Functional Model of Compound II of Cytochrome P450: Spectroscopic Characterization and Reactivity Studies of a FeIV-OH Complex.

Herein, we show that the reaction of a mononuclear FeIII(OH) complex (1) with N-tosyliminobenzyliodinane (PhINTs) resulted in the formation of a FeIV(OH) species (3). The obtained complex 3 was characterized by an array of spectroscopic techniques and represented a rare example of a synthetic FeIV(OH) complex. The reaction of 1 with the one-electron oxidizing agent was reported to form a ligand-oxidized FeIII(OH) complex (2). 3 revealed a one-electron reduction potential of -0.22 V vs Fc+/Fc at -15 °C, which was 150 mV anodically shifted than 2 (Ered = -0.37 V vs Fc+/Fc at -15 °C), inferring 3 to be more oxidizing than 2. 3 reacted spontaneously with (4-OMe-C6H4)3C• to form (4-OMe-C6H4)3C(OH) through rebound of the OH group and displayed significantly faster reactivity than 2. Further, activation of the hydrocarbon C-H and the phenolic O-H bond by 2 and 3 was compared and showed that 3 is a stronger oxidant than 2. A detailed kinetic study established the occurrence of a concerted proton-electron transfer/hydrogen atom transfer reaction of 3. Studying one-electron reduction of 2 and 3 using decamethylferrocene (Fc*) revealed a higher ket of 3 than 2. The study established that the primary coordination sphere around Fe and the redox state of the metal center is very crucial in controlling the reactivity of high-valent Fe-OH complexes. Further, a FeIII(OMe) complex (4) was synthesized and thoroughly characterized, including X-ray structure determination. The reaction of 4 with PhINTs resulted in the formation of a FeIV(OMe) species (5), revealing the presence of two FeIV species with isomer shifts of -0.11 mm/s and = 0.17 mm/s in the Mössbauer spectrum and showed FeIV/FeIII potential at -0.36 V vs Fc+/Fc couple in acetonitrile at -15 °C. The reactivity studies of 5 were investigated and compared with the FeIV(OH) complex (3).

Directed Electron Delivery from a Pb-Free Halide Perovskite to a Co(II) Molecular Catalyst Boosts CO2 Photoreduction Coupled with Water Oxidation.

The development of high-performance photocatalytic systems for CO2 reduction is appealing to address energy and environmental issues, while it is challenging to avoid using toxic metals and organic sacrificial reagents. We here immobilize a family of cobalt phthalocyanine catalysts on Pb-free halide perovskite Cs2AgBiBr6 nanosheets with delicate control on the anchors of the cobalt catalysts. Among them, the molecular hybrid photocatalyst assembled by carboxyl anchors achieves the optimal performance with an electron consumption rate of 300±13 µmol g-1 h-1 for visible-light-driven CO2-to-CO conversion coupled with water oxidation to O2, over 8 times of the unmodified Cs2AgBiBr6 (36±8 µmol g-1 h-1), also far surpassing the documented systems (<150 µmol g-1 h-1). Besides the improved intrinsic activity, electrochemical, computational, ex-/in situ X-ray photoelectron and X-ray absorption spectroscopic results indicate that the electrons photogenerated at the Bi atoms of Cs2AgBiBr6 can be directionally transferred to the cobalt catalyst via the carboxyl anchors which strongly bind to the Bi atoms, substantially facilitating the interfacial electron transfer kinetics and thereby the photocatalysis.

Mapping the Ultrafast Mechanistic Pathways of Co Photocatalysts in Pure Water through Time-Resolved X-ray Spectroscopy.

Nanosecond time-resolved X-ray (tr-XAS) and optical transient absorption spectroscopy (OTA) are applied to study 3 multimolecular photocatalytic systems with [Ru(bpy)3 ]2+ photoabsorber, ascorbic acid electron donor and Co catalysts with methylene (1), hydroxomethylene (2) and methyl (3) amine substituents in pure water. OTA and tr-XAS of 1 and 2 show that the favored catalytic pathway involves reductive quenching of the excited photosensitizer and electron transfer to the catalyst to form a CoII square pyramidal intermediate with a bonded aqua molecule followed by a CoI square planar derivative that decays within ≈8 µs. By contrast, a CoI square pyramidal intermediate with a longer decay lifetime of ≈35 µs is formed from an analogous CoII geometry for 3 in H2 O. These results highlight the protonation of CoI to form the elusive hydride species to be the rate limiting step and show that the catalytic rate can be enhanced through hydrogen containing pendant amines that act as H-H bond formation proton relays.

Precious-Metal-Free CO2 Photoreduction Boosted by Dynamic Coordinative Interaction between Pyridine-Tethered Cu(I) Sensitizers and a Co(II) Catalyst.

Improving the photocatalytic efficiency of a fully noble-metal-free system for CO2 reduction remains a fundamental challenge, which can be accomplished by facilitating electron delivery as a consequence of exploiting intermolecular interactions. Herein, we have designed two Cu(I) photosensitizers with different pyridyl pendants at the phenanthroline moiety to enable dynamic coordinative interactions between the sensitizers and a cobalt macrocyclic catalyst. Compared to the parent Cu(I) photosensitizer, one of the pyridine-tethered derivatives boosts the apparent quantum yield up to 76 ± 6% at 425 nm for selective (near 99%) CO2-to-CO conversion. This value is nearly twice that of the parent system with no pyridyl pendants (40 ± 5%) and substantially surpasses the record (57%) of the noble-metal-free systems reported so far. This system also realizes a maximum turnover number of 11 800 ± 1400. In contrast, another Cu(I) photosensitizer, in which the pyridine substituents are directly linked to the phenanthroline moiety, is inactive. The above behavior and photocatalytic mechanism are systematically elucidated by transient fluorescence, transient absorption, transient X-ray absorption spectroscopies, and quantum chemical calculations. This work highlights the advantage of constructing coordinative interactions to fine-tune the electron transfer processes within noble-metal-free systems for CO2 photoreduction.

Comparing the reactivity of an oxoiron(IV) cation radical and its oxoiron(V) tautomer towards C-H bonds.

An oxoiron(IV) cation radical is generated upon two-electron oxidation of an iron(III) complex bearing an electron-rich methoxy substituted bTAML framework and thoroughly characterized via multiple spectroscopic techniques and density functional theory (DFT). Reactivity studies demonstrate faster rates for oxidation of strong aliphatic sp3 C-H bonds than for its corresponding oxoiron(V) valence tautomer.

Surface-Promoted Evolution of Ru-bda Coordination Oligomers Boosts the Efficiency of Water Oxidation Molecular Anodes.

A new Ru oligomer of formula {[RuII(bda-κ-N2O2)(4,4'-bpy)]10(4,4'-bpy)}, 10 (bda is [2,2'-bipyridine]-6,6'-dicarboxylate and 4,4'-bpy is 4,4'-bipyridine), was synthesized and thoroughly characterized with spectroscopic, X-ray, and electrochemical techniques. This oligomer exhibits strong affinity for graphitic materials through CH-π interactions and thus easily anchors on multiwalled carbon nanotubes (CNT), generating the molecular hybrid material 10@CNT. The latter acts as a water oxidation catalyst and converts to a new species, 10'(H2O)2@CNT, during the electrochemical oxygen evolution process involving solvation and ligand reorganization facilitated by the interactions of molecular Ru catalyst and the surface. This heterogeneous system has been shown to be a powerful and robust molecular hybrid anode for electrocatalytic water oxidation into molecular oxygen, achieving current densities in the range of 200 mA/cm2 at pH 7 under an applied potential of 1.45 V vs NHE. The remarkable long-term stability of this hybrid material during turnover is rationalized based on the supramolecular interaction of the catalyst with the graphitic surface.

Characterization and reactivity study of non-heme high-valent iron-hydroxo complexes.

A terminal FeIIIOH complex, [FeIII(L)(OH)]2- (1), has been synthesized and structurally characterized (H4L = 1,2-bis(2-hydroxy-2-methylpropanamido)benzene). The oxidation reaction of 1 with one equiv. of tris(4-bromophenyl)ammoniumyl hexachloroantimonate (TBAH) or ceric ammonium nitrate (CAN) in acetonitrile at -45 °C results in the formation of a FeIIIOH ligand radical complex, [FeIII(L˙)(OH)]- (2), which is hereby characterized by UV-visible, 1H nuclear magnetic resonance, electron paramagnetic resonance, and X-ray absorption spectroscopy techniques. The reaction of 2 with a triphenylcarbon radical further gives triphenylmethanol and mimics the so-called oxygen rebound step of Cpd II of cytochrome P450. Furthermore, the reaction of 2 was explored with different 4-substituted-2,6-di-tert-butylphenols. Based on kinetic analysis, a hydrogen atom transfer (HAT) mechanism has been established. A pK a value of 19.3 and a BDFE value of 78.2 kcal/mol have been estimated for complex 2.

Structure and excited-state dynamics of dimeric copper(i) photosensitizers investigated by time-resolved X-ray and optical transient absorption spectroscopy.

Time-resolved X-ray (tr-XAS) and optical transient absorption (OTA) spectroscopy in the picosecond time scale coupled with Density Functional theory (DFT) and X-ray absorption near-edge structure (XANES) calculations are applied to study three homoleptic Cu(i) dimeric chromophores with ethyl and longer propyl spacers, denoted as [Cu2(mphenet)2]Cl2 (C1), [Cu2(mphenet)2](ClO4)2 (C2) and [Cu2(mphenpr)2](ClO4)2 (C3) (where mphenet = 1,2-bis(9-methyl-1,10-phenanthrolin-2-yl)ethane and mphenpr = 1,3-bis(9-methyl-1,10-phenanthrolin-2-yl)propane). Tr-XAS analysis after light illumination at ∼ 100 ps illustrate the formation of a flattened triplet excited state in all 3 complexes. Optical transient absorption (OTA) analysis for C1 monitored in water and C2 and C3 measured in acetonitrile reveals distinct excited-state lifetimes of 169 ps, 670 ps and 1600 ps respectively. These differences are associated to changes in the solvent (comparing C1 and C2) and the flexibility of the ligand to adapt after Cu flattening upon excitation (C2 and C3). Our results are important for the improved structural dynamics of these types of Cu-based dimeric compounds, and can guide the integration of these chromophores into more complex solar energy conversion schemes.

Prevalence of metabolic syndrome among elderly Mexicans.

BACKGROUND: One of the most prevalent chronic diseases among elderly population is the Metabolic Syndrome (MetS). The aim of this study was to assess the prevalence of MetS and associated factors among Mexican elderly people. SUBJECTS: Cross-sectional survey carried out in Mexico (2007). A random sample (n=516) of the elderly population (≥65years; 277 female, 239 male) was interviewed. Anthropometric and analytical measurements, and a general questionnaire incorporating questions related to socio-demographic and life-style factors were used. MetS definition AHA/NHLBI/IDF was applied. RESULTS: The prevalence of MetS in the elderly (≥65years) was of 72.9% (75.7% men; 70.4% women). Participants with values above MetS cut-off points were 92.4% (hypertension), 77.8% (hypertriglyceridemia), 77.1% (low HDL-cholesterol), 71.1% (hyperglycaemia), and 65.4% (central obesity). People with MetS showed higher values of anthropometric and biochemical variables than those without MetS, except for the height, cholesterol and creatinine. Mid-high education level (9-12 years), no smokers and former smokers, and Central-Western inhabitants of Mexico were associated with MetS components. BMI status was the main determinant of MetS prevalence and MetS components. CONCLUSION: The reported prevalence of MetS among the elderly Mexican population was higher than those previously obtained in the geographical area, showing a major public health problem in Mexican elders.

Role of ß-adrenoceptors, cAMP phosphodiesterase and external Ca2+ on polyamine-induced relaxation in isolated bovine tracheal strips.

Polyamines relax several smooth muscles and elicit cardiotonic effects in the rat heart via interactions with ß-adrenoceptors. The aim of this work was to establish whether ß(2)-adrenoceptors were involved in polyamine-relaxation of bovine tracheal strips. Endogenous polyamines displaced the specific radioligand, [(3)H]dihydroalprenolol, but spermine was the most potent. The polyamines elicited an acute transient relaxation, which was independent of ß-adrenoceptor activation, followed by a maintained component, which was shown to be dependent on ß-adrenoceptor activation because it was antagonized and reversed by propranolol. Polyamines did not alter salbutamol-induced acute relaxation. Polyamines modified the salbutamol-induced long-term effect on airway tone, which was shown by a partial reversal of ß-adrenoceptor desensitization. This process was delayed by α-difluoromethylornithine, but spermine increased the latency and time of reversal and decreased receptor desensitization. Putrescine prolonged the time-constant without changes in the desensitization. Spermine, but not putrescine, might block Ca(2+) channels, because it relaxed KCl- or electrical stimulated-contractions, which are related to Ca(2+) influx, and the inhibition of cAMP phosphodiesterase activity. These differences might explain the functional differences observed between putrescine and spermine. Therefore, polyamines may modulate airway smooth muscle tone and interfere with the mechanism of receptor desensitization via several mechanisms involving ß(2)-adrenoceptors, Ca(2+) influx and cAMP phosphodiesterase.

Modulatory role of endogenous androgens on airway smooth muscle tone in isolated guinea-pig and bovine trachea; involvement of beta2-adrenoceptors, the polyamine system and external calcium.

Androgens relax several smooth muscles, including the airways. They also contract ileum and myocardium via nongenomic mechanisms. To find out whether androgens modulate airway smooth muscles in different species and further assess their mechanism of action, regarding the role of beta-adrenoceptors, polyamines and extracellular Ca(2+), and the modulation of contraction, 5 alpha-dihydrotestosterone, testosterone and 5 beta-dihydrotestosterone were used. A preliminary study was performed to evaluate the effect of 5 alpha-dihydrotestosterone, a non-aromatisable derivate of testosterone, in isolated guinea-pig trachea and a more exhaustive characterisation was followed in bovine trachea, to also characterise the effect of testosterone and 5 beta-dihydrotestosterone. The androgens elicited a nongenomic epithelium-independent relaxation of the trachea which had been precontracted. In the bovine trachea, the order of potency was: testosterone>5 alpha-dihydrotestosterone=5 beta-dihydrotestosterone. This effect was inversely proportional to the magnitude of carbachol-raised tone and was independent of beta(2)-adrenoceptors, since the beta-blockers, propranolol and ICI-118,551, and beta(2)-adrenoceptor desensitisation did not modify 5 alpha-dihydrotestosterone-elicited relaxation. 5 alpha-Dihydrotestosterone was unable to displace the radiolabel, [(3)H]dihydroalprenolol, from these receptors in the binding assay. Polyamine synthesis was not involved in this androgen effect, since an ornithine decarboxylase inhibitor, alpha-difluoromethylornithine, was ineffective. The androgens were more effective relaxing bovine trachea precontracted by KCl (80 mM), suggesting a calcium entry blockade, as reported for several smooth muscles. This mechanism might be involved in the observed 5 alpha-dihydrotestosterone facilitation of salbutamol-relaxation. Androgens facilitated carbachol-elicited contraction independently of polyamine synthesis, contrary to what has been reported in the ileum. Therefore, androgens modulate tracheal smooth muscle tone which might be of importance in the regulation of airway reactivity.

Role of putrescine on androgen-elicited positive inotropism in the left atrium of rats.

Functional and biochemical studies were performed in isolated left atria of male Wistar rats to study whether endogenous polyamines may mediate androgen-elicited positive inotropism and their relationship with a rise in cAMP during the cardiotonic effect. 5 alpha-Dihydrotestosterone (100 microM) exposure increased intracellular putrescine as determined by HPLC, but it did not increase spermidine and spermine. This effect was antagonized by an inhibitor of ornithine decarboxylase, alpha-difluoromethylornithine (10 mM), suggesting enzyme activation. alpha-Difluoromethylornithine also antagonized androgens-elicited inotropism and the increase in intracellular cAMP. Putrescine (1 to 10 mM) elicited a concentration-dependent positive inotropism associated with the cAMP increase. The prior incubation with putrescine antagonized 5 alpha-dihydrotestosterone-elicited inotropism and did not produce sinergism on intracellular cAMP. Short-term incubation with 5 alpha-dihydrotestosterone or forskolin shifted to the left the cardiotonic effect of isoproterenol, an agonist of beta-adrenoceptors, without any increase in Emax, suggesting that a common mechanism was involved. Therefore, polyamines might modulate the cAMP production associated with the cardiotonic effect of androgens.

Putrescine modulation of acute activation of the beta-adrenergic system in the left atrium of rat.

Endogenous polyamines mediate acute metabolic effects and cardiac hypertrophy associated to beta-adrenoceptor stimulation. The aim of this study is to characterize the role of polyamines on beta-adrenoceptor system mediated responses. To this end, the functional interaction of polyamine modifying drugs on isoproterenol-elicited cardiotonic effect, in isolated left atria of male Wistar rats, and their effects on [(3)H]dihydroalprenolol (DHA) binding on beta-adrenoceptors and on adenylyl cyclase activity of membrane heart were studied. Polyamines interact with beta-adrenoceptors in rat heart, as shown by the displacement of [(3)H]DHA binding. Furthermore, putrescine (but not spermidine or spermine) increased adenylyl cyclase activity, elicited a positive inotropism and increased intracellular cAMP. The putrescine effect on adenylyl cyclase was not antagonized by the beta-adrenoceptors blockers, alprenolol and ICI-118,551, and facilitated the isoproterenol effect. Neither alprenolol, atenolol nor ICI-118,551 antagonized putrescine-elicited positive inotropism. However, the effect was abolished in preparations with desensitized beta-adrenoceptors. alpha-Difluoromethylornithine, an inhibitor of ornithine decarboxylase, antagonized the effect of isoproterenol on inotropism and cAMP increase. In addition, putrescine might elicit effects by mechanisms independent of beta-adrenoceptor system, since in left atria with functional desensitized receptors an interaction with ouabain-elicited cardiotonic effect was observed. These results suggest that putrescine may act as a low affinity agonist on beta-adrenoceptors and modulate acute responses mediated by beta-adrenoceptors. These findings may be of importance in the physiology and in diseases involving cardiac beta-adrenoceptors.

Interaction of androgens with cardiotonic drugs in isolated left atrium of rat.

Pharmacological concentrations of androgens are known to elicit a rapid positive inotropism in isolated left atrium of male rats. Upon short-term exposure to androgens, an increase in intracellular cAMP levels has been observed, though delayed with respect to the time course of contraction, suggesting that other mechanisms may participate in initiating the contraction. Therefore, the interaction of positive inotropism elicited by ouabain, an inhibitor of Na(+)-K(+)-ATPase, and androgens was studied in isolated left atrium of rat. Androgens antagonized ouabain-elicited positive inotropism and increased the basal tone. Vanadate, an inhibitor of the Ca(2+) pump, produced a similar effect as androgens on ouabain-elicited positive inotropism. Therefore, androgens might interact with the Ca(2+) pump and this may explain the increase in basal tone. The conjugation of 5 alpha-dihydrotestosterone with bovine serum albumin produced the same effect, suggesting an extracellular interaction of androgens inhibiting the Na(+)-K(+)-ATPase that could increase intracellular Ca(2+) via the Na(+)-Ca(2+) exchange.

Identification of a new class of inhibitors of the voltage-gated potassium channel, Kv1.3, with immunosuppressant properties.

The voltage-gated potassium channel, K(v)1.3, is a novel target for development of immunosuppressants. Using a functional (86)Rb(+) efflux assay, a new class of high-affinity K(v)1.3 inhibitors has been identified. The initial active in this series, 4-phenyl-4-[3-(2-methoxyphenyl)-3-oxo-2-azaprop-1-yl]cyclohexanone (PAC), which is representative of a disubstituted cyclohexyl (DSC) template, displays a K(i) of ca. 300 nM and a Hill coefficient near 2 in the flux assay and in voltage clamp recordings of K(v)1.3 channels in human T-lymphocytes. PAC displays excellent specificity as it only blocks members of the K(v)1 family of potassium channels but does not affect many other types of ion channels, receptors, or enzyme systems. Block of K(v)1.3 by DSC analogues occurs with a well-defined structure-activity relationship. Substitution at the C-1 ketone of PAC generates trans (down) and cis (up) isomer pairs. Whereas many DSC derivatives do not display selectivity in their interaction with different K(v)1.x channels, trans DSC derivatives distinguish between K(v)1.x channels based on their rates of C-type inactivation. DSC analogues reversibly inhibit the Ca(2+)-dependent pathway of T cell activation in in vitro assays. Together, these data suggest that DSC derivatives represent a new class of immunosuppressant agents and that specific interactions of trans DSC analogues with channel conformations related to C-type inactivation may permit development of selective K(v)1.3 channel inhibitors useful for the safe treatment of autoimmune diseases.

Intracellular cAMP increases during the positive inotropism induced by androgens in isolated left atrium of rat.

Molecular interactions of androgens with the plasma membrane may produce rapid cardiovascular effects that cannot be explained by the classic genomic mechanisms. In this sense, 5 alpha- and 5 beta-dihydrotestosterone-induced an acute positive inotropic effect in isolated left atrium of rat, an effect which may be due to cAMP-dependent mechanisms. To prove this, intracellular levels of cAMP, after exposure to androgens in the organ bath, and binding to beta(1)-adrenoceptors were evaluated. After a 4-min exposure, 5 alpha- and 5 beta-dihydrotestosterone increased cAMP levels from 3.83+/-0.61 to 6.15+/-1.1 and 11.18+/-2.4 pmol cAMP/mg of protein, respectively. These increases were inhibited by atenolol and not modified by treatment of the rats with reserpine. The androgen-induced cAMP increase seems to be produced via an extracellular interaction, because positive inotropism and raised levels of cAMP were produced by 5 alpha-dihydrotestosterone conjugated with bovine serum albumin (BSA). In addition, it is independent of beta(1)-adrenoceptor activation, because neither androgen displaced [(3)H]dihydroalprenolol binding. Therefore, the androgens induced a positive inotropic effect via a postsynaptic effect that increases intracellular levels of cAMP. This effect is modulated by transcriptional mechanisms or by a protein with a short half-life.

Características sociodemográficas de personas que murieron por tuberculosis pulmonar en Veracruz, México, 1993 / Socio-demographic characteristics of people who died from pulmonary tuberculosis in the state of Veracruz, Mexico

Objetivo. Describir las características sociodemográficas y de atención médica de las personas que murieron por tuberculosis pulmonar en el estado de Veracruz, México, durante 1993, y comparar dichas características entre quienes fueron usuarios de servicios de salud públicos y privados. Material y métodos. Se seleccionaro 300 sujetos a través de su certificado de defunción y se realizó una entrevista a su familiares más cercanos utilizando la autopsia verbal. Resultados. La información obtenida señala que aproximadamente a la mitad de personas fallecidas se les diagnóstico tuberculosis por primera vez el mismo año en que murieron. Aproximadamente el 50 por ciento de los familiares informó que aquéllos habían abandonado el tratamiento al menos una vez y el 40 por ciento abusaba en el consumo de alcohol. Las características sociodemográficas muestran que las personas fallecidas pertenecieron a los grupos sociales más desprotegidos, dada la gran proporción de analfabetas o escolaridad nula (35 por ciento) y la carencia de trabajo remunerado (67 por ciento). No se encontraron diferencias importantes entre las que asistieron a los servicios de salud privados y las que acudieron a los oficiales. Conclusiones. Se destacan como hallazgos el alto porcentaje de pacientes que son diagnosticados en etapas muy avanzadas de su enfermedad; el alcoholismo; los efectos indeseables de los medicamentos como causa de abandono; y las enfermedades concomitantes al momento del diagnóstico

Objetivo. Describir las características sociodemográficas y de atención médica de las personas que murieron por tuberculosis pulmonar en el estado de Veracruz, México, durante 1993, y comparar dichas características entre quienes fueron usuarios de servicios de salud públicos y privados. Material y métodos. Se seleccionaron 300 sujetos a través de su certificado de defunción y se realizó una entrevista a sus familiares más cercanos utilizando la autopsia verbal. Resultados. La información obtenida señala que aproximadamente a la mitad de las personas fallecidas se les diagnosticó tuberculosis por primera vez el mismo año en que murieron. Aproximadamente el 50% de los familiares informó que aquéllos habían abandonado el tratamiento al menos una vez y el 40% abusaba en el consumo de alcohol. Las características sociodemográficas muestran que las personas fallecidas pertenecieron a los grupos sociales más des-protegidos, dada la gran proporción de analfabetas o escolaridad nula (35%) y la carencia de trabajo remunerado (67%). No se encontraron diferencias importantes entre las que asistieron a los servicios de salud privados y las que acudieron a los oficiales. Conclusiones. Se destacan como hallazgos el alto porcentaje de pacientes que son diagnosticados en etapas muy avanzadas de su enfermedad; el alcoholismo; los efectos indeseables de los medicamentos como causa de abandono; y las enfermedades concomitantes al momento del diagnóstico.