Heterometallic Complexes as Models of Enzymatic Active Sites

This dissertation describes studies on two multinucleating ligand architectures: the first scaffold was designed to support tricopper complexes, while the second platform was developed to support tri- and tetrametallic clusters.

In Chapter 2, the synthesis of yttrium (and lanthanide) complexes supported by a tripodal ligand framework designed to bind three copper centers in close proximity is described. Tricopper complexes were shown to react with dioxygen in a 1:1 [Cu₃]/O₂ stoichiometry to form intermediates in which the O–O bond was fully cleaved, as characterized via UV-Vis spectroscopy and determination of the reaction stoichiometry. Pre-arrangement of the three Cu centers was pivotal to cooperative O₂ activation, as mono-copper complexes reacted differently with dioxgyen. The reactivity of the observed intermediates was studied with various substrates (reductants, O-atom acceptors, H-atom donors, Brønsted acids) to determine their properties. In Chapter 3, the reactivity of the same yttrium-tricopper complex with nitric oxide was explored. Reductive coupling to form a trans-hyponitrite complex (characterized by X-ray crystallography) was observed via cooperative reactivity by an yttrium and a copper center on two distinct tetrametallic units. The hyponitrite complex was observed to release nitrous oxide upon treatment with a Brønsted acid, supporting its viability as an intermediate in nitric oxide reduction to nitrous oxide.

In Chapter 4, a different multinucleating ligand scaffold was employed to synthesize heterometallic triiron clusters containing one oxide and one hydroxide bridges. The effects of the redox-inactive, Lewis acidic heterometals on redox potential was studied by cyclic voltammetry, unveiling a linear correlation between redox potential and heterometal Lewis acidity. Further studies on these complexes showed that the Lewis acidity of the redox-inactive metals also affected the oxygen-atom transfer reactivity of these clusters. Comparisons of this reactivity with manganese systems, collaborative efforts to reassign the structures of related manganese oxo-hydroxo clusters, and synthetic attempts to access related dioxo clusters are also described.

In Appendix A, ongoing efforts to synthesize new clusters supported by the same multinucleating ligand platform are described. Studies of novel approaches towards ligand exchange in tetrametallic clusters and incorporation of new supporting and bridging ligand motifs in trinuclear complexes are presented.

Initiatives for the improvement of continuous management training

[EN] Purpose. This work aims to present, from the company viewpoint, a structured account of management proposals and practices directed toward improving the intensity and effectiveness of continuous management training (CMT). Design/methodology/approach. The article takes as its main theoretical referents the Theory of Human Capital, the Resource-Based Vision and the contributions made via the new institutional economy with regard to the problems of information asymmetry between companies, employees and training providers and completes the proposals that derive from this theoretical approach. To do this, experience-based contributions are collected from a selection of company training and HR managers from twelve Basque companies characterised by their strong investment in management training. The methodology used was qualitative and obtained by different qualitative techniques: Focus Groups, Nominal Groups and the Delphi Method, which make up the so-called Hybrid Delphi. Findings and implications. The proposals are aimed at the main agents in training activity: training providers, associations and public agents engaged in management training and, particularly, companies themselves. The initiatives seek above all to increase training market transparency, to improve mutual commitments between companies and managers, and to link training and development with culture and strategic management, so that firms make optimal investment in management training. Originality/value. The methodology used is original, and the contributions are consistent with the theory, have a proven practical utility, and are presented in a hierarchy, which facilitates decision making.

The impact of liberalizing cost-saharing on basic models of network formation

This paper studies the impact of "liberalizing " the cost-sharing of links on some basic models of network formation. This is done in a setting where both doubly supported and singly supported links are possible, and which includes the two seminal models of network formation by Jackson and Wolinsky and Bala and Goyal as extreme cases. In this setting, the notion of pairwise stability is extended and it is proved that liberalizing cost-sharing for doubly supported links widens the range of values of the parameters where the efficient networks formed by such type of links are pairwise stable, while the range of values of the parameters where the efficient networks formed by singly supported links are pairwise stable shrinks, but the region where the latter are e¢ cient and pairwise stable remains the same.

Apaf-1 Inhibitors Protect from Unwanted Cell Death in In Vivo Models of Kidney Ischemia and Chemotherapy Induced Ototoxicity

Background: Excessive apoptosis induces unwanted cell death and promotes pathological conditions. Drug discovery efforts aimed at decreasing apoptotic damage initially targeted the inhibition of effector caspases. Although such inhibitors were effective, safety problems led to slow pharmacological development. Therefore, apoptosis inhibition is still considered an unmet medical need. Methodology and Principal Findings: The interaction between Apaf-1 and the inhibitors was confirmed by NMR. Target specificity was evaluated in cellular models by siRNa based approaches. Cell recovery was confirmed by MTT, clonogenicity and flow cytometry assays. The efficiency of the compounds as antiapoptotic agents was tested in cellular and in vivo models of protection upon cisplatin induced ototoxicity in a zebrafish model and from hypoxia and reperfusion kidney damage in a rat model of hot ischemia. Conclusions: Apaf-1 inhibitors decreased Cytc release and apoptosome-mediated activation of procaspase-9 preventing cell and tissue damage in ex vivo experiments and in vivo animal models of apoptotic damage. Our results provide evidence that Apaf-1 pharmacological inhibition has therapeutic potential for the treatment of apoptosis-related diseases.

Usage of substances and their dosage regimes in pharmacological animal models of schizophrenia

Background: Contrary to what is generally thought schizophrenia is a very common mental health issue. For this, several animal models are used to assess the illness in order to develop a definitive. The most widely spread paradigm is the use of pharmacological models. Aim: The aim of this review is to display which are the most used insults for the assessment of social behaviour related negative symptoms in animal models as well as to ascertain which is the most adequate regime. Design: Literature review. Methods: PubMed database was used for this article by the search of the indexed “schizophrenia”, “animal models”, “social behaviour” and “negative symptoms” descriptors. With the exception of a single article due to it value this review is based on articles from 10 years onwards. Besides, only clinical trials and reviews written in English or Spanish and that had laboratory rodents as target population were accepted. Results: The studies assessed agree that pharmacological models (specially those regarding the NMDA receptor antagonists) are a valuable means for the experimental investigation of negative symptoms in schizophrenia with the necessity to emphasise that only some negative symptoms (anhedonia and social interaction, mainly) can be experimentally assessed. Conclusions: There is not enough evidence regarding the fours aspects of this review. PCP, Ketamine or MK-801 in sub-acute dosage regimes are currently the most indicated insults to mimic schizophrenic symptoms in rodents, although further research in needed, albeit other substances are valuable as well. (In English language exclusively)

A Brief History of Bycatch Management Measures for Eastern Bering Sea Groundfish Fisheries

Bycatch management measures instituted for groundfish fisheries of the eastern Bering Sea have focused on reducing the incidental capture and injury of species traditionally harvested by other fisheries. These species include king crab, Paralithodes and Lithodes spp.; Tanner crab, Chionoecetes spp.; Pacific herring, Clupea harengus pallasi; Pacific halibut, Hippoglossus stenolepis; and Pacific salmon and steelhead trout, Oncorhynchus spp. Collectively, these species are called "prohibited species," as they cannot be retained as bycatch in groundfish fisheries and must be discarded with a minimum of injury.

Biological Analysis of Two Management Options for the Atlantic Menhaden Fishery

Biological implications of two managment options (the closed corridor and the recommended shortened season (Option 7) options) for the Atlantic menhaden, Brevoortia tyrannus, fishery are reported based on purse-seine landings and port sampling data from 1970 to 1984 and captain's daily fishing reports from 1978 to 1982. Large catches of age-O menhaden raise concern for growth overfishing. Area-specific yield-per-recruit analyses are used to investigate the biological consequences of these management options. The closed corridor option indicates coastwide gains in yield-per-recruit ranging from 0.3 to 7.2% depending on changes in fishing activity with most areas showing gains. The shortened fishing season indicates coastwide gains in yield per recruit ranging from O. 4 to 10.2% depending onf ishing year with most geographic areas showing gains. The shortened fishing season option offers the greatest gains when large numbers ofy oung menhaden would be caught late in the fishing year, while gains from the closed corridor option depend on how the fishing fleet responds to that management plan. The shortened season offers greater potential coastwide gains to the fishery, but also may result in greater losses to the North Carolina fall fishery. The analytical approach is applicable to the management of other coastal migratory fish stocks that fall under the Atlantic States Marine Fisheries Commission or other interstate management groups.