermal‐related gene expression. ID4, a member of inhibitors of differentiation (ID) protein family, is identified to be downregulated in intracellular MTT (in‐MTT)‐treated MCF‐7 breast cancer cells according to the whole transcriptome sequencing. Interestingly, this occurrence is not observed in the exogenous MTT‐treated cells. More importantly, ID4‐silenced tumor cells show significantly decreased cell viability after in‐MTT, whereas ID4‐overexpressed cells exhibit more resistance to the MTT. This effect is also observed in other malignant breast cells derived from the human mammary gland. Furthermore, ID4 siRNA‐loaded superparamagnetic iron oxide nanoparticles are developed and delivered them to breast cancer xenografted nude mice. It is found that the synergistic combination of ID4 gene silencing and in‐MTT greatly inhibited the tumor growth and the efficacy of tumor volume inhibition is > 98%. This study, for the first time, provides the possibility of the sensitization of breast cancer cells for efficient MTT via molecular manipulation of cell signaling.

Light manipulation in three-dimensional photonic integrated circuits using vertically inserted metasurfaces

The hybrid integration of silicon metasurfaces, in forms of insertable thin-film elements, into a multilayer polymer waveguide platform is introduced. Owing to the wavelength comparable thickness and high efficiency of the dielectric metasurfaces, the designed devices can manipulate beams in a relatively short distance with low insertion loss. They can also realize functions critical for three-dimensional (3D) photonic integrated circuits (PICs) that are difficult for conventional micro-optic elements. The designs of several key photonic components are presented in this work as proof-of-concept. Specifically, three applications based on the proposed platform are demonstrated numerically, including on-chip beam collimation, spatial mode (de)multiplexing, and focusing vertical out-coupling. These functionalities can be realized within a short propagating length. This work presents a theoretical study on the design principles and performances of the proposed devices, which can be implemented by adopting the existed technology of inserting classic thin-film elements into photonic chips in the near future. The results suggest a novel and general path for optical signal manipulations within the 3D photonic chips and may prove useful in the design of transceiver devices for optical communication, optical sensor chips, compact chips for optical computation, etc.

Guided Mid‐IR and Near‐IR Light within a Hybrid Hyperbolic‐Material/Silicon Waveguide Heterostructure

Silicon waveguides have enabled large-scale manipulation and processing of near-infrared optical signals on chip. Yet, expanding the bandwidth of guided waves to other frequencies will further increase the functionality of silicon as a photonics platform. Frequency multiplexing by integrating additional architectures is one approach to the problem, but this is challenging to design and integrate within the existing form factor due to scaling with the free-space wavelength. This paper demonstrates that a hexagonal boron nitride (hBN)/silicon hybrid waveguide can simultaneously enable dual-band operation at both mid-infrared (6.5-7.0µm) and telecom (1.55µm) frequencies, respectively. The device is realized via the lithography-free transfer of hBN onto a silicon waveguide, maintaining near-infrared operation. In addition, mid-infrared waveguiding of the hyperbolic phonon polaritons (HPhPs) supported in hBN is induced by the index contrast between the silicon waveguide and the surrounding air underneath the hBN, thereby eliminating the need for deleterious etching of the hyperbolic medium. The behavior of HPhP waveguiding in both straight and curved trajectories is validated within an analytical waveguide theoretical framework. This exemplifies a generalizable approach based on integrating hyperbolic media with silicon photonics for realizing frequency multiplexing in on-chip photonic systems.