A New Oxadiazole-Based Topsentin Derivative Modulates Cyclin-Dependent Kinase 1 Expression and Exerts Cytotoxic Effects on Pancreatic Cancer Cells

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal form of cancer characterized by drug resistance, urging new therapeutic strategies. In recent years, protein kinases have emerged as promising pharmacological targets for the treatment of several solid and hematological tumors. Interestingly, cyclin-dependent kinase 1 (CDK1) is overexpressed in PDAC tissues and has been correlated to the aggressive nature of these tumors because of its key role in cell cycle progression and resistance to the induction of apoptosis. For these reasons, CDK1 is one of the main causes of chemoresistance, representing a promising pharmacological target. In this study, we report the synthesis of new 1,2,4-oxadiazole compounds and evaluate their ability to inhibit the cell growth of PATU-T, Hs766T, and HPAF-II cell lines and a primary PDAC cell culture (PDAC3). Compound 6b was the most active compound, with IC50 values ranging from 5.7 to 10.7 M. Molecular docking of 6b into the active site of CDK1 showed the ability of the compound to interact effectively with the adenosine triphosphate binding pocket. Therefore, we assessed its ability to induce apoptosis (which increased 1.5- and 2-fold in PATU-T and PDAC3 cells, respectively) and to inhibit CDK1 expression, which was reduced to 45% in Hs766T. Lastly, compound 6b passed the ADME prediction, showing good pharmacokinetic parameters. These data demonstrate that 6b displays cytotoxic activity, induces apoptosis, and targets CDK1, supporting further studies for the development of similar compounds against PDAC

Functional Enrichment Analysis of Regulatory Elements

This work has been partially supported by FEDER/Junta de Andalucia-Consejeria de Economia y Conocimiento/(grant CV20-36723), grant PID2020-119032RB-I00, MCIN/AEI/10.13039/501100011033 and FEDER/Junta de Andalucia-Consejeria de Transformacion Economica, Industria, Conocimiento y Universidades (Grant P20_00335).Statistical methods for enrichment analysis are important tools to extract biological information from omics experiments. Although these methods have been widely used for the analysis of gene and protein lists, the development of high-throughput technologies for regulatory elements demands dedicated statistical and bioinformatics tools. Here, we present a set of enrichment analysis methods for regulatory elements, including CpG sites, miRNAs, and transcription factors. Statistical significance is determined via a power weighting function for target genes and tested by theWallenius noncentral hypergeometric distribution model to avoid selection bias. These new methodologies have been applied to the analysis of a set of miRNAs associated with arrhythmia, showing the potential of this tool to extract biological information from a list of regulatory elements. These new methods are available in GeneCodis 4, a web tool able to perform singular and modular enrichment analysis that allows the integration of heterogeneous information.FEDER/Junta de Andalucia-Consejeria de Economia y Conocimiento CV20-36723MCIN/AEI PID2020-119032RB-I00FEDER/Junta de Andalucia-Consejeria de Transformacion Economica, Industria, Conocimiento y Universidades P20_0033

A hybrid of 1-deoxynojirimycin and benzotriazole induces preferential inhibition of butyrylcholinesterase (BuChE) over acetylcholinesterase (AChE)

The synthesis of four heterodimers in which the copper(I)-catalysed azide-alkyne cycloaddition was employed to connect a 1-deoxynojirimycin moiety with a benzotriazole scaffold is reported. The heterodimers were investigated as inhibitors against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The heterodimers displayed preferential inhibition (> 9) of BuChE over AChE in the micromolar concentration range (IC50 = 7–50 µM). For the most potent inhibitor of BuChE, Cornish-Bowden plots were used, which demonstrated that it behaves as a mixed inhibitor. Modelling studies of the same inhibitor demonstrated that the benzotriazole and 1-deoxynojirimycin moiety is accommodated in the peripheral anionic site and catalytic anionic site, respectively, of AChE. The binding mode to BuChE was different as the benzotriazole moiety is accommodated in the catalytic anionic site.publishedVersio

Risk factors for mortality in patients with acute leukemia and bloodstream infections in the era of multiresistance

Objectives: We assess the epidemiology and risk factors for mortality of bloodstream infection (BSI) in patients with acute leukemia (AL). Methods: Prospectively collected data of a cohort study from July 2004 to February 2016. Multivariate analyses were performed. Results: 589 episodes of BSI were documented in 357 AL patients, 55% caused by gram-positive bacteria (coagulase-negative staphylococci 35.7%, Enterococcus spp 10.8%) and 43.5% by gram-negative bacteria (E. coli 21%, PA 12%). We identified 110 (18.7%) multidrug-resistant (MDR) microorganisms, especially MDR-Pseudomonas aeruginosa (7%) and extended-spectrum beta-lactamase producing Enterobacteriaceae (7%). The 30-day mortality was 14.8%. Age (OR 3.1; 95% CI 1.7–5.7); chronic lung disease (4.8; 1.1–21.8); fatal prognosis according to McCabe index (13.9; 6.4–30.3); shock (3.8; 1.9–7.7); pulmonary infection (3.6; 1.3–9.9); and MDR-PA infections with inappropriate treatment (12.8; 4.1–40.5) were related to mortality. MDR-PA BSI was associated to prior antipseudomonal cephalosporin use (9.31; 4.38–19.79); current use of betalactams (2.01; 1.01–4.3); shock (2.63; 1.03–6.7) and pulmonary source of infection (9.6; 3.4–27.21). Conclusions: MDR organisms were commonly isolated in BSI in AL. Inappropriate empiric antibiotic treatment for MDR-PA is the primary factor related to mortality that can be changed. New treatment strategies to improve the coverage of MDR-PA BSI should be considered in those patients with risk factors for this infection

Monitoring monkeypox virus in saliva and air samples in Spain: a cross-sectional study

Background: The transmission of monkeypox virus occurs through direct contact, but transmission through saliva or exhaled droplets and aerosols has not yet been investigated. We aimed to assess the presence of monkeypox virus DNA and infectious virus in saliva samples and droplets and aerosols exhaled from patients infected with monkeypox virus. Methods: We did a cross-sectional study in patients with monkeypox confirmed by PCR who attended two health centres in Madrid, Spain. For each patient, we collected samples of saliva, exhaled droplets within a mask, and aerosols captured by air filtration through newly developed nanofiber filters. We evaluated the presence of monkeypox virus in the samples by viral DNA detection by quantitative PCR (qPCR) and isolation of infectious viruses in cell cultures. Findings: Between May 18 and July 15, 2022, 44 patients with symptomatic monkeypox attended two health centres in Madrid and were included in the study. All were cisgender men, with a median age of 35·0 years (IQR 11·3). We identified high loads of monkeypox virus DNA by qPCR in 35 (85%) of 41 saliva samples. Infectious monkeypox virus was recovered from 22 (67%) of 33 saliva samples positive for monkeypox virus DNA. We also found a significant association between the number of affected cutaneous areas or general symptoms and the viral load present in saliva samples. Droplets exhaled from patients with monkeypox, detected inside a mask, contained monkeypox virus DNA in 32 (71%) of 45 samples, with two of the 32 positive samples showing the presence of the infectious virus. Monkeypox virus DNA in aerosols, collected from the medical consultation room, were detected in 27 (64%) of 42 samples, despite patients wearing an FFP2 mask during the visit. Infectious virus was not recovered from aerosol samples. High levels of monkeypox virus DNA were identified in aerosols collected from a hospital isolation room housing a patient with monkeypox. Interpretation: The identification of high viable monkeypox virus loads in saliva in most patients with monkeypox and the finding of monkeypox virus DNA in droplets and aerosols warrants further epidemiological studies to evaluate the potential relevance of the respiratory route of infection in the 2022 monkeypox virus outbreak.This study was funded by the EU (Nextgeneration EU), Consejo Superior de Investigaciones Científicas (PTI Salud Global), and Ciberinfec (Acción estratégica MKPXV22). We thank Milagros Guerra and the Electron Microscopy Service at CBMSO for their support. We thank the contribution of Grupo Viruela Simio Madrid ISCIII/HCSC/Sandoval.S

A Comprehensive Evaluation of Sdox, a Promising H2S-Releasing Doxorubicin for the Treatment of Chemoresistant Tumors

Sdox is a hydrogen sulfide (H2S)-releasing doxorubicin effective in P-glycoprotein-overexpressing/doxorubicin-resistant tumor models and not cytotoxic, as the parental drug, in H9c2 cardiomyocytes. The aim of this study was the assessment of Sdox drug-like features and its absorption, distribution, metabolism, and excretion (ADME)/toxicity properties, by a multi- and transdisciplinary in silico, in vitro, and in vivo approach. Doxorubicin was used as the reference compound. The in silico profiling suggested that Sdox possesses higher lipophilicity and lower solubility compared to doxorubicin, and the off-targets prediction revealed relevant differences between Dox and Sdox towards several cancer targets, suggesting different toxicological profiles. In vitro data showed that Sdox is a substrate with lower affinity for P-glycoprotein, less hepatotoxic, and causes less oxidative damage than doxorubicin. Both anthracyclines inhibited CYP3A4, but not hERG currents. Unlike doxorubicin, the percentage of zebrafish live embryos at 72 hpf was not affected by Sdox treatment. In conclusion, these findings demonstrate that Sdox displays a more favorable drug-like ADME/toxicity profile than doxorubicin, different selectivity towards cancer targets, along with a greater preclinical efficacy in resistant tumors. Therefore, Sdox represents a prototype of innovative anthracyclines, worthy of further investigations in clinical settings

Incidence of co-infections and superinfections in hospitalised patients with COVID-19: a retrospective cohort study

Objectives: To describe the burden, epidemiology and outcomes of co-infections and superinfections occurring in hospitalized patients with coronavirus disease 2019 (COVID-19). Methods: We performed an observational cohort study of all consecutive patients admitted for ≥48 hours to the Hospital Clinic of Barcelona for COVID-19 (28 February to 22 April 2020) who were discharged or dead. We describe demographic, epidemiologic, laboratory and microbiologic results, as well as outcome data retrieved from electronic health records. Results: Of a total of 989 consecutive patients with COVID-19, 72 (7.2%) had 88 other microbiologically confirmed infections: 74 were bacterial, seven fungal and seven viral. Community-acquired co-infection at COVID-19 diagnosis was uncommon (31/989, 3.1%) and mainly caused by Streptococcus pneumoniae and Staphylococcus aureus. A total of 51 hospital-acquired bacterial superinfections, mostly caused by Pseudomonas aeruginosa and Escherichia coli, were diagnosed in 43 patients (4.7%), with a mean (SD) time from hospital admission to superinfection diagnosis of 10.6 (6.6) days. Overall mortality was 9.8% (97/989). Patients with community-acquired co-infections and hospital-acquired superinfections had worse outcomes. Conclusions: Co-infection at COVID-19 diagnosis is uncommon. Few patients developed superinfections during hospitalization. These findings are different compared to those of other viral pandemics. As it relates to hospitalized patients with COVID-19, such findings could prove essential in defining the role of empiric antimicrobial therapy or stewardship strategies

Formative research contributions to the development of Risaralda

Es importante establecer y visibilizar a los estudiantes los beneficios relacionados con la formación en investigación, dentro de los cuales encontramos el fortalecimiento de las capacidades de liderazgo así como el compromiso activo y las experiencias en independencia y colaboración. Así mismo, la formación integral hacia una mayor apreciación del valor de la literatura disciplinaria, generando de esta manera habilidades de pensamiento crítico, indagación y análisis. Además, esto permite forjar la confianza en sí mismo para presentar las propias ideas a la comunidad, permitiendo al estudiante la preparación de futuras actividades académicas, incluidos estudios de posgrado. La investigación formativa tiene como propósito la difusión de la información existente y permitir que el estudiante la integre como conocimientos, considerándolo como un aprendizaje permanente y necesario. Uno de los principales problemas que debe enfrentar la investigación formativa es el número de docentes con las capacidades necesarias para generar en el estudiante capacidades investigativas, exigiendo al profesor universitario adoptar una actitud contraria al objeto de enseñanza, generando un carácter complejo y dinámico del conocimiento.CONTENTS RETOS DE LA INVESTIGACIÓN EN PREGRADO..................................................5 CHALLENGES OF UNDERGRADUATE RESEARCH.............................................9 German Oved Acevedo Osorio CHAPTER 1 HEALTH AND SPORTS SCIENCES FACTORS ASSOCIATED WITH EXACERBATIONS OR CRISIS EVENTS OF CHRONIC NON COMMUNICABLE DISEASES.........................13 Giovanni García Castro, Sandra Milena Bedoya Gaviria, Isabela Patiño Pulgarín y Valentina Valencia Flórez ORAL ANTICOAGULATION IN PATIENTS WITH NON-VALVULAR ATRIAL FIBRILLATION IN A UNIVERSITY HOSPITAL IN COLOMBIA.....................................................................................................29 María Leonor Galindo Márquez, Adrian Giraldo Diaconeasa, Juan Darío Franco Ramírez y Eduardo Ramírez Vallejo PERFORMANCE IN INITIAL TRAUMAASSESSMENT OF EMERGENCY TEAMS FROM PREHOSPITAL CARE TEAMS..................43 Giovanni García Castro, Yamileth Estrada Berrio, Manuela Aguirre Torres e Isabella Díaz Leal ACADEMIC TRAINING AND WORKING CONDITIONS OF NURSING PROFESSIONALS IN PEREIRA - RISARALDA 2020.....................55 Miguel Ángel Gómez Puerta, Laura Isabel Orozco Santamaría, Alexandra Villa Patiño y Gladys Judith Basto Hernández EFFECTS OF DYNAMIC TAPE WITH ANTI-VALGUS APPLICATION ON VERTICAL JUMP PERFORMANCE IN PHYSICALLY ACTIVE WOMEN: A CASE STUDY ..........................................73 María Camila Arias Castro, Alejandro Gómez Rodas y Ángela María Cifuentes Ríos PROPOSAL OF CARE FOR DIAGNOSTIC PREVALENT NURSES IN AN EMERGENCY DEPARTMENT................................................................89 Tatiana Restrepo Pérez, Jessica Viviana Ríos Uribe, Anyi Daniela Lemos Córdoba, Anyi Katherine Mapura Benjumea and Mónica Margarita Barón Castro FACTORS AND CONCEPTS ASSOCIATED WITH THE INITIATION OF CIGARETTE CONSUMPTION IN UNIVERSITY STUDENTS OF PEREIRA, COLOMBIA ............................................................................... 113 Giovanni García Castro, Claudia Milena Bernal Parra, Natalia Cardona Arroyave, Brahiam Stiven Moreno Bustamante y Daniela Ospina Sierra CHAPTER 2 ECONOMIC, ADMINISTRATIVE AND ACCOUNTING SCIENCES TECHNICAL-FINANCIAL EVALUATION OF BEAN (PHASEOLUS VULGARIS) VARIETY CARGAMANTO IN THE VILLAGE OF THE MUNICIPALITY OF SIBUNDOY IN THE DEPARTMENT OF PUTUMAYO ................................................................................................ 131 Adriana María Cuervo Rubio, Alejandra Arango Baranza IMPLEMENTATION OF THE NIF IN MICRO-ENTERPRISES OF PEREIRA CITY ............................................................................................ 151 Laura Cortes Correa y Nataly Andrea Gutiérrez STRATEGIC FRAMEWORK FOR SUSTAINABLE PRODUCTION IN COLOMBIA................................................................................................... 163 Paulina Murillo Gómez, Manuela Ramírez Osorio, Laura Juliana Rodríguez Henao, Lindy Neth Perea Mosquera, Isabel Redondo Ramírez SUSTAINABLE INNOVATION IN MANUFACTURING INDUSTRY........... 179 Mariana Buitrago Zuleta, Laura Juliana Rodríguez Henao, Lindy Neth Perea Mosquera y Marlen Isabel Redondo Ramírez CHAPTER 3 ARTS, HUMANITIES AND SOCIAL SCIENCES PERSONAL AND FAMILY CHANGES OF UNDERGRADUATE PSYCHOLOGY STUDENTS. IS A PROGRAM IN PSYCHOLOGY A PATHWAY TO PERSONALAND FAMILY CHANGE?...................................197 Linda Michelle De La Torre Álvarez, Mireya Ospina Botero PREGNANT MOTHERS DEPRIVED OF LIBERTY IN COLOMBIA AND MEXICO. A LOOK FROM COMPARATIVE LAW .................................225 Mary Luz Vélez Cárdenas, Katherine Almanza Astrid Milena Calderón Cárdenas CHAPTER 4 NATURAL SCIENCES DIFFERENTIAL DIAGNOSIS AND TREATMENT OF CUTANEOUS LYMPHOMA VS MASTOCYTOMA IN A 9 YEARS OLD CANINE: CASE REPORT...................................................................................................241 Diana Patricia Diaz García, Stephany Loaiza Pulgarín, Rafael R. Santisteban Arenas y Juan C. Ramírez Ante CHAPTER 5 TECHNOLOGÍES AND ENGINEERING STUDY OF INVENTORY-ROUTING PROBLEM IRP.....................................257 Frank Alejandro Hincapié Londoño, Jhonatan Stiven García Guevara y Eliana Mirldey Toro Ocamp

Low-Cost Materials for Do-It-Yourself (DIY) Installation of House Screening against <em>Aedes aegypti</em>

House-screening (HS) using fixed-aluminium frames to reduce the risk of indoor infestation with Aedes aegypti mosquitoes as well as the risk of Aedes-transmitted diseases in communities living in endemic areas. However, the success of this approach has been hindered by the elevated cost of the aluminium-based materials as well as their professional installation, which cannot be afforded by people living under vulnerable conditions. Cost-saving strategies such as the use of low-cost materials including wood, PVC, and Velcro are within the list of HS options available and offered by HS businesses and/or Do-it-yourself (DIY) packages verbi gratia ready-made and ready-to-install mosquito-screens. Here, we evaluated the efficacy of low-cost frames constructed with different materials to protect against Ae. aegypti indoor infestation using experimental huts. The efficacy of protection in preventing female mosquito passing inside the huts of any of the options of frames was high (>93%) compared to the control with no-screen. People’s perceptions on the different materials showed the most “popular” alternative was the frame made of wood (62%). All the prototype-frames of HS made of different materials were effective at blocking Ae. aegypti entering-mosquitoes particularly, low-cost options like magnets and Velcro

Red and Green Algal Origin of Diatom Membrane Transporters: Insights into Environmental Adaptation and Cell Evolution

Membrane transporters (MTs) facilitate the movement of molecules between cellular compartments. The evolutionary history of these key components of eukaryote genomes remains unclear. Many photosynthetic microbial eukaryotes (e.g., diatoms, haptophytes, and dinoflagellates) appear to have undergone serial endosymbiosis and thereby recruited foreign genes through endosymbiotic/horizontal gene transfer (E/HGT). Here we used the diatoms Thalassiosira pseudonana and Phaeodactylum tricornutum as models to examine the evolutionary origin of MTs in this important group of marine primary producers. Using phylogenomics, we used 1,014 diatom MTs as query against a broadly sampled protein sequence database that includes novel genome data from the mesophilic red algae Porphyridium cruentum and Calliarthron tuberculosum, and the stramenopile Ectocarpus siliculosus. Our conservative approach resulted in 879 maximum likelihood trees of which 399 genes show a non-lineal history between diatoms and other eukaryotes and prokaryotes (at the bootstrap value ≥70%). Of the eukaryote-derived MTs, 172 (ca. 25% of 697 examined phylogenies) have members of both red/green algae as sister groups, with 103 putatively arising from green algae, 19 from red algae, and 50 have an unresolved affiliation to red and/or green algae. We used topology tests to analyze the most convincing cases of non-lineal gene history in which red and/or green algae were nested within stramenopiles. This analysis showed that ca. 6% of all trees (our most conservative estimate) support an algal origin of MTs in stramenopiles with the majority derived from green algae. Our findings demonstrate the complex evolutionary history of photosynthetic eukaryotes and indicate a reticulate origin of MT genes in diatoms. We postulate that the algal-derived MTs acquired via E/HGT provided diatoms and other related microbial eukaryotes the ability to persist under conditions of fluctuating ocean chemistry, likely contributing to their great success in marine environments