A novel methodology to estimate metabolic flux distributions in constraint-based models

Quite generally, constraint-based metabolic flux analysis describes the space of viable flux configurations for a metabolic network as a high-dimensional polytope defined by the linear constraints that enforce the balancing of production and consumption fluxes for each chemical species in the system. In some cases, the complexity of the solution space can be reduced by performing an additional optimization, while in other cases, knowing the range of variability of fluxes over the polytope provides a sufficient characterization of the allowed configurations. There are cases, however, in which the thorough information encoded in the individual distributions of viable fluxes over the polytope is required. Obtaining such distributions is known to be a highly challenging computational task when the dimensionality of the polytope is sufficiently large, and the problem of developing cost-effective ad hoc algorithms has recently seen a major surge of interest. Here, we propose a method that allows us to perform the required computation heuristically in a time scaling linearly with the number of reactions in the network, overcoming some limitations of similar techniques employed in recent years. As a case study, we apply it to the analysis of the human red blood cell metabolic network, whose solution space can be sampled by different exact techniques, like Hit-and-Run Monte Carlo (scaling roughly like the third power of the system size). Remarkably accurate estimates for the true distributions of viable reaction fluxes are obtained, suggesting that, although further improvements are desirable, our method enhances our ability to analyze the space of allowed configurations for large biochemical reaction networks. © 2013 by the authors; licensee MDPI, Basel, Switzerland

Nucleosomes in serum as a marker for cell death

The concentration of nucleosomes is elevated in blood of patients with diseases which are associated with enhanced cell death. In order to detect these circulating nucleosomes, we used the Cell Death Detection-ELISA(Plus) (CDDE) from Roche Diagnostics (Mannheim, Germany) (details at http:\textbackslash{}\textbackslash{}biochem.roche.com). For its application in liquid materials we performed various modifications: we introduced a standard curve with nucleosome-rich material, which enabled direct quantification and improved comparability of the values within (CVinterassay:3.0-4.1%) and between several runs (CVinterassay:8.6-13.5%), and tested the analytical specificity of the ELISA. Because of the fast elimination of nucleosomes from circulation and their limited stability, we compared plasma and serum matrix and investigated in detail the pre-analytical handling of serum samples which can considerably influence the test results. Careless venipuncture producing hemolysis, delayed centrifugation and bacterial contamination of the blood samples led to false-positive results; delayed stabilization with EDTA and insufficient storage conditions resulted in false-negative values. At temperatures of -20 degreesC, serum samples which were treated with 10 mM EDTA were stable for at least 6 months. In order to avoid possible interfering factors, we recommend a schedule for the pre-analytical handling of the samples. As the first stage, the possible clinical application was investigated in the sera of 310 persons. Patients with solid tumors (n = 220; mean = 361 Arbitrary Units (AU)) had considerably higher values than healthy persons (n = 50; mean = 30 AU; P = 0.0001) and patients with inflammatory diseases (n = 40; mean = 296 AU; p = 0.096). Within the group of patients with tumors, those in advanced stages (UICC 4) showed significantly higher values than those in early stages (UICC 1-3) (P = 0.0004)

Replica theory for learning curves for Gaussian processes on random graphs

Statistical physics approaches can be used to derive accurate predictions for the performance of inference methods learning from potentially noisy data, as quantified by the learning curve defined as the average error versus number of training examples. We analyse a challenging problem in the area of non-parametric inference where an effectively infinite number of parameters has to be learned, specifically Gaussian process regression. When the inputs are vertices on a random graph and the outputs noisy function values, we show that replica techniques can be used to obtain exact performance predictions in the limit of large graphs. The covariance of the Gaussian process prior is defined by a random walk kernel, the discrete analogue of squared exponential kernels on continuous spaces. Conventionally this kernel is normalised only globally, so that the prior variance can differ between vertices; as a more principled alternative we consider local normalisation, where the prior variance is uniform

The role of suction thrust in the metachronal paddles of swimming invertebrates

© The Author(s), 2020. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Colin, S. P., Costello, J. H., Sutherland, K. R., Gemmell, B. J., Dabiri, J. O., & Du Clos, K. T. The role of suction thrust in the metachronal paddles of swimming invertebrates. Scientific Reports, 10(1), (2020): 17790, doi:10.1038/s41598-020-74745-y.An abundance of swimming animals have converged upon a common swimming strategy using multiple propulsors coordinated as metachronal waves. The shared kinematics suggest that even morphologically and systematically diverse animals use similar fluid dynamic relationships to generate swimming thrust. We quantified the kinematics and hydrodynamics of a diverse group of small swimming animals who use multiple propulsors, e.g. limbs or ctenes, which move with antiplectic metachronal waves to generate thrust. Here we show that even at these relatively small scales the bending movements of limbs and ctenes conform to the patterns observed for much larger swimming animals. We show that, like other swimming animals, the propulsors of these metachronal swimmers rely on generating negative pressure along their surfaces to generate forward thrust (i.e., suction thrust). Relying on negative pressure, as opposed to high pushing pressure, facilitates metachronal waves and enables these swimmers to exploit readily produced hydrodynamic structures. Understanding the role of negative pressure fields in metachronal swimmers may provide clues about the hydrodynamic traits shared by swimming and flying animals.This work was funded by National Science Foundation (NSF OCE 1829913 to SPC), the Alfred P. Sloan Foundation (to BJG) and the Gordon and Betty Moore Foundation (8835 to KRS). The work was also supported by the Roger Williams Foundation to Promote Scholarship and Teaching

Preoperative systemic inflammation predicts postoperative infectious complications in patients undergoing curative resection for colorectal cancer

The presence of systemic inflammation before surgery, as evidenced by the glasgow prognostic score (mGPS), predicts poor long-term survival in colorectal cancer. The aim was to examine the relationship between the preoperative mGPS and the development of postoperative complications in patients undergoing potentially curative resection for colorectal cancer. Patients (n=455) who underwent potentially curative resections between 2003 and 2007 were assessed consecutively, and details were recorded in a database. The majority of patients presented for elective surgery (85%) were over the age of 65 years (70%), were male (58%), were deprived (53%), and had TNM stage I/II disease (61%), had preoperative haemoglobin (56%), white cell count (87%) and mGPS 0 (58%) in the normal range. After surgery, 86 (19%) patients developed a postoperative complication; 70 (81%) of which were infectious complications. On multivariate analysis, peritoneal soiling (P<0.01), elevated preoperative white cell count (P<0.05) and mGPS (P<0.01) were independently associated with increased risk of developing a postoperative infection. In elective patients, only the mGPS (OR=1.75, 95% CI=1.17-2.63, P=0.007) was significantly associated with increased risk of developing a postoperative infection. Preoperative elevated mGPS predicts increased postoperative infectious complications in patients undergoing potentially curative resection for colorectal cancer

MicroRNA-222 Regulates Melanoma Plasticity

Melanoma is one of the most aggressive and highly resistant tumors. Cell plasticity in melanoma is one of the main culprits behind its metastatic capabilities. The detailed molecular mechanisms controlling melanoma plasticity are still not completely understood. Here we combine mathematical models of phenotypic switching with experiments on IgR39 human melanoma cells to identify possible key targets to impair phenotypic switching. Our mathematical model shows that a cancer stem cell subpopulation within the tumor prevents phenotypic switching of the other cancer cells. Experiments reveal that hsa-mir-222 is a key factor enabling this process. Our results shed new light on melanoma plasticity, providing a potential target and guidance for therapeutic studies

Versagenssimulation dynamisch belasteter Proben mit unterschiedlichen Mehrachsigkeitszuständen unter Verwendung des Johnson-Cook-Versagensmodells für eine Nickelbasislegierung

Das Versagensverhalten verschiedener prismatischer Scherproben wurde in einer Split-Hopkinson-Pressure-Bar-Anlage und das verschiedener gekerbter Rundzugproben in einer Schnellzerreißmaschine bei hohen Dehnraten untersucht. In Finite-Elemente-Simulationen mit ausschließlich einem viskoplastischen Deformationsmodell (Johnson-Cook), das thermische Entfestigung berücksichtigt, werden die experimentellen Kraft-Zeit-Verläufe weder bezüglich des Zeitpunktes des Einsetzens des Versagens noch bezüglich des dann auftretenden starken Kraftabfalls richtig wiedergegeben. Erst bei zusätzlicher Verwendung eines Schädigungs- bzw. Versagensmodells ist eine zufriedenstellende Übereinstimmung von Experiment und Simulation zu erzielen. Bei den vorgestellten Untersuchungen wurde das Johnson-Cook -Versagensmodell verwendet, das auch den Einfluss der Mehrachsigkeit berücksichtigt. Das Materialverhalten kann in Versuchen, die einen breiten Bereich von Mehrachsigkeiten aufweisen, mit nur einem Satz von Materialparametern simuliert werden

Design, synthesis and antiparasitic evaluation of click phospholipids

A library of seventeen novel ether phospholipid analogues, containing 5-membered heterocyclic rings (1,2,3-triazolyl, isoxazolyl, 1,3,4-oxadiazolyl and 1,2,4-oxadiazolyl) in the lipid portion were designed and synthesized aiming to identify optimised miltefosine analogues. The compounds were evaluated for their in vitro antiparasitic activity against Leishmania infantum and Leishmania donovani intracellular amastigotes, against Trypanosoma brucei brucei and against different developmental stages of Trypanosoma cruzi. The nature of the substituents of the heterocyclic ring (tail) and the oligomethylene spacer between the head group and the heterocyclic ring was found to affect the activity and toxicity of these compounds leading to a significantly improved understanding of their structure\u2013activity relationships. The early ADMET profile of the new derivatives did not reveal major liabilities for the potent compounds. The 1,2,3-triazole derivative 27 substituted by a decyl tail, an undecyl spacer and a choline head group exhibited broad spectrum antiparasitic activity. It possessed low micromolar activity against the intracellular amastigotes of two L. infantum strains and T. cruzi Y strain epimastigotes, intracellular amastigotes and trypomastigotes, while its cytotoxicity concentration (CC50) against THP-1 macrophages ranged between 50 and 100 \ub5M. Altogether, our work paves the way for the development of improved ether phospholipid derivatives to control neglected tropical diseases

Neuroprotective effects of the multitarget agent AVCRI104P3 in brain of middle-aged mice

Molecular factors involved in neuroprotection are key in the design of novel multitarget drugs in aging and neurodegeneration. AVCRI104P3 is a huprine derivative that exhibits potent inhibitory effects on human AChE, BuChE, and BACE-1 activities, as well as on AChE-induced and self-induced Aβ aggregation. More recently, cognitive protection and anxiolytic-like effects have also been reported in mice treated with this compound. Now, we have assessed the ability of AVCRI104P3 (0.43 mg/kg, 21 days) to modulate the levels of some proteins involved in the anti-apoptotic/apoptotic processes (pAkt1, Bcl2, pGSK3β, p25/p35), inflammation (GFAP and Iba1) and neurogenesis in C57BL/6 mice. The effects of AVCRI104P3 on AChE-R/AChE-S isoforms have been also determined. We have observed that chronic treatment of C57BL/6 male mice with AVCRI104P3 results in neuroprotective effects, increasing significantly the levels of pAkt1 and pGSK3β in the hippocampus and Bcl2 in both hippocampus and cortex, but slightly decreasing synaptophysin levels. Astrogliosis and neurogenic markers GFAP and DCX remained unchanged after AVCRI104P3 treatment, whereas microgliosis was found to be significantly decreased pointing out the involvement of this compound in inflammatory processes. These results suggest that the neuroprotective mechanisms that are behind the cognitive and anxiolytic effects of AVCRI104P3 could be partly related to the potentiation of some anti-apoptotic and anti-inflammatory proteins and support the potential of AVCRI104P3 for the treatment of brain dysfunction associated with aging and/or dementia

Characterizations of how species mediate ecosystem properties require more comprehensive functional effect descriptors

The importance of individual species in mediating ecosystem process and functioning is generally accepted, but categorical descriptors that summarize species-specific contributions to ecosystems tend to reference a limited number of biological traits and underestimate the importance of how organisms interact with their environment. Here, we show how three functionally contrasting sediment-dwelling marine invertebrates affect fluid and particle transport - important processes in mediating nutrient cycling - and use high-resolution reconstructions of burrow geometry to determine the extent and nature of biogenic modification. We find that individual functional effect descriptors fall short of being able to adequately characterize how species mediate the stocks and flows of important ecosystem properties and that, in contrary to common practice and understanding, they are not substitutable with one another because they emphasize different aspects of species activity and behavior. When information derived from these metrics is combined with knowledge of how species behave and modify their environment, however, detailed mechanistic information emerges that increases the likelihood that a species functional standing will be appropriately summarized. Our study provides evidence that more comprehensive functional effect descriptors are required if they are to be of value to those tasked with projecting how altered biodiversity will influence future ecosystems