Bidirectional Signaling Research Articles

Mechano-gated iontronic piezomemristor for temporal-tactile neuromorphic plasticity

In bioneuronal systems, the synergistic interaction between mechanosensitive piezo channels and neuronal synapses can convert and transmit pressure signals into complex temporal plastic pulses with excitatory and inhibitory features. However, existing artificial tactile neuromorphic systems struggle to replicate the elaborate temporal plasticity observed between excitatory and inhibitory features in biological systems, which is critical for the biomimetic processing and memorizing of tactile information. Here we demonstrate a mechano-gated iontronic piezomemristor with programmable temporal-tactile plasticity. This system utilizes a bicontinuous phase-transition heterogel as a stiffness-governed iontronic mechanogate to achieve bidirectional piezoresistive signals, resulting in wide-span dynamic tactile sensing. By micro-integrating the mechanogate with an oscillatory iontronic memristor, it exhibits stiffness-induced bipolarized excitatory and inhibitory neuromorphics, thereby enabling the activation of temporal-tactile memory and learning functions (e.g., Bienenstock–Cooper–Munro and Hebbian learning rules). Owing to dynamic covalent bond network and iontronic features, reconfigurable tactile plasticity can be achieved. Importantly, bridging to bioneuronal interfaces, these systems possess the capacity to construct a biohybrid perception-actuation circuit. We anticipate that such temporal plastic piezomemristor devices for abiotic-biotic interfaces can serve as promising hardware systems for interfacing dynamic tactile behaviors into diverse neuromodulations.

The Integrin Receptors: From Discovery to Structure to Medicines.

Innate immune cells perform vital tasks in detecting, seeking, and eliminating invading pathogens, thus ensuring host survival. However, loss of function of these cells or their overactive response to tissue injury often causes serious ailments. It is, therefore, crucial to understand at a basic level how these cells function in health and disease. A major step toward this goal came from studies I conducted in the late 1970s investigating the cause of life-threatening bacterial infections in a pediatric patient. This work led us to trace this disease to the inability of the patient's neutrophils to seek and clear infections due to an inherited deficiency in leukocyte adhesion caused by the loss of a plasma membrane glycoprotein complex now known as CD11/CD18 or β2 integrins. I followed this work by determining the 3-dimensional structures of integrins. These studies provided the foundation for understanding the unique properties of integrins in mediating bidirectional cell adhesion signaling and enabled a structure-guided design of compounds to dial down overactive integrins in common disorders, including thromboinflammatory and autoimmune diseases.

Endogenous hydrogen peroxide positively regulates secretion of a gut-derived peptide in neuroendocrine potentiation of the oxidative stress response in Caenorhabditis elegans.

The gut-brain axis mediates bidirectional signaling between the intestine and the nervous system and is critical for organism-wide homeostasis. Here, we report the identification of a peptidergic endocrine circuit in which bidirectional signaling between neurons and the intestine potentiates the activation of the antioxidant response in Caenorhabditis elegans in the intestine. We identify an FMRF-amide-like peptide, FLP-2, whose release from the intestine is necessary and sufficient to activate the intestinal oxidative stress response by promoting the release of the antioxidant FLP-1 neuropeptide from neurons. FLP-2 secretion from the intestine is positively regulated by endogenous hydrogen peroxide (H2O2) produced in the mitochondrial matrix by sod-3/superoxide dismutase, and is negatively regulated by prdx-2/peroxiredoxin, which depletes H2O2 in both the mitochondria and cytosol. H2O2 promotes FLP-2 secretion through the DAG and calcium-dependent protein kinase C family member pkc-2 and by the SNAP25 family member aex-4 in the intestine. Together, our data demonstrate a role for intestinal H2O2 in promoting inter-tissue antioxidant signaling through regulated neuropeptide-like protein exocytosis in a gut-brain axis to activate the oxidative stress response.

Contributions of the Dachsous intracellular domain to Dachsous-Fat signaling.

The protocadherins Fat and Dachsous regulate organ growth, shape, patterning, and planar cell polarity. Although Dachsous and Fat have been described as ligand and receptor, respectively, in a signal transduction pathway, there is also evidence for bidirectional signaling. Here, we assess signaling downstream of Dachsous through analysis of its intracellular domain. Genomic deletions of conserved sequences within dachsous identified regions of the intracellular domain that contribute to Dachsous activity. Deletion of the A motif increased Dachsous protein levels and decreased wing size. Deletion of the D motif decreased Dachsous levels at cell membranes, increased wing size, and disrupted wing, leg and hindgut patterning and planar cell polarity. Co-immunoprecipitation experiments established that the D motif is necessary and sufficient for association of Dachsous with key partners, including Lowfat, Dachs, Spiny-legs, Fat and MyoID. Subdivision of the D motif identified distinct regions that preferentially contribute to different Dachsous activities. Our results identify motifs that are essential for Dachsous function and are consistent with the hypothesis that the key function of Dachsous is regulation of Fat.

CNSC-64. BEYOND THE LOCAL TUMOR MICROENVIRONMENT: CHARACTERIZING CHANGES TO NEURONAL ACTIVITY INDUCED BY PEDIATRIC HIGH-GRADE GLIOMA

Abstract Bidirectional electrochemical signaling between neurons and tumor cells is emerging as a critical regulator of pediatric high-grade glioma (HGG) pathology. Neuron-tumor interactions are known to induce local neuronal hyperactivity. However, recent work tracing the projections of these neuron-tumor networks revealed that HGG neuronal recruitment extends beyond the local tumor microenvironment (TME). These findings suggest that tumor-induced hyperexcitability may spread beyond the local TME and drive brain-wide circuit-level changes. To elucidate how non-tumor innervated brain regions are affected by TME hyperactivity we first characterized neuronal hyperactivity induced by a cortical patient-derived pediatric high-grade cell line in vitro on human iPSC-derived neurons. In vitro calcium imaging experiments demonstrated an increase in the number of calcium fluctuations in glioma co-cultured neurons. In parallel, multi-electrode recordings revealed increased population spiking activity and amplitude in neurons co-cultured with glioma cells. We then xenografted these HGG cells into the prefrontal cortex of mice and performed whole brain-clearing and cFos staining on tumor-bearing vs saline-injected control samples. As cFos is an immediate early gene activated by neuronal activity, we utilized the density of cFos expression as a readout-out of neuronal activation in our atlas-aligned segmented brain section analyses. We expectedly observed increased cFos expression within the ipsilateral primary and secondary motor region, which collectively comprise the local TME. Interestingly, we additionally observed elevated cFos in non-tumor bearing brain regions on both the ipsilateral and contralateral hemispheres, largely in layer 2/3 cortical neurons. These neurons form extensive cortico-cortical projections, and we coincidingly observed increased cFos expression in known cortical projection targets of the prefrontal xenograft location, such as somatosensory, visual, and retrosplenial cortices. Our findings suggest that tumor-induced neuronal hyperactivity extends beyond the local TME in a brain-wide manner and potentially follows established neuronal circuits, rendering these connected regions vulnerable to alterations in neuronal activity.

Integrin α2 in the microenvironment and the tumor compartment of digestive (gastrointestinal) cancers: emerging regulators and therapeutic opportunities.

Integrins are a family of cell surface membrane receptors and play a crucial role in facilitating bidirectional cell signaling. Integrin α2 (ITGA2) is expressed across a range of cell types, including epithelial cells, platelets, megakaryocytes, and fibroblasts, where it functions as a surface marker and it is implicated in the cell movements. The most recent findings have indicated that ITAG2 has the potential to function as a novel regulatory factor in cancer, responsible for driving tumorigenesis, inducing chemoresistance, regulating genomic instability and remodeling tumor microenvironment. Hence, we primarily focus on elucidating the biological function and mechanism of ITGA2 within the digestive tumor microenvironment, while highlighting its prospective utilization as a therapeutic target for cancer therapy.

Endothelial cell-cardiomyocyte cross-talk: understanding bidirectional paracrine signaling in cardiovascular homeostasis and disease.

To maintain homeostasis in the heart, endothelial cells and cardiomyocytes engage in dynamic cross-talk through paracrine signals that regulate both cardiac development and function. Here, we review the paracrine signals that endothelial cells release to regulate cardiomyocyte growth, hypertrophy and contractility, and the factors that cardiomyocytes release to influence angiogenesis and vascular tone. Dysregulated communication between these cell types can drive pathophysiology of disease, as seen in ischemia-reperfusion injury, diabetes, maladaptive hypertrophy, and chemotherapy-induced cardiotoxicity. Investingating the role of cross-talk is critical in developing an understanding of tissue homeostasis, regeneration, and disease pathogenesis, with the potential to identify novel targets for diagnostic and therapeutic purposes.

Statins have profound effects on the epicardial fat transcriptome

Abstract Background Epicardial adipose tissue (EAT) has direct contact with the myocardium, which enables a common microcirculation allowing bidirectional signaling between the tissues. It is possible that a change in the balance of protective and damaging mediators produced by EAT is a major driver for myocardial dysfunction. Notably, EAT volume and thickness associate with increased pro-inflammatory secretome and with coronary artery disease (CAD). Purpose This aim of this study was to analyze the total transcriptome in EAT and relate putative differences between patient groups to metabolic parameters as well as ongoing medications. Methods Between 2011 and 2016, 44 patients (mean age 68.0 years, 18.2% women) had a biopsy taken from the epicardial fat during coronoray by-pass surgery (CABG, n=36), or during elective aortic valvular replacement due to aortic stenosis (AVR, n=8). RNA from epicardial fat biopsis was extracted and sequenced. Differentially expressed genes were obtained by custom scripts that performed a negative binomial distribution test on effective counts. Multivariate regression analysis with orthogonal partial least-squares-discriminant analysis (OPLS-DA) was applied to extract and interpret the systematic variation in the resolved RNA sequencing profiles. To identify enrichment of biologically relevant functional gene sets, our data were entered in evidence-based network enrichment analysis (EviNet). Results The CABG surgery was performed approximately 7 days after an acute coronary event (75% acute MI), and 44% of them had previously known CAD. None of the AVR cases had significant CAD. At surgery, 97% of the CABG cases were prescribed statins, and 36% of them had statins alredy before the actual admission (long-term statin treatment). 63% of the AVR cases were on statins at admission. The OPLS analysis revealed only one medication with significant outcome, i.e., patients with long-term treatment with statins (n=18) versus patients without (n=26). Long-term statin treatment associated with down-regulated gene expression involved in beta-oxidation and triglyceride biosynthesis whereas gene expression involved in extracellular matrix organization were up-regulated. Gene expression involved in MHC class II presentation and interferon signalling were also reduced in patients with long-term treatment with statisn. A downregulation of genes in the interleukin- and complement cascade genes among CABG patient (versus AVR patients) without long-term statin treatment showed normal levels in statin pretreated patients. Conclusion Long-term statin treatment has a major influence on transcriptional regulation of genes involved in beta-oxidation, triglyceride biosynthesis, extracellular matrix composition, MHC class II presentation and interferon signalling in epicardial adipose tissue. These findings support important metabolic and immune effects of statins beyond the lipid-lowering function.

Canonical ligand-dependent and non-canonical ligand-independent EphA2 signaling in the eye lens of wild-type, knockout, and aging mice.

Disruption of Eph-ephrin bidirectional signaling leads to human congenital and age-related cataracts, but the mechanisms for these opacities in the eye lens remain unclear. Eph receptors bind to ephrin ligands on neighboring cells to induce canonical ligand-mediated signaling. The EphA2 receptor also signals non-canonically without ligand binding in cancerous cells, leading to epithelial-to-mesenchymal transition (EMT). We have previously shown that the receptor EphA2 and the ligand ephrin-A5 have diverse functions in maintaining lens transparency in mice. Loss of ephrin-A5 leads to anterior cataracts due to EMT. Surprisingly, both canonical and non-canonical EphA2 activation are present in normal wild-type lenses and in the ephrin-A5 knockout lenses. Canonical EphA2 signaling is localized exclusively to lens epithelial cells and does not change with age. Non-canonical EphA2 signaling is in both epithelial and fiber cells and increases significantly with age. We hypothesize that canonical ligand-dependent EphA2 signaling is required for the morphogenesis and organization of hexagonal equatorial epithelial cells while non-canonical ligand-independent EphA2 signaling is needed for complex membrane interdigitations that change during fiber cell differentiation and maturation. This is the first demonstration of non-canonical EphA2 activation in a non-cancerous tissue or cell and suggests a possible physiological function for ligand-independent EphA2 signaling.

Bidirectional signals generated by Siglec-7 and its crucial ligand tri-sialylated T to escape of cancer cells from immune surveillance

Siglec-7, an inhibitory receptor expressed on natural killer (NK) cells, recognizes sialic acid-containing glycans. However, the ligand glycan structures of Siglec-7 and its carrier proteins have not been comprehensively investigated. Here, we identified four sialyltransferases that are used for the synthesis of ligand glycans of Siglec-7 and two ligand O-glycan-carrier proteins, PODXL and MUC13, using a colon cancer line. Upon binding of these ligand glycans, Siglec-7-expressing immune cells showed reduced cytotoxic activity, whereas cancer cells expressing ligand glycans underwent signal activation, leading to enhanced invasion activity. To clarify the structure of the ligand glycan, podoplanin (PDPN) identified as a Siglec-7 ligand-carrier protein, was transfected into HEK293T cells using sialyltransferase cDNAs. Mass spectrometry of the products revealed a ligand glycan, tri-sialylated T antigen. These results indicate that Siglec-7 interaction with its ligand generates bidirectional signals in NK and cancer cells, leading to the efficient escape of cancers from host immune surveillance.

Heterogeneous Kinetics of Nanobubble Ultrasound Contrast Agent and Angiogenic Signaling in Head and Neck Cancer.

Recently developed nanobubble ultrasound contrast agents are a promising tool for imaging and drug delivery in tumors. To better understand their unusual kinetics, we implemented a novel pixel clustering analysis, which provides unique information by accounting for spatial heterogeneity. By combining ultrasound results with proteomics of the imaged tumors, we show that this analysis is highly predictive of protein expression and that specific types of nanobubble time-intensity curve are associated with upregulation of different metabolic pathways. We applied this method to study the effects of two proteins, EphB4 and ephrinB2, which control tumor angiogenesis through bidirectional juxtacrine signaling, in mouse models of head and neck cancer. We show that ephrinB2 expression by endothelial cells and EphB4 expression by cancer cells have similar effects on tumor vasculature, despite sometimes opposite effects on tumor growth. This implicates a cancer-cell-intrinsic effect of EphB4 forward signaling and not angiogenesis in EphB4's action as a tumor suppressor.

Endogenous hydrogen peroxide positively regulates secretion of a gut-derived peptide in neuroendocrine potentiation of the oxidative stress response in C. elegans.

The gut-brain axis mediates bidirectional signaling between the intestine and the nervous system and is critical for organism-wide homeostasis. Here we report the identification of a peptidergic endocrine circuit in which bidirectional signaling between neurons and the intestine potentiates the activation of the antioxidant response in C. elegans in the intestine. We identify a FMRF-amide-like peptide, FLP-2, whose release from the intestine is necessary and sufficient to activate the intestinal oxidative stress response by promoting the release of the antioxidant FLP-1 neuropeptide from neurons. FLP-2 secretion from the intestine is positively regulated by endogenous hydrogen peroxide (H2O2) produced in the mitochondrial matrix by sod-3/superoxide dismutase, and is negatively regulated by prdx-2/peroxiredoxin, which depletes H2O2 in both the mitochondria and cytosol. H2O2 promotes FLP-2 secretion through the DAG and calciumdependent protein kinase C family member pkc-2 and by the SNAP25 family member aex-4 in the intestine. Together, our data demonstrate a role for intestinal H2O2 in promoting inter-tissue antioxidant signaling through regulated neuropeptide-like protein exocytosis in a gut-brain axis to activate the oxidative stress response.

Bidirectional Peptide Translocation through Ultrasmall Solid-State Nanopores.

It is important to obtain the configuration of polypeptides and the sequence information on amino acids for understanding various life processes and many biological applications. Nanopores, as a newly developed single-molecule detection technology, exhibit unique advantages in real-time dynamics detection. Here, we designed a special peptide chain with 10 arginine in the head and achieved successful single-molecule detection by ultrasmall solid-state nanopores (2-3 nm). Unique bidirectional translocation signals were observed and explained under the framework of charge distribution of the peptide and interaction with the nanopore wall. Two natural peptide chains, histatin-5 and angiopep-2, were also explored by nanopore experiments to confirm our conjecture. Our designed peptide chain could realize multiple detections of the same peptide chain, offering possibilities for high-resolution peptide detection and fingerprinting by solid-state nanopores in the future.

GALNT6 promotes bladder cancer malignancy and immune escape by epithelial-mesenchymal transition and CD8+ T cells

Bladder cancer (BC) ranks as the sixth cancer in males and the ninth most common cancer worldwide. Conventional treatment modalities, including surgery, radiation, chemotherapy, and immunotherapy, have limited efficacy in certain advanced instances. The involvement of GALNT6-mediated aberrant O-glycosylation modification in several malignancies and immune evasion is a subject of speculation. However, its significance in BC has not been investigated. Through the integration of bioinformatics analysis and laboratory experimentation, we have successfully clarified the role of GALNT6 in BC. Our investigation revealed that GALNT6 has significant expression in BC, and its high expression level correlates with advanced stage and high grade, leading to poor overall survival. Moreover, both in vitro and in vivo experiments demonstrate a strong correlation between elevated levels of GALNT6 and tumor growth, migration, and invasion. Furthermore, there is a negative correlation between elevated GALNT6 levels, the extent of CD8+ T cell infiltration in the tumor microenvironment, and the prognosis of patients. Functional experiments have shown that the increased expression of GALNT6 could enhance the malignant characteristics of cancer cells by activating the epithelial-mesenchymal transition (EMT) pathway. In brief, this study examined the impact of GALNT6-mediated abnormal O-glycosylation on the occurrence and progression of bladder cancer and its influence on immune evasion. It also explored the possible molecular mechanism underlying the interaction between tumor cells and immune cells, as well as the bidirectional signaling involved. These findings offer a novel theoretical foundation rooted in glycobiology for the clinical application of immunotherapy in BC.

An analog switch circuit structure suitable for low-distortion transmission

Abstract A MOSFET analog switch circuit structure suitable for low-distortion bidirectional signal transmission is proposed. By introducing a “threshold voltage matching MOSFET” into the MOSFET switch driver circuit structure, the driving voltage corrected by the threshold voltage is generated by the driving circuit, eliminating the problem of poor conduction on-resistance flatness in traditional analog switch circuit structure due to MOSFET second-order effects and non-constant overdrive voltage. The circuit completed schematic and layout design based on the 0.13 μm BCD process. Simulation results show that the switch has bidirectional transmission capability, with a typical on-resistance value of 115 Ω. It achieves less than 5% on-resistance non-flatness under resistive loads ranging from 500 Ω to 1 KΩ, which is more than 50% improvement compared to traditional analog switch structures. Moreover, the on-resistance flatness is insensitive to changes in load and temperature.

Cooperative Control for Air-Ground Systems via Bidirectional Signal Connection in Complex Environment

Cooperative Control for Air-Ground Systems via Bidirectional Signal Connection in Complex Environment

Neuregulin1 Nuclear Signaling Influences Adult Neurogenesis and Regulates a Schizophrenia Susceptibility Gene Network within the Mouse Dentate Gyrus.

Neuregulin1 (Nrg1) signaling is critical for neuronal development and function from fate specification to synaptic plasticity. Type III Nrg1 is a synaptic protein which engages in bidirectional signaling with its receptor ErbB4. Forward signaling engages ErbB4 phosphorylation, whereas back signaling engages two known mechanisms: (1) local axonal PI3K-AKT signaling and (2) cleavage by γ-secretase resulting in cytosolic release of the intracellular domain (ICD), which can traffic to the nucleus (Bao et al., 2003; Hancock et al., 2008). To dissect the contribution of these alternate signaling strategies to neuronal development, we generated a transgenic mouse with a missense mutation (V321L) in the Nrg1 transmembrane domain that disrupts nuclear back signaling with minimal effects on forward signaling or local back signaling and was previously found to be associated with psychosis (Walss-Bass et al., 2006). We combined RNA sequencing, retroviral fate mapping of neural stem cells, behavioral analyses, and various network analyses of transcriptomic data to investigate the effect of disrupting Nrg1 nuclear back signaling in the dentate gyrus (DG) of male and female mice. The V321L mutation impairs nuclear translocation of the Nrg1 ICD and alters gene expression in the DG. V321L mice show reduced stem cell proliferation, altered cell cycle dynamics, fate specification defects, and dendritic dysmorphogenesis. Orthologs of known schizophrenia (SCZ)-susceptibility genes were dysregulated in the V321L DG. These genes coordinated a larger network with other dysregulated genes. Weighted gene correlation network analysis and protein interaction network analyses revealed striking similarity between DG transcriptomes of V321L mouse and humans with SCZ.

High-performance optical dialogue for power electronic system

High-accuracy signal and high-quality power transmissions play an essential role in power electronics systems. Nowadays, the severe electromagnetic interference (EMI) by the switching converter threatens the stable operation of conventional signal and power transmissions. To mitigate the effects of EMI, optical fiber is a better solution due to its unmatched isolation properties. Here, we perform a transmission configuration, named optical dialogue, based on a single fiber for simultaneous bidirectional analog optical signal (AOS) and analog optical power (AOP) transmission, to ensure EMI immunity. This optical dialogue transmission not only utilizes AOS to achieve high-accuracy signal transmission, but also utilizes AOP to achieve high-quality power transmission. We validate the proposed optical dialogue transmission using discrete off-the-shelf components, demonstrating the high frequency signal transmission and high efficiency power transmission. Our proposed optical dialogue transmission offers a high-performance optical solution for signal and power transmission, which is significant step forward in the development of more accurate, reliable, and safer power electronic systems.

Studying the Pulmonary Endothelium in Health and Disease: An Official American Thoracic Society Workshop Report.

Lung endothelium resides at the interface between the circulation and the underlying tissue, where it senses biochemical and mechanical properties of both the blood as it flows through the vascular circuit and the vessel wall. The endothelium performs the bidirectional signaling between the blood and tissue compartments that is necessary to maintain homeostasis while physically separating both, facilitating a tightly regulated exchange of water, solutes, cells, and signals. Disruption in endothelial function contributes to vascular disease, which can manifest in discrete vascular locations along the artery-to-capillary-to-vein axis. Although our understanding of mechanisms that contribute to endothelial cell injury and repair in acute and chronic vascular disease have advanced, pathophysiological mechanisms that underlie site-specific vascular disease remain incompletely understood. In an effort to improve the translatability of mechanistic studies of the endothelium, the American Thoracic Society convened a workshop to optimize rigor, reproducibility, and translation of discovery to advance our understanding of endothelial cell function in health and disease.

A Hippocampal-parietal Network for Reference Frame Coordination.

Navigating space and forming memories based on spatial experience are crucial for survival, including storing memories in an allocentric (map-like) framework and conversion into body-centered action. The hippocampus and parietal cortex (PC) comprise a network for coordinating these reference frames, though the mechanism remains unclear. We used a task requiring remembering previous spatial locations to make correct future action and observed that hippocampus can encode the allocentric place, while PC encodes upcoming actions and relays this to hippocampus. Transformation from location to action unfolds gradually, with 'Came From' signals diminishing and future action representations strengthening. PC sometimes encodes previous spatial locations in a route-based reference frame and conveys this to hippocampus. The signal for the future location appears first in PC, and then in hippocampus, in the form of an egocentric direction of future goal locations, suggesting egocentric encoding recently observed in hippocampus may originate in PC (or another "upstream" structure). Bidirectional signaling suggests a coordinated mechanism for integrating map-like, route-centered, and person-centered spatial reference frames at the network level during navigation.