Feedforward Circuitry Research Articles

DAGLβ is the principal synthesizing enzyme of 2-AG and promotes aggressive phenotype of intrahepatic cholangiocarcinoma via AP-1/DAGLβ/miR4516 feedforward circuitry.

The endocannabinoid system (ECS) is dysregulated in various liver diseases. Previously, we had shown that the major endocannabinoid 2-arachidonoyl glycerol (2-AG) promoted tumorigenesis of intrahepatic cholangiocarcinoma (ICC). However, biosynthesis regulation and clinical significance of 2-AG remain elusive. In the present study, we quantified 2-AG by gas chromatography/mass spectrometry (GC/MS) and showed that 2-AG was enriched in patients with ICC samples as well as in thioacetamide-induced orthotopic rat ICC model. Moreover, we found that diacylglycerol lipase β (DAGLβ) was the principal synthesizing enzyme of 2-AG that significantly upregulated in ICC. DAGLβ promoted tumorigenesis and metastasis of ICC in vitro and in vivo and positively correlated with clinical stage and poor survival in patients with ICC. Functional studies showed that activator protein-1 (AP-1; heterodimers of c-Jun and FRA1) directly bound to the promoter and regulated transcription of DAGLβ, which can be enhanced by lipopolysaccharide (LPS). miR-4516 was identified as the tumor-suppressing miRNA of ICC that can be significantly suppressed by LPS, 2-AG, or ectopic DAGLβ overexpression. FRA1 and STAT3 were targets of miR-4516 and overexpression of miRNA-4516 significantly suppressed expression of FRA1, SATA3, and DAGLβ. Expression of miRNA-4516 was negatively correlated with FRA1, SATA3, and DAGLβ in patients with ICC samples. Our findings identify DAGLβ as the principal synthesizing enzyme of 2-AG in ICC. DAGLβ promotes oncogenesis and metastasis of ICC and is transcriptionally regulated by a novel AP-1/DAGLβ/miR4516 feedforward circuitry.NEW & NOTEWORTHY Dysregulated endocannabinoid system (ECS) had been confirmed in various liver diseases. However, regulation and function of 2-arachidonoyl glycerol (2-AG) and diacylglycerol lipase β (DAGLβ) in intrahepatic cholangiocarcinoma (ICC) remain to be elucidated. Here, we demonstrated that 2-AG was enriched in ICC, and DAGLβ was the principal synthesizing enzyme of 2-AG in ICC. DAGLβ promotes tumorigenesis and metastasis in ICC via a novel activator protein-1 (AP-1)/DAGLβ/miR4516 feedforward circuitry.

A novel lncRNA PTTG3P/miR-132/212-3p/FoxM1 feedback loop facilitates tumorigenesis and metastasis of pancreatic cancer

Pseudogene pituitary tumor-transforming 3 (PTTG3P) is emerging as a key player in the development and progression of cancer. However, the biological role and clinical significance of PTTG3P in pancreatic ductal adenocarcinoma (PDAC) remain unclear. Here, we found that PTTG3P was significantly upregulated in PDAC tissues. Elevated PTTG3P expression correlated with larger tumor size and worse differentiation, and reduced overall survival. Bioinformatics and experimental evidence revealed that PTTG3P promoted malignant phenotypes and FoxM1 signaling pathway in PDAC cells. Mechanistically, PTTG3P functions as a microRNA sponge to positively regulate the expression of FoxM1 through sponging miR-132/212-3p. Moreover, it showed that FoxM1 transcriptionally activated PTTG3P expression, thus forming a feedback loop to promote the aggressiveness of PDAC cells. Taken together, our findings suggest that PTTG3P promotes PDAC progression through PTTG3P/miR-132/212-3p/FoxM1 feedforward circuitry and it may serve as a promising diagnostic marker or target for treatment in PDAC patients.

Extracellular GABA waves regulate coincidence detection in excitatory circuits.

Key points Rapid changes in neuronal network activity trigger widespread waves of extracellular GABA in hippocampal neuropil.Elevations of extracellular GABA narrow the coincidence detection window for excitatory inputs to CA1 pyramidal cells.GABA transporters control the effect of extracellular GABA on coincidence detection.Small changes in the kinetics of dendritic excitatory currents amplify when reaching the soma. Coincidence detection of excitatory inputs by principal neurons underpins the rules of signal integration and Hebbian plasticity in the brain. In the hippocampal circuitry, detection fidelity is thought to depend on the GABAergic synaptic input through a feedforward inhibitory circuit also involving the hyperpolarisation‐activated Ih current. However, afferent connections often bypass feedforward circuitry, suggesting that a different GABAergic mechanism might control coincidence detection in such cases. To test whether fluctuations in the extracellular GABA concentration [GABA] could play a regulatory role here, we use a GABA 'sniffer' patch in acute hippocampal slices of the rat and document strong dependence of [GABA] on network activity. We find that blocking GABAergic signalling strongly widens the coincidence detection window of direct excitatory inputs to pyramidal cells whereas increasing [GABA] through GABA uptake blockade shortens it. The underlying mechanism involves membrane‐shunting tonic GABAA receptor current; it does not have to rely on Ih but depends strongly on the neuronal GABA transporter GAT‐1. We use dendrite‐soma dual patch‐clamp recordings to show that the strong effect of membrane shunting on coincidence detection relies on nonlinear amplification of changes in the decay of dendritic synaptic currents when they reach the soma. Our results suggest that, by dynamically regulating extracellular GABA, brain network activity can optimise signal integration rules in local excitatory circuits.

A NOTCH feed-forward loop drives reprogramming from adrenergic to mesenchymal state in neuroblastoma

Transition between differentiation states in development occurs swift but the mechanisms leading to epigenetic and transcriptional reprogramming are poorly understood. The pediatric cancer neuroblastoma includes adrenergic (ADRN) and mesenchymal (MES) tumor cell types, which differ in phenotype, super-enhancers (SEs) and core regulatory circuitries. These cell types can spontaneously interconvert, but the mechanism remains largely unknown. Here, we unravel how a NOTCH3 intracellular domain reprogrammed the ADRN transcriptional landscape towards a MES state. A transcriptional feed-forward circuitry of NOTCH-family transcription factors amplifies the NOTCH signaling levels, explaining the swift transition between two semi-stable cellular states. This transition induces genome-wide remodeling of the H3K27ac landscape and a switch from ADRN SEs to MES SEs. Once established, the NOTCH feed-forward loop maintains the induced MES state. In vivo reprogramming of ADRN cells shows that MES and ADRN cells are equally oncogenic. Our results elucidate a swift transdifferentiation between two semi-stable epigenetic cellular states.

Abstract 995: Tumor-stroma IL-1β-IRAK4 feedforward circuitry drives tumor fibrosis, chemo-resistance and is associated with poor prognosis in pancreatic cancer

Abstract Targeting the desmoplastic stroma of pancreatic ductal adenocarcinoma (PDAC) holds promise to augment the effect of chemotherapy, but so far success remains limited in the clinic. Furthermore, preclinical mouse models suggest that near-depletion of cancer-associated fibroblasts (CAFs) carries a risk of accelerating PDAC progression. These concerns underscore the need to concurrently target the key signaling mechanisms that drive the malignant attributes of both CAFs and PDAC cells. We previously reported that inhibition of Interleukin-1 Receptor Associated Kinase 4 (IRAK4) suppresses NF-kB activity and promotes chemotherapy response in PDAC cells. In this study, we show that CAFs in PDAC tumors robustly express activated IRAK4 and NF-kb. The role of IRAK4 and NF-kB in PDAC CAFs has not been reported, and should be clarified before advancing IRAK4 inhibitors to the clinic. Using shRNAs and small molecular inhibitors, we found that IRAK4 is a key driver of NF-kB activity in CAFs. We showed that CAFs utilizes IRAK4 to drive tumor fibrosis, support PDAC cells proliferation, survival and chemo-resistance in vitro and in vivo. From cytokine array analysis of CAFs and microarray analysis of PDAC cells, we identified IL-1b as a key cytokine that activates IRAK4 in CAFs. Targeting IRAK4 or IL-1b renders PDAC tumors less fibrotic and more sensitive to gemcitabine in vivo.Moreover, high IL-1b expression by immunohistochemistry in PDAC samples is strongly associated with poor overall survival. Together, our studies established a tumor-stroma IL-1b-IRAK4 feedforward circuitry that can be therapeutically disrupted to render chemotherapy more effective in PDAC. Citation Format: Daoxiang Zhang, Lin Li, Hongmei Jiang, Andrea Wang-Gillam, Jinsheng Yu, Richard Head, Jingxia Liu, Marianna B Ruzinova, Kian-Huat Lim. Tumor-stroma IL-1β-IRAK4 feedforward circuitry drives tumor fibrosis, chemo-resistance and is associated with poor prognosis in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 995.

Decoding Signal Processing at the Single-Cell Level.

The feedforward circuitry regulating ERK-dependent early response genes acts as a signal integrator rather than a signal persistence detector.

G Protein-Coupled Receptor Signaling Networks from a Systems Perspective.

The signal-transduction network of a mammalian cell integrates internal and external cues to initiate adaptive responses. Among the cell-surface receptors are the G protein-coupled receptors (GPCRs), which have remarkable signal-integrating capabilities. Binding of extracellular signals stabilizes intracellular-domain conformations that selectively activate intracellular proteins. Hereby, multiple signaling routes are activated simultaneously to degrees that are signal-combination dependent. Systems-biology studies indicate that signaling networks have emergent processing capabilities that go far beyond those of single proteins. Such networks are spatiotemporally organized and capable of gradual, oscillatory, all-or-none, and subpopulation-generating responses. Protein-protein interactions, generating feedback and feedforward circuitry, are generally required for these spatiotemporal phenomena. Understanding of information processing by signaling networks therefore requires network theories in addition to biochemical and biophysical concepts. Here we review some of the key signaling systems behaviors that have been discovered recurrently across signaling networks. We emphasize the role of GPCRs, so far underappreciated receptors in systems-biology research.

The inhibitory microcircuit of the substantia nigra provides feedback gain control of the basal ganglia output.

Dysfunction of the basal ganglia produces severe deficits in the timing, initiation, and vigor of movement. These diverse impairments suggest a control system gone awry. In engineered systems, feedback is critical for control. By contrast, models of the basal ganglia highlight feedforward circuitry and ignore intrinsic feedback circuits. In this study, we show that feedback via axon collaterals of substantia nigra projection neurons control the gain of the basal ganglia output. Through a combination of physiology, optogenetics, anatomy, and circuit mapping, we elaborate a general circuit mechanism for gain control in a microcircuit lacking interneurons. Our data suggest that diverse tonic firing rates, weak unitary connections and a spatially diffuse collateral circuit with distinct topography and kinetics from feedforward input is sufficient to implement divisive feedback inhibition. The importance of feedback for engineered systems implies that the intranigral microcircuit, despite its absence from canonical models, could be essential to basal ganglia function. DOI: http://dx.doi.org/10.7554/eLife.02397.001.

Subtractive, divisive and non-monotonic gain control in feedforward nets linearized by noise and delays.

The control of input-to-output mappings, or gain control, is one of the main strategies used by neural networks for the processing and gating of information. Using a spiking neural network model, we studied the gain control induced by a form of inhibitory feedforward circuitry—also known as “open-loop feedback”—, which has been experimentally observed in a cerebellum-like structure in weakly electric fish. We found, both analytically and numerically, that this network displays three different regimes of gain control: subtractive, divisive, and non-monotonic. Subtractive gain control was obtained when noise is very low in the network. Also, it was possible to change from divisive to non-monotonic gain control by simply modulating the strength of the feedforward inhibition, which may be achieved via long-term synaptic plasticity. The particular case of divisive gain control has been previously observed in vivo in weakly electric fish. These gain control regimes were robust to the presence of temporal delays in the inhibitory feedforward pathway, which were found to linearize the input-to-output mappings (or f-I curves) via a novel variability-increasing mechanism. Our findings highlight the feedforward-induced gain control analyzed here as a highly versatile mechanism of information gating in the brain.

The Glucocorticoid Receptor and KLF15 Regulate Gene Expression Dynamics and Integrate Signals through Feed-Forward Circuitry

The glucocorticoid receptor (GR) regulates adaptive transcriptional programs that alter metabolism in response to stress. Network properties that allow GR to tune gene expression to match specific physiologic demands are poorly understood. We analyzed the transcriptional consequences of GR activation in murine lungs deficient for KLF15, a transcriptional regulator of amino acid metabolism that is induced by glucocorticoids and fasting. Approximately 7% of glucocorticoid-regulated genes had altered expression in Klf15-knockdown (Klf15(-/-)) mice. KLF15 formed coherent and incoherent feed-forward circuits with GR that correlated with the expression dynamics of the glucocorticoid response. Coherent feed-forward gene regulation by GR and KLF15 was characterized by combinatorial activation of linked GR-KLF15 regulatory elements by both factors and increased GR occupancy, while expression of KLF15 reduced GR occupancy at the incoherent target, MT2A. Serum deprivation, which increased KLF15 expression in a GR-independent manner in vitro, enhanced glucocorticoid-mediated induction of feed-forward targets of GR and KLF15, such as the loci for the amino acid-metabolizing enzymes proline dehydrogenase and alpha-aminoadipic semialdehyde synthase. Our results establish feed-forward architecture as an organizational principle for the GR network and provide a novel mechanism through which GR integrates signals and regulates expression dynamics.

Molecular Regulation of Antibiotic Biosynthesis in Streptomyces

Streptomycetes are the most abundant source of antibiotics. Typically, each species produces several antibiotics, with the profile being species specific. Streptomyces coelicolor, the model species, produces at least five different antibiotics. We review the regulation of antibiotic biosynthesis in S. coelicolor and other, nonmodel streptomycetes in the light of recent studies. The biosynthesis of each antibiotic is specified by a large gene cluster, usually including regulatory genes (cluster-situated regulators [CSRs]). These are the main point of connection with a plethora of generally conserved regulatory systems that monitor the organism's physiology, developmental state, population density, and environment to determine the onset and level of production of each antibiotic. Some CSRs may also be sensitive to the levels of different kinds of ligands, including products of the pathway itself, products of other antibiotic pathways in the same organism, and specialized regulatory small molecules such as gamma-butyrolactones. These interactions can result in self-reinforcing feed-forward circuitry and complex cross talk between pathways. The physiological signals and regulatory mechanisms may be of practical importance for the activation of the many cryptic secondary metabolic gene cluster pathways revealed by recent sequencing of numerous Streptomyces genomes.

A sparse coding model with imperfect feed-forward circuitry

Event Abstract Back to Event A sparse coding model with imperfect feed-forward circuitry Although simple receptive fields are approximately outlined by a small set of highly specific geniculocortical afferents (Reid and Alonso, 1995, Alonso et al. 2001), the feed-forward wiring is often only an imperfect match of the receptive field, suggesting that neural response properties are also shaped by intracortical processing. While existing sparse coding network models successfully explain the emergence of simple receptive fields, they predict that receptive fields are shaped almost exclusively by feed-forward connections, e.g., (Olshausen and Field, 1996, Rehn and Sommer, 2007). Here we ask if models principled by efficient coding can reproduce response properties from real neurons even though the feedforward weights in the model match the measured receptive fields only imperfectly. We present a novel neural network model for sparse coding based on compressed sensing, a computational principle recently developed in engineering for data compression (Candès and Romberg, 2006). The model exhibits smooth and more realistic simple cell receptive fields than its "imperfect" feed-forward connections would predict, compare the two panel of Fig. 1 of the supplement. Thus, the model demonstrates that efficient coding schemes exist in which feedback connections are critical for shaping the receptive fields. We use simulation experiments with our model to characterize deviations between feed-forward circuitry and measured receptive fields.

A mathematical characterization and analysis of feedforward circuit for CDMA applications

Feedforward is known to be one of the best methods for power amplifier linearization due to its superior linearization performance albeit with relatively poor power efficiency. Here we present the derived closed-form expressions, which relate the main channel power and distortion products at the output of a simple feedforward circuitry to the circuit parameters. Consequently, a mathematical handy tool is achieved toward specifying the circuit parameters rapidly for optimum linearity performance and efficiency. The main and error amplifiers used in the feedforward are assumed to have a third-order AM/AM nonlinearity. The derived expressions are verified by simulation. The conditions for the validity of the model choice are highlighted. For the matched and lossless case, a compact relationship is obtained, which clearly demonstrates the tradeoff between nonlinearities of main and error amplifier for a given system linearity and output power. Delay mismatch is also included in the analysis.

Homeodomain factor Nkx2-5 in heart development and disease.

The mammalian heart is a highly modified muscularvessel (Fig.1). During embryonic development, it is thefirst organ to form, and contraction begins as soon as aprimitive tubular structure and vasculature are in evidence. The subsequent morphogenetic progressions thatgive rise to the four-chambered organ are the product ofboth embryonic and local patterning systems (Harvey2002b) and a feed-forward circuitry that links form withfunction (Sedmera et al. 1999). The result is a structure inwhich flow into and between chambers occurs in an elegant and efficient sling-like fashion (Kilner et al. 2000)...

TGF-beta superfamily signaling and left-right asymmetry.

Despite an outwardly bilaterally symmetrical appearance, most internal organs of vertebrates display considerable left-right (LR) asymmetry in their anatomy and physiology. The orientation of LR asymmetry with respect to the dorsoventral and anteroposterior body axes is invariant such that fewer than 1 in 10,000 individuals exhibit organ reversals. The stereotypic orientation of LR asymmetry is ensured by distinct left- and right-side signal transduction pathways that are initiated by divergent members of the transforming growth factor-beta (TGF-beta) superfamily of secreted proteins. During early embryogenesis, the TGF-beta-like protein Nodal (or a Nodal-related ortholog) is expressed by the left lateral plate mesoderm and provides essential LR cues to the developing organs. In chick embryos at least, bone morphogenetic protein (BMP) signaling is active on the right side of the embryo and must be inhibited on the left in order for Nodal to be expressed. Thus, at a key point in the determination of LR asymmetry, left-sided signaling is mediated by the transcription factors Smad2 and Smad3 (regulated by Nodal), whereas signaling on the right depends on Smad1 and Smad5 (which are regulated by BMP). This review summarizes the considerable progress that has been made in recent years in understanding the complex network of feedback and feedforward circuitry that regulates both the left- and right-sided pathways. Also discussed is the problem of how signal transduction mediated by the Smad proteins can pattern LR asymmetry without interfering with coincident dorsoventral patterning, which relies on the same Smad proteins.

Development of a hybrid PLC‐based control system applied to a monitored fermentation process

It is well known that reliable and accurate control during biochemical processes is important, but sequential and continuous treatment requirements of bioreactors make this task difficult to achieve. In this paper, we report the development of a supervisory PLC-based control system that ensures complete bioreactor operation. Sequential phases founded during sterilization are accomplished by the programmable controller, while continuous regulation of main parameters (pH, temperature, and pressure) is achieved by control units using a PID (Proportional, Integral, Derivative) algorithm with feed-forward circuitry and auto-tuning feature. Finally, an operator graphic interface was developed in FIX MMI™'s intellution ® software, the man-machine interface provides supervisory and data acquisition functions. This system was successfully tested in E. coli and termophiles cultures; satisfactory control precisions of ±0.5°C, ±0.001 bar and ±0.1 pH unit were observed. © 1999 John Wiley & Sons, Inc. Lab Robotics and Automation 11: 197–206, 1999

Active noise and vibration cancellation system

An active noise and vibration control system (20) for cancellation of noise or vibration. The system (20) provides a system whereby the adaptation path and feedforward path are implemented in separate hardware. As a result, the computational burden on the digital signal processor (DSP) (28) is reduced allowing the DSP (28) to handle multiple inputs (22), error sensors (34), and transducers (32). In one embodiment, the processing of the input signal from sensor (22) takes place in a waveform generator (24) comprising a phase-locked loop, a frequency divider, a shift register, and at least one switched capacitor filter. In another embodiment the input signal processing takes place in separate feedforward circuitry including a field programmable gate array (64).

Sequence Manipulation Using Parallel Mapping Networks

We describe a parallel mapping matrix that performs several types of sequence manipulations that are the building blocks of well-known phonological processes. Our results indicate that human phonological behavior can by modeled by a highly constrained connectionist architecture, one that uses purely feedforward circuitry and imposes tight limits on depth of derivations.

Feed‐forward inhibitory potentials and excitatory interactions in guinea‐pig hippocampal pyramidal cells.

1. The patterns of inhibition in the CA1 region of the rat hippocampus were evaluated by focal proximal and distal stratum radiatum stimulation, during intracellular recording. The characteristics of isolated inhibitory responses and the interactions of excitatory and inhibitory potentials were analysed. 2. The amplitude of minimal inhibitory postsynaptic potentials (IPSPs) evoked by both proximal and distal stimulation averaged -0.51 +/- 0.24 mV (mean +/- S.D.; n = 32). These responses demonstrated little variability from trial to trial and showed no net trends in amplitude at a stimulation rate of 1 Hz. 3. Minimal IPSPs demonstrated a short latency to onset (2.90 +/- 1.58 ms for proximal and 3.64 +/- 1.39 ms for distal) at stimulation levels which were insufficient to evoke an extracellular field potential. Thus, minimal IPSPs were recruited through feed-forward circuitry, based on the rapid onset and the lack of activation of recurrent collaterals. 4. The minimal IPSPs showed a similar 10-90% rise time for proximal and distal responses. However, the half-width and decay time constant (from the peak) were more prolonged for the distal stimulation, indicating that a late IPSP component was evoked primarily by the distal stimulation. This late component was not observed in isolation at low stimulation intensities. 5. The conductance transient underlying the IPSPs was calculated using a neurone cable model. The proximal IPSP responses were simulated by an alpha input function (at the soma) with a peak conductance in the range of 2.5-45 nS (alpha = 1.75; reversal potential -1.0 to -10 mV). The distal IPSP shape was only partially reproduced by a longer single transient (alpha = 1.25), suggesting the presence of a second, slower component. However, insufficient data on this slower component precluded a more exact simulation of the distal IPSP response. 6. Analysis of interactions between minimal excitatory postsynaptic potentials (EPSPs) and IPSPs showed that often the rising as well as the falling phase of the EPSP could be affected by the IPSP. At small stimulation levels, minimal EPSPs and IPSPs were closely overlapping, but the IPSPs were of significantly longer duration than EPSP responses. 7. The composite EPSP waveform shape became progressively truncated with increasing afferent stimulation. Feed-forward inhibition limited the time course of excitation to a narrow window, approximately 3-5 ms wide. Feed-forward postsynaptic inhibition significantly limited both the duration and the overall efficacy of small EPSPs in CA1 pyramidal neurones.