Signatures of arithmetic simplicity in metabolic network architecture

Metabolic networks perform some of the most fundamental functions in living cells, including energy transduction and building block biosynthesis. While these are the best characterized networks in living systems, understanding their evolutionary history and complex wiring constitutes one of the most fascinating open questions in biology, intimately related to the enigma of life's origin itself. Is the evolution of metabolism subject to general principles, beyond the unpredictable accumulation of multiple historical accidents? Here we search for such principles by applying to an artificial chemical universe some of the methodologies developed for the study of genome scale models of cellular metabolism. In particular, we use metabolic flux constraint-based models to exhaustively search for artificial chemistry pathways that can optimally perform an array of elementary metabolic functions. Despite the simplicity of the model employed, we find that the ensuing pathways display a surprisingly rich set of properties, including the existence of autocatalytic cycles and hierarchical modules, the appearance of universally preferable metabolites and reactions, and a logarithmic trend of pathway length as a function of input/output molecule size. Some of these properties can be derived analytically, borrowing methods previously used in cryptography. In addition, by mapping biochemical networks onto a simplified carbon atom reaction backbone, we find that several of the properties predicted by the artificial chemistry model hold for real metabolic networks. These findings suggest that optimality principles and arithmetic simplicity might lie beneath some aspects of biochemical complexity

Changes in Salivary Analytes of Horses Due to Circadian Rhythm and Season: A Pilot Study.

This study aims to evaluate the circadian and circannual variations in a panel of analytes in horse saliva that have been previously described as biomarkers related to stress and disease, in order to interpret them correctly when they are measured in this species. This panel of analytes integrated cortisol, salivary alpha-amylase (sAA), lipase (Lip), total esterase (TEA), butyrylcholinesterase (BChE), adenosine deaminase (ADA), γ-glutamyl transferase (gGT), creatine kinase (CK), urea, total bilirubin, total protein (TP), and phosphorus. These analytes were measured in saliva obtained from a population of five clinically healthy mares from 06:30 to 20:30, every 2 h over two consecutive days in two different photoperiod seasons, winter and spring. The temperature and relative humidity did not change between the two consecutive days sampled in each sampled season, and no thermal discomfort was observed. Changes throughout the course of the day were observed for cortisol, sAA, TEA, BChE, ADA, and CK. However, a circadian pattern was only observed for cortisol, TEA, BChE, ADA, and CK. Moreover, the values obtained for sAA, Lip, and BChE were significantly different between seasons, with different daily rhythms for cortisol, TEA, BChE, and ADA depending on the season. In conclusion, this pilot study indicates that the time of the day and the season influence salivary analytes in horses, showing a rhythmic pattern for cortisol, TEA, BChE, ADA, and CK. These factors should thus be taken into consideration for the interpretation of analytes in horse saliv

Effect of food contamination and collection material in the measurement of biomarkers in saliva of horses

This study aims to evaluate the effect of the presence of food and the material used in a panel of biomarkers in saliva of horses. For the food effect study, clean saliva was incubated with a known amount of food consisting of oats, hay or grass. Significant changes were observed when saliva was incubated with oats for total protein (P = .050) and phosphorus (P = .008), with grass for total protein (P = .037), salivary alpha-amylase (sAA, P = .018), total esterase (TEA, P = .018), butyrilcholinesterase (BChE, P = .037), adenosine deaminase (ADA, P = .037), and total bilirubin (P = .018), and with hay for sAA (P = .018), phosphorus (P = .037), γ-glutamyl transferase (gGT, P = .004), and creatine kinase (CK, P = .016). For the material-based collection study, saliva using a sponge and a cotton role at the same time were collected and compared. Lower values were obtained in clean saliva collected with cotton role compared to sponge for sAA (P = .030), TEA (P = .034), BChE (P = .003), gGT (P = .002) and cortisol (P < .001) In conclusion, the presence of food and the material used for its collection, can influence the results obtained when analytes are measured in saliva of horses

Lower glycolysis carries a higher flux than any biochemically possible alternative

The universality of many pathways of core metabolism suggests a strong role for evolutionary selection, but it remains unclear whether existing pathways have been selected from a large or small set of biochemical possibilities. To address this question, we construct "in silico" all possible biochemically feasible alternatives to the trunk pathway of glycolysis and gluconeogenesis, one of the most highly conserved pathways in metabolism. We show that, even though a large number of alternative pathways exist, the alternatives carry lower flux than the real pathway under typical physiological conditions. Alternative pathways that could potentially carry higher flux often lead to infeasible intermediate metabolite concentrations. We also find that if physiological conditions were different, different pathways could outperform those found in nature. Our results demonstrate how the rules of biochemistry restrict the alternatives that are open to evolution, and suggest that the existing trunk pathway of glycolysis and gluconeogenesis represents a maximal flux solution.Comment: 9 pages, 4 figure

Measurement of melatonin in body fluids: Standards, protocols and procedures

Abstract: The circadian rhythm of melatonin in saliva or plasma, or of the melatonin metabolite 6‐ sulphatoxymelatonin in urine, is a defining feature of suprachiasmatic nucleus function, the endogenous oscillatory pacemaker. These measurements are useful to evaluate problems related to the onset or offset of sleep and for assessing phase delays or advances of rhythms in entrained individuals. Additionally, they have become an important tool for psychiatric diagnosis, its use being recommended for phase typing in patients suffering from sleep and mood disorders. Thus, the development of sensitive and selective methods for the precise detection of melatonin in tissues and fluids of animals emerges as necessary. Due to its low concentration and the co‐existence of many other endogenous compounds in blood, the determination of melatonin has been an analytical challenge. This review discusses current methodologies employed for detection and quantification of melatonin in biological fluids and tissues

Shiga Toxin-B Targeted Gold Nanorods for Local Photothermal Treatment in Oral Cancer Clinical Samples

Elena Navarro-Palomares,1 Lorena García-Hevia,1 Jesús Galán-Vidal,2 Alberto Gandarillas,2 Fe García-Reija,3 Ana Sánchez-Iglesias,4,5 Luis M Liz-Marzán,4,5 Rafael Valiente,1,6 Mónica L Fanarraga1 1The Nanomedicine Group, Valdecilla Health Research Institute IDIVAL, Universidad de Cantabria, Santander, 39011, Spain; 2Cell Cycle, Stem Cell Fate & Cancer Laboratory, Valdecilla Health Research Institute IDIVAL, Santander, 39011, Spain; 3Oral and Maxillofacial Surgery Unit, Valdecilla Hospital HUVM, Santander, Spain; 4CIC biomaGUNE, Basque Research and Technology Alliance (BRTA), and CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), San Sebastián, 20014, Spain; 5Ikerbasque, Basque Foundation for Science, Bilbao, 48009, Spain; 6Dpt. Applied Physics, Facultad de Ciencias, Universidad de Cantabria, Santander, 39005, SpainCorrespondence: Mónica L Fanarraga; Lorena García-Hevia, Valdecilla Health Research Institute IDIVAL, University of Cantabria, Avda Herrera Oria s/n, Santander, 39011, Spain, Tel +34 942315515 Ext. 74101, Email [email protected]; [email protected]: A great challenge in nanomedicine, and more specifically in theranostics, is to improve the specificity, selectivity, and targeting of nanomaterials towards target tissues or cells. The topical use of nanomedicines as adjuvants to systemic chemotherapy can significantly improve the survival of patients affected by localized carcinomas, reducing the side effects of traditional drugs and preventing local recurrences.Methods: Here, we have used the Shiga toxin, to design a safe, high-affinity protein-ligand (ShTxB) to bind the globotriaosylceramide receptor (GB3) that is overexpressed on the surfaces of preneoplastic and malignant cancer cells in the head and neck tumors.Results: We find that ShTxB functionalized gold nanorods are efficiently retrotranslocated to the GB3-positive cell cytoplasms. After 3 minutes of laser radiation with a wavelength resonant with the AuNR longitudinal localized surface plasmon, the death of the targeted cancer cells is activated. Both preclinical murine models and patient biopsy cells show the non-cytotoxic nature of these functionalized nanoparticles before light activation and their treatment selectivity.Discussion: These results show how the use of nanomedicines directed by natural ligands can represent an effective treatment for aggressive localized cancers, such as squamous cell carcinoma of the oral cavity.Keywords: functionalized nanomaterial, natural ligand, nanoparticle targeting, squamous carcinoma, globotriaosylceramid

Carbon nanotubes gathered onto silica particles lose their biomimetic properties with the cytoskeleton becoming biocompatible

Elena Gonz&aacute;lez-Dom&iacute;nguez,1,* Nerea Iturrioz-Rodr&iacute;guez,2,* Esperanza Pad&iacute;n-Gonz&aacute;lez,2 Juan Villegas,2 Lorena Garc&iacute;a-Hevia,2 Mois&eacute;s P&eacute;rez-Lorenzo,1 Wolfgang J Parak,3 Miguel A Correa-Duarte,1,* M&oacute;nica L Fanarraga2,* 1Department of Physical Chemistry, Biomedical Research Center (CINBIO), Southern Galicia Institute of Health Research (IISSG), Biomedical Research Networking Center for Mental Health (CIBERSAM), Universidade de Vigo, Vigo, Spain; 2Nanomedicine Group, Universidad de Cantabria-IDIVAL, Santander, Spain; 3Department of Physics, Philipps Universit&auml;t Marburg, Marburg, Germany *These authors contributed equally to this work Abstract: Carbon nanotubes (CNTs) are likely to transform the therapeutic and diagnostic fields in biomedicine during the coming years. However, the fragmented vision of their side effects and toxicity in humans has proscribed their use as nanomedicines. Most studies agree that biocompatibility depends on the state of aggregation/dispersion of CNTs under physiological conditions, but conclusions are confusing so far. This study designs an experimental setup to investigate the cytotoxic effect of individualized multiwalled CNTs compared to that of identical nanotubes assembled on submicrometric structures. Our results demonstrate how CNT cytotoxicity is directly dependent on the nanotube dispersion at a given dosage. When CNTs are gathered onto silica templates, they do not interfere with cell proliferation or survival becoming highly compatible. These results support the hypothesis that CNT cytotoxicity is due to the biomimetics of these nanomaterials with the intracellular nanofilaments. These findings provide major clues for the development of innocuous CNT-containing nanodevices and nanomedicines. Keywords: MWCNTs, biomimetics, cytoskeleton, microtubules, apoptosis, migration, proliferatio