PUBLICACIONES
Imaging mass spectrometry and MS/MS molecular networking reveals chemical interactions among cuticular bacteria and pathogenic fungi associated with fungus-growing ants. Cristopher A. Boya P., Hermógenes Fernández-Marín, Luis C. Mejía, Carmenza Spadafora, Pieter C. Dorrestein & Marcelino Gutiérrez. Scientific Reports 7, Article number: 5604(2017) doi:10.1038/s41598-017-05515-6
Abstract The fungus-growing ant-microbe symbiosis is an ideal system to study chemistry-based microbial interactions due to the wealth of microbial interactions described, and the lack of information on the molecules involved therein. In this study, we employed a combination of MALDI imaging mass spectrometry (MALDI-IMS) and MS/MS molecular networking to study chemistry-based microbial interactions in this system. MALDI IMS was used to visualize the distribution of antimicrobials at the inhibition zone between bacteria associated to the ant Acromyrmex echinatior and the fungal pathogen Escovopsis sp. MS/MS molecular networking was used for the dereplication of compounds found at the inhibition zones. We identified the antibiotics actinomycins D, X2 and X0β, produced by the bacterium Streptomyces CBR38; and the macrolides elaiophylin, efomycin A and efomycin G, produced by the bacterium Streptomyces CBR53.These metabolites were found at the inhibition zones using MALDI IMS and were identified using MS/MS molecular networking. Additionally, three shearinines D, F, and J produced by the fungal pathogen Escovopsis TZ49 were detected. This is the first report of elaiophylins, actinomycin X0β and shearinines in the fungus-growing ant symbiotic system. These results suggest a secondary prophylactic use of these antibiotics by A. echinatior because of their permanent production by the bacteria.
Dudawalamides A-D, Antiparasitic Cyclic Depsipeptides from the Marine Cyanobacterium Moorea producens. Almaliti J, Malloy KL, Glukhov E, Spadafora C, Gutiérrez M, Gerwick WH. J Nat Prod. 2017 Jun 23;80(6):1827-1836. doi: 10.1021/acs.jnatprod.7b00034.
Abstract A family of 2,2-dimethyl-3-hydroxy-7-octynoic acid (Dhoya)-containing cyclic depsipeptides, named dudawalamides A-D (1-4), was isolated from a Papua New Guinean field collection of the cyanobacterium Moorea producens using bioassay-guided and spectroscopic approaches. The planar structures of dudawalamides A-D were determined by a combination of 1D and 2D NMR experiments and MS analysis, whereas the absolute configurations were determined by X-ray crystallography, modified Marfey’s analysis, chiral-phase GCMS, and chiral-phase HPLC. Dudawalamides A-D possess a broad spectrum of antiparasitic activity with minimal mammalian cell cytotoxicity. Comparative analysis of the Dhoya-containing class of lipopeptides reveals intriguing structure-activity relationship features of these NRPS-PKS-derived metabolites and their derivatives.
Genetic Composition and Connectivity of the Antillean Manatee (Trichechus manatus manatus) in Panama. Edgardo Díaz-Ferguson, Margaret Hunter, Héctor M. Guzmán. Aquatic Mammals 2017, 43(4), 378-386, DOI 10.1578/AM.43.4.2017.378
Abstract Genetic diversity and haplotype composition of the West Indian manatee (Trichechus manatus) population from the San San Pond Sak (SSPS) wetland in Bocas del Toro, Panama, was studied using a segment of the mitochondrial DNA (control region). No genetic information to date has been published for manatee populations in Panama. Due to the secretive behavior and small population size of the species in the area, DNA extraction was conducted from opportunistically collected fecal (N = 20), carcass tissue (N = 4), and bone (N = 4) samples. However, after DNA processing, only 10 samples provided enough quality DNA for sequencing— 3 fecal, 4 tissue, and 3 bone samples. We identified three haplotypes in total: J01 was previously published (N = 3), while the other two haplotypes, J02 (N = 3) and J03 (N = 4), are reported for the first time. The genetic diversity was similar to previous analyses conducted in the Caribbean with moderate values of nucleotide (π = 0.00152) and haplotypic (Hd = 0.57) diversity. Connectivity assessment between the SSPS population with published range-wide manatee haplotypes was based on sequence similarity, genetic distance, and genetic differentiation. The identified J01 haplotype is also found in populations to the north along the Central American and Gulf of Mexico coasts indicating reduced differentiation (Fst = 0.0094). In contrast, comparisons between SSPS sequences and South American populations (not including Colombia), the West Indies, and Florida showed fewer similarities (Fst = 0.049 and 0.058, respectively). These results corroborate previous phylogeographic patterns already established for manatee populations and situate the manatee population in Panama within the Belize/Mexico cluster. In addition, these findings provide a baseline for comparative studies of manatees in other areas of Panama and Central America. These results can assist with management decisions regarding conservation of genetic diversity, future introductions, connectivity, and effective population size of manatee populations along the Central American corridor.
Argiope submaronica (Araneidae) Silk Decoration Does Not Reduce Web Damage by Birds. Dumas Gálvez. Journal of Entomological Science Jul 2017 : Vol. 52, Issue 3, pg(s) 301- 303 Abstract Web-decorating behavior is typical of many orb-weaving spiders worldwide. The web consists of a visible structure added to the web, made of materials such as prey remains, plant material, egg sacs or silk (Herberstein et al. 2000, Biol. Rev. 75: 649–669). However, it is not clear why spiders increase the conspicuousness of their web. The fact that decorations are typical only to diurnal species suggests a visual function (Scharff and Coddington 1997, Zool. J. Linn. Soc. 120: 355–424). Thus, three hypotheses have been proposed and investigated: (1) increasing prey attraction, (2) protection against predators, and (3) advertise the presence of the web to vertebrates to reduce web damage (Bruce 2006, J. Zool. 269: 89–97). The first two hypotheses have received most support, particularly within the genus Argiope, which has become a model genus to study silk decorations (Walter and Elgar 2012, J. Zool. 269: 89–97). The first hypothesis proposes that the UV-reflective properties of decorations mimic other natural sources of UV used by prey (Craig and Bernard 1990, Ecology, 71: 616–623). The second hypothesis proposes that decorations may make the spiders seem larger or camouflage the location of the spider (Bruce 2006). However, the search of a single function has resulted in disagreement, with conflicting results across studies (Théry and Casas 2009, Philos. Trans. R. Soc. Lond. B Biol. Sci. 364: 471–480).
Disturbance and mosquito diversity in the lowland tropical rainforest of central Panama. Jose R. Loaiza, Larissa C. Dutari, Jose R. Rovira, Oris I. Sanjur, Gabriel Laporta, James Pecor, Desmond Foley, Gillian Eastwood, Laura Kramer, Meghan Radtke, and Montira Pongsiri. Scientific Reports, 2017. 7: 7248. DOI:10.1038/s41598-017-07476-2 Abstract The Intermediate Disturbance Hypothesis (IDH) is well known in ecology providing an explanation for the role of disturbance in the coexistence of climax and colonist species. Here, we used the IDH as a framework to describe the role of forest disturbance in shaping the mosquito community structure, and to identify the ecological processes that increase the emergence of vector-borne disease. Mosquitoes were collected in central Panama at immature stages along linear transects in colonising, mixed and climax forest habitats, representing different levels of disturbance. Species were identified taxonomically and classified into functional categories (i.e., colonist, climax, disturbance- generalist, and rare). Using the Huisman-Olff-Fresco multi-model selection approach, IDH testing was done. We did not detect a unimodal relationship between species diversity and forest disturbance expected under the IDH; instead diversity peaked in old-growth forests. Habitat complexity and constraints are two mechanisms proposed to explain this alternative postulate. Moreover, colonist mosquito species were more likely to be involved in or capable of pathogen transmission than climax species. Vector species occurrence decreased notably in undisturbed forest settings. Old-growth forest conservation in tropical rainforests is therefore a highly recommended solution for preventing new outbreaks of arboviral and parasitic diseases in anthropic environments.
Chromatin-bound oxidized α-Synuclein causes strand breaks in neuronal genomes in in vitro models of Parkinson’s disease Velmarini Vasquez, Joy Mitra, Pavana M. Hegde, Arvind Pandey, Shiladitya Sengupta, Sankar Mitra, K. S. Rao, Muralidhar L. Hegde J Alzheimers Dis. 2017;60(s1):S133-S150. Abstract Alpha-Synuclein (α-Syn) overexpression and misfolding/aggregation in degenerating dopaminergic neurons have long been implicated in Parkinson’s disease (PD). The neurotoxicity of α-Syn is enhanced by iron (Fe) and other pro-oxidant metals, leading to generation of reactive oxygen species (ROS) in PD brain. Although α-Syn is predominantly localized in presynaptic nerve terminals, a small fraction exists in neuronal nuclei. However, the functional and/or pathological role of nuclear α-Syn is unclear. Following up on our earlier report that α-Syn directly binds DNA in vitro, here, we confirm the nuclear localization and chromatin association of α-Syn in neurons using proximity ligation and chromatin immunoprecipitation analysis. Moderate (~2-fold) increase in α-Syn expression in neural lineage progenitor cells (NPC) derived from induced pluripotent human stem cells (iPSCs) or differentiated SHSY-5Y cells caused DNA strand breaks in the nuclear genome, which was further enhanced synergistically by Fe salts. Furthermore, α-Syn-induced genome damage required its nuclear localization, as revealed by the expression of nucleus versus cytosol-specific mutants. Enhanced DNA damage by oxidized and misfolded/oligomeric α-Syn suggests that DNA nicking activity is mediated by a chemical nuclease reaction by an oxidized peptide segment in the misfolded α-Syn. Consistent with this finding, a marked increase in Fe-dependent DNA breaks was observed in NPCs from a PD patient-derived iPSC line harboring α-Syn SNCA gene triplication. Finally, α-Syn combined with Fe significantly promoted neuronal cell death. Together, these findings provide a novel molecular insight into the direct role of α-Syn in inducing neuronal genome damage, which could possibly contribute to neurodegeneration in PD.
Luring prey to the web: the case of Argiope and Nephila. Dumas Gálvez. Animal Biology, 2017, doi 10.1163/15707563-00002528 Abstract The view that orb webs are imperceptible traps has changed since it was discovered that some spiders possess body colorations or web designs that are attractive to prey. Spiders of the genera Argiope and Nephila exemplify both cases and are able to adjust their webs to increase foraging success. In this study, I compared the foraging strategies of A. submanorica and N. clavipes as they foraged on the same natural prey (stingless bees). Argiope submanorica adds UV-reflective decorations while N. clavipes builds non-UV-reflective golden webs. Based on studies that suggest a lack of niche separation between these two species, the objective of this study was to test whether this hypothesis holds when the spiders are competing for a limited resource. In addition, I investigated whether the colorations of the spiders influence their foraging success. The golden webs of N. clavipes intercepted more bees than the decorated webs of A. submanorica, suggesting that some type of niche separation must occur in nature, as otherwise competition would lead to the local extinction of A. submanorica. These differences in foraging success, leading to its ability to outcompete other spider species exploiting the same resource, could explain in part the abundance and distribution of the N. clavipes on the American continent.
Anti-amyloid aggregation activity of novel carotenoids: implications for Alzheimer’s drug discovery Johant Lakey-Beitia, Deborah Doens, D Jagadeesh Kumar, Enrique Murillo, Patricia L Fernandez, KS Rao, Armando A Durant-Archibold. Clinical Interventions in Aging. 2017 May 15;12:815-822. doi: 10.2147/CIA.S134605.
Abstract Alzheimer’s disease (AD) is the leading cause of dementia, affecting approximately 33.5 million people worldwide. Aging is the main risk factor associated with AD. Drug discovery based on nutraceutical molecules for prevention and treatment of AD is a growing topic. In this sense, carotenoids are phytochemicals present mainly in fruits and vegetables with reported benefits for human health. In this research, the anti-amyloidogenic activity of three carotenoids, cryptocapsin, cryptocapsin-5,6-epoxide, and zeaxanthin, was assessed. Cryptocapsin showed the highest bioactivity, while cryptocapsin-5,6-epoxide and zeaxanthin exhibited similar activity on anti-aggregation assays. Molecular modeling analysis revealed that the evaluated carotenoids might follow two mechanisms for inhibiting Aβ aggregation: by preventing the formation of the fibril and through disruption of the Aβ aggregates. Our studies provided evidence that cryptocapsin, cryptocapsin-5,6-epoxide, and zeaxanthin have anti-amyloidogenic potential and could be used for prevention and treatment of AD.
American trypanosomiasis, or Chagas disease, in Panama: a chronological synopsis of ecological and epidemiological research. Indra G. Rodriguez, Jose R. Loaiza Parasites and Vectors, 2017, in press
Abstract American trypanosomiasis, or Chagas disease, is a growing public health problem in Panama, and further forest degradation due to human population growth is expected to worsen its situation. Most people infected with the parasite Trypanosoma cruzi are silently ill, and their life expectancy is severely compromised, which contributes to further deterioration of living conditions in endemic regions. Here, we review the outcomes of nearly 100 years of ecologic and epidemiologic investigation about Chagas disease in Panama, in an attempt to highlight progress, identify needs, and re- orient future efforts. Rhodnius pallescens and Triatoma dimidiata are both primary vectors of T. cruzi in Panama, but R. pallescens seems more efficient in human-altered forest ecosystems due to a greater degree of association with Attalea butyraceae. In contrast, T. dimidiata transmits T. cruzi efficiently under more sylvatic conditions (e.g., settlements inside old-growth or secondary forest patches), where its populations reach considerable numbers irrespective of the absence of A. butyraceae. A trend of increasing forest degradation, suburbanization, and development of tourism in Panama favoring the establishment of A. butyraceae and other palm tree species (Acrocomia sp.) suggests that a generalist species like R. pallescens will continue to play a more prominent role in the transmission of T. cruzi than a forest specialist like T. dimidiata. However, studies about the taxonomic status and ecology of these vectors are still needed in Panama to fully address their transmission potential. The implementation of an active surveillance system and education programs could greatly minimize the risk of Chagas transmission in Panama, preventing fatal infections in children from endemic areas.
Breeding decisions and output are correlated with both temperature and rainfall in an arid-region passerine, the sociable weaver. Rafael Mares, Claire Doutrelant, Matthieu Paquet, Claire N. Spottiswoode, Rita Covas Royal Society Open Science, 4(9), 170835 Abstract Animal reproductive cycles are commonly triggered by environmental cues of favourable breeding conditions. In arid environments, rainfall may be the most conspicuous cue, but the effects on reproduction of the high inter- and intra-annual variation in temperature remain poorly understood, despite being relevant to the current context of global warming. Here, we conducted a multiyear examination of the relationships between a suite of measures of temperature and rainfall, and the onset and length of the breeding season, the probability of breeding and reproductive output in an arid-region passerine, the sociable weaver (Philetairus socius). As expected, reproductive output increased with rainfall, yet specific relationships were conditional on the timing of rainfall: clutch production was correlated with rainfall throughout the season, whereas fledgling production was correlated with early summer rainfall. Moreover, we reveal novel correlations between aspects of breeding and temperature, indicative of earlier laying dates after warmer springs, and longer breeding seasons during cooler summers. These results have implications for understanding population trends under current climate change scenarios and call for more studies on the role of temperature in reproduction beyond those conducted on temperate-region species.
Protecting Children in Low- and Middle-Income Countries from Abuse and Neglect: Critical Challenges for Successful Implementation of Parenting Programs. Mejia, A., Haslam, D., Penman, N., Sanders, MR. European Journal of Development Research
Abstract Child maltreatment in low- and middle-income countries overburdens health systems, compromises education, perpetuates gender inequalities and slows down development. Research suggests that parenting programs are effective for the early prevention of child maltreatment. However, wide deployment in LMICs where violence towards children is high is yet to take place. In this overview article, we identify some critical challenges that LMICs currently face in ensuring the sustained implementation of parenting programs for the early prevention of child maltreatment. The article is structured in three main sections: 1) a brief review of the effectiveness of parenting programs for preventing child maltreatment; 2) a discussion of the critical challenges in LMICs for the widespread and sustained implementation of parenting programs; and finally 3) we propose recommendations to promote effective implementation in these countries. We also suggest a series of steps to overcome these challenges, such as investing on capacity building for sustainability.
Exposure to the leaf litter microbiome of healthy adults protects seedlings from pathogen damage. Natalie Christian, Edward Allen Herre, Luis C. Mejia and Keith Clay. Proceedings of the Royal Society B. 2017 Jul 12;284(1858). pii: 20170641. doi: 10.1098/rspb.2017.0641.
Abstract It is increasingly recognized that microbiota affect host health and physiology. However, it is unclear what factors shape microbiome community assembly in nature, and how microbiome assembly can be manipulated to improve host health. All plant leaves host foliar endophytic fungi, which make up a diverse, environmentally acquired fungal microbiota. Here, we experimentally manipulated assembly of the cacao tree (Theobroma cacao) fungal microbiome in nature and tested the effect of assembly outcome on host health. Using next-generation sequencing, as well as culture-based methods coupled with Sanger sequencing, we found that manipulating leaf litter exposure and location within the forest canopy significantly altered microbiome composition in cacao. Exposing cacao seedlings to leaf litter from healthy conspecific adults enriched the seedling microbiome with Colletotrichum tropicale, a fungal endophyte known to enhance pathogen resistance of cacao seedlings by upregulating host defensive pathways. As a result, seedlings exposed to healthy conspecific litter experienced reduced pathogen damage. Our results link processes that affect the assembly and composition of microbiome communities to their functional consequences for host success, and have broad implications for understanding plant-microbe interactions. Deliberate manipulation of the plant-fungal microbiome also has potentially important applications for cacao production and other agricultural systems in general.
“Discovery, Semisynthesis, Antiparasitic and Cytotoxic Evaluation of 14-Membered Resorcylic Acid Lactones and Their Derivatives” Xue-Qing Zhang, Carmenza Spadafora, Laura M. Pineda, Michelle G. Ng, Ji-Hong Sun, Wei Wang, Changyun Wang, Yucheng Gu, Chang-Lun Shao. Sci Rep. 2017 Sep 18;7(1):11822.
Abstract Ten antifouling 14-membered resorcylic acid lactones 1–10 were isolated previously with low or trace natural abundance from the zoanthid-derived Cochliobolus lunatus fungus. Further optimization of fermentation conditions led to the isolation of two major natural compounds 7 and 8 with multi-gram quantities. By one or two steps, we semisynthesized the six trace natural compounds 1–6 and a series of derivatives 11–27 of compounds 7 and 8 with high yields (65–95%). Compounds 11–13 showed strong antiplasmodial activity against Plasmodium falciparum with IC50 values of 1.84, 8.36, and 6.95 μM, respectively. Very importantly, 11 and 12 were non-toxic with very safety and high therapeutic indices (CC50/IC50 > 180), and thus representing potential promising leads for antiplasmodial drug discovery. Furthermore, 11 was the only compound showed obvious antileishmanial activity against Leishmania donovani with an IC50 value of 9.22 μM. Compounds 11 and 12 showed the values of IC50 at 11.9 and 17.2 μM against neglected Chagas’ disease causing Trypanosoma cruzi, respectively.
Novel role and regulation of HDAC4 in cocaine-related behaviors. Penrod RD, Carreira MB, Taniguchi M, Kumar J, Maddox SA, Cowan CW Addict Biol. 2017 Jun 21. doi: 10.1111/adb.12522.
Abstract Epigenetic mechanisms have been proposed to contribute to persistent aspects of addiction-related behaviors. One family of epigenetic molecules that may regulate maladaptive behavioral changes produced by cocaine use are the histone deacetylases (HDACs)-key regulators of chromatin and gene expression. In particular, the class IIa HDACs (HDAC4, HDAC5, HDAC7 and HDAC9) respond to changes in neuronal activity by modulating their distribution between the nucleus and cytoplasm-a process controlled in large part by changes in phosphorylation of conserved residues. Cocaine triggers a transient nuclear accumulation of HDAC5 that functions to limit the development of cocaine reward behavior. However, the role and regulation of the close family member, HDAC4, in cocaine behaviors remain largely unknown. In this study, we report that cocaine and cAMP signaling in striatum produced differential phosphorylation and subcellular localization of HDAC4 and HDAC5. Unlike HDAC5, cocaine exposure induced a modest hyperphosphorylation and nuclear export of HDAC4. Genetic deletion of HDAC4 in the nucleus accumbens reduced acute cocaine-produced locomotion, maximum locomotor sensitization and cocaine reward-related behavior. Interestingly, overexpression of an HDAC4 cytoplasm-concentrated mutant (S266E) increased cocaine reward behavior in the cocaine conditioned place preference assay, suggesting that cocaine-induced nuclear export of HDAC4 might function to facilitate the development of cocaine reward behaviors through a role in the cell cytoplasm. Together, our findings suggest that, despite high sequence homology, HDAC4 and HDAC5 are oppositely regulated by cocaine-induced signaling in vivo and have distinct roles in regulating cocaine behaviors.
Percepciones y Prácticas Relacionadas a la Excelencia Educativa en las Escuelas Oficiales de Panamá. Dra. Nadia De León Investigación y Pensamiento Crítico, (ISSN 1812-3864) Vol. 5, No. 1, enero-abril 2017, pp. 17-27. Abstract Este estudio se basa en un análisis de correlación entre los resultados del Concurso Nacional por la Excelencia Educativa 2016 provenientes de todo Panamá, y las percepciones y prácticas encontradas en los ensayos y entrevistas presentadas por las escuelas como parte de su aplicación para el concurso. Las escuelas ganadoras fueron aquellas cuyos estudiantes obtuvieron los puntajes más altos en pruebas de lenguaje, ciencias, y matemáticas. Se encontró que las percepciones con un impacto significativo en la calidad educativa incluyen: la percepción de falta de capacitación docente como barrera a la excelencia; y tener un concepto de excelencia educativa que incluye la inclusión, y los logros de estudiantes y egresados. Las siguientes practicas están correlacionadas con puntajes más altos, pero individualmente no llegan a tener un impacto significativo en las pruebas: el acompañamiento pedagógico a los docentes, el uso de métodos de enseñanza activa; participar de ciertos programas de capacitación docente a largo plazo y con seguimiento adicionales a aquellos obligatorios presentados por el Ministerio de Educación (particularmente en más de uno de ellos ya que se dirigen en parte a aspectos diferentes); ejemplos de esfuerzos hacia la excelencia que involucren la evaluación de aprendizajes y el liderazgo, definido como diagnosis de problemas utilizando indicadores, toma de decisiones informadas para implementar intervenciones, y evaluación de impacto de dichas acciones. Las siguientes prácticas están significativa e inversamente relacionadas con la excelencia educativa: haber mencionado ejemplos de esfuerzo hacia la excelencia relacionados a la infraestructura, actividades adicionales, y/o disciplina.
Discovery and Synthesis of Caracolamide A, a Calcium Channel Modulating Dichlorovinylidene Containing Acyl Amide from a Panamanian Marine Cyanobacterium cf. Symploca sp. C. Benjamin Naman, Jehad Almaliti, Lorene Armstrong, Eduardo J. Caro-Diaz, Marsha L. Pierce, Evgenia Glukhov, Amanda Fenner, Carmenza Spadafora, Hosana M. Debonsi, Pieter C. Dorrestein, Thomas F. Murray, William H. Gerwick J Nat Prod. 2017 Aug 25;80(8):2328-2334.
Abstract A recent untargeted metabolomics investigation into the chemical profile of 10 organic extracts from cf. Symploca spp. revealed several interesting chemical leads for further natural product drug discovery. Subsequent target-directed isolation efforts with one of these, a Panamanian marine cyanobacterium cf. Symploca sp., yielded a phenethylamide metabolite that terminates in a relatively rare gem-dichlorovinylidene moiety, caracolamide A (1), along with a known isotactic polymethoxy-1-alkene (2). Detailed NMR and HRESIMS analyses were used to determine the structures of these molecules, and compound 1 was confirmed by a three-step synthesis. Pure compound 1 was shown to have in vitro calcium influx and calcium channel oscillation modulatory activity when tested as low as 10 pM using cultured murine cortical neurons, but was not cytotoxic to NCI-H460 human non-small-cell lung cancer cells in vitro (IC50 > 10 μM).
Phage-Displayed Peptides Selected to Bind Envelope Glycoprotein Show Antiviral Activity against Dengue Virus Serotype 2. Carolina de la Guardia, Mario Quijada, Ricardo Lleonart Advances in Virology Volume 2017 (2017), Article ID 1827341, 11 pages Abstract Dengue virus is a growing public health threat that affects hundreds of million peoples every year and leave huge economic and social damage. The virus is transmitted by mosquitoes and the incidence of the disease is increasing, among other causes, due to the geographical expansion of the vector’s range and the lack of effectiveness in public health interventions in most prevalent countries. So far, no highly effective vaccine or antiviral has been developed for this virus. Here we employed phage display technology to identify peptides able to block the DENV2. A random peptide library presented in M13 phages was screened with recombinant dengue envelope and its fragment domain III. After four rounds of panning, several binding peptides were identified, synthesized, and tested against the virus. Three peptides were able to block the infectivity of the virus while not being toxic to the target cells. Blind docking simulations were done to investigate the possible mode of binding, showing that all peptides appear to bind domain III of the protein and may be mostly stabilized by hydrophobic interactions. These results are relevant to the development of novel therapeutics against this important virus.
Efficacy of 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine against acute otitis media and nasopharyngeal carriage in Panamanian children – A randomized controlled trial. Xavier Saez-Llorens, Stella Rowley, Digna Wong, Mirna Rodriguez, Arlene Calvo, Marisol Troitino, Albino Salas, Vielka Vega, Maria Mercedes Castrejon, Patricia Lommel, Thierry G. Pascal, William P. Hausdorff, Dorota Borys, Javier Ruiz-Guinazu, Eduardo Ortega-Barria, Juan Pablo Yarzabal & Lode Schuerman Hum Vaccin Immunother. 2017 Jun 3;13(6):1-16. doi: 10.1080/21645515.2017
Abstract We previously reported 10-valent pneumococcal non-typeable Haemophilus influenzae (NTHi) protein D conjugate vaccine (PHiD-CV) efficacy in a double-blind randomized trial (ClinicalTrials.gov: NCT00466947) against various diseases, including acute otitis media (AOM). Here, we provide further analyses. In the Panamanian subset, 7,359 children were randomized (1:1) to receive PHiD-CV or control vaccine at age 2/4/6 and 15-18 months. Of these, 2,000 had nasopharyngeal swabs collected. AOM cases were captured when parents sought medical attention for children with AOM symptoms; surveillance was enhanced approximately 2 y into the study through regular telephone calls or home visits by study personnel, who advised parents to visit the clinic if their child had AOM symptoms. Mean follow-up was 31.4 months. Clinical AOM (C-AOM) cases were assessed by physicians and confirmed by otorhinolaryngologists. Middle ear fluid samples, taken from children with C-AOM after specific informed consent, and nasopharyngeal samples were cultured for pathogen identification. For 7,359 children, 2,574 suspected AOM cases were assessed by a primary healthcare physician; 649 cases were C-AOM cases as per protocol definition. From the 503 MEF samples collected, 158 resulted in a positive culture. In the intent-to-treat cohort (7,214 children), PHiD-CV showed VE against first C-AOM (24.0% [95% CI: 8.7, 36.7]) and bacterial (B-AOM) episodes (48.0% [20.3, 66.1]) in children <24 months, which declined thereafter with age. Pre-booster VE against C-AOM was 30.7% [12.9, 44.9]; post-booster, -6.7% [-36.4, 16.6]. PHiD-CV VE was 17.7% [-6.1, 36.2] against moderate and 32.7% [-20.5, 62.4] against severe C-AOM. VE against vaccine-serotype pneumococcal NPC was 31.2% [5.3, 50.3] 3 months post-booster, and 25.6% [12.7, 36.7] across all visits. NTHi colonization rates were low and no significant reduction was observed. PHiD-CV showed efficacy against C-AOM and B-AOM in children younger than 24 months, and reduced vaccine-serotype NPC.
Healthcare Access and Quality Index based on mortality from causes amenable to personal health care in 195 countries and territories, 1990–2015: a novel analysis from the Global Burden of Disease Study 2015. Dr. Amador Goodridge from INDICASAT AIP and team The Lancet Summary Background: National levels of personal health-care access and quality can be approximated by measuring mortality rates from causes that should not be fatal in the presence of effective medical care (ie, amenable mortality). Previous analyses of mortality amenable to health care only focused on high-income countries and faced several methodological challenges. In the present analysis, we use the highly standardised cause of death and risk factor estimates generated through the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) to improve and expand the quantification of personal health-care access and quality for 195 countries and territories from 1990 to 2015. Methods: We mapped the most widely used list of causes amenable to personal health care developed by Nolte and McKee to 32 GBD causes. We accounted for variations in cause of death certification and misclassifications through the extensive data standardisation processes and redistribution algorithms developed for GBD. To isolate the effects of personal health-care access and quality, we risk-standardised cause-specific mortality rates for each geography-year by removing the joint effects of local environmental and behavioural risks, and adding back the global levels of risk exposure as estimated for GBD 2015. We employed principal component analysis to create a single, interpretable summary measure–the Healthcare Quality and Access (HAQ) Index–on a scale of 0 to 100. The HAQ Index showed strong convergence validity as compared with other health-system indicators, including health expenditure per capita (r=0·88), an index of 11 universal health coverage interventions (r=0·83), and human resources for health per 1000 (r=0·77). We used free disposal hull analysis with bootstrapping to produce a frontier based on the relationship between the HAQ Index and the Socio-demographic Index (SDI), a measure of overall development consisting of income per capita, average years of education, and total fertility rates. This frontier allowed us to better quantify the maximum levels of personal health-care access and quality achieved across the development spectrum, and pinpoint geographies where gaps between observed and potential levels have narrowed or widened over time. Findings: Between 1990 and 2015, nearly all countries and territories saw their HAQ Index values improve; nonetheless, the difference between the highest and lowest observed HAQ Index was larger in 2015 than in 1990, ranging from 28·6 to 94·6. Of 195 geographies, 167 had statistically significant increases in HAQ Index levels since 1990, with South Korea, Turkey, Peru, China, and the Maldives recording among the largest gains by 2015. Performance on the HAQ Index and individual causes showed distinct patterns by region and level of development, yet substantial heterogeneities emerged for several causes, including cancers in highest-SDI countries; chronic kidney disease, diabetes, diarrhoeal diseases, and lower respiratory infections among middle-SDI countries; and measles and tetanus among lowest-SDI countries. While the global HAQ Index average rose from 40·7 (95% uncertainty interval, 39·0–42·8) in 1990 to 53·7 (52·2–55·4) in 2015, far less progress occurred in narrowing the gap between observed HAQ Index values and maximum levels achieved; at the global level, the difference between the observed and frontier HAQ Index only decreased from 21·2 in 1990 to 20·1 in 2015. If every country and territory had achieved the highest observed HAQ Index by their corresponding level of SDI, the global average would have been 73·8 in 2015. Several countries, particularly in eastern and western sub-Saharan Africa, reached HAQ Index values similar to or beyond their development levels, whereas others, namely in southern sub-Saharan Africa, the Middle East, and south Asia, lagged behind what geographies of similar development attained between 1990 and 2015. Interpretation: This novel extension of the GBD Study shows the untapped potential for personal health-care access and quality improvement across the development spectrum. Amid substantive advances in personal health care at the national level, heterogeneous patterns for individual causes in given countries or territories suggest that few places have consistently achieved optimal health-care access and quality across health-system functions and therapeutic areas. This is especially evident in middle-SDI countries, many of which have recently undergone or are currently experiencing epidemiological transitions. The HAQ Index, if paired with other measures of health-system characteristics such as intervention coverage, could provide a robust avenue for tracking progress on universal health coverage and identifying local priorities for strengthening personal health-care quality and access throughout the world.
Global, regional, and national under-5 mortality, adult mortality, age-specific mortality, and life expectancy, 1970–2016: a systematic analysis for the Global Burden of Disease Study 2016. Mushraf Tarajia Lancet 2017; 390: 1084–1150 Summary Background: Detailed assessments of mortality patterns, particularly age-specific mortality, represent a crucial input that enables health systems to target interventions to specific populations. Understanding how all-cause mortality has changed with respect to development status can identify exemplars for best practice. To accomplish this, the Global Burden of Diseases, Injuries, and Risk Factors Study 2016 (GBD 2016) estimated age-specific and sex-specific all-cause mortality between 1970 and 2016 for 195 countries and territories and at the subnational level for the five countries with a population greater than 200 million in 2016. Methods: We have evaluated how well civil registration systems captured deaths using a set of demographic methods called death distribution methods for adults and from consideration of survey and census data for children younger than 5 years. We generated an overall assessment of completeness of registration of deaths by dividing registered deaths in each location-year by our estimate of all-age deaths generated from our overall estimation process. For 163 locations, including subnational units in countries with a population greater than 200 million with complete vital registration (VR) systems, our estimates were largely driven by the observed data, with corrections for small fluctuations in numbers and estimation for recent years where there were lags in data reporting (lags were variable by location, generally between 1 year and 6 years). For other locations, we took advantage of different data sources available to measure under-5 mortality rates (U5MR) using complete birth histories, summary birth histories, and incomplete VR with adjustments; we measured adult mortality rate (the probability of death in individuals aged 15–60 years) using adjusted incomplete VR, sibling histories, and household death recall. We used the U5MR and adult mortality rate, together with crude death rate due to HIV in the GBD model life table system, to estimate age-specific and sex-specific death rates for each location-year. Using various international databases, we identified fatal discontinuities, which we defined as increases in the death rate of more than one death per million, resulting from conflict and terrorism, natural disasters, major transport or technological accidents, and a subset of epidemic infectious diseases; these were added to estimates in the relevant years. In 47 countries with an identified peak adult prevalence for HIV/AIDS of more than 0·5% and where VR systems were less than 65% complete, we informed our estimates of age-sex-specific mortality using the Estimation and Projection Package (EPP)-Spectrum model fitted to national HIV/AIDS prevalence surveys and antenatal clinic serosurveillance systems. We estimated stillbirths, early neonatal, late neonatal, and childhood mortality using both survey and VR data in spatiotemporal Gaussian process regression models. We estimated abridged life tables for all location-years using age-specific death rates. We grouped locations into development quintiles based on the Sociodemographic Index (SDI) and analysed mortality trends by quintile. Using spline regression, we estimated the expected mortality rate for each age-sex group as a function of SDI. We identified countries with higher life expectancy than expected by comparing observed life expectancy to anticipated life expectancy on the basis of development status alone. Findings: Completeness in the registration of deaths increased from 28% in 1970 to a peak of 45% in 2013; completeness was lower after 2013 because of lags in reporting. Total deaths in children younger than 5 years decreased from 1970 to 2016, and slower decreases occurred at ages 5–24 years. By contrast, numbers of adult deaths increased in each 5-year age bracket above the age of 25 years. The distribution of annualised rates of change in age-specific mortality rate differed over the period 2000 to 2016 compared with earlier decades: increasing annualised rates of change were less frequent, although rising annualised rates of change still occurred in some locations, particularly for adolescent and younger adult age groups. Rates of stillbirths and under-5 mortality both decreased globally from 1970. Evidence for global convergence of death rates was mixed; although the absolute difference between age-standardised death rates narrowed between countries at the lowest and highest levels of SDI, the ratio of these death rates—a measure of relative inequality—increased slightly. There was a strong shift between 1970 and 2016 toward higher life expectancy, most noticeably at higher levels of SDI. Among countries with populations greater than 1 million in 2016, life expectancy at birth was highest for women in Japan, at 86·9 years (95% UI 86·7–87·2), and for men in Singapore, at 81·3 years (78·8–83·7) in 2016. Male life expectancy was generally lower than female life expectancy between 1970 and 2016, and the gap between male and female life expectancy increased with progression to higher levels of SDI. Some countries with exceptional health performance in 1990 in terms of the difference in observed to expected life expectancy at birth had slower progress on the same measure in 2016. Interpretation Globally, mortality rates have decreased across all age groups over the past five decades, with the largest improvements occurring among children younger than 5 years. However, at the national level, considerable heterogeneity remains in terms of both level and rate of changes in age-specific mortality; increases in mortality for certain age groups occurred in some locations. We found evidence that the absolute gap between countries in age-specific death rates has declined, although the relative gap for some age-sex groups increased. Countries that now lead in terms of having higher observed life expectancy than that expected on the basis of development alone, or locations that have either increased this advantage or rapidly decreased the deficit from expected levels, could provide insight into the means to accelerate progress in nations where progress has stalled. Funding: Bill & Melinda Gates Foundation, and the National Institute on Aging and the National Institute of Mental Health of the National Institutes of Health.
Total IgM and anti-phosphatidylcholine IgM antibody secretion continues after clearance of Mycobacterium bovis Bacillus Calmette Guerin pleural infection. Ciara Ordoñez, Musharaf Tarajia, Rene Rivera, Dilcia Sambrano, Victoria Batista, Mónica Chavez, Denis Tapia, Patricia L. Fernández, Amador Goodridge Lung (an international journal on lungs, airway and breathing) Abstract The cellular immune response to Mycobacterium tuberculosis infection has been well characterized, while the humoral antibody response remains underexplored. We aimed to examine the total and anti-phospholipid IgM levels in the pleural lavage from mice with Mycobacterium bovis BCG extrapulmonary infection. We found that the levels of total and anti-phosphatidylcholine IgM antibodies remained significantly higher in infected mice as compared to non-infected mice up to day 90 after BCG infection, while the anti-cardiolipin IgM antibody levels decreased with bacteria clearance. Our findings suggest that IgM antibodies are secreted and their composition vary during early and late immune response to BCG pleurisy.
HDAC5 and Its Target Gene, Npas4, Function in the Nucleus Accumbens to Regulate Cocaine-Conditioned Behaviors. Makoto Taniguchi, Maria B. Carreira, Yonatan A. Cooper, Ana-Clara Bobadilla, Jasper A. Heinsbroek, Nobuya Koike, Erin B. Larson, Evan A. Balmuth, Brandon W. Hughes, Rachel D. Penrod, Jaswinder Kumar, Laura N. Smith, Daniel Guzman, Joseph S. Takahashi, Tae-Kyung Kim, Peter W. Kalivas, David W. Self, Yingxi Lin, Christopher W. Cowan. Neuron Volume 96, Issue 1, p130–144.e6, 27 September 2017
Abstract Individuals suffering from substance-use disorders develop strong associations between the drug’s rewarding effects and environmental cues, creating powerful, enduring triggers for relapse. We found that dephosphorylated, nuclear histone deacetylase 5 (HDAC5) in the nucleus accumbens (NAc) reduced cocaine reward-context associations and relapse-like behaviors in a cocaine self-administration model. We also discovered that HDAC5 associates with an activity-sensitive enhancer of the Npas4 gene and negatively regulates NPAS4 expression. Exposure to cocaine and the test chamber induced rapid and transient NPAS4 expression in a small subpopulation of FOS-positive neurons in the NAc. Conditional deletion of Npas4 in the NAc significantly reduced cocaine conditioned place preference and delayed learning of the drug-reinforced action during cocaine self-administration, without affecting cue-induced reinstatement of drug seeking. These data suggest that HDAC5 and NPAS4 in the NAc are critically involved in reward-relevant learning and memory processes and that nuclear HDAC5 limits reinstatement of drug seeking independent of NPAS4.
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