Identification of L. infantum trypanothione synthetase inhibitors with leishmanicidal activity from a (non-biased) in-house chemical library.

Redox homeostasis in trypanosomatids is based on the low-molecular-weight trypanothione, an essential dithiol molecule that is synthetized by trypanothione synthetase (TryS) and maintained in its reduced state by trypanothione disulfide reductase (TryR). The fact that both enzymes are indispensable for parasite survival and absent in the mammalian hosts makes them ideal drug targets against leishmaniasis. Although many efforts have been directed to developing TryR inhibitors, much less attention has been focused on TryS. The screening of an in-house library of 144 diverse molecules using two parallel biochemical assays allowed us to detect 13 inhibitors of L. infantum TryS. Compounds 1 and 3 were characterized as competitive inhibitors with Ki values in the low micromolar range and plausible binding modes for them were identified by automated ligand docking against refined protein structures obtained through computational simulation of an entire catalytic cycle. The proposed binding site for both inhibitors overlaps the polyamine site in the enzyme and, additionally, 1 also occupies part of the ATP site. Compound 4 behaves as a mixed hyperbolic inhibitor with a Ki of 0.8 µM. The activity of 5 is clearly dependent on the concentration of the polyamine substrate, but its kinetic behavior is clearly not compatible with a competitive mode of inhibition. Analysis of the activity of the six best inhibitors against intracellular amastigotes identified 5 as the most potent leishmanicidal candidate, with an EC50 value of 0.6 µM and a selectivity index of 35.

Human influenza A virus causes myocardial and cardiac-specific conduction system infections associated with early inflammation and premature death.

AIMS: Human influenza A virus (hIAV) infection is associated with important cardiovascular complications, although cardiac infection pathophysiology is poorly understood. We aimed to study the ability of hIAV of different pathogenicity to infect the mouse heart, and establish the relationship between the infective capacity and the associated in vivo, cellular and molecular alterations. METHODS AND RESULTS: We evaluated lung and heart viral titres in mice infected with either one of several hIAV strains inoculated intranasally. 3D reconstructions of infected cardiac tissue were used to identify viral proteins inside mouse cardiomyocytes, Purkinje cells, and cardiac vessels. Viral replication was measured in mouse cultured cardiomyocytes. Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were used to confirm infection and study underlying molecular alterations associated with the in vivo electrophysiological phenotype. Pathogenic and attenuated hIAV strains infected and replicated in cardiomyocytes, Purkinje cells, and hiPSC-CMs. The infection was also present in cardiac endothelial cells. Remarkably, lung viral titres did not statistically correlate with viral titres in the mouse heart. The highly pathogenic human recombinant virus PAmut showed faster replication, higher level of inflammatory cytokines in cardiac tissue and higher viral titres in cardiac HL-1 mouse cells and hiPSC-CMs compared with PB2mut-attenuated virus. Correspondingly, cardiac conduction alterations were especially pronounced in PAmut-infected mice, associated with high mortality rates, compared with PB2mut-infected animals. Consistently, connexin43 and NaV1.5 expression decreased acutely in hiPSC-CMs infected with PAmut virus. YEM1L protease also decreased more rapidly and to lower levels in PAmut-infected hiPSC-CMs compared with PB2mut-infected cells, consistent with mitochondrial dysfunction. Human IAV infection did not increase myocardial fibrosis at 4-day post-infection, although PAmut-infected mice showed an early increase in mRNAs expression of lysyl oxidase. CONCLUSION: Human IAV can infect the heart and cardiac-specific conduction system, which may contribute to cardiac complications and premature death.

Revistas de acceso abierto y voracidad editorial en cuidados paliativos / Open access journals and predatory publishing in palliative care

OBJETIVO: Las revistas de acceso abierto han aumentado en los últimos años en todos los ámbitos de la medicina. Una corrupción de este acceso abierto es lo que se ha llamado voracidad editorial (predatory publishing). Pretendemos conocer qué revistas del ámbito de cuidados paliativos están disponibles en acceso abierto y saber si pueden tener perfil de voracidad editorial. MÉTODO: Búsqueda de revistas sobre cuidados paliativos en acceso abierto en buscadores online, registros de revistas y correos electrónicos recibidos de estas publicaciones. Variables registradas: nombre, editorial y página web de la revista, perfil del pago, inclusión en lista de Beall, registro e indexación, correos electrónicos solicitando trabajos, posibilidad de optar a revisor o comité editorial. RESULTADOS: Se encontraron 32 revistas del ámbito de cuidados paliativos con opción total o parcial de acceso abierto; tres de ellas no se encontraban activas. La mediana de coste por publicación de un trabajo original fue de 1.389€. Se encontraron tres perfiles de publicación: nueve revistas de editoriales reconocidas, indexadas e incluso con factor de impacto que admiten la posibilidad de publicar con acceso abierto; siete revistas de editoriales de perfil académico (open access scholarly), algunas indexadas y con factor de impacto, que solo publican con acceso abierto, y 16 revistas sospechosas de voracidad editorial. Encontramos asociación entre la presencia en la lista de Beall y algunos criterios de sospecha de voracidad editorial: ausencia de factor de impacto (p = 0,004) o de indexación en PubMed (p = 0,001); ausencia de registro en OASPA (p = 0,001); envío de correos electrónicos solicitando trabajos (p = 0,05); opción de pago único por periodo de tiempo (p = 0,02), y flexibilidad en el pago según tipo de artículo (p = 0,02). CONCLUSIONES: En el ámbito de los cuidados paliativos hay publicaciones de acceso abierto, algunas de ellas sospechosas de ser voracidad editorial

OBJECTIVE: Open access journals have increased in recent years in all areas of medicine. Predatory publishing is corrupting this open access. The objective of this study is to find out the medical journals that are available in open access in the field of Palliative Care and establish whether they could have a predatory publishing profile. Method: Online search with Google and Bing, and a search in open access journal registries, and e-mails from open access Palliative Care journals. Registered variables: name, editorial and website of the journal, payment profile, inclusion in Beall's list register and indexation, e-mails requesting articles, and possibility to become reviewer or editorial committee. RESULTS: We found 32 journals in the field of Palliative Care with full or partial open access option; three of them were not active. The median original publication fee was 1389€. Globally, three types of journal could be distinguished: 9 journals of recognized publishers, indexed and even with impact factor, that allow the possibility of publishing with open access; 7 open access scholarly journals, some indexed and with impact factor, that only publish open access, and 16 suspected predatory journals. We found an association between the presence of the journal on Beall's list and some suspicion criteria for predatory publishing such as: absence of impact factor (P=.004) or PubMed indexation (P=.001); no OASPA registration (P=.001); e-mails requesting works (P=.05); option of payment per time period (P=.02); and flexibility in payment according to type of article (P=.02). CONCLUSIONS: In the field of Palliative Care there open access publications, however some of them are suspected predatory publishing