Dual electro-/pH-responsive nanoparticle/hydrogel system for controlled delivery of anticancer peptide.

An electro-chemo-responsive carrier has been engineered for the controlled release of a highly hydrophilic anticancer peptide, CR(NMe)EKA (Cys-Arg- N-methyl-Glu-Lys-Ala). Remotely controlled on demand release of CR(NMe)EKA, loaded in electro-responsive poly(3,4-ethylenedioxythiophene) (PEDOT) nanoparticles, has been achieved by applying electrical stimuli consisting of constant positive (+0.50 V) or negative voltages (-0.50 V) at pre-defined time intervals. In addition, after loading CR(NMe)EKA/PEDOT nanoparticles into an injectable pH responsive hydrogel formed by phenylboronic acid grafted to chitosan (PBA-CS), the efficiency of the controlled peptide release has increased approximately by a factor of 2.6. The hydration ratio of such hydrogel is significantly lower in acidic environments than in neutral and basic media, which has been attributed to the dissociation of the boronate bonds between polymer chains. Hence, the electro-controlled peptide release from PBA-CS/CR(NMe)EKA/PEDOT hydrogels, in the acidic environment of tumors, combines the effects of the oxidation and reduction of PEDOT chains on the interactions with the peptide and the carrier, with the peptide concentration gradient at the interface between the collapsed hydrogel and the release medium. Furthermore, the peptide released by electro-stimulation preserved its bioactivity assessed by promoting human prostate cancer cells death. Overall, this work is a promising attempt to develop a carrier platform for small hydrophilic anticancer peptides, which delivery rationale is synergistically regulated by the electrical and pH responsiveness of the carrier.

Wireless electrostimulation for cancer treatment: An integrated nanoparticle/coaxial fiber mesh platform.

Cancer, namely breast and prostate cancers, is the leading cause of death in many developed countries. Controlled drug delivery systems are key for the development of new cancer treatment strategies, to improve the effectiveness of chemotherapy and tackle off-target effects. In here, we developed a biomaterials-based wireless electrostimulation system with the potential for controlled and on-demand release of anti-cancer drugs. The system is composed of curcumin-loaded poly(3,4-ethylenedioxythiophene) nanoparticles (CUR/PEDOT NPs), encapsulated inside coaxial poly(glycerol sebacate)/poly(caprolactone) (PGS/PCL) electrospun fibers. First, we show that the PGS/PCL nanofibers are biodegradable, which allows the delivery of NPs closer to the tumoral region, and have good mechanical properties, allowing the prolonged storage of the PEDOT NPs before their gradual release. Next, we demonstrate PEDOT/CUR nanoparticles can release CUR on-demand (65 % of release after applying a potential of -1.5 V for 180 s). Finally, a wireless electrostimulation platform using this NP/fiber system was set up to promote in vitro human prostate cancer cell death. We found a decrease of 67 % decrease in cancer cell viability. Overall, our results show the developed NP/fiber system has the potential to effectively deliver CUR in a highly controlled way to breast and prostate cancer in vitro models. We also show the potential of using wireless electrostimulation of drug-loaded NPs for cancer treatment, while using safe voltages for the human body. We believe our work is a stepping stone for the design and development of biomaterial-based future smarter and more effective delivery systems for anti-cancer therapy.

Production of Blended Poly(acrylonitrile): Poly(ethylenedioxythiophene):Poly(styrene sulfonate) Electrospun Fibers for Neural Applications.

This study describes, for the first time, the successful incorporation of poly(ethylenedioxythiophene):poly(styrene sulfonate) (PEDOT:PSS) in Poly(acrylonitrile) (PAN) fibers. While electroconductive PEDOT:PSS is extremely challenging to electrospun into fibers. Therefore, PAN, a polymer easy to electrospun, was chosen as a carrier due to its biocompatibility and tunable chemical stability when cross-linked, particularly using strong acids. PAN:PEDOT:PSS blends, prepared from PEDOT:PSS Clevios PH1000, were electrospun into fibers (PH1000) with a diameter of 515 ± 120 nm, which after being thermally annealed (PH1000 24H) and treated with heated sulfuric acid (PH1000 H2SO4), resulted in fibers with diameters of 437 ± 109 and 940 ± 210 nm, respectively. The fibers obtained over the stepwise process were characterized through infra-red/Raman spectroscopy and cyclic voltammetry. The final fiber meshes showed enhanced electroconductivity (3.2 × 10-3 S cm-1, four-points-assay). Fiber meshes biocompatibility was evaluated using fibroblasts and neural stem cells (NSCs) following, respectively, the ISO10993 guidelines and standard adhesion/proliferation assay. NSCs cultured on PH1000 H2SO4 fibers presented normal morphology and high proliferation rates (0.37 day-1 vs. 0.16 day-1 for culture plate), indicating high biocompatibility for NSCs. Still, the low initial NSC adhesion of 7% calls for improving seeding methodologies. PAN:PEDOT:PSS fibers, here successful produced for the first time, have potential applications in neural tissue engineering and soft electronics.

Protein-imprinted polymers: How far have "plastic antibodies" come?

Antibodies are highly selective and sensitive, making them the gold standard for recognition affinity tools. However, their production cost is high and their downstream processing is time-consuming. Molecularly imprinted polymers (MIPs) are tailor-made by incorporating specific molecular recognition sites in their structure, thus translating into receptor-like activity mode of action. The interest in molecular imprinting technology, applied to biomacromolecules, has increased in the past decade. MIPs, produced using biomolecules as templates, commonly referred to as "plastic antibodies" or "artificial receptors", have been considered as suitable cheaper and easy to produce alternatives to antibodies. Research on MIPs, designed to recognize proteins or peptides is particularly important, with potential contributions towards biomedical applications, namely biosensors and targeted drug delivery systems. This mini review will cover recent advances on (bio)molecular imprinting technology, where proteins or peptides are targeted or mimicked for sensing and therapeutic applications. Polymerization methods are reviewed elsewhere, being out of the scope of this review. Template selection and immobilization approaches, monomers and applications will be discussed, highlighting possible drawbacks and gaps in research.

Substrates of Opposite Polarities and Downstream Processing for Efficient Production of the Biosurfactant Mannosylerythritol Lipids from Moesziomyces spp.

Biosurfactants can replace fossil-driven surfactants with positive environmental impacts, owing to their low eco-toxicity and high biodegradability. However, their large-scale production and application are restricted by high production costs. Such costs can be reduced using renewable raw materials and facilitated downstream processing. Here, a novel strategy for mannosylerythritol lipid (MEL) production explores the combination of hydrophilic and hydrophobic carbon sources sideways with a novel downstream processing strategy, based on nanofiltration technology. Co-substrate MEL production by Moesziomyces antarcticus was threefold higher than using D-glucose with low levels of residual lipids. The use of waste frying oil instead of soybean oil (SBO) in co-substrate strategy resulted in similar MEL production. Moesziomyces antarcticus cultivations, using 3.9 M of total carbon in substrates, yields 7.3, 18.1, and 20.1 g/L of MEL, and 2.1, 10.0, and 5.1 g/L of residual lipids, for D-glucose, SBO, and a combination of D-Glucose and SBO, respectively. Such approach makes it possible to reduce the amount of oil used, offset by the equivalent molar increase in D-glucose, improving sustainability and decreasing residual unconsumed oil substrates, facilitating downstream processing. Moesziomyces spp. also produces lipases that broken down the oil and, thus, residual unconsumed oils are in the form of free fatty-acids or monoacylglycerol, which are smaller molecules than MEL. Therefore, nanofiltration of ethyl acetate extracts from co-substrate-based culture broths allows to improve MEL purity (ratio of MEL per total MEL and residual lipids) from 66 to 93% using 3-diavolumes.

Electroresponsive and pH-Sensitive Hydrogel as Carrier for Controlled Chloramphenicol Release.

Multiresponsive hydrogels, which are smart soft materials that respond to more than one external stimulus, have emerged as powerful tools for biomedical applications, such as drug delivery. Within this context and with the aim of eliminating the systematic administration of antibiotics, special attention is being paid to the development of systems for controlled delivery of antibiotic for topical treatment of bacterial infections. In this work, an electro-chemo responsive hydrogel able to release chloramphenicol (CAM), a broad spectrum antibiotic also used for anticancer therapy, is proposed. This has been prepared by grafting poly(acrylic acid) (PAA) to sodium alginate (Alg) and in situ encapsulation of poly(3,4-ethylenedioxythiophene) nanoparticles loaded with CAM (PEDOT/CAM NPs), which were obtained by emulsion polymerization. Although the response to electrical stimuli of PEDOT was the main control for the release of CAM from PEDOT/CAM NPs, the release by passive diffusion had a relatively important contribution. Conversely, the passive release of antibiotic from the whole engineered hydrogel system, Alg-g-PAA/PEDOT/CAM, was negligible, whereas significant release was achieved under electrostimulation in an acid environment. Bacterial tests and assays with cancer cells demonstrated that the biological activity of CAM remained after release by electrical stimulation. Notably, the successful dual-response of the developed hydrogel to electrical stimuli and pH changes evidence the great prospect of this smart material in the biomedical field, as a tool to fight against bacterial infections and to provide local cancer treatment.

Dendritic Self-assembled Structures from Therapeutic Charged Pentapeptides.

CRENKA [Cys-Arg-(NMe)Glu-Lys-Ala, where (NMe)Glu refers to N-methyl-Glu], an anti-cancer pentapeptide that induces prostate tumor necrosis and significant reduction in tumor growth, was engineered to increase the resistance to endogenous proteases of its parent peptide, CREKA (Cys-Arg-Glu-Lys-Ala). Considering their high tendency to aggregate, the self-assembly of CRENKA and CREKA into well-defined and ordered structures has been examined as a function of peptide concentration and pH. Spectroscopic studies and atomistic molecular dynamics simulations reveal significant differences between the secondary structures of CREKA and CRENKA. Thus, the restrictions imposed by the (NMe)Glu residue reduce the conformational variability of CRENKA with respect to CREKA, which significantly affects the formation of well-defined and ordered self-assembly morphologies. Aggregates with poorly defined morphology are obtained from solutions with low and moderate CREKA concentrations at pH 4, whereas well-defined dendritic microstructures with fractal geometry are obtained from CRENKA solutions with similar peptide concentrations at pH 4 and 7. The formation of dendritic structures is proposed to follow a two-step mechanism: (1) pseudo-spherical particles are pre-nucleated through a diffusion-limited aggregation process, pre-defining the dendritic geometry, and (2) such pre-nucleated structures coalesce by incorporating conformationally restrained CRENKA molecules from the solution to their surfaces, forming a continuous dendritic structure. Instead, no regular assembly is obtained from solutions with high peptide concentrations, as their dynamics is dominated by strong repulsive peptide-peptide electrostatic interactions, and from solutions at pH 10, in which the total peptide charge is zero. Overall, results demonstrate that dendritic structures are only obtained when the molecular charge of CRENKA, which is controlled through the pH, favors kinetics over thermodynamics during the self-assembly process.

Greener Strategy for Lupanine Purification from Lupin Bean Wastewaters Using a Molecularly Imprinted Polymer.

Lupanine is an alkaloid used in the pharma industry as a building block or precursor in the synthesis of sparteine and also explored for drug synthesis in the pharma industry as a chiral selector. This alkaloid is found in lupin bean processing wastewaters originated from the debittering process to make these beans edible. In this work, a computational chemistry approach was taken to design molecularly imprinted polymers (MIPs) selecting itaconic acid, a biobased building block, as a functional monomer that can provide higher affinities for lupanine. MIP-1 was prepared using lupanine as the template, itaconic acid as a functional monomer, and ethylene glycol dimethacrylate as a cross-linker by bulk polymerization. Lupanine was concentrated from lupin bean wastewater by nanofiltration, extracted with ethyl acetate, and purified using the synthesized MIP. MIP-1 was able to selectively recognize lupanine and improve the purity of lupanine from 78 to 88%, with 82% recovery of the alkaloid. These results show the potential application of this strategy to render the industrial process more sustainable.

Microfluidic device for multiplexed detection of fungal infection biomarkers in grape cultivars.

Early diagnosis of fungal infections, which have seen an increase due to different environmental factors, is essential to an appropriate treatment of the plant by avoiding proliferation of the pathogen without excessive fungicide applications. In this work, we propose a microfluidic based approach to a multiplexed, point-of-need detection system capable of identifying infected grape cultivars. The system relies on the simultaneous detection of three plant hormones: salicylic, azelaic and jasmonic acids with a total assay time under 7 minutes, with LODs of 15 µM, 10 µM and 4.4 nM respectively. The three detection assays are based on optical transduction, with the detection of salicylic and azelaic acids using transmission measurements, while the detection of jasmonic acid is a fluorescence-based assay. The molecular recognition event for each metabolite is different: nanoparticle conjugation for salicylic acid, enzymatic reaction for azelaic acid and antibody-antigen recognition for jasmonic acid. In this work, two cultivars, Trincadeira and Carignan, presented infections with two fungal pathogens, Botrytis cinerea and Erysiphe necator. The grapes were tested using the microfluidic system alongside the benchmark techniques such as, high-performance liquid chromatography and enzyme-linked immunosorbent assay. The microfluidic system was not only capable of distinguishing infected from healthy samples, but also capable of distinguishing between different infection types.

Comparison and Combination of Organic Solvent Nanofiltration and Adsorption Processes: A Mathematical Approach for Mitigation of Active Pharmaceutical Ingredient Losses during Genotoxin Removal.

Active pharmaceutical ingredients (API) are synthesized using highly reactive reagents, catalysts, and solvents. Some of those persist as impurities in the final product and are genotoxic or carcinogenic. The conventional processes used for API purification and isolation are able to achieve the limits imposed by regulatory agencies, but at the expense of significant API losses. Here we report the development of a model to aid in the decision of which dedicated purification process, membrane or adsorption, is most suitable for removal of genotoxic impurities (GTIs), according with a small set of key intrinsic parameters. A hybrid process was developed, combining these two unit operations, to be applied when the use of OSN or adsorption alone result on non-acceptable API losses. Membrane solute rejection and solvent flux was used as parameter for OSN. In the case of adsorption, two isotherm models, Langmuir and Freundlich, were considered. The effect of the recirculation stream and amount of adsorber used on the hybrid process was investigated. Case studies were experimentally validated, confirming that combining the two unit operations can reduce API loss from 24.76% in OSN to 9.76% in a hybrid process. Economic and environmental analyses were performed.

Luminescence studies on green emitting InGaN/GaN MQWs implanted with nitrogen.

We studied the optical properties of metalorganic chemical vapour deposited (MOCVD) InGaN/GaN multiple quantum wells (MQW) subjected to nitrogen (N) implantation and post-growth annealing treatments. The optical characterization was carried out by means of temperature and excitation density-dependent steady state photoluminescence (PL) spectroscopy, supplemented by room temperature PL excitation (PLE) and PL lifetime (PLL) measurements. The as-grown and as-implanted samples were found to exhibit a single green emission band attributed to localized excitons in the QW, although the N implantation leads to a strong reduction of the PL intensity. The green band was found to be surprisingly stable on annealing up to 1400°C. A broad blue band dominates the low temperature PL after thermal annealing in both samples. This band is more intense for the implanted sample, suggesting that defects generated by N implantation, likely related to the diffusion/segregation of indium (In), have been optically activated by the thermal treatment.

Azacalix[2]arene[2]triazine-based receptors bearing carboxymethyl pendant arms on nitrogen bridges: synthesis and evaluation of their coordination ability towards copper(II).

For functional nitrogen-bridged calix(hetero)aromatic platforms to be further used in the design of more sophisticated receptors, the azacalix[2]arene[2]triazine nitrogen bridges were functionalised with methyl bromoacetate. Three new macrocycles with four N-methyl ester pendant arms were straightforwardly prepared in good yields from the undecorated azacalix[2]arene[2]triazine precursors with chlorine, dimethylamine or dihexylamine substituted triazines. These intermediate macrocycles exhibited different reactivity towards the nucleophilic replacement, which was rationalized from the computed electrostatic potential for these molecules. Subsequently, the N-methyl ester appendages were hydrolyzed with each dialkylamine derivative providing a single macrocycle with four carboxylic groups. In contrast, the hydrolysis of the dichlorinated azacalix[2]arene[2]triazine analogue yielded a mixture of three isomeric macrocycles having two N-methyl esters and two carboxylmethyl pendant arms and the triazine chlorine atoms replaced by hydroxyl groups. The coordination ability of two macrocycles with four carboxylic groups for transition metals was evaluated with copper(ii) by UV-vis titrations.

Essential oil characterization of two Azorean Cryptomeria japonica populations and their biological evaluations.

Essential oils from foliage, bark and heartwood of Cryptomeriajaponica D. Don from Azores Archipelago (Portugal) were analyzed by GC and GC-MS. Two populations, of black and reddish heartwood color, were studied. The main compounds found in the foliage of both populations were alpha-pinene (9.6-29.5%), (+)-phyllocladene (3.5-26.5%), ent-kaur-16-ene (0.2-20.6%), sabinene (0.5-19.9%) and limonene (1.4-11.5%), with a large variation in individual compounds from each population. Heartwood oils were characterized by a high content of cubebol (2.8-39.9%) and epi-cubebol (4.1-26.9%) isomers, which were absent in the foliage. Elemol and eudesmol isomers were found in the foliage and heartwood oils, while (+)-phyllocladene was absent in heartwood. Black and reddish bark oils were composed of the diterpenes dehydroferruginol (1.9-5.1%) and ferruginol (2.6-11.5%), along with the sesquiterpenes delta-cadinene (10.4-15.9%), alpha-muurolene (3.3-5.4%), epi-zonarene (4.0-5.0%), cubenol (9.3-14.0%), tau-muurolol (4.8-10.7%), beta-eudesmol (3.0-9.9%), gamma-eudesmol (1.9-7.0%) and hedycariol (1.4-6.2%). Azorean C. japonica oils exhibited significant chemical differences compared with native plants from Asia. The essential oils showed moderate antimicrobial activity against the pathogenic fungus Cryptococcus neoformans and human pathogenic bacteria (especially against multidrug-resistant Mycobacterium tuberculosis). The antimicrobial activity of the essential oils may be attributed to compounds such as ent-kaur-16-ene, (+)-phyllocladene, ferruginol and elemol, which are present in different proportions within the complex oil mixture. These results suggest a potential use for C. japonica oils obtained from wood industry leftovers.

Synthesis and biological studies of pyrazolyl-diamine Pt(II) complexes containing polyaromatic DNA-binding groups.

New [PtCl(pz*NN)](n+) complexes anchored by pyrazolyl-diamine (pz*NN) ligands incorporating anthracenyl or acridine orange DNA-binding groups have been synthesized so as to obtain compounds that would display synergistic effects between platination and intercalation of DNA. Study of their interaction with supercoiled DNA indicated that the anthracenyl-containing complex L(2) Pt displays a covalent type of binding, whereas the acridine orange counterpart L(3) Pt shows a combination of intercalative and covalent binding modes with a strong contribution from the former. L(2) Pt showed a very strong cytotoxic effect on ovarian carcinoma cell lines A2780 and A2780cisR, which are, respectively, sensitive to and resistant to cisplatin. In these cell lines, L(2) Pt is nine to 27 times more cytotoxic than cisplatin. In the sensitive cell line, L(3) Pt showed a cytotoxic activity similar to that of cisplatin, but like L(2) Pt was able significantly to overcome cisplatin cross-resistance. Cell-uptake studies showed that L(2) Pt accumulates preferentially in the cytoplasm, whereas L(3) Pt reaches the cell nucleus more easily, as clearly visualized by time-lapse confocal imaging of live A2870 cells. Altogether, these findings seem to indicate that interaction with biological targets other than DNA might be involved in the mechanism of action of L(2) Pt because this compound, despite having a weaker ability to target the cell nucleus than L(3) Pt, as well as an inferior DNA affinity, is nevertheless more cytotoxic. Furthermore, ultrastructural studies of A2870 cells exposed to L(2) Pt and L(3) Pt revealed that these complexes induce different alterations in cell morphology, thus indicating the involvement of different modes of action in cell death.

Nuclear targeting with cell-specific multifunctional tricarbonyl M(I) (M is Re, (99m)Tc) complexes: synthesis, characterization, and cell studies.

Auger-emitting radionuclides such as (99m)Tc have been the focus of recent studies aiming at finding more selective therapeutic approaches. To explore the potential usefulness of (99m)Tc as an Auger emitter, we have synthesized and biologically evaluated novel multifunctional structures comprising (1) a pyrazolyl-diamine framework bearing a set of donor atoms to stabilize the [M(CO)(3)](+) (M is Re, (99m)Tc) core; (2) a DNA intercalating moiety of the acridine orange type to ensure close proximity of the radionuclide to DNA and to follow the internalization and subcellular trafficking of the compounds by confocal fluorescence microscopy; and (3) a bombesin (BBN) analogue of the type X-BBN[7-14] (where X is SGS, GGG) to provide specificity towards cells expressing the gastrin releasing peptide receptor (GRPr). Of the evaluated (99m)Tc complexes, Tc ( 3 ) containing the GGG-BBN[7-14] peptide showed the highest cellular internalization in GRPr-positive PC3 human prostate tumor cells, presenting a remarkably high nuclear uptake in the same cell line. Live-cell confocal imaging microscopy studies with the congener Re complex, Re ( 3 ), showed a considerable accumulation of fluorescence in the nucleus, with kinetics of uptake similar to that exhibited by Tc ( 3 ). Together, these data show that the acridine orange intercalator and the metal fragment are colocalized in the nucleus, which indicates that they remain connected despite the lysosomal degradation of Tc ( 3 )/Re ( 3 ). These compounds are the first examples of (99m)Tc bioconjugates that combine specific cell targeting with nuclear internalization, a crucial issue to explore use of (99m)Tc in Auger therapy.

Práticas de gestão de recursos humanos e resultados organizacionais: estudos, controvérsias teóricas e metodológicas / Human resource management practices and organizational performance: research, theoretical and methodological controversies

Analisa-se a relação entre práticas de gestão de recursos humanos (PGRH) e resultados organizacionais, a qual tem suscitado o interesse nas comunidades acadêmica e empresarial ao longo de várias décadas. Essa questão tem sido objeto de pesquisa em vários setores da atividade econômica em diversas regiões e países. Os resultados obtidos nesses estudos evidenciaram que o sucesso empresarial está relacionado com a forma como as empresas gerem as pessoas que nelas trabalham. Com base em uma análise de estudos publicados em diversas revistas internacionais nas duas últimas décadas, entre outras na Academy of Management Journal, salientamos as controvérsias teóricas e metodológicas que envolvem essa problemática, bem como as questões em aberto e as tendências da investigação. Sugerimos a adoção de enquadramentos teóricos multidisciplinares para explicar a relação entre PGRH e resultados organizacionais, o recurso e as metodologias qualitativas que permitam recolher informação sobre as PGRH de forma aprofundada. Sugerimos também que é conveniente pesquisar a possível existência de PGRH diferenciadas, no interior da empresa, para grupos funcionais distintos. Propomos ainda um conjunto de indicadores que podem ser utilizados no estudo sistemático das práticas de gestão de recursos humanos de elevado desempenho(AU)

This article examines the impact of human resource management (HRM) practices on organizational performance, which in recent years has seen considerable amounts of research conducted in a number of business sectors in various regions and countries. In general, the studies conclude that there is a positive relationship between the quality of HRM practices and organizational performance. Based on empirical works on this issue, published in a variety of international journals in the last two decades, we analyze the theoretical and methodological controversy, open issues, and future research directions. We suggest: considering multidisciplinary approaches to explain the relationship between high-performance HRM practices and organizational performance; the adoption of qualitative methodologies in order to deepen our understanding of HRM practices in organizations; collecting different HRM data for distinct job groups within the same organization. We also suggest a scale that may be used for a systematic analysis of high-performance human resource management practices(AU)

Práticas de gestão de recursos humanos e resultados organizacionais: estudos, controvérsias teóricas e metodológicas / Human resource management practices and organizational performance: research, theoretical and methodological controversies

Analisa-se a relação entre práticas de gestão de recursos humanos (PGRH) e resultados organizacionais, a qual tem suscitado o interesse nas comunidades acadêmica e empresarial ao longo de várias décadas. Essa questão tem sido objeto de pesquisa em vários setores da atividade econômica em diversas regiões e países. Os resultados obtidos nesses estudos evidenciaram que o sucesso empresarial está relacionado com a forma como as empresas gerem as pessoas que nelas trabalham. Com base em uma análise de estudos publicados em diversas revistas internacionais nas duas últimas décadas, entre outras na Academy of Management Journal, salientamos as controvérsias teóricas e metodológicas que envolvem essa problemática, bem como as questões em aberto e as tendências da investigação. Sugerimos a adoção de enquadramentos teóricos multidisciplinares para explicar a relação entre PGRH e resultados organizacionais, o recurso e as metodologias qualitativas que permitam recolher informação sobre as PGRH de forma aprofundada. Sugerimos também que é conveniente pesquisar a possível existência de PGRH diferenciadas, no interior da empresa, para grupos funcionais distintos. Propomos ainda um conjunto de indicadores que podem ser utilizados no estudo sistemático das práticas de gestão de recursos humanos de elevado desempenho.

This article examines the impact of human resource management (HRM) practices on organizational performance, which in recent years has seen considerable amounts of research conducted in a number of business sectors in various regions and countries. In general, the studies conclude that there is a positive relationship between the quality of HRM practices and organizational performance. Based on empirical works on this issue, published in a variety of international journals in the last two decades, we analyze the theoretical and methodological controversy, open issues, and future research directions. We suggest: considering multidisciplinary approaches to explain the relationship between high-performance HRM practices and organizational performance; the adoption of qualitative methodologies in order to deepen our understanding of HRM practices in organizations; collecting different HRM data for distinct job groups within the same organization. We also suggest a scale that may be used for a systematic analysis of high-performance human resource management practices.

Tricarbonyl M(I) (M = Re, (99m)Tc) complexes bearing acridine fluorophores: synthesis, characterization, DNA interaction studies and nuclear targeting.

New pyrazolyl-diamine ligands with acridine derivatives at the 4-position of the pyrazolyl ring were synthesized and characterized (L1 and L2). Coordination towards the fac-[M(CO)(3)](+) (M = Re, (99m)Tc) led to complexes fac-[M(CO)(3)(kappa(3)-L)] (L = L1: M = Re1, Tc1; L = L2: M = Re2, Tc2). The interaction of the novel pyrazolyl-diamine ligands (L1 and L2) and rhenium(i) complexes (Re1 and Re2) with calf thymus DNA (CT-DNA) was investigated by a variety of techniques, namely UV-visible, fluorescence spectroscopy and circular and linear dichroism. Compounds L1 and Re1 have moderate affinity to CT-DNA and bind to DNA by intercalation, while L2 and Re2 have a poor affinity for CT-DNA. Moreover, LD measurements showed that L1 and Re1 act as perfect intercalators. By confocal fluorescence microscopy we found that L1 and Re1 internalize and localize in the nucleus of B16F1 murine melanoma cells. The congener Tc1 complex also targets the cell nucleus exhibiting a time-dependent cellular uptake and a fast and high nuclear internalization (67.2% of activity after 30 min). Plasmid DNA studies have shown that Tc1 converts supercoiled (sc) puc19 DNA to the open circular (oc) form.

(99m)Tc-tricarbonyl complexes functionalized with anthracenyl fragments: synthesis, characterization, and evaluation of their radiotoxic effects in murine melanoma cells.

Different pyrazolyl-diamine ligands bearing anthracenyl or anthrapyrazole functionalities as DNA-binding groups, at different positions of the chelator framework, were labeled with the fac-[(99m)Tc(CO)(3)](+) core. The resulting complexes, 1-4, are highly stable in vitro under physiologic conditions; all of them have been identified by high-performance liquid chromatography comparison with the Re congeners, with the exception of 3, that is anchored by an anthrapyrazole diamine ligand. Aiming to assess the ability of these complexes to target the cell nucleus and to induce enhanced cell death by effect of the Auger electrons emitted by (99m)Tc, the intracellular distribution and radiotoxicity of 1-4 were evaluated by using B16F1 murine melanoma cells. The radiotoxic effects depend very much on the position used to introduce the DNA-binding group and are well correlated with the nuclear uptake of the compounds. Complex 2, having the anthracenyl substituent at the 4-position of the pyrazolyl ring, rapidly entered the cells and accumulated inside the nucleus, exhibiting the highest radiotoxic effects. This compound induced an apoptotic cellular outcome, and its enhanced radiotoxic effects were certainly due to the Auger electrons emitted by the radiometal in close proximity to DNA.

Efficient conversion of 6-cyanopurines into 6-alkoxyformimidoylpurines.

An extremely simple method for the selective synthesis of 9-aryl and 9-alkyl 6-alkoxy or 6-alkoxyformimidoylpurines from the corresponding 6-cyanopurines is described. The reaction is carried out with methanol or ethanol in the presence of DBU. At room temperature, nucleophilic attack by the primary alcohol occurs selectively on the cyano carbon atom, leading to 6-alkoxyformimidoylpurines in good yields. Heating the reaction mixture at a temperature greater than or equal to 78 degrees C leads to nucleophilic substitution of the substituent in the 6-position by the alkoxy group, generating the corresponding 6-alkoxypurines, also in excellent yields. The 6-alkoxyformimidoylpurines were used as intermediates in the synthesis of 6-carboxamidinopurines by reaction with methylamine (for 9-methylpurine 5a) or methyl ammonium chloride (for 9-arylpurines and 5b and 5c).