Background compensation revisited: Conserved phase response curves in frequency controlled homeostats with coherent feedback.

Background compensation is the ability of a controlled variable to respond to an applied perturbation in an unchanged manner and independent of different but constant background signals which act in parallel to the perturbation. Background compensation occurs by 'coherent feedback' mechanisms where additional control variables feed directly back to the controlled variable. This paper extends a previous study on background compensation to include phase responses in frequency controlled coherent feedback oscillators.

Coherent feedback leads to robust background compensation in oscillatory and non-oscillatory homeostats.

When in a reaction kinetic integral controller a step perturbation is applied besides a constant background, the concentration of a controlled variable (described as A) will generally respond with decreased response amplitudes ΔA as backgrounds increase. The controller variable E will at the same time provide the necessary compensatory flux to move A back to its set-point. A typical example of decreased response amplitudes at increased backgrounds is found in retinal light adaptation.

Homeostasis at different backgrounds: The roles of overlayed feedback structures in vertebrate photoadaptation.

We have studied the resetting behavior of eight basic integral controller motifs with respect to different but constant backgrounds. We found that the controllers split symmetrically into two classes: one class, based on derepression of the compensatory flux, leads to more rapid resetting kinetics as backgrounds increase. The other class, which directly activates the compensatory flux, shows a slowing down in the resetting at increased backgrounds.

Modeling the interaction between donor-derived regulatory T cells and effector T cells early after allogeneic hematopoietic stem cell transplantation.

While allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potential curative therapy against hematological malignancies, modulation of donor T cell alloreactivity is required to enhance the graft-versus-leukemia (GVL) effect and control graft-versus-host-disease (GVHD) after allo-HSCT. Donor-derived regulatory CD4CD25Foxp3 T cells (Tregs) play a central role in establishing of immune tolerance after allo-HSCT. They could be a key target to be modulated for increasing the GVL effect and control of GVHD.

Kinetics and mechanisms of catalyzed dual-E (antithetic) controllers.

Homeostasis plays a central role in our understanding how cells and organisms are able to oppose environmental disturbances and thereby maintain an internal stability. During the last two decades there has been an increased interest in using control engineering methods, especially integral control, in the analysis and design of homeostatic networks. Several reaction kinetic mechanisms have been discovered which lead to integral control.

DOPA Homeostasis by Dopamine: A Control-Theoretic View.

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.

Personalized Medicine to Improve Treatment of Dopa-Responsive Dystonia-A Focus on Tyrosine Hydroxylase Deficiency.

Dopa-responsive dystonia (DRD) is a rare movement disorder associated with defective dopamine synthesis. This impairment may be due to the fact of a deficiency in GTP cyclohydrolase I (GTPCHI, gene), sepiapterin reductase (SR), tyrosine hydroxylase (TH), or 6-pyruvoyl tetrahydrobiopterin synthase (PTPS) enzyme functions. Mutations in are most frequent, whereas fewer cases have been reported for individual SR-, PTP synthase-, and TH deficiencies.

Alleviation of C⋅C Mismatches in DNA by the Fpg Protein.

DNA polymerase III mis-insertion may, where not corrected by its 3'→ 5' exonuclease or the mismatch repair (MMR) function, result in all possible non-cognate base pairs in DNA generating base substitutions. The most thermodynamically unstable base pair, the cytosine (C)⋅C mismatch, destabilizes adjacent base pairs, is resistant to correction by MMR in , and its repair mechanism remains elusive. We present here evidence that C⋅C mismatch can be processed by base excision repair initiated by the formamidopyrimidine-DNA glycosylase (Fpg) protein.

An amplified derepression controller with multisite inhibition and positive feedback.

How organisms are able to maintain robust homeostasis has in recent years received increased attention by the use of combined control engineering and kinetic concepts, which led to the discovery of robust controller motifs. While these motifs employ kinetic conditions showing integral feedback and homeostasis for step-wise perturbations, the motifs' performance differ significantly when exposing them to time dependent perturbations. One type of controller motifs which are able to handle exponentially and even hyperbolically growing perturbations are based on derepression.

Frequency switching between oscillatory homeostats and the regulation of p53.

Homeostasis is an essential concept to understand the stability of organisms and their adaptive behaviors when coping with external and internal assaults. Many hormones that take part in homeostatic control come in antagonistic pairs, such as glucagon and insulin reflecting the inflow and outflow compensatory mechanisms to control a certain internal variable, such as blood sugar levels. By including negative feedback loops homeostatic controllers can exhibit oscillations with characteristic frequencies.

The Goodwin Oscillator and its Legacy.

In the 1960's Brian Goodwin published a couple of mathematical models showing how feedback inhibition can lead to oscillations and discussed possible implications of this behaviour for the physiology of the cell. He also presented key ideas about the rich dynamics that may result from the coupling between such biochemical oscillators. Goodwin's work motivated a series of theoretical investigations aiming at identifying minimal mechanisms to generate limit cycle oscillations and deciphering design principles of biological oscillators.

The Gene Is Activated to Alleviate Mutagenesis by an Oxidized Deoxynucleoside.

The cellular methyl donor -adenosylmethionine (SAM) and other endo/exogenous agents methylate DNA bases non-enzymatically into products interfering with replication and transcription. An important product is 3-methyladenine (mA), which in is removed by mA-DNA glycosylase I (Tag) and II (AlkA). The gene is constitutively expressed, while is induced by sub-lethal concentrations of methylating agents.

Homeostatic controllers compensating for growth and perturbations.

Cells and organisms have developed homeostatic mechanisms which protect them against a changing environment. How growth and homeostasis interact is still not well understood, but of increasing interest to the molecular and synthetic biology community to recognize and design control circuits which can oppose the diluting effects of cell growth. In this paper we describe the performance of selected negative feedback controllers in response to different applied growth laws and time dependent outflow perturbations of a controlled variable.

Sensitivity analysis of a pathway with respect to fast and small temperature change.

Temperature affects all enzymes simultaneously in a metabolic system. The enzyme concentration in a biochemical system can be considered as invariant under fast and small temperature change. Therefore, the total sensitivity of a steady state flux through a pathway with respect to the temperature can be expressed as: the apparent activation energy of a steady state pathway flux equals the sum of weighted activation energies of the individual reactions contributing to the flux, where the weighting factors are the flux control coefficients of these reactions in the context of the network.

Considerably Lower Levels of Hypocretin-1 in Cerebrospinal Fluid Is Revealed by a Novel Mass Spectrometry Method Compared with Standard Radioimmunoassay.

Low levels of hypocretin-1 (Hcrt1) in cerebrospinal fluid (CSF) are associated with narcolepsy type 1 (NT1). Although immunoassays are prone to antibody batch differences, detection methods and variation between laboratories, the standard method for Hcrt1 measurement is a radioimmunoassay (RIA). Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) is an antibody- and radioactive free alternative for precise measurement of Hcrt1.

Fatigue in primary Sjögren's syndrome: A proteomic pilot study of cerebrospinal fluid.

Objectives: Fatigue is a frequent and often disabling phenomenon that occurs in patients with chronic inflammatory and immunological diseases, and the underlying biological mechanisms are largely unknown. Because fatigue is generated in the brain, we aimed to investigate cerebrospinal fluid and search for molecules that participate in the pathophysiology of fatigue processes.

Methods: A label-free shotgun proteomics approach was applied to analyze the cerebrospinal fluid proteome of 20 patients with primary Sjögren's syndrome.

Interleukin-1-related activity and hypocretin-1 in cerebrospinal fluid contribute to fatigue in primary Sjögren's syndrome.

Background: Fatigue is a common and sometimes debilitating phenomenon in primary Sjögren's syndrome (pSS) and other chronic inflammatory diseases. We aimed to investigate how IL-1 β-related molecules and the neuropeptide hypocretin-1 (Hcrt1), a regulator of wakefulness, influence fatigue.

Methods: Hcrt1 was measured by radioimmunoassay (RIA) in cerebrospinal fluid (CSF) from 49 patients with pSS.

Excision of uracil from DNA by hSMUG1 includes strand incision and processing.

Uracil arises in DNA by hydrolytic deamination of cytosine (C) and by erroneous incorporation of deoxyuridine monophosphate opposite adenine, where the former event is devastating by generation of C → thymine transitions. The base excision repair (BER) pathway replaces uracil by the correct base. In human cells two uracil-DNA glycosylases (UDGs) initiate BER by excising uracil from DNA; one is hSMUG1 (human single-strand-selective mono-functional UDG).

Variable setpoint as a relaxing component in physiological control.

Setpoints in physiology have been a puzzle for decades, and especially the notion of fixed or variable setpoints have received much attention. In this paper, we show how previously presented homeostatic controller motifs, extended with saturable signaling kinetics, can be described as variable setpoint controllers. The benefit of a variable setpoint controller is that an observed in the concentration of the regulated biochemical species (the controlled variable) is fully characterized, and is not considered a deviation from a fixed setpoint.

Systems biology of the modified branched Entner-Doudoroff pathway in Sulfolobus solfataricus.

Sulfolobus solfataricus is a thermoacidophilic Archaeon that thrives in terrestrial hot springs (solfatares) with optimal growth at 80°C and pH 2-4. It catabolizes specific carbon sources, such as D-glucose, to pyruvate via the modified Entner-Doudoroff (ED) pathway. This pathway has two parallel branches, the semi-phosphorylative and the non-phosphorylative.

PLATINUM SENSITIVE 2 LIKE impacts growth, root morphology, seed set, and stress responses.

Eukaryotic protein phosphatase 4 (PP4) is a PP2A-type protein phosphatase that is part of a conserved complex with regulatory factors PSY2 and PP4R2. Various lines of Arabidopsis thaliana with mutated PP4 subunit genes were constructed to study the so far completely unknown functions of PP4 in plants. Mutants with knocked out putative functional homolog of the PSY2 LIKE (PSY2L) gene were dwarf and bushy, while plants with knocked out PP4R2 LIKE (PP4R2L) looked very similar to WT.

Performance of Homeostatic Controller Motifs Dealing with Perturbations of Rapid Growth and Depletion.

An essential property of life is that cells and organisms have the ability to protect themselves against external disturbances/attacks by using homeostatic mechanisms. These defending mechanisms are based on negative feedback regulation and often contain additional features, such as integral control, where the integrated error between a controlled variable and its set-point is used to achieve homeostasis. Although the concept of integral control has its origin in industrial processes, recent findings suggest that biological systems are also capable of showing integral control.

Modeling the diversion of primary carbon flux into secondary metabolism under variable nitrate and light/dark conditions.

In plants, the partitioning of carbon resources between growth and defense is detrimental for their development. From a metabolic viewpoint, growth is mainly related to primary metabolism including protein, amino acid and lipid synthesis, whereas defense is based notably on the biosynthesis of a myriad of secondary metabolites. Environmental factors, such as nitrate fertilization, impact the partitioning of carbon resources between growth and defense.

The Organization of Controller Motifs Leading to Robust Plant Iron Homeostasis.

Iron is an essential element needed by all organisms for growth and development. Because iron becomes toxic at higher concentrations iron is under homeostatic control. Plants face also the problem that iron in the soil is tightly bound to oxygen and difficult to access.

A rapid method for preparation of the cerebrospinal fluid proteome.

The cerebrospinal fluid (CSF) proteome is of great interest for investigation of diseases and conditions involving the CNS. However, the presence of high-abundance proteins (HAPs) can interfere with the detection of low-abundance proteins, potentially hindering the discovery of new biomarkers. Therefore, an assessment of the CSF subproteome composition requires depletion strategies.