Expanding the Chemical Space of Withaferin A by Incorporating Silicon to Improve its Clinical Potential on Human Ovarian Carcinoma Cells

Ovarian cancer represents the seventh most commonly diagnosed cancer worldwide. Herein, we report on the development of a withaferin A (WA)-silyl ether library with 30 analogues reported for the first time. Cytotoxicity assays on human epithelial ovarian carcinoma cisplatin-sensitive and -resistant cell lines identified eight analogues displaying nanomolar potency (IC50 ranging from 1 to 32 nM), higher than that of the lead compound and reference drug. This cytotoxic potency is also coupled with a good selectivity index on a nontumoral cell line. Cell cycle analysis of two potent analogues revealed cell death by apoptosis without indication of cell cycle arrest in G0/G1 phase. The structure–activity relationship and in silico absorption, distribution, metabolism, and excretion studies demonstrated that the incorporation of silicon and a carbonyl group at C-4 in the WA framework enhances potency, selectivity, and drug likeness. These findings reveal analogues 22, 23, and 25 as potential candidates for clinical translation in patients with relapsed ovarian cancer

Open-Source 3D Printable GPS Tracker to Characterize the Role of Human Population Movement on Malaria Epidemiology in River Networks: A Proof-of-Concept Study in the Peruvian Amazon.

Human movement affects malaria epidemiology at multiple geographical levels; however, few studies measure the role of human movement in the Amazon Region due to the challenging conditions and cost of movement tracking technologies. We developed an open-source low-cost 3D printable GPS-tracker and used this technology in a cohort study to characterize the role of human population movement in malaria epidemiology in a rural riverine village in the Peruvian Amazon. In this pilot study of 20 participants (mean age = 40 years old), 45,980 GPS coordinates were recorded over 1 month. Characteristic movement patterns were observed relative to the infection status and occupation of the participants. Applying two analytical animal movement ecology methods, utilization distributions (UDs) and integrated step selection functions (iSSF), we showed contrasting environmental selection and space use patterns according to infection status. These data suggested an important role of human movement in the epidemiology of malaria in the Peruvian Amazon due to high connectivity between villages of the same riverine network, suggesting limitations of current community-based control strategies. We additionally demonstrate the utility of this low-cost technology with movement ecology analysis to characterize human movement in resource-poor environments

Chronic Hypoxia Impairs Muscle Function in the Drosophila Model of Duchenne's Muscular Dystrophy (DMD)

Duchenne's muscular dystrophy (DMD) is a severe progressive myopathy caused by mutations in the DMD gene leading to a deficiency of the dystrophin protein. Due to ongoing muscle necrosis in respiratory muscles late-stage DMD is associated with respiratory insufficiency and chronic hypoxia (CH). To understand the effects of CH on dystrophin-deficient muscle in vivo, we exposed the Drosophila model for DMD (dmDys) to CH during a 16-day ascent to the summit of Mount Denali/McKinley (6194 meters above sea level). Additionally, dmDys and wild type (WT) flies were also exposed to CH in laboratory simulations of high altitude hypoxia. Expression profiling was performed using Affymetrix GeneChips® and validated using qPCR. Hypoxic dmDys differentially expressed 1281 genes, whereas the hypoxic WT flies differentially expressed 56 genes. Interestingly, a number of genes (e.g. heat shock proteins) were discordantly regulated in response to CH between dmDys and WT. We tested the possibility that the disparate molecular responses of dystrophin-deficient tissues to CH could adversely affect muscle by performing functional assays in vivo. Normoxic and CH WT and dmDys flies were challenged with acute hypoxia and time-to-recover determined as well as subjected to climbing tests. Impaired performance was noted for CH-dmDys compared to normoxic dmDys or WT flies (rank order: Normoxic-WT ≈ CH-WT> Normoxic-dmDys> CH-dmDys). These data suggest that dystrophin-deficiency is associated with a disparate, pathological hypoxic stress response(s) and is more sensitive to hypoxia induced muscle dysfunction in vivo. We hypothesize that targeting/correcting the disparate molecular response(s) to hypoxia may offer a novel therapeutic strategy in DMD

G6PD deficiency in Latin America: systematic review on prevalence and variants

Plasmodium vivax radical cure requires the use of primaquine (PQ), a drug that induces haemolysis in glucose-6-phosphate dehydrogenase deficient (G6PDd) individuals, which further hampers malaria control efforts. The aim of this work was to study the G6PDd prevalence and variants in Latin America (LA) and the Caribbean region. A systematic search of the published literature was undertaken in August 2013. Bibliographies of manuscripts were also searched and additional references were identified. Low prevalence rates of G6PDd were documented in Argentina, Bolivia, Mexico, Peru and Uruguay, but studies from Curaçao, Ecuador, Jamaica, Saint Lucia, Suriname and Trinidad, as well as some surveys carried out in areas of Brazil, Colombia and Cuba, have shown a high prevalence (> 10%) of G6PDd. The G6PD A-202A mutation was the variant most broadly distributed across LA and was identified in 81.1% of the deficient individuals surveyed. G6PDd is a frequent phenomenon in LA, although certain Amerindian populations may not be affected, suggesting that PQ could be safely used in these specific populations. Population-wide use of PQ as part of malaria elimination strategies in LA cannot be supported unless a rapid, accurate and field-deployable G6PDd diagnostic test is made available

Carbones fósiles de Riosucio

MapasIlustracionesEn general, la formación constituye un conjunto compuesto en lo esencial de conglomerados escasos, areniscas, arcilla plásticas, arcillas bituminosas, arcillas compactas —shales— y lechos de carbón. Esta formación descansa sobre las varias instrusiones ígneas de carácter andesítico que aparecen en le Croquis bajo los nombres de >, >, >, etc. etc. (Texto tomado de la fuente)Desde sus inicios en 1912 se llamó "Anales de la Escuela Nacional de Minas", a partir del No. 48 en 1940 cambio a "Anales de la Facultad Nacional de Minas".Trabajo presentado como Tesis para optar el título de Ingeniero Civil y de Mina

Carbones fósiles de Riosucio

MapasIlustracionesEn general, la formación constituye un conjunto compuesto en lo esencial de conglomerados escasos, areniscas, arcilla plásticas, arcillas bituminosas, arcillas compactas —shales— y lechos de carbón. Esta formación descansa sobre las varias instrusiones ígneas de carácter andesítico que aparecen en le Croquis bajo los nombres de >, >, >, etc. etc. (Texto tomado de la fuente)Desde sus inicios en 1912 se llamó "Anales de la Escuela Nacional de Minas", a partir del No. 48 en 1940 cambio a "Anales de la Facultad Nacional de Minas".Trabajo presentado como Tesis para optar el título de Ingeniero Civil y de Mina