RESUMEN
Emerging and re-emerging pathogens often stem from zoonotic origins, cycling between humans and animals, and are frequently vectored and maintained by hematophagous arthropod vectors. The efficiency by which these disease agents are successfully transmitted between vertebrate hosts is influenced by many factors, including the host on which a vector feeds. The Lyme disease bacterium Borrelia burgdorferi sensu lato has adapted to survive in complex host environments, vectored by Ixodes ticks, and maintained in multiple vertebrate hosts. The versatility of Lyme borreliae in disparate host milieus is a compelling platform to investigate mechanisms dictating pathogen transmission through complex networks of vertebrates and ticks. Squamata, one of the most diverse clade of extant reptiles, is comprised primarily of lizards, many of which are readily fed upon by Ixodes ticks. Yet, lizards are one of the least studied taxa at risk of contributing to the transmission and life cycle maintenance of Lyme borreliae. In this review, we summarize the current evidence, spanning from field surveillance to laboratory infection studies, supporting their contributions to Lyme borreliae circulation. We also summarize the current understanding of divergent lizard immune responses that may explain the underlying molecular mechanisms to confer Lyme spirochete survival in vertebrate hosts. This review offers a critical perspective on potential enzootic cycles existing between lizard-tick-Borrelia interactions and highlights the importance of an eco-immunology lens for zoonotic pathogen transmission studies.
Asunto(s)
Ixodes , Lagartos , Enfermedad de Lyme , Animales , Lagartos/microbiología , Enfermedad de Lyme/microbiología , Enfermedad de Lyme/transmisión , Ixodes/microbiología , Humanos , Grupo Borrelia Burgdorferi/fisiología , Grupo Borrelia Burgdorferi/genética , Borrelia burgdorferi/genética , Borrelia burgdorferi/fisiologíaRESUMEN
Tick vectors and tick-borne disease are increasingly impacting human populations globally. An important challenge is to understand tick movement patterns, as this information can be used to improve management and predictive modelling of tick population dynamics. Evolutionary analysis of genetic divergence, gene flow and local adaptation provides insight on movement patterns at large spatiotemporal scales. We develop low coverage, whole genome resequencing data for 92 blacklegged ticks, Ixodes scapularis, representing range-wide variation across the United States. Through analysis of population genomic data, we find that tick populations are structured geographically, with gradual isolation by distance separating three population clusters in the northern United States, southeastern United States and a unique cluster represented by a sample from Tennessee. Populations in the northern United States underwent population contractions during the last glacial period and diverged from southern populations at least 50 thousand years ago. Genome scans of selection provide strong evidence of local adaptation at genes responding to host defences, blood-feeding and environmental variation. In addition, we explore the potential of low coverage genome sequencing of whole-tick samples for documenting the diversity of microbial pathogens and recover important tick-borne pathogens such as Borrelia burgdorferi. The combination of isolation by distance and local adaptation in blacklegged ticks demonstrates that gene flow, including recent expansion, is limited to geographical scales of a few hundred kilometres.
Asunto(s)
Flujo Génico , Genética de Población , Ixodes , Animales , Ixodes/genética , Estados Unidos , Secuenciación Completa del Genoma , Adaptación Fisiológica/genética , Variación GenéticaRESUMEN
[This corrects the article DOI: 10.1371/journal.pbio.3001066.].
RESUMEN
Lyme disease is common in the northeastern United States, but rare in the southeast, even though the tick vector is found in both regions. Infection prevalence of Lyme spirochetes in host-seeking ticks, an important component to the risk of Lyme disease, is also high in the northeast and northern midwest, but declines sharply in the south. As ticks must acquire Lyme spirochetes from infected vertebrate hosts, the role of wildlife species composition on Lyme disease risk has been a topic of lively academic discussion. We compared tick-vertebrate host interactions using standardized sampling methods among 8 sites scattered throughout the eastern US. Geographical trends in diversity of tick hosts are gradual and do not match the sharp decline in prevalence at southern sites, but tick-host associations show a clear shift from mammals in the north to reptiles in the south. Tick infection prevalence declines north to south largely because of high tick infestation of efficient spirochete reservoir hosts (rodents and shrews) in the north but not in the south. Minimal infestation of small mammals in the south results from strong selective attachment to lizards such as skinks (which are inefficient reservoirs for Lyme spirochetes) in the southern states. Selective host choice, along with latitudinal differences in tick host-seeking behavior and variations in tick densities, explains the geographic pattern of Lyme disease in the eastern US.
Asunto(s)
Vectores de Enfermedades , Conducta de Búsqueda de Hospedador/fisiología , Enfermedad de Lyme/epidemiología , Animales , Animales Salvajes , Borrelia burgdorferi/fisiología , Clima , Reservorios de Enfermedades/microbiología , Reservorios de Enfermedades/estadística & datos numéricos , Vectores de Enfermedades/clasificación , Geografía , Especificidad del Huésped/fisiología , Humanos , Lagartos/microbiología , Enfermedad de Lyme/transmisión , Ratones , Densidad de Población , Prevalencia , Ratas , Sciuridae/microbiología , Musarañas/microbiología , Infestaciones por Garrapatas/epidemiología , Infestaciones por Garrapatas/microbiología , Infestaciones por Garrapatas/transmisión , Garrapatas/microbiología , Estados Unidos/epidemiologíaRESUMEN
The implementation of targeted therapies for acute myeloid leukaemia (AML) has been challenging because of the complex mutational patterns within and across patients as well as a dearth of pharmacologic agents for most mutational events. Here we report initial findings from the Beat AML programme on a cohort of 672 tumour specimens collected from 562 patients. We assessed these specimens using whole-exome sequencing, RNA sequencing and analyses of ex vivo drug sensitivity. Our data reveal mutational events that have not previously been detected in AML. We show that the response to drugs is associated with mutational status, including instances of drug sensitivity that are specific to combinatorial mutational events. Integration with RNA sequencing also revealed gene expression signatures, which predict a role for specific gene networks in the drug response. Collectively, we have generated a dataset-accessible through the Beat AML data viewer (Vizome)-that can be leveraged to address clinical, genomic, transcriptomic and functional analyses of the biology of AML.
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Regulación Neoplásica de la Expresión Génica/genética , Genoma Humano/genética , Genómica , Leucemia Mieloide Aguda/genética , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , ADN (Citosina-5-)-Metiltransferasas/genética , ADN Metiltransferasa 3A , Conjuntos de Datos como Asunto , Exoma/genética , Femenino , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/metabolismo , Masculino , Terapia Molecular Dirigida , Proteínas Nucleares/genética , Nucleofosmina , Proteínas Proto-Oncogénicas/genética , Proteínas Represoras/genética , Análisis de Secuencia de ARN , Factores de Empalme Serina-Arginina/genéticaRESUMEN
The effect of the 20th-century functional extinction of the American Chestnut (Fagaceae: Castanea dentata (Marshall) Borkh) on associated herbivorous insects is unknown. These insects include leafminers that spend at least part of their larval phase feeding between the epidermises of leaves. We surveyed leafminers on C. dentata, nonnative Castanea spp., and hybrids on Long Island, NY. We found 10 leafminer species feeding on Castanea spp. A first New York State record was documented for Stigmella castaneaefoliella (Chambers) (Lepidoptera: Nepticulidae). New host records are established for 6 lepidopterans, including a new host genus for Phyllonorycter basistrigella (Clemens) (Lepidoptera: Gracillariidae). We found no significant differences in the mean intensity of S. castaneaefoliella leaf mines on native and nonnative Castanea spp.; however, our sample size was small. Thus, we guardedly conclude that nonnative Castanea spp. can serve as refugia for C. dentata leafminers native to North America while acknowledging that the extent to which nonnative species are utilized requires further investigation.
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Fagaceae , Herbivoria , Mariposas Nocturnas , Animales , New York , Mariposas Nocturnas/crecimiento & desarrollo , Mariposas Nocturnas/fisiología , Larva/crecimiento & desarrollo , Hojas de la PlantaRESUMEN
B-cell receptor (BCR) associated kinases including spleen tyrosine kinase (SYK) contribute to the pathogenesis of B-cell malignancies. SYK is persistently phosphorylated in a subset of non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL), and SYK inhibition results in abrogation of downstream kinase activity and apoptosis. P505-15 (also known as PRT062607) is a novel, highly selective, and orally bioavailable small molecule SYK inhibitor (SYK IC(50) = 1 nM) with anti-SYK activity that is at least 80-fold greater than its affinity for other kinases. We evaluated the preclinical characteristics of P505-15 in models of NHL and CLL. P505-15 successfully inhibited SYK-mediated B-cell receptor signaling and decreased cell viability in NHL and CLL. Oral dosing in mice prevented BCR-mediated splenomegaly and significantly inhibited NHL tumor growth in a xenograft model. In addition, combination treatment of primary CLL cells with P505-15 plus fludarabine produced synergistic enhancement of activity at nanomolar concentrations. Our findings support the ongoing development of P505-15 as a therapeutic agent for B-cell malignancies. A dose finding study in healthy volunteers has been completed.
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Antineoplásicos/farmacología , Linfocitos B/efectos de los fármacos , Ciclohexilaminas/farmacología , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Linfoma no Hodgkin/tratamiento farmacológico , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Pirimidinas/farmacología , Vidarabina/análogos & derivados , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Linfocitos B/enzimología , Linfocitos B/patología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Ciclohexilaminas/administración & dosificación , Ciclohexilaminas/farmacocinética , Ciclohexilaminas/uso terapéutico , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Citometría de Flujo , Humanos , Leucemia Linfocítica Crónica de Células B/enzimología , Leucemia Linfocítica Crónica de Células B/patología , Linfoma no Hodgkin/enzimología , Linfoma no Hodgkin/patología , Ratones , Ratones Endogámicos BALB C , Ratones SCID , Fosforilación , Pirimidinas/administración & dosificación , Pirimidinas/farmacocinética , Pirimidinas/uso terapéutico , Bazo/efectos de los fármacos , Bazo/enzimología , Quinasa Syk , Vidarabina/administración & dosificación , Vidarabina/farmacocinética , Vidarabina/farmacología , Vidarabina/uso terapéutico , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Transacting siRNA (tasiRNA) biogenesis in Arabidopsis is initiated by microRNA (miRNA) -guided cleavage of primary transcripts. In the case of TAS3 tasiRNA formation, ARGONAUTE7 (AGO7)-miR390 complexes interact with primary transcripts at two sites, resulting in recruitment of RNA-DEPENDENT RNA POLYMERASE6 for dsRNA biosynthesis. An extensive screen for Arabidopsis mutants with specific defects in TAS3 tasiRNA biogenesis or function was done. This yielded numerous ago7 mutants, one dcl4 mutant, and two mutants that accumulated low levels of miR390. A direct genome sequencing-based approach to both map and rapidly identify one of the latter mutant alleles was developed. This revealed a G-to-A point mutation (mir390a-1) that was calculated to stabilize a relatively nonpaired region near the base of the MIR390a foldback, resulting in misprocessing of the miR390/miR390* duplex and subsequent reduced TAS3 tasiRNA levels. Directed substitutions, as well as analysis of variation at paralogous miR390-generating loci (MIR390a and MIR390b), indicated that base pair properties and nucleotide identity within a region 4-6 bases below the miR390/miR390* duplex region contributed to the efficiency and accuracy of precursor processing.
Asunto(s)
Arabidopsis/genética , MicroARNs/genética , Precursores del ARN/metabolismo , Análisis de Secuencia de ADN , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Secuencia de Bases , Análisis Mutacional de ADN , Regulación de la Expresión Génica de las Plantas , Genoma de Planta , MicroARNs/química , MicroARNs/metabolismo , Datos de Secuencia Molecular , Mutación , Conformación de Ácido Nucleico , Precursores del ARN/genéticaRESUMEN
In North America, Lyme disease is primarily caused by the spirochetal bacterium Borrelia burgdorferi sensu stricto (Bb), which is transmitted between multiple vertebrate hosts and ixodid ticks, and is a model commonly used to study host-pathogen interactions. While Bb is consistently observed in its mammalian and avian reservoirs, the bacterium is rarely isolated from North American reptiles. Two closely related lizard species, the eastern fence lizard (Sceloporus undulatus) and the western fence lizard (Sceloporus occidentalis), are examples of reptiles parasitized by Ixodes ticks. Vertebrates are known to generate complement as an innate defense mechanism, which can be activated before Bb disseminate to distal tissues. Complement from western fence lizards has proven lethal against one Bb strain, implying the role of complement in making those lizards unable to serve as hosts to Bb. However, Bb DNA is occasionally identified in distal tissues of field-collected eastern fence lizards, suggesting some Bb strains may overcome complement-mediated clearance in these lizards. These findings raise questions regarding the role of complement and its impact on Bb interactions with North American lizards. In this study, we found Bb seropositivity in a small population of wild-caught eastern fence lizards and observed Bb strain-specific survivability in lizard sera. We also found that a Bb outer surface protein, OspE, from Bb strains viable in sera, promotes lizard serum survivability and binds to a complement inhibitor, factor H, from eastern fence lizards. Our data thus identify bacterial and host determinants of eastern fence lizard complement evasion, providing insights into the role of complement influencing Bb interactions with North American lizards.
Asunto(s)
Antígenos Bacterianos , Proteínas de la Membrana Bacteriana Externa , Borrelia burgdorferi , Proteínas del Sistema Complemento , Evasión Inmune , Lipoproteínas , Lagartos , Enfermedad de Lyme , Animales , Borrelia burgdorferi/inmunología , Lagartos/sangre , Lagartos/inmunología , Lagartos/microbiología , América del Norte , Antígenos Bacterianos/sangre , Antígenos Bacterianos/inmunología , Proteínas de la Membrana Bacteriana Externa/sangre , Proteínas de la Membrana Bacteriana Externa/inmunología , Lipoproteínas/sangre , Lipoproteínas/inmunología , Proteínas del Sistema Complemento/inmunología , Enfermedad de Lyme/sangre , Enfermedad de Lyme/inmunología , Enfermedad de Lyme/microbiología , Enfermedad de Lyme/virologíaRESUMEN
Questing behavior and host associations of immature blacklegged ticks, Ixodes scapularis Say, from the southeastern United States are known to differ from those in the north. To elucidate these relationships we describe host associations of larval and nymphal I. scapularis from 8 lizard species sampled from 5 sites in the southeastern U.S. Larvae and nymphs attached in greater numbers to larger lizards than to smaller lizards, with differential levels of attachment to different lizard species. Blacklegged ticks are generally attached to skinks of the genus Plestiodon in greater numbers per unit lizard weight than to anoles (Anolis) or fence lizards (Sceloporus). The broad-headed skink, Plestiodon laticeps (Schneider), was a particularly important host for immature I. scapularis in our study and in several previous studies of tick-host associations in the southeast. Blacklegged ticks show selective attachment to Plestiodon lizard hosts in the southeast, but whether this results from behavioral host preferences or from ecological factors such as timing or microhabitat distributions of tick questing and host activity remains to be determined.
Asunto(s)
Ixodes , Lagartos/parasitología , Animales , Vectores Artrópodos/clasificación , Biodiversidad , Ecosistema , Interacciones Huésped-Parásitos , Larva , Ninfa , Densidad de Población , Estaciones del Año , Sudeste de Estados Unidos , Especificidad de la Especie , Infestaciones por GarrapatasRESUMEN
Acute myeloid leukemia (AML) is a cancer of myeloid-lineage cells with limited therapeutic options. We previously combined ex vivo drug sensitivity with genomic, transcriptomic, and clinical annotations for a large cohort of AML patients, which facilitated discovery of functional genomic correlates. Here, we present a dataset that has been harmonized with our initial report to yield a cumulative cohort of 805 patients (942 specimens). We show strong cross-cohort concordance and identify features of drug response. Further, deconvoluting transcriptomic data shows that drug sensitivity is governed broadly by AML cell differentiation state, sometimes conditionally affecting other correlates of response. Finally, modeling of clinical outcome reveals a single gene, PEAR1, to be among the strongest predictors of patient survival, especially for young patients. Collectively, this report expands a large functional genomic resource, offers avenues for mechanistic exploration and drug development, and reveals tools for predicting outcome in AML.
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Leucemia Mieloide Aguda , Diferenciación Celular , Estudios de Cohortes , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Receptores de Superficie Celular/genética , TranscriptomaRESUMEN
Tissue damage triggers a rapid innate immune response that mediates host defense. Previously we reported that thermal damage of the larval zebrafish fin disrupts collagen organization and induces a robust and potentially damaging innate immune response. The mechanisms that drive damaging versus protective neutrophil inflammation in interstitial tissues remain unclear. Here we identify distinct cues in the tissue microenvironment that differentially drive neutrophil and macrophage responses to sterile injury. Using live imaging, we found a motile zone for neutrophils, but not macrophages, in collagen-free regions and identified a specific role for interleukin-6 (IL-6) receptor signaling in neutrophil responses to thermal damage. IL-6 receptor mutants show impaired neutrophil recruitment to sterile thermal injury that was not present in tissues infected with Pseudomonas aeruginosa. These findings identify distinct signaling networks during neutrophil recruitment to sterile and microbial damage cues and provide a framework to limit potentially damaging neutrophil inflammation.
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Turtles and tortoises (chelonians) have been integral components of global ecosystems for about 220 million years and have played important roles in human culture for at least 400,000 years. The chelonian shell is a remarkable evolutionary adaptation, facilitating success in terrestrial, freshwater and marine ecosystems. Today, more than half of the 360 living species and 482 total taxa (species and subspecies combined) are threatened with extinction. This places chelonians among the groups with the highest extinction risk of any sizeable vertebrate group. Turtle populations are declining rapidly due to habitat loss, consumption by humans for food and traditional medicines and collection for the international pet trade. Many taxa could become extinct in this century. Here, we examine survival threats to turtles and tortoises and discuss the interventions that will be needed to prevent widespread extinction in this group in coming decades.
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Conservación de los Recursos Naturales , Tortugas , Animales , Especies en Peligro de Extinción , Extinción Biológica , Dinámica PoblacionalRESUMEN
Restoration efforts with native eastern oyster, Crassostrea virginica, in Chesapeake Bay and elsewhere have been limited by shell availability, necessitating the use of alternative structures as subtidal reefs, yet these have rarely been evaluated quantitatively. We quantified population structure, density, abundance and biomass of eastern oyster and hooked mussel, Ischadium recurvum, on a concrete modular reef (75 m2 surface area over 5 m2 of river bottom) deployed subtidally at 7 m depth in the Rappahannock River, Virginia during October, 2000. After nearly 5 y (May 2005), we took 120 stratified random samples over the reef. The reef was heavily colonized by 28-168 oysters and 14-2177 mussels m-2 surface area. These densities translate to 1085 oysters and 8617 mussels m-2 river bottom, which are the highest recorded for artificial oyster reefs. Size structure of oysters reflected four year classes, with over half of oysters more than 1 y old and of reproductive age. Oyster biomass (1663 g dry mass m-2 river bottom) and condition index were equally high, whereas parasite prevalence and intensity were low. Oyster density correlated positively in a sigmoid fashion with mussel density up to high densities, then declined. This modular reef is one of the most successful artificial reefs for eastern oyster and hooked mussel restoration, and details features that are conducive for successful settlement, growth and survival in subtidal habitats.
Asunto(s)
Bahías , Conservación de los Recursos Naturales/métodos , Crassostrea , Mytilidae , Ríos , Distribución Animal , Animales , Biomasa , Tamaño Corporal , Crassostrea/anatomía & histología , Crassostrea/parasitología , Diseño de Equipo , Mytilidae/anatomía & histología , Mytilidae/parasitología , Densidad de Población , VirginiaRESUMEN
Surveys of restored oyster reefs need to produce accurate population estimates to assess the efficacy of restoration. Due to the complex structure of subtidal oyster reefs, one effective and efficient means to sample is by patent tongs, rather than SCUBA, dredges, or bottom cores. Restored reefs vary in relief and oyster density, either of which could affect survey efficiency. This study is the first to evaluate gear (the first full grab) and survey (which includes selecting a specific half portion of the first grab for further processing) efficiencies of hand-operated patent tongs as a function of reef height and oyster density on subtidal restoration reefs. In the Great Wicomico River, a tributary of lower Chesapeake Bay, restored reefs of high- and low-relief (25-45 cm, and 8-12 cm, respectively) were constructed throughout the river as the first large-scale oyster sanctuary reef restoration effort (sanctuary acreage > 20 ha at one site) in Chesapeake Bay. We designed a metal frame to guide a non-hydraulic mechanical patent tong repeatedly into the same plot on a restored reef until all oysters within the grab area were captured. Full capture was verified by an underwater remotely-operated vehicle. Samples (n = 19) were taken on nine different reefs, including five low- (n = 8) and four high-relief reefs (n = 11), over a two-year period. The gear efficiency of the patent tong was estimated to be 76% (± 5% standard error), whereas survey efficiency increased to 81% (± 10%) due to processing. Neither efficiency differed significantly between young-of-the-year oysters (spat) and adults, high- and low-relief reefs, or years. As this type of patent tong is a common and cost-effective tool to evaluate oyster restoration projects as well as population density on fished habitat, knowing the gear and survey efficiencies allows for accurate and precise population estimates.
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Restauración y Remediación Ambiental , Ostreidae , Animales , Conservación de los Recursos Naturales , Arrecifes de Coral , Restauración y Remediación Ambiental/instrumentación , Restauración y Remediación Ambiental/métodos , Restauración y Remediación Ambiental/estadística & datos numéricos , Ostreidae/crecimiento & desarrollo , PoblaciónRESUMEN
The tumor suppressor protein p53 is central to the cellular stress response and may be a predictive biomarker for cancer treatments. Upon stress, wildtype p53 accumulates in the nucleus where it enforces cellular responses, including cell cycle arrest and cell death. p53 is so dominant in its effects, that p53 enforcement - or - restoration therapy is being studied for anti-cancer therapy. Two mechanistically distinct small molecules that act via p53 are the selective inhibitor of nuclear export, selinexor, and MDM2 inhibitor, nutlin-3a. Here, individual cells are studied to define cell cycle response signatures, which captures the variability of responses and includes the impact of loss of p53 expression on cell fates. The individual responses are then used to build the population level response. Matched cell lines with and without p53 expression indicate that while loss-of-function results in altered cell cycle signatures to selinexor treatment, it does not diminish overall cell loss. On the contrary, response to single-agent nutlin-3a shows a strong p53-dependence. Upon treatment with both selinexor and nutlin-3a there are combination effects in at least some cell lines - even when p53 is absent. Collectively, the findings indicate that p53 does act downstream of selinexor and nutlin-3a, and that p53 expression is dispensable for selinexor to cause cell death, but nutlin-3a response is more p53-dependent. Thus, TP53 disruption and lack of expression may not predict poor cell response to selinexor, and selinexor's mechanism of action potentially provides for strong efficacy regardless of p53 function.
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Apoptosis , Ciclo Celular , Carioferinas/metabolismo , Receptores Citoplasmáticos y Nucleares/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Antineoplásicos/farmacología , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Linaje de la Célula/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Fase G1/efectos de los fármacos , Humanos , Hidrazinas/farmacología , Imidazoles/metabolismo , Neoplasias/metabolismo , Neoplasias/patología , Piperazinas/metabolismo , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Triazoles/farmacología , Proteína Exportina 1RESUMEN
The seasonal activity pattern of immature Ixodes scapularis Say (Acari: Ixodidae) varies geographically in the United States, which may affect the efficiency of transmission cycles of pathogens transmitted by this species. To study the factors that determine seasonality, a multiyear study at seven sites across the geographic range of I. scapularis systematically collected questing ticks by flagging/dragging, and feeding ticks by capture of their hosts. The observed phenology patterns were consistent with previous studies reporting geographic variation in seasonal tick activity. Predictions of seasonal activity for each site were obtained from an I. scapularis simulation model calibrated using contemporaneous weather data. A range of scenarios for life-cycle processes-including different regimes of temperature-independent behavioral and developmental diapause, variations in temperature-development rate relationships, and temperature-dependent tick activity-were used in model formulations. These formulations produced a range of simulations of seasonal activity for each site and were compared against the field observed tick data using negative binomial regression models. Best fit scenarios were chosen for each site on the basis of Akaike's information criterion and regression model parameters. This analysis suggests that temperature-independent diapause mechanisms explain some key observed variations in I. scapularis seasonality, and are responsible in part for geographic variations in I. scapularis seasonality in the United States. However, diapause appears to operate in idiosyncratic ways in different regions of the United States, so further studies on populations in different regions will be needed to enable predictive modeling of climatic and climate change effects on I. scapularis seasonal activity and pathogen transmission.
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Vectores Arácnidos/crecimiento & desarrollo , Diapausa de Insecto , Ixodes/crecimiento & desarrollo , Animales , Enfermedad de Lyme/transmisión , Modelos Biológicos , Estaciones del Año , Estados UnidosRESUMEN
Selective inhibitors of nuclear export (SINE) are small molecules in development as anti-cancer agents. The first-in-class SINE, selinexor, is in clinical trials for blood and solid cancers. Selinexor forms a covalent bond with exportin-1 at cysteine-528, and blocks its ability to export cargos. Previous work has shown strong cell cycle effects and drug-induced cell death across many different cancer-derived cell lines. Here, we report strong cell cycle-associated DNA double-stranded break formation upon the treatment of cancer cells with SINE. In multiple cell models, selinexor treatment results in the formation of clustered DNA damage foci in 30-40% of cells within 8 hours that is dependent upon cysteine-528. DNA damage strongly correlates with G1/S-phase and decreased DNA replication. Live cell microscopy reveals an association between DNA damage and cell fate. Cells that form damage in G1-phase more often die or arrest, while those damaged in S/G2-phase frequently progress to cell division. Up to half of all treated cells form damage foci, and most cells that die after being damaged, were damaged in G1-phase. By comparison, non-transformed cell lines show strong cell cycle effects but little DNA damage and less death than cancer cells. Significant drug combination effects occur when selinexor is paired with different classes of agents that either cause DNA damage or that diminish DNA damage repair. These data present a novel effect of exportin-1 inhibition and provide a strong rationale for multiple combination treatments of selinexor with agents that are currently in use for the treatment of different solid cancers.
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Ciclo Celular/efectos de los fármacos , Daño del ADN/efectos de los fármacos , Carioferinas/antagonistas & inhibidores , Receptores Citoplasmáticos y Nucleares/antagonistas & inhibidores , Antineoplásicos/farmacología , Muerte Celular/efectos de los fármacos , Muerte Celular/genética , Línea Celular Tumoral , Replicación del ADN/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Humanos , Hidrazinas/farmacología , Unión Proteica , Triazoles/farmacología , Proteína Exportina 1RESUMEN
Diamondback terrapins (Malaclemys terrapin) are a threatened or endangered species in much of their range along the U.S. Atlantic and Gulf coasts. Over an approximately three-week period from late April to mid-May 2015, hundreds of adult diamondback terrapins were found dead on the shores of Flanders Bay, Long Island, New York, USA. Concurrent with the mortality event, elevated densities of the paralytic shellfish toxin (PST)-producing dinoflagellate, Alexandrium fundyense (>104 cells L-1) and high levels of PST in bivalves (maximal levels = 540 µg STX eq. 100 g-1 shellfish tissue) were observed in the Flanders Bay region, resulting in shellfish bed closures in regional tributaries. Gross and histologic postmortem examinations of terrapins revealed no physical trauma to individuals or a common, underlying disease process to explain the deaths. PST compounds (0.2-12.5 µg STX eq. 100 g-1) were present in various M. terrapin tissues collected over the duration of the mortality event. High-throughput sequencing revealed that the ribbed mussel (Geukensia demissa, a PST vector) was present in the gastrointestinal tracks of all terrapin samples tested. While the potential of PST to cause mortality in chelonians has not been well-characterized, in the absence of other significant findings from necropsies and pathological analyses, we provide evidence that PST in shellfish was likely high enough to cause or contribute to the mortality in these small (<2.0 kg) animals.
Asunto(s)
Enfermedades de los Animales/mortalidad , Dinoflagelados/química , Floraciones de Algas Nocivas , Toxinas Marinas/toxicidad , Intoxicación por Mariscos/veterinaria , Tortugas , Enfermedades de los Animales/inducido químicamente , Animales , Bahías/química , Bivalvos , Complejo IV de Transporte de Electrones/genética , Complejo IV de Transporte de Electrones/metabolismo , Secuenciación de Nucleótidos de Alto Rendimiento , New York , Saxitoxina/toxicidad , MariscosRESUMEN
The response of single cells to anti-cancer drugs contributes significantly in determining the population response, and therefore is a major contributing factor in the overall outcome. Immunoblotting, flow cytometry and fixed cell experiments are often used to study how cells respond to anti-cancer drugs. These methods are important, but they have several shortcomings. Variability in drug responses between cancer and normal cells, and between cells of different cancer origin, and transient and rare responses are difficult to understand using population averaging assays and without being able to directly track and analyze them longitudinally. The microscope is particularly well suited to image live cells. Advancements in technology enable us to routinely image cells at a resolution that enables not only cell tracking, but also the observation of a variety of cellular responses. We describe an approach in detail that allows for the continuous time-lapse imaging of cells during the drug response for essentially as long as desired, typically up to 96 hr. Using variations of the approach, cells can be monitored for weeks. With the employment of genetically encoded fluorescent biosensors numerous processes, pathways and responses can be followed. We show examples that include tracking and quantification of cell growth and cell cycle progression, chromosome dynamics, DNA damage, and cell death. We also discuss variations of the technique and its flexibility, and highlight some common pitfalls.