Polyamines modulate mouse sperm motility.

Polyamines are polycationic molecules which contains two or more amino groups (-NH3+) highly charged at physiological pH, and among them we found spermine, spermidine, putrescine, and cadaverine. They interact with proteins, nucleic acids, modulate Ca2+, K+, and Na+ channels, and protect sperm from oxidative stress. In this work, we evaluate the effect of spermine, spermidine, and putrescine on the total, progressive and kinematic parameters of motility, capacitation, acrosome reaction, also in presence and absence of the dbcAMP, an analogue of the cAMP, and the IBMX, a phosphodiesterase inhibitor. In addition, we evaluated the intracellular concentrations of cAMP [cAMP]i, and performed an in silico analysis between polyamines and the sAC from mouse to predict the possible interaction among them. Our results showed that all polyamines decrease drastically the total, progressive and the kinetic parameters of sperm motility, decrease the capacitation, and only spermidine and putrescine impeded the acquisition of acrosome reaction. Moreover, the effect of polyamines was attenuated but not countered by the addition of db-cAMP and IBMX, suggesting a possible inhibition of the sAC. Also, the presence of polyamines induced a decrease of the [cAMP]i, and the in silico analysis predicted a strong interaction among polyamines and the sAC. Overall, the evidence suggests that probably the polyamines interact and inhibit the activity of the sAC.

Síndrome coronario agudo en el servicio de emergencias del Hospital Universitario Clínico Quirúrgico Comandante Faustino Pérez Hernández, de Matanzas

RESUMEN Introducción: el infarto agudo de miocardio con elevación del segmento ST como parte del síndrome coronario agudo, es una afección frecuente que cursa con una elevada mortalidad. En los últimos años, las enfermedades cardiovasculares han constituido la primera causa de muerte en Cuba, y en 2018 lo fueron en la provincia de Matanzas. Objetivo: caracterizar la morbimortalidad de los pacientes atendidos con síndrome coronario agudo. Materiales y métodos: se realizó un estudio transversal, descriptivo de 106 pacientes ingresados con diagnóstico de síndrome coronario agudo en la Unidad de Cuidados Intensivos Emergentes del Hospital Universitario Clínico Quirúrgico Comandante Faustino Pérez Hernández, de Matanzas, en 2019. Resultados: 83 % de los pacientes llegaron en trasporte sanitario a la Unidad de Emergencia. El grupo de edad más afectado fue el de 70 a 79 años (28,30 %). Predominó el sexo masculino, con 51,89 %. El síndrome coronario agudo con elevación del segmento ST prevaleció sobre el síndrome coronario agudo sin elevación del segmento ST, en un total de 58 pacientes. El mayor número de casos se diagnosticó en los meses de invierno y en horas de la mañana. Prevaleció el tratamiento trombolítico en las primeras seis horas de iniciados los síntomas. Se demostró la desaparición del dolor y la regresión de los cambios electrocardiográficos como resultados de la reperfusión. Las arritmias malignas constituyeron la principal causa de muerte en los pacientes no trombolizados. Conclusiones: el uso de la trombólisis en servicios de emergencias disminuyó la mortalidad en las primeras horas, por enfermedades cardiovasculares, en la provincia de Matanzas en 2019.

ABSTRACT Introduction: Acute myocardium infarct with elevation of the ST segment as a part of the acute coronary syndrome, is a frequent disease that causes a high mortality. In the last years, cardiovascular diseases have constituted the first cause of death in Cuba, and in 2018 they were in the province of Matanzas. Objective: to characterize morbidity and mortality in patients attended with acute coronary syndrome. Materials and methods: a cross-sectional, descriptive study was carried out in 106 patients admitted with diagnosis of acute coronary syndrome in the Unit of Emergent Intensive Care of the Teaching Clinical-surgical Hospital Comandante Faustino Perez Hernandez, of Matanzas, in 2019. Results: 83 % of patients arrived in sanitary transportation to the Emergency Unit. The most affected age group was the one aged 70-79 years (28.30 %). Male sex predominated, with 51.89 %. Acute coronary syndrome with elevation of ST segment prevailed over the acute coronary syndrome without elevation of the ST segment, in a total of 58 patients. The biggest number of cases was diagnosed in the winter months and in the morning. Thrombolytic treatment prevailed in the first six hours after the beginning of the symptoms. There it was demonstrated the disappearance of the pain and the regression of the electrocardiographic changes as a result of the reperfusion. Malignant arrhythmias were the main causes of death in non thrombolyzed patients. Conclusions: the use of thrombolysis in emergency services diminished mortality caused by cardiovascular diseases in the first hours in the province of Matanzas in 1919.

[Osteoclast-Like giant cell bladder carcinoma: Case report]. / Carcinoma de vejiga de células gigantes parecidas a osteoclasto: reporte de caso.

BACKGROUND: Osteoclast-like giant cell bladder carcinomas are an extremely unusual and aggressive histological subtype of urothelial carcinomas. Only 30 cases are reported in the international literature. CLINICAL CASE: A 79-year-old male patient attended our Urology department for a six-month history of macroscopic hematuria. As part of its diagnostic protocol, a CT scan of the abdomen and pelvis with elimination phase was performed, finding a 12-mm filling defect at the level of the posterior wall of the bladder; subsequently, a cystoscopy was performed confirming the presence of a 1.5 cm bladder tumor, which was completely resected. Pathology analysis with hematoxylin and eosin staining revealed a composition of mononuclear cells and osteoclast-like giant cells; immunohistochemistry was positive for epithelial markers CK AE-1 / AE-3, EMA, P53 and CD68. CONCLUSIONS: These tumors are extremely unusual and aggressive. The only diagnostic method is through immunohistochemistry where the presence of epithelial markers for urothelium in neoplastic cells is confirmed. Radical surgical treatment is recommended and to date there is no proven effective adjuvant treatment. Its median overall survival is 15 months.

INTRODUCCIÓN: los carcinomas de vejiga de células gigantes parecidas a osteoclasto son un subtipo histológico extremadamente inusual y agresivo de los carcinomas uroteliales. Solamente se encuentran reportados 30 casos en la literatura internacional. CASO CLÍNICO: un paciente masculino de 79 años acudió a valoración a nuestro departamento de Urología por un cuadro de hematuria macroscópica de seis meses de evolución. Como parte de su protocolo diagnóstico se realizó una TC de abdomen y pelvis con fase de eliminación, encontrando un defecto de llenado de 12 mm a nivel de la pared posterior de la vejiga; posteriormente se realizó una cistoscopia confirmando la presencia de un tumor vesical de 1.5 cm, el cuál fue resecado en su totalidad. El análisis por Patología con tinción de hematoxilina y eosina reveló una composición por células mononucleares y células gigantes parecidas a osteoclasto; la inmunohistoquímica fue positiva para marcadores epiteliales CK AE-1/AE-3, EMA, P53 y CD68. CONCLUSIONES: estos tumores son extremadamente inusuales y agresivos. El único método diagnóstico es a través de inmunohistoquímica en donde se confirme la presencia de marcadores epiteliales para urotelio en las células neoplásicas. Se recomienda un tratamiento quirúrgico radical y a la fecha no existe un tratamiento adyuvante efectivo demostrado. Su supervivencia media global es de 15 meses.

Improving prostate biopsy decision making in Mexican patients: Still a major public health concern.

BACKGROUND: Prostate cancer screening has reduced its mortality in 21%. However, this has also led to an increased number of biopsies in order to establish the diagnosis, many of them unnecessary. Current screening guidelines prioritize use of prostatic magnetic resonance and new biomarkers to reduce unnecessary biopsies, however, their implementation in developing countries screening programs is mainly limited by its costs. OBJECTIVE: We aimed to evaluate Prostate Biopsy Risk Collaborative Group (PBCG) and Prostate Cancer Prevention Trial Risk Calculator (PCPTRC) 2.0 predictions accuracy in Mexican patients in order to guide prostate biopsy decision making and reduce unnecessary biopsies. MATERIALS AND METHODS: We retrospectively analyzed patients between 55 and 90 years old who underwent prostate biopsy in a high-volume center in Mexico between January 2017 and June 2020. Clinical utility of PBCG and PCPTRC 2.0 to predict high-grade prostate cancer (HGPCa) biopsy outcomes was evaluated using decision curve analysis and compared to actual biopsy decision making. Receiver operating characteristics area under the curve (AUC) was used to measure discrimination and external validation. RESULTS: From 687 patients eligible for prostate biopsy, 433 met selections criteria. One hundred and thirty-five (31.17%) patients were diagnosed with HGPCa, 63 (14.54%) with low-grade disease and 235 (54.27%) had a negative biopsy. PCPTRC 2.0 ≥15% threshold got a standardized net benefit (sNB) of 0.70, while PBCG ≥30% and ≥35% had a sNB of 0.27 and 0.15, respectively. Use of both models for guiding prostate biopsy decision resulted in no statistical difference for HGCPa detection rates, while achieved a significant difference in reducing total and unnecessary biopsies. However, this difference was lower (better) for PCPTRC 2.0, being statistically significative when compared against PBCG thresholds. Both models were well calibrated (AUC 0.79) and achieved external validation compared with international cohorts. CONCLUSIONS: Our study is the first to effectively validate both PCPTRC 2.0 and PBCG predictions for the Mexican population, proving that their use in daily practice improves biopsy decision making by accurately predicting HGPCa and limit unnecessary biopsies without representing additional costs to screening programs.

Efficient Detection of Longitudinal Bacteria Fission Using Transfer Learning in Deep Neural Networks.

A very common way to classify bacteria is through microscopic images. Microscopic cell counting is a widely used technique to measure microbial growth. To date, fully automated methodologies are available for accurate and fast measurements; yet for bacteria dividing longitudinally, as in the case of Candidatus Thiosymbion oneisti, its cell count mainly remains manual. The identification of this type of cell division is important because it helps to detect undergoing cellular division from those which are not dividing once the sample is fixed. Our solution automates the classification of longitudinal division by using a machine learning method called residual network. Using transfer learning, we train a binary classification model in fewer epochs compared to the model trained without it. This potentially eliminates most of the manual labor of classifying the type of bacteria cell division. The approach is useful in automatically labeling a certain bacteria division after detecting and segmenting (extracting) individual bacteria images from microscopic images of colonies.

The analysis on the human protein domain targets and host-like interacting motifs for the MERS-CoV and SARS-CoV/CoV-2 infers the molecular mimicry of coronavirus.

The MERS-CoV, SARS-CoV, and SARS-CoV-2 are highly pathogenic viruses that can cause severe pneumonic diseases in humans. Unfortunately, there is a non-available effective treatment to combat these viruses. Domain-motif interactions (DMIs) are an essential means by which viruses mimic and hijack the biological processes of host cells. To disentangle how viruses achieve this process can help to develop new rational therapies. Data mining was performed to obtain DMIs stored as regular expressions (regexp) in 3DID and ELM databases. The mined regexp information was mapped on the coronaviruses' proteomes. Most motifs on viral protein that could interact with human proteins are shared across the coronavirus species, indicating that molecular mimicry is a common strategy for coronavirus infection. Enrichment ontology analysis for protein domains showed a shared biological process and molecular function terms related to carbon source utilization and potassium channel regulation. Some of the mapped motifs were nested on B, and T cell epitopes, suggesting that it could be as an alternative way for reverse vaccinology. The information obtained in this study could be used for further theoretic and experimental explorations on coronavirus infection mechanism and development of medicines for treatment.

Computational Drug Repositioning for Chagas Disease Using Protein-Ligand Interaction Profiling.

Chagas disease, caused by Trypanosoma cruzi (T. cruzi), affects nearly eight million people worldwide. There are currently only limited treatment options, which cause several side effects and have drug resistance. Thus, there is a great need for a novel, improved Chagas treatment. Bifunctional enzyme dihydrofolate reductase-thymidylate synthase (DHFR-TS) has emerged as a promising pharmacological target. Moreover, some human dihydrofolate reductase (HsDHFR) inhibitors such as trimetrexate also inhibit T. cruzi DHFR-TS (TcDHFR-TS). These compounds serve as a starting point and a reference in a screening campaign to search for new TcDHFR-TS inhibitors. In this paper, a novel virtual screening approach was developed that combines classical docking with protein-ligand interaction profiling to identify drug repositioning opportunities against T. cruzi infection. In this approach, some food and drug administration (FDA)-approved drugs that were predicted to bind with high affinity to TcDHFR-TS and whose predicted molecular interactions are conserved among known inhibitors were selected. Overall, ten putative TcDHFR-TS inhibitors were identified. These exhibited a similar interaction profile and a higher computed binding affinity, compared to trimetrexate. Nilotinib, glipizide, glyburide and gliquidone were tested on T. cruzi epimastigotes and showed growth inhibitory activity in the micromolar range. Therefore, these compounds could lead to the development of new treatment options for Chagas disease.

Pranlukast Antagonizes CD49f and Reduces Stemness in Triple-Negative Breast Cancer Cells.

INTRODUCTION: Cancer stem cells (CSCs) drive the initiation, maintenance, and therapy response of breast tumors. CD49f is expressed in breast CSCs and functions in the maintenance of stemness. Thus, blockade of CD49f is a potential therapeutic approach for targeting breast CSCs. In the present study, we aimed to repurpose drugs as CD49f antagonists. MATERIALS AND METHODS: We performed consensus molecular docking using a subdomain of CD49f that is critical for heterodimerization and a collection of pharmochemicals clinically tested. Molecular dynamics simulations were employed to further characterize drug-target binding. Using MDA-MB-231 cells, we evaluated the effects of potential CD49f antagonists on 1) cell adhesion to laminin; 2) mammosphere formation; and 3) cell viability. We analyzed the effects of the drug with better CSC-selectivity on the activation of CD49f-downstream signaling by Western blot (WB) and co-immunoprecipitation. Expressions of the stem cell markers CD44 and SOX2 were analyzed by flow cytometry and WB, respectively. Transactivation of SOX2 promoter was evaluated by luciferase reporter assays. Changes in the number of CSCs were assessed by limiting-dilution xenotransplantation. RESULTS: Pranlukast, a drug used to treat asthma, bound to CD49f in silico and inhibited the adhesion of CD49f+ MDA-MB-231 cells to laminin, indicating that it antagonizes CD49f-containing integrins. Molecular dynamics analysis showed that pranlukast binding induces conformational changes in CD49f that affect its interaction with ß1-integrin subunit and constrained the conformational dynamics of the heterodimer. Pranlukast decreased the clonogenicity of breast cancer cells on mammosphere formation assay but had no impact on the viability of bulk tumor cells. Brief exposure of MDA-MB-231 cells to pranlukast altered CD49f-dependent signaling, reducing focal adhesion kinase (FAK) and phosphatidylinositol 3-kinase (PI3K) activation. Further, pranlukast-treated cells showed decreased CD44 and SOX2 expression, SOX2 promoter transactivation, and in vivo tumorigenicity, supporting that this drug reduces the frequency of CSC. CONCLUSION: Our results support the function of pranlukast as a CD49f antagonist that reduces the CSC population in triple-negative breast cancer cells. The pharmacokinetics and toxicology of this drug have already been established, rendering a potential adjuvant therapy for breast cancer patients.

Influence of Echeveria gibbiflora DC aqueous crude extract on mouse sperm energy metabolism and calcium-dependent channels.

ETHNOPHARMACOLOGY RELEVANCE: In traditional Mexican medicine, Echeveria gibbiflora DC has been used as a vaginal post-coital rinse to prevent pregnancy. The aqueous crude extract (OBACE) induces sperm immobilization/agglutination and a hypotonic-like effect, likely attributed to the high concentration of calcium bis-(hydrogen-1-malate) hexahydrate [Ca2+ (C4H5O5)2•6H2O]. Likewise, OBACE impedes the increase of [Ca2+]i during capacitation. AIM OF THE STUDY: Evaluate the effect of OBACE on sperm energy metabolism and the underlying mechanism of action on sperm-specific channel. MATERIAL AND METHODS: In vitro, we quantified the mouse sperm immobilization effect and the antifertility potential of OBACE. The energetic metabolism status was also evaluated by assessing the ATP levels, general mitochondrial activity, mitochondrial membrane potential, and enzymatic activity of three key enzymes of energy metabolism. Furthermore, the effect of the ion efflux of Cl- and K+, as well as the pHi, were investigated in order to elucidate which channel is suitable to perform an in silico study. RESULTS: Total and progressive motility notably decreased, as did fertility rates. ATP levels, mitochondrial activity and membrane potential were reduced. Furthermore, the activities of the three enzymes decreased. Neither Cl- or K+ channels activities were affected at low concentrations of OBACE; nevertheless, pHi did not alkalinize. Finally, an in silico analysis was performed between the Catsper channel and calcium bis-(hydrogen-1-malate) hexahydrate, which showed a possible blockade of this sperm cation channel. CONCLUSION: The results were useful to elucidate the effect of OBACE and to propose it as a future male contraceptive.

In Silico Analysis of Homologous Heterodimers of Cruzipain-Chagasin from Structural Models Built by Homology.

The present study gives an overview of the binding energetics of the homologous heterodimers of cruzipain-chagasin based on the binding energy (ΔGb) prediction obtained with FoldX. This analysis involves a total of 70 homologous models of the cruzipain-chagasin complex which were constructed by homology from the combinatory variation of nine papain-like cysteine peptidase structures and seven cysteine protease inhibitor structures (as chagasin-like and cystatin-like inhibitors). Only 32 systems have been evaluated experimentally, ΔGbexperimental values previously reported. Therefore, the result of the multiple analysis in terms of the thermodynamic parameters, are shown as relative energy |ΔΔG| = |ΔGbfrom FoldX - ΔGbexperimental|. Nine models were identified that recorded |ΔΔG| < 1.3, five models to 2.8 > |ΔΔG| > 1.3 and the other 18 models, values of |ΔΔG| > 2.8. The energetic analysis of the contribution of ΔH and ΔS to ΔGb to the 14-molecular model presents a ΔGb mostly ΔH-driven at neutral pH and at an ionic strength (I) of 0.15 M. The dependence of ΔGb(I,pH) at 298 K to the cruzipain-chagasin complex predicts a linear dependence of ΔGb(I). The computational protocol allowed the identification and prediction of thermodynamics binding energy parameters for cruzipain-chagasin-like heterodimers.

Proteome-wide analysis of human motif-domain interactions mapped on influenza a virus.

BACKGROUND: The influenza A virus (IAV) is a constant threat for humans worldwide. The understanding of motif-domain protein participation is essential to combat the pathogen. RESULTS: In this study, a data mining approach was employed to extract influenza-human Protein-Protein interactions (PPI) from VirusMentha,Virus MINT, IntAct, and Pfam databases, to mine motif-domain interactions (MDIs) stored as Regular Expressions (RegExp) in 3DID database. A total of 107 RegExp related to human MDIs were searched on 51,242 protein fragments from H1N1, H1N2, H2N2, H3N2 and H5N1 strains obtained from Virus Variation database. A total 46 MDIs were frequently mapped on the IAV proteins and shared between the different strains. IAV kept host-like MDIs that were associated with the virus survival, which could be related to essential biological process such as microtubule-based processes, regulation of cell cycle check point, regulation of replication and transcription of DNA, etc. in human cells. The amino acid motifs were searched for matches in the immune epitope database and it was found that some motifs are part of experimentally determined epitopes on IAV, implying that such interactions exist. CONCLUSION: The directed data-mining method employed could be used to identify functional motifs in other viruses for envisioning new therapies.

Repositioning FDA Drugs as Potential Cruzain Inhibitors from Trypanosoma cruzi: Virtual Screening, In Vitro and In Vivo Studies.

Chagas disease (CD) is a neglected disease caused by the parasite Trypanosoma cruzi, which affects underdeveloped countries. The current drugs of choice are nifurtimox and benznidazole, but both have severe adverse effects and less effectivity in chronic infections; therefore, the need to discover new drugs is essential. A computer-guided drug repositioning method was applied to identify potential FDA drugs (approved and withdrawn) as cruzain (Cz) inhibitors and trypanocidal effects were confirmed by in vitro and in vivo studies. 3180 FDA drugs were virtually screened using a structure-based approach. From a first molecular docking analysis, a set of 33 compounds with the best binding energies were selected. Subsequent consensus affinity binding, ligand amino acid contact clustering analysis, and ranked position were used to choose four known pharmacological compounds to be tested in vitro. Mouse blood samples infected with trypomastigotes from INC-5 and NINOA strains were used to test the trypanocidal effect of four selected compounds. Among these drugs, one fibrate antilipemic (etofyllin clofibrate) and three ß-lactam antibiotics (piperacillin, cefoperazone, and flucloxacillin) showed better trypanocidal effects (LC50 range 15.8-26.1 µg/mL) in comparison with benznidazole and nifurtimox (LC50 range 33.1-46.7 µg/mL). A short-term in vivo evaluation of these compounds showed a reduction of parasitemia in infected mice (range 90-60%) at 6 h, but this was low compared to benznidazole (50%). This work suggests that four known FDA drugs could be used to design and obtain new trypanocidal agents.

An in vitro and in vivo evaluation of new potential trans-sialidase inhibitors of Trypanosoma cruzi predicted by a computational drug repositioning method.

Chagas disease is one of the most important neglected parasitic diseases afflicting developed and undeveloped countries. There are currently limited options for inexpensive and secure pharmacological treatment. In this study, we employed a structure-based virtual screening protocol for 3180 FDA-approved drugs for repositioning of them as potential trans-sialidase inhibitors. In vitro and in vivo evaluations were performed for the selected drugs against trypomastigotes from the INC-5 and NINOA strains of T. cruzi. Also, inhibition of sialylation by the trans-sialidase enzyme reaction was evaluated using high-performance anion-exchange chromatography with pulse amperometric detection to confirm the mechanism of action. Results from the computational study showed 38 top drugs with the best binding-energies. Four compounds with antihistaminic, anti-hypertensive, and antibiotic properties showed better trypanocidal effects (LC50 range = 4.5-25.8 µg/mL) than the reference drugs, nifurtimox and benznidazole (LC50 range = 36.1-46.8 µg/mL) in both strains in the in vitro model. The anti-inflammatory, sulfasalazine showed moderate inhibition (37.6%) of sialylation in a trans-sialidase enzyme inhibition reaction. Sulfasalazine also showed the best trypanocidal effects in short-term in vivo experiments on infected mice. This study suggests for the first time that the anti-inflammatory sulfasalazine could be used as a lead compound to develop new trans-sialidase inhibitors.

Theoretical and experimental study of polycyclic aromatic compounds as ß-tubulin inhibitors.

In this work, through a docking analysis of compounds from the ZINC chemical library on human ß-tubulin using high performance computer cluster, we report new polycyclic aromatic compounds that bind with high energy on the colchicine binding site of ß-tubulin, suggesting three new key amino acids. However, molecular dynamic analysis showed low stability in the interaction between ligand and receptor. Results were confirmed experimentally in in vitro and in vivo models that suggest that molecular dynamics simulation is the best option to find new potential ß-tubulin inhibitors. Graphical abstract Bennett's acceptance ratio (BAR) method.

JADOPPT: java based AutoDock preparing and processing tool.

Motivation: AutoDock is a very popular software package for docking and virtual screening. However, currently it is hard work to visualize more than one result from the virtual screening at a time. To overcome this limitation we have designed JADOPPT, a tool for automatically preparing and processing multiple ligand-protein docked poses obtained from AutoDock. It allows the simultaneous visual assessment and comparison of multiple poses through clustering methods. Moreover, it permits the representation of reference ligands with known binding modes, binding site residues, highly scoring regions for the ligand, and the calculated binding energy of the best ranked results. Availability and Implementation: JADOPPT, supplementary material (Case Studies 1 and 2) and video tutorials are available at http://visualanalytics.land/cgarcia/JADOPPT.html. Contacts: carlosgarcia@usal.es or pelaez@usal.es. Supplementary information: Supplementary data are available at Bioinformatics online.

Virtual screening-driven repositioning of etoposide as CD44 antagonist in breast cancer cells.

CD44 is a receptor for hyaluronan (HA) that promotes epithelial-to-mesenchymal transition (EMT), induces cancer stem cell (CSC) expansion, and favors metastasis. Thus, CD44 is a target for the development of antineoplastic agents. In order to repurpose drugs as CD44 antagonists, we performed consensus-docking studies using the HA-binding domain of CD44 and 11,421 molecules. Drugs that performed best in docking were examined in molecular dynamics simulations, identifying etoposide as a potential CD44 antagonist. Ligand competition and cell adhesion assays in MDA-MB-231 cells demonstrated that etoposide decreased cell binding to HA as effectively as a blocking antibody. Etoposide-treated MDA-MB-231 cells developed an epithelial morphology; increased their expression of E-cadherin; and reduced their levels of EMT-associated genes and cell migration. By gene expression analysis, etoposide reverted an EMT signature similarly to CD44 knockdown, whereas other topoisomerase II (TOP2) inhibitors did not. Moreover, etoposide decreased the proportion of CD44+/CD24- cells, lowered chemoresistance, and blocked mammosphere formation. Our data indicate that etoposide blocks CD44 activation, impairing key cellular functions that drive malignancy, thus rendering it a candidate for further translational studies and a potential lead compound in the development of new CD44 antagonists.

Draft Genome Sequence of Aeromonas caviae Strain 429865 INP, Isolated from a Mexican Patient.

Aeromonas caviae is an emerging human pathogen. Here, we report the draft genome sequence of Aeromonas caviae strain 429865 INP which shows the presence of various putative virulence-related genes.

Associations of SNPs located at candidate genes to bovine growth traits, prioritized with an interaction networks construction approach.

BACKGROUND: For most domestic animal species, including bovines, it is difficult to identify causative genetic variants involved in economically relevant traits. The candidate gene approach is efficient because it investigates genes that are expected to be associated with the expression of a trait and defines whether the genetic variation present in a population is associated with phenotypic diversity. A potential limitation of this approach is the identification of candidates. This study used a bioinformatics approach to identify candidate genes via a search guided by a functional interaction network. RESULTS: A functional interaction network tool, BosNet, was constructed for Bos taurus. Predictions for candidate genes were performed using the guilt-by-association principle in BosNet. Association analyses identified five novel markers within BosNet-prioritized genes that had significant effects on different growth traits in Charolais and Brahman cattle. CONCLUSIONS: BosNet is an excellent tool for the identification of single nucleotide polymorphisms that are potentially associated with complex traits.

Anti-Trypanosoma cruzi and anti-leishmanial activity by quinoxaline-7-carboxylate 1,4-di-N-oxide derivatives.

In this work, a novel series of ethyl and methyl quinoxaline-7-carboxylate 1,4-di-N-oxide derivatives were evaluated in vitro on Trypanosoma cruzi trypomastigotes and Leishmania mexicana promastigotes, and cytotoxicity activity in murine macrophages was tested. In silico molecular docking simulations of trypanothione reductase were also done. Three compounds of 33 quinoxaline-7-carboxylate 1,4-di-N-oxide derivatives showed better anti-T. cruzi activity than nifurtimox and beznidazole; two compounds had better anti-leishmanial activity that amphotericin-B, and two compounds showed better activity against both parasites than reference drugs. Compounds M2, M7, M8 and E5, showed low cytotoxic activity on the host cell. The in silico studies suggest that compound M2 is a potential trypanothione reductase inhibitor.

A viral-human interactome based on structural motif-domain interactions captures the human infectome.

Protein interactions between a pathogen and its host are fundamental in the establishment of the pathogen and underline the infection mechanism. In the present work, we developed a single predictive model for building a host-viral interactome based on the identification of structural descriptors from motif-domain interactions of protein complexes deposited in the Protein Data Bank (PDB). The structural descriptors were used for searching, in a database of protein sequences of human and five clinically important viruses; therefore, viral and human proteins sharing a descriptor were predicted as interacting proteins. The analysis of the host-viral interactome allowed to identify a set of new interactions that further explain molecular mechanism associated with viral infections and showed that it was able to capture human proteins already associated to viral infections (human infectome) and non-infectious diseases (human diseasome). The analysis of human proteins targeted by viral proteins in the context of a human interactome showed that their neighbors are enriched in proteins reported with differential expression under infection and disease conditions. It is expected that the findings of this work will contribute to the development of systems biology for infectious diseases, and help guide the rational identification and prioritization of novel drug targets.