Feedback loop

The large overlap between bistable region and PLS- PAI1 positive feedback region is also an interesting prop- erty of the system, since it suggests that in reality, a bistable TGF-β1 activation system most likely also has positive PLS-PAI1 feedback. Although negative feedback loop between PLS-PAI1 has been observed repeatedly and is well accepted [17, 18], positive feedback would be novel. We tested the sign of the feedback from PLS to PAI1 using an experimental system known to exhibit TGF-β1 bistability [5], a cell culture model of liver fibro- sis. In this co-culture with primary hepatocytes and HSC-T6 cell lines, we added different levels of PLS and we measured PAI1 mRNA levels using RT-PCR (Fig. 3b). Increasing PLS was found to cause decreased ex- pression of PAI1 in this bistable system, implying that PLS and PAI1 can indeed exhibit positive feedback.

In the context of gene regulatory networks, a negative feedback loop is modeled by N -coupled ordinary differential equations. The resulting system is highly non-linear due to the use of smooth Hill functions. This classical dynamical system properly captures the two main biological behaviors arising from this type of recurrent network motif: homeostasis under global stability of the unique fixed point, and biochemical oscillations otherwise. When homeostatic conditions are disrupted, undesired sustained oscillations can appear. In this context, a biologically relevant control strategy is designed in order to suppress these undesirable oscillations. As biological measurement techniques do not provide a quantitative knowledge of the system, the control law is chosen piecewise constant and dependent on specific regions of the state space. Moreover, due to biological devices inaccuracies, the measurements are considered uncertain leading to regions in which the control law is undefined. Under appropriate conditions on the control inputs, successive repelling regions of the state space are determined in order to prove the global convergence of the system towards an adjustable zone around the fixed point. These results are illustrated with the well-known p53-Mdm2 genetic feedback loop.

SUMMARY Caspase-2 is an evolutionarily conserved caspase, yet its biological function and cleavage targets are poorly understood. Caspase-2 is activated by the p53 target gene product PIDD (also known as LRDD) in a complex called the Caspase-2-PIDDosome. We show that PIDD expression promotes growth arrest and chemotherapy resistance by a mechanism that depends on Caspase-2 and wild-type p53. PIDD- induced Caspase-2 directly cleaves the E3 ubiquitin ligase Mdm2 at Asp 367, leading to loss of the C-terminal RING domain responsible for p53 ubiquiti- nation. As a consequence, N-terminally truncated Mdm2 binds p53 and promotes its stability. Upon DNA damage, p53 induction of the Caspase-2-PIDD- osome creates a positive feedback loop that inhibits Mdm2 and reinforces p53 stability and activity, contributing to cell survival and drug resis- tance. These data establish Mdm2 as a cleavage target of Caspase-2 and provide insight into a mecha- nism of Mdm2 inhibition that impacts p53 dynamics upon genotoxic stress.

Our finding that let-7 targets H19 for destabilization in response to extracellular cues establishes the first example of miRNAs regulating their own sponges as a part of a reg- ulatory feedback loop. This regulation appears to serve as a protective mechanism in non-diabetic individuals. Results from both in vivo (Figures 4 D and 5 A) and in vitro (Fig- ures 4 A and 5 B) studies demonstrate that acute high dose insulin stimulation increases let-7 and decreases H19, and that these effects are dependent on intact insulin signaling, as such effects are not observed in HFD muscle (Supple- mentary Figure S8). This suggests that in healthy individu- als the ‘off-signal’ for the H19 /let-7 axis is the normal rise and fall of plasma insulin following regular meals. During acute hyperinsulinemia, the axis is activated and serves as a protective mechanism to prevent muscle from overusing cir- culatory glucose at later time points which otherwise would be toxic to the muscle (Figure 7 ). The axis corrects itself following acute high insulin assault, which is supported by results from C3H myotubes (Figure 6 E–G).

voltage of the feedback-loop starts to change in less than 1ns just after the GaN transistor v DS falling-edge. Fig. 9. Experimental waveforms of the propsed system showing an open-loop response with a resistive load (R G =14.7Ω) connected to v DRV . VI. C ONCLUSION This paper develops a theoretical analysis to provide the optimum distribution between the gains of the two current mirrors and the value of the sensing capacitor to maximize the bandwidth of a dv/dt feedback control loop. It is demonstrated that the bandwidth of the proposed circuit is correlated to the transition frequency of the CMOS technology. Therefore, choosing a technology with the highest transition frequency, with appropriate voltage capabilities to sustain 5V for GaN and 25V for SiC and IGBT applications, is the best choice. It is also demonstrated that for a given constant GC S product, the higher the sensing

In this context, this paper presents a N-dimensional com- petitive dynamical model for a genetic negative feedback loop that displays dyshomeostasis, leading to the emergence of undesired oscillations. This typically happens when its unique steady state is unstable. A simple affine control law is designed in order to stabilize the system and recover homeostasis properties. The control strategy only depends on the measurement of a unique gene and only acts on a unique genetic interaction. From a biological point of view, this simple control guarantees a minimal biological set-up and helps reducing the complexity of measurement and control devices. However, the resulting controlled system loses its competitive property. Hence, a new methodology is presented in order to prove that this simple control law stabilizes the unstable steady state. The proof is based on the construction of successive repelling nested hyperrectangles that act as Lyapunov function level-sets.

Feedback loop in supersonic impinging round jets An additional indirect evidence of the role of the neutral acoustic wave modes in the upstream part of feedback loop is provided by the a[r]

remained possible that NO from the exogenous donor was provided at levels in excess of those generated by the Fas 兾NO pathway, and thereby led to nonphysiological activation of Fas. We therefore looked for evidence of the feedback loop in neurons triggered to die by another element of the pathway, the Fas receptor itself. Mutant SOD1 motoneurons were exposed to agonistic anti-Fas antibodies in the absence or presence of Fas-Fc (Fig. 3 C and D). Fas-Fc does not functionally interact with the Fas antibodies used to trigger death (Fig. 7C). Blockade of FasL 兾Fas interactions by Fas-Fc gave nearly complete protection against cell death (Fig. 3 C and D). This result demonstrates that even when the pathway is triggered by the endogenous Fas receptor, further activation of Fas by FasL is required for cell death to occur (Fig. 3E).

Abstract High-risk neuroblastomas show a paucity of recurrent somatic mutations at diagnosis. As a result, the molecular basis for this aggressive phenotype remains elusive. Recent progress in regulatory network analysis helped us elucidate disease-driving mechanisms downstream of genomic alterations, including recurrent chromosomal alterations. Our analysis identified three molecular subtypes of high-risk neuroblastomas, consistent with chromosomal alterations, and identified subtype-specific master regulator (MR) proteins that were conserved across independent cohorts. A 10–protein transcriptional module – centered around a TEAD4 ↔ MYCN positive-feedback loop – emerged as the regulatory driver of the high-risk subtype associated with MYCN amplification. Silencing of either gene collapsed MYCN-amplified (MYCN Amp ) neuroblastoma transcriptional hallmarks and abrogated viability in vitro and in vivo. Consistently, TEAD4 emerged as a robust prognostic marker of poor survival, with activity independent of the canonical Hippo pathway transcriptional co-activators, YAP and TAZ. These results suggest novel

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Strikingly, mutations or physiological perturbations altering pore integrity decrease the levels of the NPC-associated SUMO protease Ulp1, and trigger the accumulation of sumoylated vers[r]

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Abstract. Computing systems are becoming more and more dynamically recon- figurable or adaptive, to be flexible w.r.t. their environment and to automate their administration. Autonomic computing proposes a general structure of feedback loop to take this into account. In this paper, we are particularly interested in ap- proaches where this feedback loop is considered as a case of control loop where techniques stemming from Control Theory can be used to design efficient safe, and predictable controllers. This approach is emerging, with separate and dis- persed e ffort, in different areas of the field of reconfigurable or adaptive comput- ing, at software or architecture level. This paper surveys these approaches from the point of view of control theory techniques, continuous and discrete (super- visory), in their application to the feedback control of computing systems, and proposes detailed interpretations of feedback control loops as MAPE-K loop, il- lustrated with case studies.

Le premier élément qui ressort de ces entretiens est finalement le dernier évoqué, à savoir, le facteur culturel. Nous l'avions dit en introduction, le silence ainsi que l'absence d'autres vecteurs de communication (gestes, expressions faciales...), constituent des caractéristiques propres au peuple finlandais (Piechnik, 2008 ; Kerbrat-Orecchioni, 1994). Ces particularités, observables en dehors et dans la salle de classe, ont été largement utilisées par les enseignants pour justifier le feedback inexpressif de leurs apprenants mais aussi leurs propres (ré)actions. C'est par exemple parce que les apprenants réfléchissent sans rien dire que l'enseignant se sent obligé de les solliciter en répétant, en reformulant ou en les interrogeant directement. Et même lorsqu'ils ne correspondent pas à des moments de réflexion, les feedbacks inexpressifs des apprenants sont justifiables par la culture du silence présente en Finlande. Comme dans toutes situations, les enseignants doivent faire preuve d'une grande capacité d'adaptation. Nous remarquons ici que, quel que soit l'âge et le niveau du public ou encore l'expérience de l'enseignant, chacun d'eux s'adapte à la culture finlandaise en usant de différentes stratégies pour mettre fin au silence et à l'inexpression dont font souvent preuve les apprenants de l'IFF. Notons que les enseignants sont bien conscients de cette influence culturelle sur l'interaction mais aussi et surtout sur leur agir professoral. E1 établit une distinction entre ses débuts dans l'enseignement du FLE en Finlande, lorsqu'il faisai[t] le clown et gesticulai[t] partout dans la

Figure 6: Tid1 affects kinetics of D-loop extension and cell survival depending on the length of homology between the donor and MAT during mating type switch (A) Schematic of the primer extension assay adopted from ( Mehta et al., 2017 ). Homology length to the invading Z-end (green) was altered at HML to be either 148 bp or 2,216 bp. Arrowhead indicates HO-cut site. Primers (indicated by black arrows as p3 and p4) specific to the newly synthesized DNA (shown by dotted lines) after strand invasion into HML was used to quantify extended D-loops by the primer extension assay. (B, C) Kinetics of new DNA synthesis post D-loop formation as measured the primer extension assay. Graphs show qRT-PCR product at intervals post HO endonuclease induction by galactose in strains with 148 bp or 2,216 bp homology at the Z-end. The amount of PCR product obtained from a switched MATα-inc colony was set to 100%. The Cp values were normalized to Arginine PCR product formation as in ( Mehta et al., 2017 ). Mean ± SD (n = 3). (D) Viability of strains having 148 bp or 2,216 bp homology at the Z-end between HML and MAT loci after HO endonuclease induction by galactose. Mean ± SD (n ≥ 3). * indicates p-value < 0.05 with paired two-tailed t-test.

Accepted Manuscript ABSTRACT Purpose: The purpose of the current study was to use diffusion tensor imaging (DTI) to conduct tractography of the optic radiations (OR) and its component bundles and to assess both the degree of hemispheric asymmetry and the inter-subject variability of Meyer’s Loop (ML). We hypothesized that there are significant left versus right differences in the anterior extent of ML to the temporal pole (TP) in healthy subjects. Materials and Methods: DTI data were acquired on a 3T Siemens MRI system using a single-shot Spin Echo EPI sequence. The dorsal, central and ML bundles of the OR were tracked and visualized in forty hemispheres of twenty healthy volunteers. The uncinate fasciculus (UF) was also tracked in these subjects so that it could be used as a distinct anatomical reference. Measurements were derived for the distance between ML-TP, ML and the temporal horn (ML-TH) and ML and the uncinate fasciculus (ML-UF). Paired difference t-tests were carried out with SPSS 14.0.

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zeroes of E ∞ (x). It is regular at even zeroes, it just vanishes there. It can be seen easily that the fact that the W n ’s satisfy loop equations, implies by recursion, that each W n (g) is an algebraic function, with possible branchcut singularities at the odd zeroes, and poles at the even zeroes.

All these methods that produce candidate loop invariants need some kind of decision procedure to ensure the candi- dates are indeed invariant. This is also true for user provided loop invariants. Handcrafted invariants may contain errors, and if so, the error must be detected before further usage of the invariant. Conversely, user invariants may be a desired specification from which a programmer writes the loop body code: a decision procedure is then needed to verify that the written code meets the loop invariant. In this paper, we pro- pose to use constraint solvers for the automatic verification of candidate loop invariants in single-loop imperative proce- dures. Our approach is based on a translation of Java-like methods annotated with JML statements into a constraint problem. This translation was described in [3] and imple- mented in the CPBPV system. Besides the implementation in CPBPV of a more generic handling of JML “exist” and “for all” quantifiers, our contributions are:

The purpose of this paper is to prove loop equations in an algebraic manner in a totally general case. Somehow this can serve as a lemma to be used in many applica- tions. A consequence of having loop equations, is that, if our differential system satisfies further nice properties (called “topological type”, see section 5.1), then we automati- cally have “topological recursion” [ 13 ].