Titanocene–gold complexes containing N-heterocyclic carbene ligands inhibit growth of prostate, renal, and colon cancers in vitro

We report on the synthesis, characterization, and stability studies of new titanocene complexes containing a methyl group and a carboxylate ligand (mba = −OC(O)-p-C6H4-S−) bound to gold(I)−N-heterocyclic carbene fragments through the thiolate group: [(η5 -C5H5)2TiMe(μ-mba)Au(NHC)]. The cytotoxicities of the heterometallic compounds along with those of novel monometallic gold−N-heterocyclic carbene precursors [(NHC)Au(mbaH)] have been evaluated against renal, prostate, colon, and breast cancer cell lines. The highest activity and selectivity and a synergistic effect of the resulting heterometallic species was found for the prostate and colon cancer cell lines. The colocalization of both titanium and gold metals (1:1 ratio) in PC3 prostate cancer cells was demonstrated for the selected compound 5a, indicating the robustness of the heterometallic compound in vitro. We describe here preliminary mechanistic data involving studies on the interaction of selected mono- and bimetallic compounds with plasmid (pBR322) used as a model nucleic acid and the inhibition of thioredoxin reductase in PC3 prostate cancer cells. The heterometallic compounds, which are highly apoptotic, exhibit strong antimigratory effects on the prostate cancer cell line PC3

HCV eradication with IFN-based therapy does not completely restore gene expression in PBMCs from HIV/HCV-coinfected patients.

To evaluate the impact of hepatitis C virus (HCV) elimination via interferon (IFN)-based therapy on gene expression profiles related to the immune system in HIV/HCV-coinfected patients. We conducted a prospective study in 28 HIV/HCV-coinfected patients receiving IFN-based therapy at baseline (HIV/HCV-b) and week 24 after sustained virological response (HIV/HCV-f). Twenty-seven HIV-monoinfected patients (HIV-mono) were included as a control. RNA-seq analysis was performed on peripheral blood mononuclear cells (PBMCs). Genes with a fold-change (FC) ≥ 1.5 (in either direction) and false discovery rate (FDR) ≤ 0.05 were identified as significantly differentially expressed (SDE). HIV/HCV-b showed six SDE genes compared to HIV-mono group, but no significantly enriched pathways were observed. For HIV/HCV-f vs. HIV/HCV-b, we found 58 SDE genes, 34 upregulated and 24 downregulated in the HIV/HCV-f group. Of these, the most overexpressed were CXCL2, PDCD6IP, ATP5B, IGSF9, RAB26, and CSRNP1, and the most downregulated were IFI44 and IFI44L. These 58 SDE genes revealed two significantly enriched pathways (FDR < 0.05), one linked to Epstein-Barr virus infection and another related to p53 signaling. For HIV/HCV-f vs. HIV-mono group, we found 44 SDE genes that revealed 31 enriched pathways (FDR < 0.05) related to inflammation, cancer/cell cycle alteration, viral and bacterial infection, and comorbidities associated with HIV/HCV-coinfection. Five genes were overrepresented in most pathways (JUN, NFKBIA, PIK3R2, CDC42, and STAT3). HIV/HCV-coinfected patients who eradicated hepatitis C with IFN-based therapy showed profound gene expression changes after achieving sustained virological response. The altered pathways were related to inflammation and liver-related complications, such as non-alcoholic fatty liver disease and hepatocellular carcinoma, underscoring the need for active surveillance for these patients.This study was supported by grants from Instituto de Salud Carlos III (ISCII; Grant Numbers PI20/00474 and PI17/00657 to JB, PI20/00507 and PI17/00903 to JGG, PI18CIII/00020 to AFR, and PI20CIII/00004 and PI17CIII/00003 to SR). The study was also funded by the RD16CIII/0002/0002 and RD16/0025/0017, and RD16/0025/0018 projects as part of the Plan Nacional R + D + I and co-funded by ISCIII- Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER). JB is an investigator from the Programa de Intensificación de la Actividad Investigadora en el Sistema Nacional de Salud (I3SNS), Ref. INT16/00100.S

Gene Editing in Adult Hematopoietic Stem Cells

Over the last years, an important development has allowed the scientific community to address a precise and accurate modification of the genome. The first probe of concept appeared with the design and use of engineered zinc-finger nucleases (ZFNs), which was expanded later on with the discovery and engineering of meganucleases and transcription activator-like effector nucleases (TALENs) and finally democratized and made easily available to the whole scientific community with the discovery of the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 nuclease combination technology. The availability of these tools has allowed a precise gene editing, such as knockout of a specific gene or the correction of a defective gene by means of homologous recombination (HR), taking advantage of the endogenous cell repair machinery. This process was already known and used but was inefficient—efficiency that has been increased more than 100-fold with the addition of the mentioned specific nucleases to the process. Apart from the proper design of the nucleases to recognize and cut the selected site in the cell genome, two main goals need to be adequately addressed to optimize its function: the delivery of the tools into the desired cells and the selection of those where the gene editing process has occurred correctly. Both steps can be easily solved when the source of cells is extensive or can be expanded and manipulated in vitro extensively, such as immortalized cell lines or pluripotent stem cells (embryonic stem cells and induced pluripotent stem cells). However, both steps are critical in the case of primary cells, such as the hematopoietic stem cells (HSCs). HSCs are a rare cell population present in the bone marrow (BM) of higher mammals, and it is the responsible for the maintenance and replenishment of all hematopoietic cells for the lifespan of the animals by means of two fundamental properties: self-renewal and multipotency. HSC population is then the ideal target for the correction of hematopoietic genetic diseases and also for the knockout of the responsible genes to in vitro and in vivo model those hematopoietic diseases. This rare population cannot be expanded and its in vitro manipulation and culture negatively affects their fundamental properties of self-renewal and multipotency. These factors challenge the application of gene editing to HSCs. Important efforts are now ongoing trying to optimize the protocols of gene delivery and selection for HSCs. This chapter will review and discuss how researchers are trying to solve them, all attempts that are ongoing and the potential application of the technology to the patients affected with hematopoietic genetic diseases

Older Adult Patients in the Emergency Department: Which Patients should be Selected for a Different Approach?

Background: While multidimensional and interdisciplinary assessment of older adult patients improves their short-term outcomes after evaluation in the emergency department (ED), this assessment is time-consuming and ill-suited for the busy environment. Thus, identifying patients who will benefit from this strategy is challenging. Therefore, this study aimed to identify older adult patients suitable for a different ED approach as well as independent variables associated with poor short-term clinical outcomes. Methods: We included all patients >= 65 years attending 52 EDs in Spain over 7 days. Sociodemographic, comorbidity, and baseline functional status data were collected. The outcomes were 30 -day mortality, re -presentation, hospital readmission, and the composite of all outcomes. Results: During the study among 96,014 patients evaluated in the ED, we included 23,338 patients >= 65 years-mean age, 78.4 +/- 8.1 years; 12,626 (54.1%) women. During follow-up, 5,776 patients (24.75%) had poor outcomes after evaluation in the ED: 1,140 (4.88%) died, 4,640 (20.51) returned to the ED, and 1,739 (7.69%) were readmitted 30 days after discharge following the index visit. A model including male sex, age >= 75 years, arrival by ambulance, Charlson Comorbidity Index >= 3, and functional impairment had a C -index of 0.81 (95% confidence interval, 0.80-0.82) for 30 -day mortality. Conclusion: Male sex, age >= 75 years, arrival by ambulance, functional impairment, or severe comorbidity are features of patients who could benefit from approaches in the ED different from the common triage to improve the poor short-term outcomes of this population

Measurement of the Lifetime Difference Between B_s Mass Eigenstates

We present measurements of the lifetimes and polarization amplitudes for B_s --> J/psi phi and B_d --> J/psi K*0 decays. Lifetimes of the heavy (H) and light (L) mass eigenstates in the B_s system are separately measured for the first time by determining the relative contributions of amplitudes with definite CP as a function of the decay time. Using 203 +/- 15 B_s decays, we obtain tau_L = (1.05 +{0.16}/-{0.13} +/- 0.02) ps and tau_H = (2.07 +{0.58}/-{0.46} +/- 0.03) ps. Expressed in terms of the difference DeltaGamma_s and average Gamma_s, of the decay rates of the two eigenstates, the results are DeltaGamma_s/Gamma_s = (65 +{25}/-{33} +/- 1)%, and DeltaGamma_s = (0.47 +{0.19}/-{0.24} +/- 0.01) inverse ps.Comment: 8 pages, 3 figures, 2 tables; as published in Physical Review Letters on 16 March 2005; revisions are for length and typesetting only, no changes in results or conclusion

Ciencias de la Biología y Agronomía

Este volumen I contiene 17 capítulos arbitrados que se ocupan de estos asuntos en Tópicos Selectos de Ciencias de la Biología y Agronomía, elegidos de entre las contribuciones, reunimos algunos investigadores y estudiantes. Se presenta un Estudio Comparativo de los Recursos Hidrológico-Forestales de la Microcuenca de la Laguna de Epatlan, Pue. (1993 a 2014); la Situación Actual de la Mancha de Asfalto en Maíz (Zea mays L.) en los Municipios de Jiquipilas y Ocozocoautla, Chiapas, México; las poblaciones sobresalientes de maíz de la raza Zapalote Chico, en la Región Istmeña de Oaxaca; Se indica el índice de área foliar de cultivo de Chile Poblano mediante dos métodos en condiciones protegidas; Esquivel, Urzúa y Ramírez exploran el efecto de la biofertilización con Azospirillum en el crecimiento y producción de Jitomate; esbozan su artículo sobre la determinación del nivel de Heterosis en híbridos de Maíz para la Comarca Lagunera; una investigación sobre la estabilización de semilla de Solanum lycopersicum durante el almacenamiento y estimulación de la germinación; acotan sobre el CTAB como una nueva opción para la detección de Huanglongbing en cítricos, plantean su evaluación sobre el aluminio y cómo afecta la vida de florero de Heliconia psittacorum; indican sobre el impacto del H-564C, como un híbrido de maíz con alta calidad de proteina para el trópico húmedo de México; presetan su investigación sobre la producción de Piña Cayena Lisa y MD2 (Ananas comosus L.) en condiciones de Loma Bonita, en Oaxaca; acotan sobre el efecto de coberteras como control biológico por conservación contra áfidos en Nogal Pecanero; esbozan sobre la caracterización de cuatro genotipos de Frijol Negro en Martínez de la Torre, Veracruz, México; presentan una caracterización hidroecológica de la microcuenca de Arroyo Prieto, Yuriría, Gto., y alternativas para su restauración ambiental; presentan su investigación sobre el efecto del hongo Beauveria bassiana sobre solubilización de fosfatos y la disponibilidad de fósforo en el suelo; plantean su investigación sobre la Germinación y regeneración in vitro de Epidendrum falcatum LINDL; esbozan su artículo sobre genotipos de frijol negro y su tolerancia a sequía terminal en Veracruz, México

Multi-ancestry GWAS reveals excitotoxicity associated with outcome after ischaemic stroke

During the first hours after stroke onset, neurological deficits can be highly unstable: some patients rapidly improve, while others deteriorate. This early neurological instability has a major impact on long-term outcome. Here, we aimed to determine the genetic architecture of early neurological instability measured by the difference between the National Institutes of Health Stroke Scale (NIHSS) within 6 h of stroke onset and NIHSS at 24 h. A total of 5876 individuals from seven countries (Spain, Finland, Poland, USA, Costa Rica, Mexico and Korea) were studied using a multi-ancestry meta-analyses. We found that 8.7% of NIHSS at 24 h of variance was explained by common genetic variations, and also that early neurological instability has a different genetic architecture from that of stroke risk. Eight loci (1p21.1, 1q42.2, 2p25.1, 2q31.2, 2q33.3, 5q33.2, 7p21.2 and 13q31.1) were genome-wide significant and explained 1.8% of the variability suggesting that additional variants influence early change in neurological deficits. We used functional genomics and bioinformatic annotation to identify the genes driving the association from each locus. Expression quantitative trait loci mapping and summary data-based Mendelian randomization indicate that ADAM23 (log Bayes factor = 5.41) was driving the association for 2q33.3. Gene-based analyses suggested that GRIA1 (log Bayes factor = 5.19), which is predominantly expressed in the brain, is the gene driving the association for the 5q33.2 locus. These analyses also nominated GNPAT (log Bayes factor = 7.64) ABCB5 (log Bayes factor = 5.97) for the 1p21.1 and 7p21.1 loci. Human brain single-nuclei RNA-sequencing indicates that the gene expression of ADAM23 and GRIA1 is enriched in neurons. ADAM23, a presynaptic protein and GRIA1, a protein subunit of the AMPA receptor, are part of a synaptic protein complex that modulates neuronal excitability. These data provide the first genetic evidence in humans that excitotoxicity may contribute to early neurological instability after acute ischaemic stroke. Ibanez et al. perform a multi-ancestry meta-analysis to investigate the genetic architecture of early stroke outcomes. Two of the eight genome-wide significant loci identified-ADAM23 and GRIA1-are involved in synaptic excitability, suggesting that excitotoxicity contributes to neurological instability after ischaemic stroke.Peer reviewe

Efficacy and Safety of Ixekizumab in the Treatment of Radiographic Axial Spondyloarthritis:Sixteen-Week Results From a Phase III Randomized, Double-Blind, Placebo-Controlled Trial in Patients With Prior Inadequate Response to or Intolerance of Tumor Necrosis Factor Inhibitors

Objective: To investigate the efficacy and safety of ixekizumab in patients with active radiographic axial spondyloarthritis (SpA) and prior inadequate response to or intolerance of 1 or 2 tumor necrosis factor inhibitors (TNFi). Methods: In this phase III randomized, double-blind, placebo-controlled trial, adult patients with an inadequate response to or intolerance of 1 or 2 TNFi and an established diagnosis of axial SpA (according to the Assessment of SpondyloArthritis international Society [ASAS] criteria for radiographic axial SpA, with radiographic sacroiliitis defined according to the modified New York criteria and ≥1 feature of SpA) were recruited and randomized 1:1:1 to receive placebo or 80-mg subcutaneous ixekizumab every 2 weeks (IXEQ2W) or 4 weeks (IXEQ4W), with an 80-mg or 160-mg starting dose. The primary end point was 40% improvement in disease activity according to the ASAS criteria (ASAS40) at week 16. Secondary outcomes and safety were also assessed. Results: A total of 316 patients were randomized to receive placebo (n = 104), IXEQ2W (n = 98), or IXEQ4W (n = 114). At week 16, significantly higher proportions of IXEQ2W patients (n = 30 [30.6%]; P = 0.003) or IXEQ4W patients (n = 29 [25.4%]; P = 0.017) had achieved an ASAS40 response versus the placebo group (n = 13 [12.5%]), with statistically significant differences reported as early as week 1 with ixekizumab treatment. Statistically significant improvements in disease activity, function, quality of life, and spinal magnetic resonance imaging–evident inflammation were observed after 16 weeks of ixekizumab treatment versus placebo. Treatment-emergent adverse events (AEs) with ixekizumab treatment were more frequent than with placebo. Serious AEs were similar across treatment arms. One death was reported (IXEQ2W group). Conclusion: Ixekizumab treatment for 16 weeks in patients with active radiographic axial SpA and previous inadequate response to or intolerance of 1 or 2 TNFi yields rapid and significant improvements in the signs and symptoms of radiographic axial SpA versus placebo

FULL Investiga Enero a Junio 2020 Número 1

Contiene: A propósito del coronavirus: pandemia o acontecimiento / Carol Fernandez Jaimes -- Desarrollo de nuevos materiales en el contexto de la IV Revolución Industrial y sus efectos en el COVID-19 / Jesús Manuel Gutiérrez Bernal -- El virus que coronó la vulnerabilidad de la formación remota en la educación Chilena y Colombiana” / Marcelo Palominos Bastias, Lupe García Cano y Víctor Martínez Gutiérrez -- Intuiciones psicosociales sobre la pandemia en el Siglo XXI / Rocío Venegas Luque -- Pensar la economía en tiempos de crisis / Oscar Esteban Morillo Martínez -- Acercamiento al concepto de educación superior en el marco normativo de la educación inclusiva en Colombia / Jose Escobar Romero -- Educación para la paz y la resiliencia en infancias vulneradas, fase II / Ana Dolores Gómez Romero -- Fútbol, de la mediatización global al lavado deportivo / Luis Francisco Buitrago -- Antea, proyecto de investigación que pone en reto a la comunicación como escenario para la transformación ambiental / Janneth Arley Palacios Chavarro -- Del desarrollo económico al desarrollo sos- tenible y el papel de la educación ambiental / Gloria Castaño-Camacho y Rosa Eugenia Reyes Gil -- Investigación en el ámbito turístico y gastronómico / Jesús Alexis Barón Chivara y Sandra Patricia Cote Daza -- Mercado de trabajo y empleabilidad de los profesionales en Colombia / Orlando Salinas Gómez -- El rol de la investigación contable en la academia y la sociedad / Paula Andrea Navarro Pérez -- Hacia la formación competitiva y de desarrollo empresarial / Melva Inés Gómez Caicedo y Diana Geraldine Jiménez García -- El comercio internacional como motor del crecimiento económico / José Vidal Castaño Ramírez -- Hacia el concepto transformacional de la educación superior inclusiva en el contexto colombiano / Castelblanco Daniela, Coronado Laura, Jiménez Wendy, Ocampo Yessica, Pachón Jose, Reyes María, Sánchez Vanesa -- La Inteligencia Artificial como quehacer investigativo y de formación al servicio de la humanidad en el seno del Semillero SofIA / Lucy Nohemy Medina Velandia -- “Un nuevo mundo”. Historieta ilustrada sobre el COVID-19 -- Camilo Rojas Zapata.Fundación Universitaria los Libertadore