GDP-mannose pyrophosphorylase is an efficient target in Xanthomonas citri for citrus canker control.

Xanthomonas citri subsp. citri (Xcc) is a bacterium that causes citrus canker, an economically important disease that results in premature fruit drop and reduced yield of fresh fruit. In this study, we demonstrated the involvement of XanB, an enzyme with phosphomannose isomerase (PMI) and guanosine diphosphate-mannose pyrophosphorylase (GMP) activities, in Xcc pathogenicity. Additionally, we found that XanB inhibitors protect the host against Xcc infection. Besides being deficient in motility, biofilm production, and ultraviolet resistance, the xanB deletion mutant was unable to cause disease, whereas xanB complementation restored wild-type phenotypes. XanB homology modeling allowed in silico virtual screening of inhibitors from databases, three of them being suitable in terms of absorption, distribution, metabolism, excretion, and toxicity (ADME/Tox) properties, which inhibited GMP (but not PMI) activity of the Xcc recombinant XanB protein in more than 50%. Inhibitors reduced citrus canker severity up to 95%, similarly to copper-based treatment. xanB is essential for Xcc pathogenicity, and XanB inhibitors can be used for the citrus canker control. IMPORTANCE: Xcc causes citrus canker, a threat to citrus production, which has been managed with copper, being required a more sustainable alternative for the disease control. XanB was previously found on the surface of Xcc, interacting with the host and displaying PMI and GMP activities. We demonstrated by xanB deletion and complementation that GMP activity plays a critical role in Xcc pathogenicity, particularly in biofilm formation. XanB homology modeling was performed, and in silico virtual screening led to carbohydrate-derived compounds able to inhibit XanB activity and reduce disease symptoms by 95%. XanB emerges as a promising target for drug design for control of citrus canker and other economically important diseases caused by Xanthomonas sp.

Ni lobos sueltos ni corderos atados en las organizaciones sociosanitarias(Parte1) / Neither wolves loose nor lambs tied in social and health organizations (Part 1)

Las dinámicas y lógicas laborales en las organizaciones socio-sanitarias del sector público, son muy complejas. En un texto anterior (la primera parte del presente ensayo) revisamos diferentes posicionamientos teóricos sociológicos (el análisis burocrático de Weber, el estructuralismo constructivista de Bourdieu, la perspectiva pragmática de la crítica de Boltanski), así como también textos de otros autores, tendientes a profundizar la reflexión sobre las prácticas en estas organizaciones. Apelamos además a la música, el baile y las canciones del grupo de rock argentino "Patricio Rey y sus redonditos de ricota" como un ejercicio de intertextualidad metafórica que nos permita vincular dicha reflexión con otras dimensiones de lo social. En este texto (segunda parte), ahondamos en su condición de burocracias profesionales caracterizadas por los amplios márgenes de autonomía con que cuentan sus trabajadores al actuar. Tal indagación se enfoca en la dimensión micropolítica y afectiva de sus prácticas porque, a pesar de ser organizaciones menos piramidales que otras, también se reproducen en ellas dinámicas y lógicas de explotación y alienación que despotencian a sus trabajadores. Proponemos al reconocimiento mutuo, no jerárquico y situacional, como un dinamizador y potenciador de individuos y equipos para desarmar los mecanismos alienantes de capturazgo pasional que a menudo encarnan y perpetúan.

The dynamics and labor logics in socio-sanitary organisations in the public sector are highly complex. In a previous part (the first part of this essay), we explored different theoretical sociological perspectives (Weber's bureaucratic analysis, Bourdieu's constructivist structuralism, Boltanski's critical programmatic perspective), as well as texts from other authors that deepen the reflection on the practices within these organisations. We also drew on the music, dance, and songs of the Argentine rock band "Patricio Rey y sus Redonditos de Ricota" as a metaphorical exercise in intertextuality, allowing us to link this reflection to other social dimensions. In this text (second part), we delve into their status as professional bureaucracies characterized by the ample autonomy enjoyed by their workers in their actions. This inquiry focuses on the micropolitical and affective dimension of their practices because, despite being less pyramidal than others, these organizations also replicate dynamics and logics of exploitation and alienation that disempower their workers. We propose mutual recognition, devoid of hierarchy and situational context, as a catalyst and enhancer for individuals and teams to dismantle the alienating mechanisms of passionate capture that they often embody and perpetuate.

Ligand-based virtual screening, molecular dynamics, and biological evaluation of repurposed drugs as inhibitors of Trypanosoma cruzi proteasome.

Chagas disease is a well-known Neglected Tropical Disease, mostly endemic in continental Latin America, but that has spread to North America and Europe. Unfortunately, current treatments against such disease are ineffective and produce known and undesirable side effects. To find novel effective drug candidates to treat Chagas disease, we uniquely explore the Trypanosoma cruzi proteasome as a recent biological target and, also, apply drug repurposing through different computational methodologies. For this, we initially applied protein homology modeling to build a robust model of proteasome ß4/ß5 subunits, since there is no crystallographic structure of this target. Then, we used it on a drug repurposing via a virtual screening campaign starting with more than 8,000 drugs and including the methodologies: ligand-based similarity, toxicity predictions, and molecular docking. Three drugs were selected concerning their favorable interactions at the protein binding site and subsequently submitted to molecular dynamics simulations, which allowed us to elucidate their behavior and compare such theoretical results with experimental ones, obtained in biological assays also described in this paper.Communicated by Ramaswamy H. Sarma.

Novel chalcones derivatives with potential antineoplastic activity investigated by docking and molecular dynamics simulations.

Glioblastoma is an aggressive primary tumor of the central nervous system (CNS). Is the most aggressive among infiltrative gliomas arising from the CNS. This tumor has low patient survival rate and several studies aiming at developing new drugs have increased. Patients with this cancer type face significant morbidity and mortality. This study evaluated the antineoplastic activity of synthetic chalcones (3a-3f) using in vitro glioblastoma models and molecular modeling. Cytotoxicity assay showed that Astrocitoma Hospital Ofir Loyola No 1 (AHOL1) and Uppsala 87 neoplastic glioblastoma lines (U87) cellular viability were significantly reduced compared to Healthy human fibroblasts cell lines (AN27) when exposed to chalcones. Interaction with the serine amino acid was present in the most promising and the reference binder docking, suggesting its importance inhibiting cell growth. Comparative analysis between the reference ligands and the molecules showed that the amino acid LYS352 present in all fittings, suggesting that this is the main amino acid for interaction with tubulin and are consistent with those in cytotoxicity assay, suggesting antineoplastic potential in glioblastoma. Long trajectory molecular dynamics studies were also carried out in order to investigate stability and conformations amongst the chalcones bound tubulin as well, in comparison to doxorubicin (here used as control), however future studies are needed to further assess the mechanism of inhibition of chalcones used in this investigation.Communicated by Ramaswamy H. Sarma.

Potential colchicine binding site inhibitors unraveled by virtual screening, molecular dynamics and MM/PBSA.

Microtubules have been widely studied in recent decades as an important pharmacological target for the treatment of cancer especially due to its key role in the mitosis process. Among the constituents of the microtubules, αß-tubulin dimers stand out in view of their four distinct interaction sites, including the so-called colchicine binding site (CBS) - a promising target for the development of new tubulin modulators. When compared to other tubulin sites, targeting the CBS is advantageous because this site is able to host ligands with lower molecular volume and lipophilicity, thus reducing the chances of entailing the phenomenon of multiple drug resistance (MDR) - one of the main reasons of failure in chemotherapy. However, colchicine, the first ligand ever discovered with affinity towards the CBS, despite modulating the action of microtubules, has shown toxicity in clinical studies. Therefore, in order to expand the known chemical space of scaffolds capable of interacting with CBS and to design non-toxic colchicine binding site inhibitors, we conducted a robust virtual screening pipeline. This has been rigorously validated and consisted of ligand- and structure-based methodologies, which allowed us to select four promising CBS inhibitors called tubLCQF1-4. These four compounds were also evaluated with long trajectories molecular dynamics simulations and respective results were used for the theoretical determination of the free energy released in the formation of the complexes, using the Molecular Mechanics Poisson-Boltzmann Surface Area (MM/PBSA) methodology.

Revisiting the Proposition of Binding Pockets and Bioactive Poses for GSK-3ß Allosteric Modulators Addressed to Neurodegenerative Diseases.

Glycogen synthase kinase-3 beta (GSK-3ß) is an enzyme pertinently linked to neurodegenerative diseases since it is associated with the regulation of key neuropathological features in the central nervous system. Among the different kinds of inhibitors of this kinase, the allosteric ones stand out due to their selective and subtle modulation, lowering the chance of producing side effects. The mechanism of GSK-3ß allosteric modulators may be considered still vague in terms of elucidating a well-defined binding pocket and a bioactive pose for them. In this context, we propose to reinvestigate and reinforce such knowledge by the application of an extensive set of in silico methodologies, such as cavity detection, ligand 3D shape analysis and docking (with robust validation of corresponding protocols), and molecular dynamics. The results here obtained were consensually consistent in furnishing new structural data, in particular by providing a solid bioactive pose of one of the most representative GSK-3ß allosteric modulators. We further applied this to the prospect for new compounds by ligand-based virtual screening and analyzed the potential of the two obtained virtual hits by quantum chemical calculations. All potential hits achieved will be subsequently tested by in vitro assays in order to validate our approaches as well as to unveil novel chemical entities as GSK-3ß allosteric modulators.

Identification of known drugs as potential SARS-CoV-2 Mpro inhibitors using ligand- and structure-based virtual screening.

Background: The new coronavirus pandemic has had a significant impact worldwide, and therapeutic treatment for this viral infection is being strongly pursued. Efforts have been undertaken by medicinal chemists to discover molecules or known drugs that may be effective in COVID-19 treatment - in particular, targeting the main protease (Mpro) of the virus. Materials & methods: We have employed an innovative strategy - application of ligand- and structure-based virtual screening - using a special compilation of an approved and diverse set of SARS-CoV-2 crystallographic complexes that was recently published. Results and conclusion: We identified seven drugs with different original indications that might act as potential Mpro inhibitors and may be preferable to other drugs that have been repurposed. These drugs will be experimentally tested to confirm their potential Mpro inhibition and thus their effectiveness against COVID-19.

[Health policy and healthcare work: the COVID-19 pandemic as an event?] / Política y trabajo en salud: ¿la pandemia de COVID-19 como acontecimiento?

The COVID-19 pandemic has taken the world by surprise, disturbing the previous situation affecting countries and the situation of their respective States. "Reality" has been redefined by the pandemic's serious effects. Argentina is no exception, and the citizenry and the State itself have thus been challenged to take a unique position based on values and to conduct action to deal with the consequences in both the immediate and medium terms. Therefore, the current Essay views the pandemic in terms of an "event", according to the concept proposed by French philosopher Alain Badiou, and analyzes its implications for individual and collective subjectivation, the values orienting practices, the role of the communications media, and the position taken by the Argentine State; as well as the more specific repercussions on health policy and healthcare work, drawing on other theoretical references from the field. The essay highlights the way "policy" is implemented in the current context: if it fails to mediate in-depth reflection and reorientation of practices, prioritizing the micropolitical sphere, it will result in greater disaggregation and alienation of individual and collective subjects. Thus, the event, more than the pandemic, which is already a fact, should be constituted by the intersubjective articulation of a healthy approach to its consequences, tending towards comprehensiveness and equality in defense of life.

La pandemia de COVID-19 ha irrumpido en el mundo de un modo sorpresivo, trastocando el estado previo de la situación de los países afectados, así como la situación de sus respectivos Estados. "Lo real" se ha resignificado a partir de sus graves derivaciones. La Argentina no constituye una excepción y, por lo tanto, sus ciudadanos y el propio Estado fueron interpelados y convocados a asumir un posicionamiento singular basado en valores, y realizar acciones tendientes a afrontar sus consecuencias, tanto inmediatas como mediatas. Por ello, en el presente Ensayo se piensa la pandemia en términos de "acontecimiento", siguiendo la propuesta conceptual del filósofo francés Alain Badiou, y se analizan sus implicancias sobre la subjetivación individual y colectiva, los valores que orientan las prácticas, el rol de los medios de comunicación, y el posicionamiento asumido por el Estado argentino; así como también sus repercusiones más específicas en la política y el trabajo en salud, apelando a otros referentes teóricos del campo. Se destaca que el modo en que se implementa "la política" en el presente contexto, de no mediar una profunda reflexión y reorientación de las prácticas priorizando lo micropolítico, redundará en una mayor desvinculación y alienación de los sujetos individuales y colectivos. El acontecimiento entonces, más que la pandemia, que ya es un hecho, deberá constituirlo la articulación intersubjetiva de un abordaje saludable de sus consecuencias, tendiente a la integralidad y la igualdad en defensa de la vida.

A pandemia de COVID-19 irrompeu no mundo de forma surpreendente, perturbando o estado anterior da situação dos países afetados, bem como a situação de seus respectivos Estados. "O real" foi ressignificado de suas derivações graves. A Argentina não é exceção e, portanto, seus cidadãos e o próprio Estado foram questionados e convocados a assumir uma posição única baseada em valores e a realizar ações destinadas a enfrentar suas consequências, imediatas e mediatas. Por isso, neste Ensaio a pandemia é pensada em termos de "acontecimento", seguindo a proposta conceitual do filósofo francês Alain Badiou, e suas implicações na subjetivação individual e coletiva, os valores que norteiam as práticas, o papel da mídia e a posição assumida pelo Estado argentino; bem como suas repercussões mais específicas na política de saúde e no trabalho, recorrendo a outros referenciais teóricos da área. Ressalta-se que a forma como a "política" se concretiza no contexto atual, se não houver profunda reflexão e reorientação das práticas priorizando a micropolítica, resultará em um maior desengajamento e alienação dos sujeitos individuais e coletivos. O evento então, mais do que a pandemia, que já é um fato, deve se constituir na articulação intersubjetiva de uma abordagem saudável de suas consequências, visando a integralidade e a igualdade em defesa da vida.

Política y trabajo en salud: ¿la pandemia de COVID-19 como acontecimiento? / Health policy and healthcare work: the COVID-19 pandemic as an event? / Política e trabalho em saúde: a pandemia de COVID-19 como evento?

Resumen: La pandemia de COVID-19 ha irrumpido en el mundo de un modo sorpresivo, trastocando el estado previo de la situación de los países afectados, así como la situación de sus respectivos Estados. "Lo real" se ha resignificado a partir de sus graves derivaciones. La Argentina no constituye una excepción y, por lo tanto, sus ciudadanos y el propio Estado fueron interpelados y convocados a asumir un posicionamiento singular basado en valores, y realizar acciones tendientes a afrontar sus consecuencias, tanto inmediatas como mediatas. Por ello, en el presente Ensayo se piensa la pandemia en términos de "acontecimiento", siguiendo la propuesta conceptual del filósofo francés Alain Badiou, y se analizan sus implicancias sobre la subjetivación individual y colectiva, los valores que orientan las prácticas, el rol de los medios de comunicación, y el posicionamiento asumido por el Estado argentino; así como también sus repercusiones más específicas en la política y el trabajo en salud, apelando a otros referentes teóricos del campo. Se destaca que el modo en que se implementa "la política" en el presente contexto, de no mediar una profunda reflexión y reorientación de las prácticas priorizando lo micropolítico, redundará en una mayor desvinculación y alienación de los sujetos individuales y colectivos. El acontecimiento entonces, más que la pandemia, que ya es un hecho, deberá constituirlo la articulación intersubjetiva de un abordaje saludable de sus consecuencias, tendiente a la integralidad y la igualdad en defensa de la vida.

Abstract: The COVID-19 pandemic has taken the world by surprise, disturbing the previous situation affecting countries and the situation of their respective States. "Reality" has been redefined by the pandemic's serious effects. Argentina is no exception, and the citizenry and the State itself have thus been challenged to take a unique position based on values and to conduct action to deal with the consequences in both the immediate and medium terms. Therefore, the current Essay views the pandemic in terms of an "event", according to the concept proposed by French philosopher Alain Badiou, and analyzes its implications for individual and collective subjectivation, the values orienting practices, the role of the communications media, and the position taken by the Argentine State; as well as the more specific repercussions on health policy and healthcare work, drawing on other theoretical references from the field. The essay highlights the way "policy" is implemented in the current context: if it fails to mediate in-depth reflection and reorientation of practices, prioritizing the micropolitical sphere, it will result in greater disaggregation and alienation of individual and collective subjects. Thus, the event, more than the pandemic, which is already a fact, should be constituted by the intersubjective articulation of a healthy approach to its consequences, tending towards comprehensiveness and equality in defense of life.

Resumo: A pandemia de COVID-19 irrompeu no mundo de forma surpreendente, perturbando o estado anterior da situação dos países afetados, bem como a situação de seus respectivos Estados. "O real" foi ressignificado de suas derivações graves. A Argentina não é exceção e, portanto, seus cidadãos e o próprio Estado foram questionados e convocados a assumir uma posição única baseada em valores e a realizar ações destinadas a enfrentar suas consequências, imediatas e mediatas. Por isso, neste Ensaio a pandemia é pensada em termos de "acontecimento", seguindo a proposta conceitual do filósofo francês Alain Badiou, e suas implicações na subjetivação individual e coletiva, os valores que norteiam as práticas, o papel da mídia e a posição assumida pelo Estado argentino; bem como suas repercussões mais específicas na política de saúde e no trabalho, recorrendo a outros referenciais teóricos da área. Ressalta-se que a forma como a "política" se concretiza no contexto atual, se não houver profunda reflexão e reorientação das práticas priorizando a micropolítica, resultará em um maior desengajamento e alienação dos sujeitos individuais e coletivos. O evento então, mais do que a pandemia, que já é um fato, deve se constituir na articulação intersubjetiva de uma abordagem saudável de suas consequências, visando a integralidade e a igualdade em defesa da vida.

Virtual screening, ADME/Tox predictions and the drug repurposing concept for future use of old drugs against the COVID-19.

The new Coronavirus (SARS-CoV-2) is the cause of a serious infection in the respiratory tract called COVID-19. Structures of the main protease of SARS-CoV-2 (Mpro), responsible for the replication of the virus, have been solved and quickly made available, thus allowing the design of compounds that could interact with this protease and thus to prevent the progression of the disease by avoiding the viral peptide to be cleaved, so that smaller viral proteins can be released into the host's plasma. These structural data are extremely important for in silico design and development of compounds as well, being possible to quick and effectively identify potential inhibitors addressed to such enzyme's structure. Therefore, in order to identify potential inhibitors for Mpro, we used virtual screening approaches based with the structure of the enzyme and two compounds libraries, targeted to SARS-CoV-2, containing compounds with predicted activity against Mpro. In this way, we selected, through docking studies, the 100 top-ranked compounds, which followed to subsequent studies of pharmacokinetic and toxicity predictions. After all the simulations and predictions here performed, we obtained 10 top-ranked compounds that were again in silico analyzed inside the Mpro catalytic site, together some drugs that are being currently investigated for treatment of COVID-19. After proposing and analyzing the interaction modes of these compounds, we submitted one molecule then selected as template to a 2D similarity study in a database containing drugs approved by FDA and we have found and indicated Apixaban as a potential drug for future treatment of COVID-19.

Identification of novel αß-tubulin modulators with antiproliferative activity directed to cancer therapy using ligand and structure-based virtual screening.

Among several strategies related to cancer therapy targeting the modulation of αß-tubulin has shown encouraging findings, more specifically when this is achieved by inhibitors located at the colchicine binding site. In this work, we aim to fish new αß-tubulin modulators through a diverse and rational VS study, and thus, exhibiting the development of two VS pipelines. This allowed us to identify two compounds 5 and 9 that showed IC50 values of 19.69 and 21.97 µM, respectively, towards possible modulation of αß-tubulin, such as assessed by in vitro assays in C6 glioma and HEPG2 cell lines. We also evaluated possible mechanisms of action of obtained hits towards the colchicine binding site of αß-tubulin by using docking approaches. In addition, assessment of the stability of the active (5 and 9) and inactive compounds (3 and 13) within the colchicine binding site was carried out by molecular dynamics (MD) simulations, highlighting the solvent effect and revealing the compound 5 as the most stable in the complex. At last, deep analysis of these results provided some valuable insights on the importance of using mixed ligand- and structure-based strategies in VS campaigns, in order to achieve higher chemical diversity and biological effect as well.

Identification of New Inhibitors with Potential Antitumor Activity from Polypeptide Structures via Hierarchical Virtual Screening.

Leukemias are neoplasms that affect hematopoietic cells, which are developed by genetic alterations (mutations) that lead to the loss of proliferation control mechanisms (maturation and/or cell death). The α4ß1 integrin receptor is a therapeutic target for inflammation, autoimmune diseases and lymphoid tumors. This study was carried out to search through the antagonists-based virtual screening for α4ß1 receptor. Initially, seventeen (17) structures were selected (based on the inhibitory activity values, IC50) and the structure with the best value was chosen as the pivot. The pharmacophoric pattern was determined from the online PharmaGist server and resulted in a model of score value equal to 97.940 with 15 pharmacophoric characteristics that were statistically evaluated via Pearson correlations, principal component analysis (PCA) and hierarchical clustering analysis (HCA). A refined model generated four pharmacophoric hypotheses totaling 1.478 structures set of Zinc_database. After, the pharmacokinetic, toxicological and biological activity predictions were realized comparing with pivot structure that resulted in five (ZINC72088291, ZINC68842860, ZINC14365931, ZINC09588345 and ZINC91247798) structures with optimal in silico predictions. Therefore, future studies are needed to confirm antitumor potential activity of molecules selected this work with in vitro and in vivo assays.

Hierarchical Virtual Screening of Potential Insectides Inhibitors of Acetylcholinesterase and Juvenile Hormone from Temephos.

Aedes aegypti (Linnaeus, 1762; Diptera: Culicidae) is the main vector transmitting viral diseases such as dengue fever, dengue haemorrhagic fever, urban yellow fever, zika and chikungunya. Worldwide, especially in the Americas and Brazil, many cases of dengue have been reported in recent years, which have shown significant growth. The main control strategy is the elimination of the vector, carried out through various education programs, to change human habits, but the most usual is biological control, together with environmental management and chemical control. The most commonly insecticide used is temephos (an organophosphorus compound), but Aedes aegypti populations have shown resistance and the product is highly toxic, so we chose it as a template molecule to perform a ligand-based virtual screening in the ChemBrigde (DIVERSet-CL subcollection) database, searching for derivatives with similarity in shape (ROCS) and electrostatic potential (EON). Thus, fourty-five molecules were filtered based on their pharmacokinetic and toxicological properties and 11 molecules were selected by a molecular docking study, including binding affinity and mode of interaction. The L46, L66 and L68 molecules show potential inhibitory activity for both the insect (-9.28, -10.08 and -6.78 Kcal/mol, respectively) and human (-6.05, 6.25 and 7.2 Kcal/mol respectively) enzymes, as well as the juvenile hormone protein (-9.2; -10.96 and -8.16 kcal/mol, respectively), showing a significant difference in comparison to the template molecule temephos. Molecules L46, L66 and L68 interacted with important amino acids at each catalytic site of the enzyme reported in the literature. Thus, the molecules here investigated are potential inhibitors for both the acetylcholinesterase enzymes and juvenile hormone protein-from insect and humans, characterizing them as a potential insecticide against the Aedes aegypti mosquito.

Pharmacophore and structure-based drug design, molecular dynamics and admet/tox studies to design novel potential pad4 inhibitors.

We have used docking (GLIDE), pharmacophore modeling (Discovery Studio), long trajectory molecular dynamics (Discovery Studio) and ADMET/Tox (QikProp and DEREK) to investigate PAD4 in order to determine potential novel inhibitors and hits. We have carried out virtual screening in the ZINC natural compounds database. Pharmacokinetics and Toxicity of the best hits were assessed using databases implemented in softwares that create models based on chemical structures taking into account consideration about the toxicophoric groups. A wide variety of pharmaceutical relevant properties are determined in order to make decisions about molecular suitability. After screening and analysis, the 6 most promising PAD4 inhibitors are suggested, with strong interactions (pi-stacking, hydrogen bonds, hydrophobic contacts) and suitable pharmacotherapeutic profile as well.

Molecular modeling and statistical analysis in the design of derivatives of human dipeptidyl peptidase IV.

Human dipeptidyl peptidase IV (hDDP-IV) has a considerable importance in inactivation of glucagon-like peptide-1, which is related to type 2 diabetes. One approach for the treatment is the development of small hDDP-IV inhibitors. In order to design better inhibitors, we analyzed 5-(aminomethyl)-6-(2,4-dichlrophenyl)-2-(3,5-dimethoxyphenyl)pyrimidin-4-amine and a set of 24 molecules found in the BindingDB web database for model designing. The analysis of their molecular properties allowed the design of a multiple linear regression model for activity prediction. Their docking analysis allowed visualization of the interactions between the pharmacophore regions and hDDP-IV. After both analyses were performed, we proposed a set of nine molecules in order to predict their activity. Four of them displayed promising activity, and thus, had their docking performed, as well as, the pharmacokinetic and toxicological study. Two compounds from the proposed set showed suitable pharmacokinetic and toxicological characteristics, and therefore, they were considered promising for future synthesis and in vitro studies.

GRIND2-based 3D-QSAR and prediction of activity spectra for symmetrical bis-pyridinium salts with promastigote antileishmanial activity.

Leishmaniasis is a major group of neglected tropical diseases caused by the protozoan parasite Leishmania. About 12 million people are affected in 98 countries and 350 million people worldwide are at risk of infection. Current leishmaniasis treatments rely on a relatively small arsenal of drugs, including amphotericin B, pentamidine and others, which in general have some type of inconvenience. Recently, we have synthesized antileishmanial bis-pyridinium derivatives and symmetrical bis-pyridinium cyclophanes. These compounds are considered structural analogues of pentamidine, where the amidino moiety, protonated at physiological pH, is replaced by a positively charged nitrogen atom as a pyridinium ring. In this work, a statistically significant GRIND2-based 3D-QSAR model was built and biological activity predictions were in silico carried out allowing rationalization of the different activities recently obtained against Leishmania donovani (in L. donovani promastigotes) for a data set of 19 bis-pyridinium compounds. We will emphasize the most important structural requirements to improve the biological activity and probable interactions with the biological receptor as a guide for lead and prototype optimization. In addition, since no information about the actual biological target for this series of active compounds is provided, we have used Prediction of Activity Spectra for Biologically Active Substances to propose our compounds as potential nicotinic α6ß3ß4α5 receptor antagonists. This proposal is reinforced by the high structural similarity observed between our compounds and several anthelmintic drugs in current clinical use, which have the same drug action mechanism here predicted. Such new findings would be confirmed with further and additional experimental assays.

Development of a score based on urinalysis to improve the management of urinary tract infection in children.

BACKGROUND: The need for reducing unnecessary antibiotic treatment is being emphasized in the management of urinary tract infections (UTI), a disease frequent in childhood. An ideal test should provide early diagnosis without the waiting times of urine culture, but even a simple test of exclusion could significantly improve patient management. METHODS: We evaluated the sensitivity, specificity, negative and positive predictive value of automated microscopy IRIS iQ200 combined with the dipstick analyses in children with suspected UTI. Multivariable logistic regression analysis was used to identify the set of variables that best predict positive culture results and develop a numerical risk score. RESULTS: Of 474 consecutive urine samples retrospectively analyzed, 69 were positive at urine culture with prevalence of infection of 14.6%. Parameters significantly associated with the presence of infection in multivariable analysis were age <1 year (p<0.001), leukocyte esterase ≥ 15×10^6/L (p<0.001), number of small particles (ASP) ≥ 5500 × 10^6/L (p<0.001) and bacteria ≥ 3 × 10^6/L (p=0.01). The derived score ranged from 0 to 10, with higher values indicating higher risk of UTI. The area under the score ROC curve was 79% (95% CI 0.72-0.85), and was better than those of the individual urinary chemical and microscopic analyses. CONCLUSIONS: This routine method could improve the management of UTI in children by early identifying patients with low probability of infection, for whom antibiotic treatment can be withheld until the results of urine culture become available.

Homicidios diarios: análisis del discurso periodístico sobre homicidios por armas de fuego. Buenos Aires (Argentina) 2001-2002 / Daily homicides: an analysis of the media discourse on homicides by firearms. Buenos Aires (Argentina) 2001-2002

Durante los años 2001 y 2002, la Argentina atravesó una grave crisis política y social, alcanzando niveles de pobreza y exclusión inauditos. En esos años, los diferentes tipos de violencia urbana mostraron un marcado incremento, en especial los homicidios cometidos mediante el uso de armas de fuego, constituyéndose en una problemática social con importantes repercusiones para la salud pública. El presente artículo es producto de una investigación cualitativa que indagó, mediante un análisis crítico del discurso, las diferentes modalidades con que los diarios La Nación y Clarín dieron cuenta de los hechos acaecidos -durante dicho período- en la Ciudad Autónoma de Buenos Aires. Los datos se obtuvieron de la recopilación de material de hemeroteca, y fueron analizados a partir de una técnica propia referenciada en la Escuela Francesa de Análisis del Discurso. En cuanto a los resultados del estudio, se subraya: el posicionamiento más popular adoptado por el diario Clarín (lógica enunciativa de la verosimilitud), en contraposición con la búsqueda de objetividad de La Nación (lógica de la verificación), asumiendo ambos un carácter complementario en la producción y reproducción social de sentido, al dar cuenta de las muertes por homicidios ocasionadas mediante el uso de armas de fuego.

During 2001 and 2002, Argentina traversed a serious social and political crisis, reaching unprecedented levels of poverty and exclusion. In this time period all types of urban violence -and especially homicides committed using firearms- increased significantly, turning this cause of death into a social issue with important implications for public health. The present article is the product of a qualitative investigation that uses critical discourse analysis to understand the different ways in which the newspapers La Nación and Clarín reported on the events occurring in the aforementioned period in the city of Buenos Aires. Data was obtained by compiling material from the newspaper archives and was analyzed using a unique technique derived from the French School of Discourse Analysis. Two elements of the results were most notable: the more popular position adopted by Clarín newspaper (declarative logic of likelihood), as opposed to the search for objectivity in La Nación (verification logic); both strategies assume a complementary nature in the social production and reproduction of meaning in accounting for deaths by homicides using firearms.