negative feedback loop
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2022 ◽  
Uramogi Wang

Continuous persist activity of the competitive network is related to many functions, such as working memory, oculomotor integrator and decision making. Many competition models with mutual inhibition structures achieve activity maintenance via positive feedback, which requires meticulous fine tuning of the network parameters strictly. Negative derivative feedback, according to recent research, might represent a novel mechanism for sustaining neural activity that is more resistant to multiple neural perturbations than positive feedback. Many classic models with only mutual inhibition structure are not capable of providing negative derivative feedback because double-inhibition acts as a positive feedback loop, and lack of negative feedback loop that is indispensable for negative derivative feedback. Here in the proposal, we aim to derive a new competition network with negative derivative feedback. The network is made up of two symmetric pairs of EI populations that the four population are completely connected. We conclude that the negative derivative occurs in two circumstances, in which one the activity of the two sides is synchronous but push-pull-like in the other, as well as the switch of two conditions in mathematical analysis and numerical simulation.

2021 ◽  

High sensitive (S = 11.2 ± 1.8 mV/V/kPa with nonlinearity error 2KNL = 0.15 ± 0.09%/FS) small-sized (4.00x4.00 mm2) silicon pressure sensor chip utilizing new electrical circuit for microelectromechanical systems (MEMS) in the form of differential amplifier with negative feedback loop (PDA-NFL) for 5 kPa differential was developed. The advantages are demonstrated in the array of output characteristics, which prove the relevance of the presented development, relative to modern developments of pressure sensors with Wheatstone bridge electrical circuit for 5 kPa range.

Development ◽  
2021 ◽  
Diego J. Hoyle ◽  
Daniel B. Dranow ◽  
Thomas F. Schilling

Secreted signals in patterning systems often induce repressive signals that shape their distributions in space and time. In developing growth plates (GPs) of endochondral long bones, Parathyroid hormone-like hormone (Pthlh) inhibits Indian hedgehog (Ihh) to form a negative feedback loop that controls GP progression and bone size. Whether similar systems operate in other bones and how they arise during embryogenesis remain unclear. We show that Pthlha expression in the zebrafish craniofacial skeleton precedes chondrocyte differentiation and restricts where cells undergo hypertrophy, thereby initiating a future GP. Loss of Pthlha leads to an expansion of cells expressing a novel early marker of the hypertrophic zone (HZ), entpd5a, and later HZ markers such as ihha, while local Pthlha misexpression induces ectopic entpd5a expression. Formation of this early pre-HZ correlates with onset of muscle contraction and requires mechanical force; paralysis leads to loss of entpd5a and ihha expression in the pre-HZ, mislocalized pthlha expression, and no subsequent ossification. These results suggest that local Pthlh sources combined with force determine HZ locations, establishing the negative feedback loop that later maintains GPs.

Cancers ◽  
2021 ◽  
Vol 13 (24) ◽  
pp. 6197
Nihad Boukrout ◽  
Mouloud Souidi ◽  
Fatima Lahdaoui ◽  
Belinda Duchêne ◽  
Bernadette Neve ◽  

Background: Pancreatic adenocarcinoma (PDAC) is a deadly cancer with an extremely poor prognosis. MUC4 membrane-bound mucin is neoexpressed in early pancreatic neoplastic lesions and is associated with PDAC progression and chemoresistance. In cancers, microRNAs (miRNAs, small noncoding RNAs) are crucial regulators of carcinogenesis, chemotherapy response and even metastatic processes. In this study, we aimed at identifying and characterizing miRNAs activated downstream of MUC4-associated signaling in pancreatic adenocarcinoma. MiRnome analysis comparing MUC4-KD versus Mock cancer cells showed that MUC4 inhibition impaired miR-210-3p expression. Therefore, we aimed to better understand the miR-210-3p biological roles. Methods: miR-210-3p expression level was analyzed by RT-qPCR in PDAC-derived cell lines (PANC89 Mock and MUC4-KD, PANC-1 and MiaPACA-2), as well as in mice and patients tissues. The MUC4-miR-210-3p regulation was investigated using luciferase reporter construct and chromatin immunoprecipitation experiments. Stable cell lines expressing miR-210-3p or anti-miR-210-3p were established using CRISPR/Cas9 technology or lentiviral transduction. We evaluated the biological activity of miR-210-3p in vitro by measuring cell proliferation and migration and in vivo using a model of subcutaneous xenograft. Results: miR-210-3p expression is correlated with MUC4 expression in PDAC-derived cells and human samples, and in pancreatic PanIN lesions of Pdx1-Cre; LstopL-KrasG12D mice. MUC4 enhances miR-210-3p expression levels via alteration of the NF-κB signaling pathway. Chromatin immunoprecipitation experiments showed p50 NF-κB subunit binding on miR-210-3p promoter regions. We established a reciprocal regulation since miR-210-3p repressed MUC4 expression via its 3′-UTR. MiR-210-3p transient transfection of PANC89, PANC-1 and MiaPACA-2 cells led to a decrease in cell proliferation and migration. These biological effects were validated in cells overexpressing or knocked-down for miR-210-3p. Finally, we showed that miR-210-3p inhibits pancreatic tumor growth and proliferation in vivo. Conclusion: We identified a MUC4-miR-210-3p negative feedback loop in early-onset PDAC, but also revealed new functions of miR-210-3p in both in vitro and in vivo proliferation and migration of pancreatic cancer cells, suggesting a complex balance between MUC4 pro-oncogenic roles and miR-210-3p anti-tumoral effects.

2021 ◽  
Vol 22 (23) ◽  
pp. 12862
Rune Kleppe ◽  
Qaiser Waheed ◽  
Peter Ruoff

Dopamine (DA) is an important signal mediator in the brain as well as in the periphery. The term “dopamine homeostasis” occasionally found in the literature refers to the fact that abnormal DA levels can be associated with a variety of neuropsychiatric disorders. An analysis of the negative feedback inhibition of tyrosine hydroxylase (TH) by DA indicates, with support from the experimental data, that the TH-DA negative feedback loop has developed to exhibit 3,4-dihydroxyphenylalanine (DOPA) homeostasis by using DA as a derepression regulator. DA levels generally decline when DOPA is removed, for example, by increased oxidative stress. Robust DOPA regulation by DA further implies that maximum vesicular DA levels are established, which appear necessary for a reliable translation of neural activity into a corresponding chemical transmitter signal. An uncontrolled continuous rise (windup) in DA occurs when Levodopa treatment exceeds a critical dose. Increased oxidative stress leads to the successive breakdown of DOPA homeostasis and to a corresponding reduction in DA levels. To keep DOPA regulation robust, the vesicular DA loading requires close to zero-order kinetics combined with a sufficiently high compensatory flux provided by TH. The protection of DOPA and DA due to a channeling complex is discussed.

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