RESUMEN
Owl monkeys (genus Aotus), or "night monkeys" are platyrrhine primates in the Aotidae family. Early taxonomy only recognized one species, Aotus trivirgatus, until 1983, when Hershkovitz proposed nine unique species designations, classified into red-necked and gray-necked species groups based predominately on pelage coloration. Recent studies questioned this conventional separation of the genus and proposed designations based on the geographical location of wild populations. Alu retrotransposons are a class of mobile element insertion (MEI) widely used to study primate phylogenetics. A scaffold-level genome assembly for one Aotus species, Aotus nancymaae [Anan_2.0], facilitated large-scale ascertainment of nearly 2000 young lineage-specific Alu insertions. This study provides candidate oligonucleotides for locus-specific PCR assays for over 1350 of these elements. For 314 Alu elements across four taxa with multiple specimens, PCR analyses identified 159 insertion polymorphisms, including 21 grouping A. nancymaae and Aotus azarae (red-necked species) as sister taxa, with Aotus vociferans and A. trivirgatus (gray-necked) being more basal. DNA sequencing identified five novel Alu elements from three different taxa. The Alu datasets reported in this study will assist in species identification and provide a valuable resource for Aotus phylogenetics, population genetics and conservation strategies when applied to wild populations.
Asunto(s)
Elementos Alu , Aotidae , Animales , Filogenia , Aotus trivirgatus/genética , Aotidae/genética , Análisis de Secuencia de ADN , Elementos Alu/genéticaRESUMEN
South American night monkeys (genus Aotus) are the only nocturnal simian primates. Early activity recordings in North Colombian A. griseimembra monkeys kept under semi-natural conditions and extensive chronobiological studies carried out in laboratory settings revealed a strictly nocturnal behavior and strong activity enhancing (disinhibiting) effects of moonlight or corresponding luminosities during the dark time. To check whether the results from captive individuals correspond to the behavior of wild monkeys, we carried out long-term activity recordings of a wild female A. griseimembra in a tropical rainforest near San Juan de Carare, Northern Colombia. Our data from about 150 days of continuous activity records with an "Actiwatch Mini" (CamNtech, UK) accelerometer-data logger device, confirmed: (1) strictly nocturnal behavior, (2) a pronounced bimodal activity pattern with prominent peaks during dusk and dawn, and (3) a lunar periodic modulation (masking) of the night monkey's circadian activity rhythm due to distinct activity inhibiting effects of the absence of moonlight throughout the night. The results from this wild-living tropical night monkey are consistent with those from captive conspecifics studied decades earlier.
Asunto(s)
Ritmo Circadiano , Actividad Motora , Animales , Aotidae , Aotus trivirgatus , Colombia , Femenino , LuzRESUMEN
BACKGROUND: Toxoplasmosis is an important disease affecting captive non-human primates. The goal of this study was to assess the seroprevalence and pathological findings of toxoplasmosis in different species of captive primates. METHODS: Six captive neotropical primates died naturally due to Toxoplasma gondii infection and were necropsied. Tissue samples were evaluated by histopathology and immunohistochemistry. Serum samples from 57 captive neotropical and Old-world primates housed at the Belo Horizonte zoological garden were analyzed by indirect fluorescent antibody test (IFAT), enzyme-linked immunosorbent assay (ELISA), and indirect hemagglutination assay (IHA). RESULTS: Neotropical primates had lesions compatible with toxoplasmosis with immunolabeled intralesional T gondii. All Old-World primates (10/10), but only three neotropical primates (3/47), all belonging to the Sapajus apella species (3/6), were serologically positive. CONCLUSIONS: Our results suggest a higher susceptibility of neotropical primates to toxoplasmosis. However, this study also supports the hypothesis that Sapajus apella may be naturally resistant.
Asunto(s)
Especificidad del Huésped , Enfermedades de los Monos , Pitheciidae , Toxoplasma/fisiología , Toxoplasmosis Animal/diagnóstico , Animales , Animales de Zoológico , Aotus trivirgatus , Brasil , Resultado Fatal , Femenino , Leontopithecus , Masculino , Toxoplasmosis Animal/parasitologíaRESUMEN
The pulvinar receives direct visual information from the retina and indirect visual information from several cortical and subcortical areas. In this chapter, we discuss the visuotopic organization of the primate pulvinar. Electrophysiological techniques have been systematically employed to study pulvinar visuotopy in the owl, capuchin, and macaque monkeys. A single map of the visual field has been described in the pulvinar of the owl monkey, while two independent maps have been described in the capuchin and macaque pulvinar.
Asunto(s)
Mapeo Encefálico , Primates , Pulvinar , Vías Visuales , Animales , Aotus trivirgatus , Primates/fisiología , Pulvinar/fisiología , Retina , Campos VisualesRESUMEN
Fully-protective, long-lasting, immunological (FPLLI) memory against Plasmodium falciparum malaria regarding immune protection-inducing protein structures (IMPIPS) vaccinated into monkeys previously challenged and re-challenged 60 days later with a lethal Aotus monkey-adapted P. falciparum strain was found to be associated with preferential high binding capacity to HLA-DRß1* allelic molecules of the major histocompatibility class II (MHC-II), rather than HLA-DRß3*, ß4*, ß5* alleles. Complete PPIIL 3D structure, a longer distance (26.5 Å ± 1.5 Å) between residues perfectly fitting into HLA-DRß1*PBR pockets 1 and 9, a gauche(-) rotamer orientation in p8 TCR-contacting polar residue and a larger volume of polar p2 residues was also found. This data, in association with previously-described p3 and p7 apolar residues having gauche(+) orientation to form a perfect MHC-II-peptide-TCR complex, determines the stereo-electronic and topochemical characteristics associated with FPLLI immunological memory.
Asunto(s)
Cadenas beta de HLA-DR/química , Cadenas beta de HLA-DR/inmunología , Malaria/inmunología , Plasmodium falciparum/inmunología , Receptores de Antígenos de Linfocitos T/química , Receptores de Antígenos de Linfocitos T/inmunología , Animales , Aotus trivirgatus , Sitios de Unión , Inmunidad Innata/inmunología , Memoria Inmunológica/inmunología , Unión Proteica , Relación Estructura-ActividadRESUMEN
Antigenic diversity has posed a critical barrier to vaccine development against the pathogenic blood-stage infection of the human malaria parasite Plasmodium falciparum. To date, only strain-specific protection has been reported by trials of such vaccines in nonhuman primates. We recently showed that P. falciparum reticulocyte binding protein homolog 5 (PfRH5), a merozoite adhesin required for erythrocyte invasion, is highly susceptible to vaccine-inducible strain-transcending parasite-neutralizing antibody. In vivo efficacy of PfRH5-based vaccines has not previously been evaluated. Here, we demonstrate that PfRH5-based vaccines can protect Aotus monkeys against a virulent vaccine-heterologous P. falciparum challenge and show that such protection can be achieved by a human-compatible vaccine formulation. Protection was associated with anti-PfRH5 antibody concentration and in vitro parasite-neutralizing activity, supporting the use of this in vitro assay to predict the in vivo efficacy of future vaccine candidates. These data suggest that PfRH5-based vaccines have potential to achieve strain-transcending efficacy in humans.
Asunto(s)
Proteínas Portadoras/inmunología , Inmunidad Heteróloga , Vacunas contra la Malaria/inmunología , Malaria/prevención & control , Animales , Anticuerpos Neutralizantes/sangre , Anticuerpos Antiprotozoarios/sangre , Antígenos de Protozoos/inmunología , Aotus trivirgatus , Modelos Animales de Enfermedad , Femenino , Malaria/inmunología , Vacunas contra la Malaria/administración & dosificación , Pruebas de NeutralizaciónRESUMEN
Uniformity, local variability, and systematic variation in neuron numbers per unit of cortical surface area across species and cortical areas have been claimed to characterize the isocortex. Resolving these claims has been difficult, because species, techniques, and cortical areas vary across studies. We present a stereological assessment of neuron numbers in layers II-IV and V-VI per unit of cortical surface area across the isocortex in rodents (hamster, Mesocricetus auratus; agouti, Dasyprocta azarae; paca, Cuniculus paca) and primates (owl monkey, Aotus trivigratus; tamarin, Saguinus midas; capuchin, Cebus apella); these chosen to vary systematically in cortical size. The contributions of species, cortical areas, and techniques (stereology, "isotropic fractionator") to neuron estimates were assessed. Neurons per unit of cortical surface area increase across the rostro-caudal (RC) axis in primates (varying by a factor of 1.64-2.13 across the rostral and caudal poles) but less in rodents (varying by a factor of 1.15-1.54). Layer II-IV neurons account for most of this variation. When integrated into the context of species variation, and this RC gradient in neuron numbers, conflicts between studies can be accounted for. The RC variation in isocortical neurons in adulthood mirrors the gradients in neurogenesis duration in development.
Asunto(s)
Neocórtex/citología , Neuronas/citología , Animales , Aotus trivirgatus , Cebus , Recuento de Células , Cuniculidae , Dasyproctidae , Mesocricetus , Neuroglía/citología , Saguinus , Especificidad de la EspecieRESUMEN
The palmaris longus is considered a phylogenetic degenerate metacarpophalangeal joint flexor muscle in humans, a small vestigial forearm muscle; it is the most variable muscle in humans, showing variation in position, duplication, slips and could be reverted. It is frequently studied in papers about human anatomical variations in cadavers and in vivo, its variation has importance in medical clinic, surgery, radiological analysis, in studies about high-performance athletes, in genetics and anthropologic studies. Most studies about palmaris longus in humans are associated to frequency or case studies, but comparative anatomy in primates and comparative morphometry were not found in scientific literature. Comparative anatomy associated to morphometry of palmaris longus could explain the degeneration observed in this muscle in two of three of the great apes. Hypothetically, the comparison of the relative length of tendons and belly could indicate the pathway of the degeneration of this muscle, that is, the degeneration could be associated to increased tendon length and decreased belly from more primitive primates to those most derivate, that is, great apes to modern humans. In conclusion, in primates, the tendon of the palmaris longus increase from Lemuriformes to modern humans, that is, from arboreal to terrestrial primates and the muscle became weaker and tending to be missing.
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Modelos Anatómicos , Músculo Esquelético/anatomía & histología , Animales , Aotus trivirgatus , Atelinae , Brasil , Cadáver , Callithrix , Interpretación Estadística de Datos , Femenino , Antebrazo/anatomía & histología , Humanos , Lemur , Macaca , Masculino , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Especificidad de la Especie , StrepsirhiniRESUMEN
Topological and stereo-electron characteristics are essential in major histocompability class II-peptide-T-cell receptor (MHC-p-TCR) complex formation for inducing an appropriate immune response. Modified high activity binding peptides (mHABPs) were synthesised for complete full protection antimalarial vaccine development producing a large panel of individually fully protection-inducing protein structures (FPIPS) and very high long-lasting antibody-inducing (VHLLAI) mHABPs. Most of those which did not interfere, compete, inhibit or suppress their individual VHLLAI or FPIPS activity contained or displayed a polyproline II-like (PPIIL) structure when mixed. Here we show that amino acid side-chains located in peptide binding region (PBR) positions p3 and p7 displayed specific electron charges and side-chain gauche(+) orientation for interacting with the TCR. Based on the above, and previously described physicochemical principles, non-interfering, long-lasting, full protection-inducing, multi-epitope, multistage, minimal subunit-based chemically synthesised mHABP mixtures can be designed for developing vaccines against diseases scourging humankind, malaria being one of them.
Asunto(s)
Vacunas contra la Malaria/química , Oligopéptidos/inmunología , Conformación Proteica , Adyuvantes Inmunológicos/administración & dosificación , Secuencia de Aminoácidos , Animales , Anticuerpos Antiprotozoarios/sangre , Formación de Anticuerpos , Aotus trivirgatus , Sitios de Unión , Cadenas beta de HLA-DR/inmunología , Malaria Falciparum/prevención & control , Datos de Secuencia Molecular , Oligopéptidos/síntesis químicaRESUMEN
Parietal and frontal cortex are central to controlling forelimb movements. We previously showed that movements such as reach, grasp, and defense can be evoked from primary motor (M1), premotor (PMC), and posterior parietal (PPC) cortex when 500-ms trains of electrical pulses are delivered via microelectrodes. Stimulation sites that evoked a specific movement clustered into domains, which shared a topographic pattern in New World monkeys and prosimian galagos. Matched functional domains in parietal and frontal cortex were preferentially interconnected. We reasoned that matched functional domains form parallel networks involved in specific movements. To test the roles of domains in M1, PMC, and PPC, we systematically inactivated with muscimol domains in one region and determined if functional changes occurred in matching domains in other regions. The most common changes were higher current thresholds for stimulation-evoked movements and shorter, not fully developed, trajectories of movements. Inactivations of an M1 functional domain greatly reduced or abolished movements evoked from the matching domains in PMC or PPC, whereas movements evoked from nonmatching domains remained mostly unaffected. In contrast, inactivating PMC or PPC domains did not consistently abolish the ability to evoke movements from matching M1 domains. However, inactivation of PMC domains suppressed or altered the movements evoked from PPC domains. Thus movement sequences evoked from PMC depend on M1 and movement sequences evoked from PPC depend on both M1 and PMC. Overall, the results support the conclusion that PPC, PMC, and M1 are subdivided into functional domains that are hierarchically related within parallel networks.
Asunto(s)
Corteza Motora/fisiología , Movimiento/fisiología , Red Nerviosa/fisiología , Lóbulo Parietal/fisiología , Animales , Aotus trivirgatus , Estimulación Eléctrica , Femenino , Agonistas de Receptores de GABA-A/farmacología , Galago , Masculino , Corteza Motora/efectos de los fármacos , Movimiento/efectos de los fármacos , Muscimol/farmacología , Lóbulo Parietal/efectos de los fármacos , SaimiriRESUMEN
BACKGROUND: In vitro evidence indicates that tetrandrine (TT) can potentiate the action of chloroquine 40-fold against choloquine-resistant Plasmodium falciparum. The key question emanating from that study is "would tetrandine and chloroquine be highly effective in a live Aotus monkey model with chloroquine-resistant parasites". This study was designed to closely mimic the pharmacological/anti-malarial activity in man. METHODS: The Vietnam Smith/RE strain of P. falciparum, which is chloroquine-resistant was used in this study. Previous experimental procedures were followed. Panamanian owl monkeys (Aotus) were inoculated with 5×10(6) erythrocytes parasitized with the CQ-resistant strain of P. falciparum. Oral drug treatment was with CQ (20 mg/kg) and/or tetrandrine at 15 mg/Kg, 30 mg/Kg or 60 mg/Kg or 25 mg/Kg depending on experimental conditions. RESULTS AND DISCUSSION: Parasitaemia was cleared rapidly with CQ and TT while CQ treatment alone was ineffective. Recrudescence of malaria occurred after seven days post-infection. However, four animals were treated orally with TT and CQ parasites were cleared. It is likely that monkeys were cured via a combination of both drug and host immune responses. A single Aotus monkey infected with P. falciparum and untreated with drugs, died. No side effects were observed with these drug treatments. CONCLUSIONS: This combination of chloroquine and tetrandrine forms the basis of a new attack on chloroquine-resistant malaria - one based upon inhibition of the basis of chloroquine resistance, the multiple drug resistance pump. Previous studies demonstrated that the parasite MDR pump was found on parasite membranes using 3H azidopine photoaffinity labelling.Since MDR-based choloroquine resistance is induced by chloroquine, the basis of the action of tetrandrine is the following: 1) tetrandrine inhibits the MDR pump by stimulating MDR ATPase which limits the energy of the pump by depletion of parasite ATP, 2) tetrandrine blocks the genetic factor which controls the induction of the pump. Therefore, it appears that the parasite cannot outsmart these mechanisms and produce a new mode of resistance. Only time will tell if this is correct.
Asunto(s)
Antimaláricos/administración & dosificación , Bencilisoquinolinas/administración & dosificación , Cloroquina/administración & dosificación , Malaria Falciparum/tratamiento farmacológico , Plasmodium falciparum/aislamiento & purificación , Administración Oral , Animales , Aotus trivirgatus , Modelos Animales de Enfermedad , Resistencia a Medicamentos , Quimioterapia Combinada/métodos , Malaria Falciparum/parasitología , Parasitemia/tratamiento farmacológico , Parasitemia/parasitología , Plasmodium falciparum/efectos de los fármacos , Recurrencia , Resultado del TratamientoRESUMEN
The importance of CSP- and STARP-derived Ï and ψ dihedral angles in mHABP structure was analysed by (1)H NMR in the search for molecules which can be included as components of a first-line-of-defence Plasmodium falciparum sporozoite multi-epitope vaccine against the most lethal form of human malaria. Most of the aforementioned dihedral angles were left-hand-like polyproline type II (PPII(L)) structures whilst others had right-hand-like α-helix (α(R)), thus allowing mHABPS to fit better into MHCII molecules and thereby form an appropriate pMHCII complex and also establish the H-bonds which stabilise such complex and by this means induce an appropriate immune response. This information has great implications for vaccine development, malaria being one of them.
Asunto(s)
Antígenos de Protozoos/química , Antígenos de Protozoos/inmunología , Vacunas contra la Malaria/química , Vacunas contra la Malaria/inmunología , Plasmodium falciparum/inmunología , Proteínas Protozoarias/química , Proteínas Protozoarias/inmunología , Secuencia de Aminoácidos , Animales , Aotus trivirgatus , Cadenas beta de HLA-DR/química , Cadenas beta de HLA-DR/inmunología , Humanos , Datos de Secuencia Molecular , Resonancia Magnética Nuclear Biomolecular , Fragmentos de Péptidos/química , Fragmentos de Péptidos/inmunología , Péptidos/química , Péptidos/inmunología , Estructura Secundaria de Proteína , Esporozoítos/inmunologíaRESUMEN
Modified HABP (mHABP) regions interacting with HLA-DRß1(∗) molecules have a more restricted conformation and/or sequence than other mHABPs which do not fit perfectly into their peptide binding regions (PBR) and do not induce an acceptable immune response due to the critical role of their Φ and Ψ torsion angles. These angle's critical role was determined in such highly immunogenic, protection-inducing response against experimental malaria using the conformers (mHABPs) obtained by (1)H-NMR and superimposed into HLA-DRß1(∗)-like Aotus monkey molecules; their phi (Φ) and psi (Ψ) angles were measured and the H-bond formation between these molecules was evaluated. The aforementioned mHABP propensity to assume a regular conformation similar to a left-handed polyproline type II helix (PPII(L)) led to suggesting that favouring these conformations according to their amino acid sequence would lead to high antibody titre production and sterile protective immunity induction against malaria, thereby adding new principles or rules for vaccine development, malaria being one of them.
Asunto(s)
Vacunas contra la Malaria/química , Vacunas contra la Malaria/inmunología , Malaria Falciparum/prevención & control , Fragmentos de Péptidos/química , Fragmentos de Péptidos/inmunología , Plasmodium falciparum/inmunología , Secuencia de Aminoácidos , Animales , Aotus trivirgatus , Cadenas beta de HLA-DR/inmunología , Datos de Secuencia Molecular , Resonancia Magnética Nuclear Biomolecular , Péptidos/química , Péptidos/inmunología , Estructura Secundaria de ProteínaRESUMEN
Conserved Plasmodium falciparum high activity binding peptides' (HABPs) most relevant proteins involved in malaria parasite invasion are immunologically silent; critical binding residues must therefore be specifically replaced to render them highly immunogenic and protection-inducing. Such changes have a tremendous impact on these peptides' steric-electronic effects, such as modifications to peptide length peptide bonds and electronic orbitals' disposition, to allow a better fit into immune system MHCII molecules and better interaction with the TCR which might account for the final immunological outcome.
Asunto(s)
Malaria/prevención & control , Péptidos/inmunología , Plasmodium falciparum/inmunología , Animales , Aotus trivirgatus , Electrones , Sistema Inmunológico/inmunología , Inmunidad , Malaria/inmunología , Péptidos/química , Conformación Proteica , Receptores de Antígenos de Linfocitos T/inmunologíaRESUMEN
A group of 5 genes, OCC1, testican-1, testican-2, 5-HT1B, and 5-HT2A, are selectively expressed in layer 4 (4C of Brodmann) of striate cortex (visual area V1) of both Old World macaques and New World marmoset monkeys. The expression of these genes is activity dependent, as expression is reduced after blocking retinal activity. Surprisingly, the pronounced expression pattern has not been found in rodents or carnivores. Thus, these genes may be highly expressed in V1 of some but perhaps not all primates. Here, we compared the gene expression in members of 3 major branches of primate evolution: prosimians, New World monkeys, and Old World monkeys. Although the expression pattern of 5-HT1B was well conserved, those of the other genes varied from the least distinct in prosimian galagos to successively more in New World owl monkeys, marmosets, squirrel monkeys, and Old World macaque monkeys. In owl monkeys, the expression of 5-HT2A was significantly reduced by monocular tetrodotoxin injection, while those of OCC1 and 5-HT1B were not. Thus, we propose that early primates had low levels of expression and higher levels emerged with anthropoid primates and became further enhanced in the Old World catarrhine monkeys that are more closely related to humans.
Asunto(s)
Aotus trivirgatus/metabolismo , Callithrix/metabolismo , Proteínas de la Matriz Extracelular/metabolismo , Galago/metabolismo , Macaca mulatta/metabolismo , Receptores de Serotonina/metabolismo , Corteza Visual/metabolismo , Animales , Expresión Génica/fisiología , Especificidad de la EspecieRESUMEN
Several sporozoite proteins have been associated with Plasmodium falciparum cell traversal and hepatocyte invasion, including the cell-traversal protein for ookinetes and sporozoites (CelTOS), and thrombospondin-related sporozoite protein (TRSP). CelTOS and TRSP amino acid sequences have been finely mapped to identify regions specifically binding to HeLa and HepG2 cells, respectively. Three high-activity binding peptides (HABPs) were found in CelTOS and one HABP was found in TRSP, all of them having high α-helical structure content. These HABPs' specific binding was sensitive to HeLa and HepG2 cells' pre-treatment with heparinase I and chondroitinase ABC. Despite their similarity at three-dimensional (3D) structural level, TRSP and TRAP HABPs located in the TSR domain did not compete for the same binding sites. CelTOS and TRSP HABPs were used as a template for designing modified sequences to then be assessed in the Aotus monkey experimental model. Antibodies directed against these modified HABPs were able to recognize both the native parasite protein by immunofluorescence assay and the recombinant protein (expressed in Escherichia coli) by Western blot and ELISA assays. The results suggested that these modified HABPs could be promising targets in designing a fully effective, antimalarial vaccine.
Asunto(s)
Plasmodium falciparum/inmunología , Proteínas Protozoarias , Trombospondinas , Secuencia de Aminoácidos , Animales , Aotus trivirgatus , Sitios de Unión , Línea Celular Tumoral , Condroitina ABC Liasa/farmacología , Células HeLa , Células Hep G2 , Liasa de Heparina/farmacología , Hepatocitos/inmunología , Hepatocitos/metabolismo , Hepatocitos/parasitología , Humanos , Vacunas contra la Malaria/inmunología , Péptidos/análisis , Péptidos/inmunología , Péptidos/aislamiento & purificación , Plasmodium falciparum/citología , Plasmodium falciparum/metabolismo , Unión Proteica , Estructura Secundaria de Proteína , Proteínas Protozoarias/química , Proteínas Protozoarias/inmunología , Proteínas Protozoarias/aislamiento & purificación , Proteínas Recombinantes/síntesis química , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Esporozoítos/citología , Esporozoítos/inmunología , Esporozoítos/metabolismo , Trombospondinas/química , Trombospondinas/inmunología , Trombospondinas/aislamiento & purificaciónRESUMEN
Identifying the ligands or regions derived from them which parasites use to invade their target cells has proved to be an excellent strategy for identifying targets for vaccine development. Members of the reticulocyte-binding homologue family (PfRH), including RH5, have been implicated in invasion as adhesins binding to specific receptors on erythrocyte surface. The regions mediating PfRH5-RBC specific interactions have been identified here by fine mapping the whole PfRH5 protein sequence. These regions, called high activity binding peptides (HABPs), bind to a receptor which is sensitive to trypsin treatment and inhibit merozoite invasion of RBCs by up to 80%, as has been found for HABP 36727. Our results show that a single amino acid change in the HABP 36727 sequence modifies a peptide's 3D structure, thereby resulting in a loss of specific binding to human RBCs and its inhibition ability, while binding to Aotus RBC remains unmodified. Such invasion differences and binding ability produced by replacing a single amino acid in an essential molecule, such as PfRH5, highlight the inherent difficulties associated with developing a fully effective vaccine against malaria.
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Sustitución de Aminoácidos , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Adhesión Celular , Eritrocitos/parasitología , Mutación Missense , Plasmodium falciparum/patogenicidad , Secuencia de Aminoácidos , Animales , Aotus trivirgatus , Proteínas Portadoras/química , Eritrocitos/metabolismo , Humanos , Datos de Secuencia Molecular , Proteínas Mutantes/química , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Unión Proteica , Conformación Proteica , Alineación de SecuenciaRESUMEN
Febrifugine is an alkaloid isolated from Dichroa febrifuga Lour as the active component against Plasmodium falciparum, but exhibits toxic side effects. In this study novel febrifugine analogues were designed and efficiently synthesized. New compounds underwent efficacy and toxicity evaluation. Some compounds are much less toxic than the natural product febrifugine and existing antimalarial drugs and are expected to possess wide therapeutic windows. In Aotus monkeys infected with the chloroquine resistant FVO strain of P. falciparum, one interesting compound possesses a 50% curative dose of 2mg/kg/day and a 100% curative dose of 8 mg/kg/day. These compounds, as well as the underlying design rationale, may find usefulness in the discovery and development of new antimalarial drugs.
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Antimaláricos/síntesis química , Antimaláricos/farmacología , Piperidinas/química , Piperidinas/farmacología , Plasmodium falciparum/efectos de los fármacos , Quinazolinas/química , Quinazolinas/farmacología , Animales , Antimaláricos/uso terapéutico , Antimaláricos/toxicidad , Aotus trivirgatus , Evaluación Preclínica de Medicamentos , Malaria/tratamiento farmacológico , Piperidinas/uso terapéutico , Piperidinas/toxicidad , Quinazolinas/uso terapéutico , Quinazolinas/toxicidadRESUMEN
Plasmodium falciparum malaria continues being one of the parasitic diseases causing the highest worldwide mortality due to the parasite's multiple evasion mechanisms, such as immunological silence. Membrane and organelle proteins are used during invasion for interactions mediated by high binding ability peptides (HABPs); these have amino acids which establish hydrogen bonds between them in some of their critical binding residues. Immunisation assays in the Aotus model using HABPs whose critical residues had been modified have revealed a conformational change thereby enabling a protection-inducing response. This has improved fitting within HLA-DRß1(∗) molecules where amino acid electron-donor atoms present in ß-turn, random or distorted α-helix structures preferentially bound to HLA-DR53 molecules, whilst HABPs having amino acid electron-acceptor atoms present in regular α-helix structure bound to HLA-DR52. This data has great implications for vaccine development.
Asunto(s)
Aminoácidos/inmunología , Electrones , Antígenos HLA-DR/inmunología , Vacunas contra la Malaria/inmunología , Malaria/inmunología , Péptidos/inmunología , Plasmodium falciparum/inmunología , Secuencia de Aminoácidos , Aminoácidos/química , Animales , Aotus trivirgatus , Antígenos HLA-DR/química , Antígenos HLA-DR/genética , Humanos , Malaria/prevención & control , Vacunas contra la Malaria/química , Vacunas contra la Malaria/genética , Datos de Secuencia Molecular , Péptidos/química , Péptidos/genética , Conformación ProteicaRESUMEN
In order to confirm a microscopic diagnosis of 'eperythrozoonosis' made over 40 years ago in a captive owl monkey (Aotus trivirgatus), DNA was extracted from archived fixed and stained blood smears and subjected to generic haemotropic mycoplasma (haemoplasma) quantitative real-time PCR (qPCR) and a human glyceraldehyde-3-phosphate dehydrogenase qPCR as an amplification control. The qPCRs confirmed the extraction of host DNA from the samples and the presence of a haemoplasma species. Partial 16S rRNA and ribonuclease P ribosomal gene fragments were amplified by PCR, cloned and sequenced. Sequence data and phylogeny showed the owl monkey haemoplasma to lie in the haemominutum clade of haemoplasmas, most closely related to 'Candidatus Mycoplasma kahaneii'. This study confirms the use of generic haemoplasma qPCRs to successfully amplify haemoplasma DNA from fixed, stained and archived blood smears from the early 1970s and provides molecular confirmation of the existence of a novel haemoplasma species in an owl monkey, for which the name 'Candidatus Mycoplasma aoti' sp. nov. is proposed.