Regulation Of Systemic Levels Research Articles

Design of a Multi-loop PI Controller for Minimum Phase System Level Regulation in a Quadruple Tank: A Method for Constraint Optimization

Design of a Multi-loop PI Controller for Minimum Phase System Level Regulation in a Quadruple Tank: A Method for Constraint Optimization

Converging neural-centric and mechano-regulation in organoid modeling for system biology and medicine

<p>The understanding of complex biological systems and the development of effective precision medicine strategies necessitate controllable and tractable experimental models. The human body is composed of systemic and systematic interactions at multiple levels such as occurs between cells, tissues, and organs. Hence, how to recapitulate the system complexity of the human body has become an inevitable problem. This review emphasizes the need to understand complex interactions between organs by exploring the potential use of organoids and their derivatives. We focus on the nervous system and its pivotal roles in the regulation of peripheral organs, and meanwhile, highlight the importance of often overlooked mechanobiological factors. The nervous system controls many neuromodulation processes and is capable of transmitting biological information through electrophysiology. In addition, mechano-regulation operates at the cellular and microenvironment levels, functioning through system-level regulation. It can influence neural tissue or collaborate with nerves to direct skin and visceral tissue responses and their immunity. To achieve <i>in situ</i> probing and manipulation of such processes, we recommend the use of organoid assembloids that directly fusion individual organoids to create interactive structures of neural-centric complexes and mechano-regulation conditions, or organoids-on-a-chip that relies on microfluidic chips as tailorable bioreactors to form multi-organ associations and simulate and incorporate mechanobiological and neurological regulations. Based on mechano-regulatory influence at the cellular and microenvironment levels, we may develop more systematic, biomimetic, and robust in-vitro models. These models not only approach genuine physiology and pathology in humans without sacrificing real-time observation capabilities but present minimal ethical concerns and offer substantial potential for industrial scalability.</p>

An interactive two-stage retail electricity market for microgrids with peer-to-peer flexibility trading

To accommodate the proliferation of microgrids (MGs) that manage various distributed energy resources (DERs) to ensure secure internal operations, an interactive two-stage retail electricity market based on the transactive energy is proposed to provide an effective platform for these prosumers to participate in distribution-side retail transactions. Firstly, given the unpredictability of uncertainty, the centralized day-ahead stochastic energy trading between the distribution system operator (DSO) and MGs is performed, where the chance-constrained uncertainty distribution locational marginal price (CC-UDLMP) that quantifies the cost of uncertainty precautions is used to settle the transactions. Secondly, in the intra-day stage, to eliminate power imbalances from rolling estimates by exploiting the adjustability capacity of the DERs within the MGs, the peer-to-peer (P2P) based flexibility service sharing is implemented between MGs under the system-level regulation of DSO. Thirdly, a fully distributed iterative algorithm is adopted to find the Nash equilibrium solution of this two-stage sequential game under the market machanism, where the Lp-box alternating direction methods of multipliers algorithm (Lp-box ADMM) is adopted to efficiently resolve the stochastic market clearing with a mixed-integer programming structure to improve the versatility of this work. It is verified that the proposed market mechanism can effectively leverage the flexibility potentials of the MGs and improve the overall market efficiency under uncertain environments.

Systems-level regulation of microRNA networks by miR-130/301 promotes pulmonary hypertension.

Systems-level regulation of microRNA networks by miR-130/301 promotes pulmonary hypertension.

Effects of glucose concentration in the tumor microenvironment on Non Small Lung Cancer (NSCLC) Progression

Abstract Lung cancer is one of the most common cancer types in the western world, with a high lethality and increasing incidence. One major factor, supporting tumor growth is a high sugar diet. Thus, reducing the sugar intake by different diets might be a way to improve current cancer treatment. These metabolic changes are accompanied by regulation of systemic levels of Insulin and insulin like growth factors. As oppose to normal cells, tumor cells metabolism mainly depends on glycolysis. Thus, reducing diet carbohydrate intake might be a way to improve current immunotherapy by inducing immunological changes caused by the extracellular glucose concentration in tumor microenvironment. Therefore, we cultured the human lung adenocarcinoma (ADC) cell line A549 with different extracellular glucose concentrations to analyze effects by flow cytometry and qPCR. Moreover, lung tissue samples from patients with non small cell lung cancer (NSCLC), were analyzed by qPCR. In a murine model of lung ADC, tumor cells were injected intravenously and mice were fed with different diets. Lung cells were isolated and analyzed by flow cytometry. Here we show that, IGF1R expression is upregulated in A549 cells line, depending on increasing extracellular glucose concentration. Moreover, in studies on human cohorts of patients with NSCLC, we found a direct correlation between BMI and IGF1R expression and its downstream signaling. Finally, in a murine model of disease, diet glucose restriction decreased significantly tumor load associated with increased lung infiltrating CD8+ T-cells and tissue-resident memory T-cells. Thus, this study supports the need to introduce glucose restrictions in the diet of patients with NSCLC in association with current immunotherapy.

Sirtuins-Mediated System-Level Regulation of Mammalian Tissues at the Interface between Metabolism and Cell Cycle: A Systematic Review.

Simple SummaryA vast number of molecules are involved in regulating metabolism in mammals. Among these molecules, Sirtuins play pivotal roles in the regulation of metabolism. Sirtuins are a family of seven members that are expressed in several tissues/organs and connect the inner and outer environment of the mammalian body to ensure a proper balance of metabolic activities. Deregulation of Sirtuins can be involved in a disturbed balance that is found in metabolic diseases such as obesity and cancer. The level and function of Sirtuins differ per tissue/organ and among mammals and shall be taken into account when envisioning administration of drugs that may affect Sirtuin activity. This systematic review provides an overview of the function of Sirtuins in six metabolic tissues/organs, and of the relevant processes that they regulate. Both healthy and metabolic disease conditions are discussed.Sirtuins are a family of highly conserved NAD+-dependent proteins and this dependency links Sirtuins directly to metabolism. Sirtuins’ activity has been shown to extend the lifespan of several organisms and mainly through the post-translational modification of their many target proteins, with deacetylation being the most common modification. The seven mammalian Sirtuins, SIRT1 through SIRT7, have been implicated in regulating physiological responses to metabolism and stress by acting as nutrient sensors, linking environmental and nutrient signals to mammalian metabolic homeostasis. Furthermore, mammalian Sirtuins have been implicated in playing major roles in mammalian pathophysiological conditions such as inflammation, obesity and cancer. Mammalian Sirtuins are expressed heterogeneously among different organs and tissues, and the same holds true for their substrates. Thus, the function of mammalian Sirtuins together with their substrates is expected to vary among tissues. Any therapy depending on Sirtuins could therefore have different local as well as systemic effects. Here, an introduction to processes relevant for the actions of Sirtuins, such as metabolism and cell cycle, will be followed by reasoning on the system-level function of Sirtuins and their substrates in different mammalian tissues. Their involvement in the healthy metabolism and metabolic disorders will be reviewed and critically discussed.

Steady-State Parametric Optimization and Transient Characterization of Heat Flow Regulation With Binary Diffusion

Thermal regulators and switches are nonlinear devices that can greatly aid in the management of transient and/or spatially varying heating events. Various physical mechanisms have been harnessed to achieve nonlinear and switchable thermal behavior, though device characteristics are often evaluated in terms of steady-state performance only. Accurately capturing the transient behavior of these devices is a crucial missing link required for assessing the effectiveness of implementation in real-world scenarios. Here, we explore the physics of binary vapor diffusion through a noncondensable gas cavity as a promising mechanism for high-resistance contrast thermal regulation. Through a parametric steady-state optimization, we present a roadmap for future designs that can potentially reach switching ratios of up to 14.5. In addition, we perform a transient investigation to characterize the thermal response time of the device. The device possesses an extremely desirable attribute under certain transient heat loads, where the effective switching ratio appears significantly greater than the steady-state ratio due to a temporary increase in the OFF-state resistance immediately after switching. This work informs future experimental efforts for design optimization of binary-diffusion-based regulators and establishes simple modeling schemes to approximate device performance in system-level regulation scenarios.

Abstract B43: A systems biology approach to elucidate the mechanism of EGFR inhibitor sensitivity in mutant KRAS-driven colorectal cancer

Abstract Standard protocol to treat colorectal cancer (CRC) includes surgery, chemotherapy and radiotherapy as first-line treatment options. When applicable, targeting agents such as anti-EGFR therapies (i.e., cetuximab and panitumumab) have become important long-term neoadjuvant therapies that increase survival in some patients. In recent years it has become common practice to sequence patients and their tumor specimens’ DNA. This recent push in genomic medicine has led to the identification that 30-40% of CRC patient harbor an activating KRAS mutation. These mutations are thought to be an early driver in the cancer’s progression. KRAS is also considered to be the key player in conferring resistance to the anti-EGFR treatments cetuximab and panitumumab. That Ras mutations confer resistance to EGFR inhibitors is intuitive. In recent years, clinical guidelines have extended the list of contraindicated genotypes to many mutations in both the KRAS and NRAS genes. In contrast with the current guidelines for managing CRC with EGFR inhibitors, it has been shown that patients harboring a KRAS G13D mutation are sensitive to cetuximab. This has been reproducibly shown in both in vitro and in vivo model systems and is supported by retrospective analysis of initial clinical trial data. The current mutant-RAS restrictive guidelines are supported by a method that relied upon the grouping of all common Ras mutations as “equal,” which potentially washes out less common yet sensitive mutations. Whether KRAS G13D mutations are sensitive to cetuximab has remained a controversial topic for many years due to the lack of understanding of a mechanism, as it is counterintuitive to the current understanding of EGFR signaling cascade. We here identify a novel mechanism by which G13D RAS mutant is sensitive to EGFR inhibition by a nonintuitive process of reliance upon WT RAS molecules. We utilized a computational model of RAS signaling previously developed by our laboratory to explore mutant Ras signaling and thereby investigated the controversial response of KRAS G13D to anti-EGFR agents. Our computational studies of the historically reported biochemical processes that regulate Ras signals reveal a nonintuitive, mutant-specific dependency of wild-type RAS activation on EGFR. The model also reveals this dependency is determined by the interaction strength between a KRAS mutant and tumor suppressor neurofibromin. Our prospective experiments confirm this mechanism that arises from the systems-level regulation of Ras pathway signaling. Overall, our work demonstrates how systems approaches enable mechanism-based inference in genomic medicine. Citation Format: Thomas McFall, Jolene Diedrich, Stacy L. Littlechild, Laura Sisk-Hackworth, James Moresco, Meron Mengistu1, Andrey Shaw, Ed Stites. A systems biology approach to elucidate the mechanism of EGFR inhibitor sensitivity in mutant KRAS-driven colorectal cancer [abstract]. In: Proceedings of the AACR Special Conference on Targeting RAS-Driven Cancers; 2018 Dec 9-12; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(5_Suppl):Abstract nr B43.

The Helios Theory: The Sun as a Self-Regulating System and as a Cosmic Living Organism

Abstract I summarize here the recent scientific achievements exploring the causal chain of solar activity. Following the causal chain has led to a novel, comprehensive picture, including system-level regulation of local processes, such as the mass flows in the solar interior. I call attention to some crucial aspects of solar activity and present a series of facts that demand a revision of the old picture, according to which the Sun is a mere “hot ball of gas.” For example, the magnetic changes of solar activity are accelerated more than a billion times faster in comparison to theoretical expectations. The closer aspects of the comprehensive picture show that the mass flows accelerating magnetic changes deviate significantly from their physically prescribed behavior corresponding to the given physical conditions of the solar interior. I argue that they must be orchestrated in a highly sophisticated manner. Another novel aspect that has been found is that the dynamo process is not enough to give an account of the magnetic cycle, since a regulative factor is needed to make the dynamo a machine. I show that the existence of a machine within the Sun introduces novel conceptual issues transcending the conceptual framework of physics. The novel problems have guided my search for the ultimate causes of solar activity toward biology. I present arguments showing the difference between the thermodynamic behavior of far-from-equilibrium open systems and the non-physical behavior of solar activity initiated by biological causes determining and organizing quantum uncertainties. Remarkably, the results fit adequately with the Whiteheadean view of organizational duality and show that the Sun can be regarded as a compound individual.

GW27-e0098 Systems-level regulation of microRNAs networks by statin in patients with unstable angina

GW27-e0098 Systems-level regulation of microRNAs networks by statin in patients with unstable angina

Fermentation of mixed substrates by Clostridium pasteurianum and its physiological, metabolic and proteomic characterizations.

BackgroundClostridium pasteurianum is becoming increasingly attractive for the production of chemicals and fuels such as n-butanol and 1,3-propanediol. Previously we have shown that dual substrate fermentation using glucose and glycerol enhanced the cell growth and butanol production significantly. Although C. pasteurianum can grow efficiently with either glucose or glycerol alone, under certain conditions, glucose limitation in the mixed substrate fermentation leads to growth cessation. To understand this phenomenon and for process optimization, fermentation experiments were performed in the presence of excess glycerol but with varied initial concentrations of glucose which were followed by physiological, metabolic and proteomic analyses.ResultsPhysiological characterization showed that the observed cease of growth is not due to the toxicity of n-butanol. Furthermore, the growth can be resumed by addition of glucose or the intermediate oxaloacetate. Proteomic analysis shed more light on the system-level regulation of many proteins directly or indirectly associated with this phenomenon. Surprisingly, it is found that the specific growth rate of C. pasteurianum in the different growth phases (e.g. before and after glucose limitation) correlated well with the expression level of the ATP dependent pyruvate carboxylase and with the expression level of biotin synthase which provides the cofactor biotin for the formation of oxaloacetate from pyruvate. Bioenergetic analysis based on the formation rates of metabolites further show that ATP supply is not a limiting factor for the pyruvate carboxylation to oxaloacetate.ConclusionsThe results of physiological and proteomic analyses clearly show that the anaplerotic synthesis of oxaloacetate plays a key role in determining the growth behaviour of C. pasteurianum in fermentations with mixed substrates of glucose and glycerol. This study provides interesting targets for metabolic engineering of this emerging industrial microorganism.Electronic supplementary materialThe online version of this article (doi:10.1186/s12934-016-0497-4) contains supplementary material, which is available to authorized users.

Protein phosphatase modulation of somatostatin receptor signaling in the mouse hippocampus

Many inhibitory interneurones in the hippocampus release the neuropeptide somatostatin (SST) which inhibits neuronal excitability through Gi/Go-coupled receptors. To investigate the signaling pathways underlying the SST inhibition of neuronal excitability in the hippocampus, we performed perforated patch-clamp recordings from CA1 pyramidal neurones in acute brain slices from P14–P18 mice. Bath application of 1 μM SST reversibly reduces the frequency of action potential firing in response to depolarising current steps, and is associated with neuronal hyperpolarisation and a reduction in membrane resistance. This effect is mediated by potassium channels with KCNK-like pharmacology. In addition, in slices that have been cultured in vitro for seven days or more, SST also produces a hyperpolarisation independent reduction in action potential firing, which can be also observed in acute slices when the Ser/Thr protein phosphatases PP2A and PP4 are inhibited selectively with fostriecin. This hyperpolarisation independent effect of SST appears to be mediated by G-protein-activated inwardly rectifying K+ (GIRK) channels. Knockdown of protein phosphatase 5, by Cre recombinase mediated deletion of the floxed Ppp5c gene, blocks the hyperpolarisation independent effect of SST, and reduces the hyperpolarisation dependent effect in a manner consistent with increased SST receptor desensitisation. Thus, reversible protein phosphorylation provides a mechanism to enhance or diminish the inhibitory effect of SST, which could allow system level regulation of circuit excitability in the hippocampus.

Co-operative intermolecular kinetics of 2-oxoglutarate dependent dioxygenases may be essential for system-level regulation of plant cell physiology.

Can the stimulus-driven synergistic association of 2-oxoglutarate dependent dioxygenases be influenced by the kinetic parameters of binding and catalysis?In this manuscript, I posit that these indices are necessary and specific for a particular stimulus, and are key determinants of a dynamic clustering that may function to mitigate the effects of this trigger. The protein(s)/sequence(s) that comprise this group are representative of all major kingdoms of life, and catalyze a generic hydroxylation, which is, in most cases accompanied by a specialized conversion of the substrate molecule. Iron is an essential co-factor for this transformation and the response to waning levels is systemic, and mandates the simultaneous participation of molecular sensors, transporters, and signal transducers. Here, I present a proof-of-concept model, that an evolving molecular network of 2OG-dependent enzymes can maintain iron homeostasis in the cytosol of root hair cells of members of the family Gramineae by actuating a non-reductive compensatory chelation by the phytosiderophores. Regression models of empirically available kinetic data (iron and alpha-ketoglutarate) were formulated, analyzed, and compared. The results, when viewed in context of the superfamily responding as a unit, suggest that members can indeed, work together to accomplish system-level function. This is achieved by the establishment of transient metabolic conduits, wherein the flux is dictated by kinetic compatibility of the participating enzymes. The approach adopted, i.e., predictive mathematical modeling, is integral to the hypothesis-driven acquisition of experimental data points and, in association with suitable visualization aids may be utilized for exploring complex plant biochemical systems.

Abstract 18705: The miR-130/301 Family Exerts Systems-level Regulation of Proliferation, Vasoconstriction, and Extracellular Matrix Deposition to Control Pulmonary Hypertension

Background: Pulmonary hypertension (PH) is a deadly vascular disease with enigmatic molecular origins. Facets of PH have been characterized in isolation, but many have yet to be unified by a common upstream regulator. Methods & Results: We constructed a network in silico of 247 genes and 2,274 functional interactions involved in PH. Using this model and advanced network analysis, we predicted the miR-130/301 family to have the most diverse pool of PH-relevant target genes among conserved microRNAs (miRNAs). Guided by these predictions, we found that this family was up-regulated by hypoxia, inflammatory cytokines, and factors genetically linked to PH. MiR-130/301 family members were also up-regulated in remodeled pulmonary vessels in 7 animal models and 3 human subtypes of PH. Via gain- and loss-of-function experiments in vitro , we found that miR-130/301 suppressed a cohort of PPARgamma-related targets to regulate two pro-proliferative pathways (the apelin-miR-424/503-FGF2 axis in PAECs and the STAT3-miR-204-SRC axis in PASMCs); vasomotor tone ( e.g. , endothelin-1 and endothelial nitric oxide synthase); and extracellular matrix remodeling ( e.g. , the collagen crosslinking enzyme LOX). In turn, delivery of miR-130a mimic oligonucleotides in pulmonary vessels of mice altered expression of the predicted cohort of PPARgamma-related factors, leading to increased vascular remodeling (19.62±1.36 percent muscularized arterioles for miR-130a vs. 6.98±0.55 percent for scrambled control, p<0.05, mean±SEM), pulmonary vascular resistance (791±124.5 [10 3 *dyn*s*cm -5 ] for miR-130a vs. 462±25.4 for control, p<0.05), and perivascular collagen deposition and cross-linking (9.67±1.24 percent of perivascular area positive for Picrosirius Red stain vs 1.24±0.15 percent for scrambled control, p<0.05). After PH initiation in mice (chronic hypoxia+SU5416), coordinated inhibition of these miRNAs in vivo via antisense oligonucleotides mitigated these effects. Conclusions: We used network modeling to identify miR-130/301 as a master regulator of PH and a novel potential therapeutic target. These findings provide critical support for the evolving application of network modeling to discover the hidden molecular origins of PH and other human diseases.

Systems-level regulation of microRNA networks by miR-130/301 promotes pulmonary hypertension.

Development of the vascular disease pulmonary hypertension (PH) involves disparate molecular pathways that span multiple cell types. MicroRNAs (miRNAs) may coordinately regulate PH progression, but the integrative functions of miRNAs in this process have been challenging to define with conventional approaches. Here, analysis of the molecular network architecture specific to PH predicted that the miR-130/301 family is a master regulator of cellular proliferation in PH via regulation of subordinate miRNA pathways with unexpected connections to one another. In validation of this model, diseased pulmonary vessels and plasma from mammalian models and human PH subjects exhibited upregulation of miR-130/301 expression. Evaluation of pulmonary arterial endothelial cells and smooth muscle cells revealed that miR-130/301 targeted PPARγ with distinct consequences. In endothelial cells, miR-130/301 modulated apelin-miR-424/503-FGF2 signaling, while in smooth muscle cells, miR-130/301 modulated STAT3-miR-204 signaling to promote PH-associated phenotypes. In murine models, induction of miR-130/301 promoted pathogenic PH-associated effects, while miR-130/301 inhibition prevented PH pathogenesis. Together, these results provide insight into the systems-level regulation of miRNA-disease gene networks in PH with broad implications for miRNA-based therapeutics in this disease. Furthermore, these findings provide critical validation for the evolving application of network theory to the discovery of the miRNA-based origins of PH and other diseases.

An EMI Evaluation Method for Integrated Circuits in Mobile Devices

This paper presents an electromagnetic interference (EMI) evaluation method for ICs in mobile devices. The evaluation method consists of a noise measurement method for ICs and a qualification specification, which has a direct correlation with system-level radiated emissions. The 1-Ω direct coupling method, which belongs to the IEC 61967 standard, is adopted to measure the conducted emission from a specially designed low-voltage differential signaling loop-back test IC. To devise the specification for the IC-level EMI evaluation, a definite correlation between the conducted emission from the IC and the radiated emission from a test system, which consists of a printed circuit board with the IC and an attached power cable, was obtained as a radiation transfer function (RTF). By combining the RTF with the system-level regulation specification provided by CISPR or FCC, an EMI evaluation specification for the test IC was derived. For several test cases, we measured the conducted emissions from the IC to assess the noise level and pass/fail statement. Compared with the radiated emissions from the test system, it was observed that there is a meaningful correlation in terms of the emission peak level and the pass/fail decision. The proposed methodology can be applied to component-level EMI assessment at the early design stage of modern high-speed mobile devices and will be very helpful in reducing system-level EMI problems and design failures in advance.

Coregulation of Terpenoid Pathway Genes and Prediction of Isoprene Production in Bacillus subtilis Using Transcriptomics

The isoprenoid pathway converts pyruvate to isoprene and related isoprenoid compounds in plants and some bacteria. Currently, this pathway is of great interest because of the critical role that isoprenoids play in basic cellular processes, as well as the industrial value of metabolites such as isoprene. Although the regulation of several pathway genes has been described, there is a paucity of information regarding system level regulation and control of the pathway. To address these limitations, we examined Bacillus subtilis grown under multiple conditions and determined the relationship between altered isoprene production and gene expression patterns. We found that with respect to the amount of isoprene produced, terpenoid genes fall into two distinct subsets with opposing correlations. The group whose expression levels positively correlated with isoprene production included dxs, which is responsible for the commitment step in the pathway, ispD, and two genes that participate in the mevalonate pathway, yhfS and pksG. The subset of terpenoid genes that inversely correlated with isoprene production included ispH, ispF, hepS, uppS, ispE, and dxr. A genome-wide partial least squares regression model was created to identify other genes or pathways that contribute to isoprene production. These analyses showed that a subset of 213 regulated genes was sufficient to create a predictive model of isoprene production under different conditions and showed correlations at the transcriptional level. We conclude that gene expression levels alone are sufficiently informative about the metabolic state of a cell that produces increased isoprene and can be used to build a model that accurately predicts production of this secondary metabolite across many simulated environmental conditions.

Dynamic modeling of yeast meiotic initiation

BackgroundMeiosis is the sexual reproduction process common to eukaryotes. The diploid yeast Saccharomyces cerevisiae undergoes meiosis in sporulation medium to form four haploid spores. Initiation of the process is tightly controlled by intricate networks of positive and negative feedback loops. Intriguingly, expression of early meiotic proteins occurs within a narrow time window. Further, sporulation efficiency is strikingly different for yeast strains with distinct mutations or genetic backgrounds. To investigate signal transduction pathways that regulate transient protein expression and sporulation efficiency, we develop a mathematical model using ordinary differential equations. The model describes early meiotic events, particularly feedback mechanisms at the system level and phosphorylation of signaling molecules for regulating protein activities.ResultsThe mathematical model is capable of simulating the orderly and transient dynamics of meiotic proteins including Ime1, the master regulator of meiotic initiation, and Ime2, a kinase encoded by an early gene. The model is validated by quantitative sporulation phenotypes of single-gene knockouts. Thus, we can use the model to make novel predictions on the cooperation between proteins in the signaling pathway. Virtual perturbations on feedback loops suggest that both positive and negative feedback loops are required to terminate expression of early meiotic proteins. Bifurcation analyses on feedback loops indicate that multiple feedback loops are coordinated to modulate sporulation efficiency. In particular, positive auto-regulation of Ime2 produces a bistable system with a normal meiotic state and a more efficient meiotic state.ConclusionsBy systematically scanning through feedback loops in the mathematical model, we demonstrate that, in yeast, the decisions to terminate protein expression and to sporulate at different efficiencies stem from feedback signals toward the master regulator Ime1 and the early meiotic protein Ime2. We argue that the architecture of meiotic initiation pathway generates a robust mechanism that assures a rapid and complete transition into meiosis. This type of systems-level regulation is a commonly used mechanism controlling developmental programs in yeast and other organisms. Our mathematical model uncovers key regulations that can be manipulated to enhance sporulation efficiency, an important first step in the development of new strategies for producing gametes with high quality and quantity.

Current understanding of the bi-directional relationship of major depression with inflammation

Consistent evidence links major depression and its affective components to negative health outcomes. Although the pathways of these effects are likely complex and multifactorial, recent evidence suggests that innate inflammatory processes may play a role. An overview of current literature suggests that pathways between negative moods and inflammation are bi-directional. Indeed, negative moods activate peripheral physiologic mechanisms that result in an up regulation of systemic levels of inflammation. Conversely, peripheral inflammatory mediators signal the brain to affect behavioral, affective and cognitive changes that are consistent with symptoms of major depressive disorder. It is likely that these pathways are part of a complex feedback loop that involves the nervous, endocrine, and immune systems and plays a role in the modulation of peripheral inflammatory responses to central and peripheral stimuli, in central responses to peripheral immune activation and in the maintenance of homeostatic balance. Further research is warranted to fully understand the role of central processes in this feedback loop, which likely contributes to the pathophysiology of mental and physical health.

Collective and single cell behavior in epithelial contact inhibition

Control of cell proliferation is a fundamental aspect of tissue physiology central to morphogenesis, wound healing, and cancer. Although many of the molecular genetic factors are now known, the system level regulation of growth is still poorly understood. A simple form of inhibition of cell proliferation is encountered in vitro in normally differentiating epithelial cell cultures and is known as "contact inhibition." The study presented here provides a quantitative characterization of contact inhibition dynamics on tissue-wide and single cell levels. Using long-term tracking of cultured Madin-Darby canine kidney cells we demonstrate that inhibition of cell division in a confluent monolayer follows inhibition of cell motility and sets in when mechanical constraint on local expansion causes divisions to reduce cell area. We quantify cell motility and cell cycle statistics in the low density confluent regime and their change across the transition to epithelial morphology which occurs with increasing cell density. We then study the dynamics of cell area distribution arising through reductive division, determine the average mitotic rate as a function of cell size, and demonstrate that complete arrest of mitosis occurs when cell area falls below a critical value. We also present a simple computational model of growth mechanics which captures all aspects of the observed behavior. Our measurements and analysis show that contact inhibition is a consequence of mechanical interaction and constraint rather than interfacial contact alone, and define quantitative phenotypes that can guide future studies of molecular mechanisms underlying contact inhibition.