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INTRODUCTION: Genetic associations with Alzheimer's disease (AD) age at onset (AAO) could reveal genetic variants with therapeutic applications. We present a large Colombian kindred with autosomal dominant AD (ADAD) as a unique opportunity to discover AAO genetic associations. METHODS: A genetic association study was conducted to examine ADAD AAO in 340 individuals with the PSEN1 E280A mutation via TOPMed array imputation. Replication was assessed in two ADAD cohorts, one sporadic early-onset AD study and four late-onset AD studies. RESULTS: 13 variants had p<1×10-7 or p<1×10-5 with replication including three independent loci with candidate associations with clusterin including near CLU. Other suggestive associations were identified in or near HS3ST1, HSPG2, ACE, LRP1B, TSPAN10, and TSPAN14. DISCUSSION: Variants with suggestive associations with AAO were associated with biological processes including clusterin, heparin sulfate, and amyloid processing. The detection of these effects in the presence of a strong mutation for ADAD reinforces their potentially impactful role.
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Enfermedad de Alzheimer , Clusterina , Humanos , Clusterina/genética , Colombia , Enfermedad de Alzheimer/diagnóstico , Mutación/genética , Amiloide , Presenilina-1/genética , Edad de InicioRESUMEN
Freshwater fishes are the second most threatened group of vertebrates after amphibians. In most developing countries, the conservation of freshwater fishes is largely hampered by limited information and data. The Red List assessments by the International Union for Conservation of Nature (IUCN) provide a benchmark for monitoring and mitigating species extinction risk, but these assessments require, inter alia, quantitative information on the species range in the wild. This information is largely missing for many species that face extinction threats. Here, we combine species occurrence data, expert knowledge, and literature to (i) review and update the distribution of non-Haplochromis fish species native to Uganda and (ii) determine the national geographical range of these fish species relative to their global range. For the latter, we use the IUCN's standard protocol for mapping distribution of freshwater species from which we derive both the national and global extent of occurrence (EOO) and area of occupancy (AOO). We show that at least 110 non-Haplochromis species occur in Uganda, with the majority species having a wide distribution outside the national boundaries. However, substantial gaps exist in data on presence of the species in their native range, where more than 60% of the species are designated as "possibly extant." We elaborate on fish species previously believed to occur in Uganda, e.g., Amphilius kivuensis Pellegrin, 1933; Bagrus degeni Boulenger, 1906; Marcusenius macrolepidotus (Peters, 1852); Petrocephalus catostoma (Günther, 1866); and Lacustricola pumilus (Boulenger, 1906), but where recent studies suggest they lack a native distribution within the country. In addition, we highlight fishes with occurrence records that site them in areas beyond their previously known range, requiring further investigations to ascertain their present status. This work has potential to (i) trigger evidence-driven policies aimed at site-based conservation and rethinking of extent of protected areas, (ii) stimulate data collection, especially in areas where fishes are designated as "possibly extant" and "presence uncertain," and (iii) aid the IUCN Red List assessments, for which conservation status of the majority non-Haplochromis species is outdated and many others remain unevaluated due to lack of quantitative information on their range.
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Bagres , Monitoreo del Ambiente , Animales , Uganda , Benchmarking , Recolección de DatosRESUMEN
Estimates of species geographic ranges constitute critical input for biodiversity assessments, including those for the International Union for the Conservation of Nature (IUCN) Red List of Threatened Species. Area of occupancy (AOO) is one metric that IUCN uses to quantify a species' range, but data limitations typically lead to either under- or overestimates (and unnecessarily wide bounds of uncertainty). Fortunately, existing methods in which range maps and land-cover data are used to estimate the area currently holding habitat for a species can be extended to yield an unbiased range of plausible estimates for AOO. Doing so requires estimating the proportion of sites (currently containing habitat) that a species occupies within its range (i.e., prevalence). Multiplying a quantification of habitat area by prevalence yields an estimate of what the species inhabits (i.e., AOO). For species with intense sampling at many sites, presence-absence data sets or occupancy modeling allow calculation of prevalence. For other species, primary biodiversity data (records of a species' presence at a point in space and time) from citizen-science initiatives and research collections of natural history museums and herbaria could be used. In such cases, estimates of sample prevalence should be corrected by dividing by the species' detectability. To estimate detectability from these data sources, extensions of inventory-completeness analyses merit development. With investments to increase the quality and availability of online biodiversity data, consideration of prevalence should lead to tighter and more realistic bounds of AOO for many taxonomic groups and geographic regions. By leading to more realistic and representative characterizations of biodiversity, integrating maps of current habitat with estimates of prevalence should empower conservation practitioners and decision makers and thus guide actions and policy worldwide.
Estimaciones de las distribuciones geográficas de las especies constituyen insumos críticos para evaluaciones de la biodiversidad, incluyendo la Lista Roja de Especies Amenazadas de la Unión Internacional de la Conservación de la Naturaleza (UICN). El área de ocupación (AOO) es una métrica que usa la UICN para cuantificar la distribución de una especie aunque, típicamente, limitaciones en los datos disponibles hacen que métodos actuales produzcan subestimaciones o sobreestimaciones del área (y rangos de incertidumbre innecesariamente amplios). Afortunadamente, para producir un rango no sesgado de estimaciones plausibles para AOO se pueden desarrollar extensiones de métodos existentes en los cuales se usan mapas de distribución y datos de cobertura del suelo para estimar el área que efectivamente ofrece hábitat para una especie. Tal proceso requiere estimar la proporción de sitios que ocupa una especie dentro de su distribución (de las que actualmente proveen hábitat; i.e., prevalencia). Multiplicar una cuantificación del área con hábitat por la prevalencia resulta en un estimado del área que ocupa la especie (i.e., AOO). Para especies con muestreos intensivos en muchos sitios, la prevalencia se puede calcular utilizando conjuntos de datos de presencia/ausencia o el modelado de ocupación. Para otras especies se podrían usar datos primarios de biodiversidad (registros de la ocurrencia de una especie en un punto en el espacio y el tiempo) provenientes de iniciativas de ciencia ciudadana y colecciones de referencia de herbarios y museos de historia natural. En tales casos, estimaciones de la prevalencia de una muestra deben ser corregidas, dividiendo por la detectabilidad de la especie. Estimar la detectabilidad utilizando estas fuentes de datos amerita desarrollar extensiones de análisis de completitud de inventarios. Con esfuerzos para aumentar la calidad y disponibilidad de datos de biodiversidad en línea, el uso de prevalencia en el cálculo de AOO debe resultar en estimaciones más realistas y con rangos de incertidumbre reducidos para muchos grupos taxonómicos y regiones geográficas. Debido a que conducen hacía caracterizaciones más reales y representativas de la biodiversidad, técnicas que integran mapas de hábitat actual y estimaciones de prevalencia pueden empoderar a profesionales de la conservación y tomadores de decisiones, y así guiar acciones y políticas alrededor del mundo.
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Conservación de los Recursos Naturales , Extinción Biológica , Animales , Conservación de los Recursos Naturales/métodos , Prevalencia , Especies en Peligro de Extinción , Ecosistema , BiodiversidadRESUMEN
Ochrobactrum sp. XKL1, previously found to have the ability to efficiently degrade quinoline, was bioaugmented into a lab-scale A/O/O system to treat real coking wastewater. During the bioaugmentation stage, the removal of quinoline and pyridine of the O1 tank could be enhanced by 9.88% and 7.96%, respectively. High-throughput sequencing analysis indicated that the addition of XKL1 could significantly affect the alteration of microbial community structure in the sludge. In addition, the relative abundance of Ochrobactrum has demonstrated a trend of increasing first followed by decreasing with the highest abundance of 7.87% attained on the 94th day. The bioaugmentation effects lasted for about 14 days after the strains was inoculated into the reactor. Although a decrease in the relative abundance of XKL1 was observed for a rather short period of time, the bioaugmented A/O/O system has been proven to be more effective in the removal of organic pollutants than the control. Hence, the results of this study indicated that the bioaugmentation with XKL1 is a feasible operational strategy that would be able to enhance the removal of NHCs in the treatment of coking wastewater with complex composition and high organic concentrations.
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Coque , Microbiota , Ochrobactrum , Quinolinas , Bacterias/genética , Bacterias/metabolismo , Reactores Biológicos/microbiología , Quinolinas/metabolismo , Aguas del Alcantarillado/microbiología , Aguas Residuales/químicaRESUMEN
The seabird meta-population viability model (mPVA) uses a generalized approach to project abundance and quasi-extinction risk for 102 seabird species under various conservation scenarios. The mPVA is a stage-structured projection matrix that tracks abundance of multiple populations linked by dispersal, accounting for breeding island characteristics and spatial distribution. Data are derived from published studies, grey literature, and expert review (with over 500 contributions). Invasive species impacts were generalized to stage-specific vital rates by fitting a Bayesian state-space model to trend data from Islands where invasive removals had occurred, while accounting for characteristics of seabird biology, breeding islands and invasive species. Survival rates were estimated using a competing hazards formulation to account for impacts of multiple threats, while also allowing for environmental and demographic stochasticity, density dependence and parameter uncertainty.â¢The mPVA provides resource managers with a tool to quantitatively assess potential benefits of alternative management actions, for multiple speciesâ¢The mPVA compares projected abundance and quasi-extinction risk under current conditions (no intervention) and various conservation scenarios, including removal of invasive species from specified breeding islands, translocation or reintroduction of individuals to an island of specified location and size, and at-sea mortality amelioration via reduction in annual at-sea deaths.
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Climate change is an important driver of biodiversity loss and extinction of endemic montane species. In China, three endemic Juniperus spp. (Juniperus pingii var. pingii, J. tibetica, and J. komarovii) are threatened and subjected to the risk of extinction. This study aimed to predict the potential distribution of these three Juniperus species under climate change and dispersal scenarios, to identify critical drivers explaining their potential distributions, to assess the extinction risk by estimating the loss percentage in their area of occupancy (AOO), and to identify priority areas for their conservation in China. We used ensemble modeling to evaluate the impact of climate change and project AOO. Our results revealed that the projected AOOs followed a similar trend in the three Juniperus species, which predicted an entire loss of their suitable habitats under both climate and dispersal scenarios. Temperature annual range and isothermality were the most critical key variables explaining the potential distribution of these three Juniperus species; they contribute by 16-56.1% and 20.4-38.3%, respectively. Accounting for the use of different thresholds provides a balanced approach for species distribution models' applications in conservation assessment when the goal is to assess potential climatic suitability in new geographical areas. Therefore, south Sichuan and north Yunnan could be considered important priority conservation areas for in situ conservation and search for unknown populations of these three Juniperus species.
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We compared clinical outcomes after ventral fixation in dogs with atlantoaxial instability (AAI) on the basis of the presence or absence of atlantooccipital overlapping (AOO). Of 41 dogs diagnosed with AAI and treated ventral fixation, 12 exhibited AOO (AOO group), whereas 29 did not (non-AOO group). The AOO group had significantly higher neurological scores before (P=0.024) and 1 month after (P=0.033) surgery compared with the non-AOO group; however, no significant differences were observed between the groups 2 months after surgery. The presence of complicating AOO affected the clinical signs for dogs with AAI, but did not directly affect the outcome of surgical stabilization of AAI.
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Articulación Atlantoaxoidea/cirugía , Enfermedades de los Perros/cirugía , Inestabilidad de la Articulación/veterinaria , Procedimientos Ortopédicos/veterinaria , Animales , Articulación Atlantoaxoidea/anomalías , Articulación Atlantoaxoidea/diagnóstico por imagen , Enfermedades de los Perros/diagnóstico por imagen , Perros , Femenino , Inestabilidad de la Articulación/diagnóstico por imagen , Inestabilidad de la Articulación/cirugía , Masculino , Tomografía Computarizada por Rayos X/veterinaria , Resultado del TratamientoRESUMEN
In the EU, chemicals with a production or import volume in quantities of one metric ton per year or more have to be tested for skin sensitizing properties under the REACH regulation. The murine Local Lymph Node Assay (LLNA) and its modifications are widely used to fulfil the data requirement, as it is currently considered the first-choice method for in vivo testing to cover this endpoint. This manuscript describes a case study highlighting the importance of understanding the chemistry of the test material during testing for 'skin sensitization' of MCDA (mixture of 2,4- and 2,6-diamino-methylcyclohexane) with particular focus on the vehicle used. While the BrdU-ELISA modification of the LLNA using acetone/olive oil (AOO) as vehicle revealed expectable positive results. However, the concentration control analysis unexpectedly revealed an instability of MCDA in the vehicle AOO. Further studies on the reactivity showed MCDA to rapidly react with AOO under formation of various imine structures, which might have caused the positive LLNA result. The repetition of the LLNA using propylene glycol (PG) as vehicle did not confirm the positive results of the LLNA using AOO. Finally, a classification of MCDA as skin sensitizer according to the Globally Harmonized System (GHS) was not justified.
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Alérgenos , Ciclohexilaminas , Excipientes/química , Haptenos , Acetona/química , Alérgenos/química , Alérgenos/clasificación , Alérgenos/toxicidad , Animales , Ciclohexilaminas/química , Ciclohexilaminas/clasificación , Ciclohexilaminas/toxicidad , Dermatitis Alérgica por Contacto , Femenino , Haptenos/química , Haptenos/clasificación , Haptenos/toxicidad , Ensayo del Nódulo Linfático Local , Ratones Endogámicos CBA , Aceite de Oliva/química , Propilenglicol/química , Sensibilidad y EspecificidadRESUMEN
Introducción: Se expone la evolución de las diferentes técnicas y filosofías que a través del tiempo ha presentado la corticotomía, desde su origen o primer registro en 1892 hasta el momento presente o última modificación del 2012. Método: Se realiza una búsqueda bibliográfica sobre el tema de corticotomía con la finalidad de documentar las modificaciones que ha tenido esta técnica quirúrgica y ofrecer la evidencia que permita la toma de decisiones basadas en una evidencia científica. Resultados: Se presenta una serie de cuadros en los cuales se registra cada una de las técnicas, su o sus autores y el año en el que fue descrita o propuesta. Conclusiones: El mecanismo detrás de la corticotomía puede resumirse como la inducción del metabolismo óseo mediante la decorticación que se realiza alrededor de los dientes que van a moverse para aumentar el recambio óseo, esto mejora y acelera el movimiento dentario ortodóncico.
Introduction: An exposition is presented of different techniques and philosophies provided through time for corticotomy procedures from its origin or first listing in 1892 to the present or last modification in 2012. Method: Bibliographic search was undertaken on the subject of corticotomy in order to document modifications experienced by their surgical technique and offer evidence which might allow to make decisions based on scientific evidence. Results: Presentation of a series of tables where all techniques are recorded, including authors and years of description or proposal. Conclusions: Mechanism behind corticotomy procedures can be summarized as the induction of bone metabolism through decortication executed around teeth that are going to be moved to increase bone replacement, this improves and accelerates orthodontic tooth movement.
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Recent changes in regulatory requirements and social views on animal testing have accelerated the development of reliable alternative tests for predicting skin sensitizing potential of chemicals. In this study, we aimed to develop a new in vitro skin sensitization assay using reconstructed human epidermis, RhE model, which is expected to have broader applicability domain rather than existing in vitro assays. Microarray analysis revealed that the expression of five genes (ATF3, DNAJB4, GCLM, HSPA6 and HSPH1) related to cellular stress response were significantly up-regulated in RhE model after 6h treatment with representative skin sensitizers, 1-fluoro-2,4-dinitrobenzene and oxazolone, but not a non-sensitizer, benzalkonium chloride. The predictive performance of five genes was examined with eight skin sensitizers (e.g., cinnamic aldehyde), four non-sensitizers (e.g., sodium lauryl sulfate) and four pre-/pro-haptens (e.g., p-phenylenediamine, isoeugenol). When the positive criteria were set to obtain the highest accuracy with the animal testing (LLNA), ATF3, DNAJB4 and GCLM exhibited a high predictive accuracy (100%, 93.8% and 87.5%, respectively). All tested pre-/pro-haptens were correctly predicted by both ATF3 and DNAJB4. These results suggested that the RhE-based assay, termed epidermal sensitization assay (EpiSensA), could be an useful skin sensitization assay with a broad applicability domain including pre-/pro-haptens.
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Alérgenos/toxicidad , Perfilación de la Expresión Génica , Haptenos/toxicidad , Pruebas de Irritación de la Piel , Alternativas a las Pruebas en Animales , Compuestos de Benzalconio/toxicidad , Dinitrofluorobenceno/toxicidad , Epidermis , Humanos , Técnicas In Vitro , Análisis de Secuencia por Matrices de Oligonucleótidos , Oxazolona/toxicidadRESUMEN
BACKGROUND: Innate immune sensors control key cytokines that regulate T-cell priming and T-cell fate. This is particularly evident in allergic reactions, which represent ideal systems to study the interplay of innate and adaptive immunity. In patients with contact dermatitis, inflammasome-mediated IL-1 activation is responsible for a TH1 immune response. Surprisingly, the IL-1 signaling pathway was also proposed to control the activation of thymic stromal lymphopoietin (TSLP), a cytokine implicated in development of the T(H)2 response in patients with atopic dermatitis (AD) and asthma. OBJECTIVES: We sought to assess the effect of the inflammasome on TSLP expression levels and the development of AD. METHODS: We studied the effect of the inflammasome activator 2,4-dinitrofluorobenzene, and IL-1ß on TSLP mRNA expression levels in mouse and human cell lines (in vitro assays), as well as in live mice and on human skin transplants. We also assessed the effect of 2,4-dinitrofluorobenzene on TSLP and the TH2 response in mice in which the inflammasome and IL-1 signaling pathways were blocked, either genetically or pharmacologically, in 2 models of AD. RESULTS: We provide in vitro and in vivo evidence that inflammasome activation has an inhibitory role on TSLP mRNA expression and T(H)2 cell fate in the skin. We also show that solvents influence the activation of TSLP and IL-1ß and direct the T-cell fate to a given hapten. CONCLUSION: Our observations strongly suggest that the TH1 versus TH2 cell fate decision is regulated at multiple levels and starts with innate immune events occurring within peripheral epithelial tissues.
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Citocinas/metabolismo , Dermatitis Alérgica por Contacto/inmunología , Inflamasomas/metabolismo , Queratinocitos/inmunología , Células TH1/inmunología , Células Th2/inmunología , Animales , Línea Celular , Citocinas/genética , Dinitrofluorobenceno/inmunología , Modelos Animales de Enfermedad , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/genética , Humanos , Inflamasomas/inmunología , Proteína Antagonista del Receptor de Interleucina 1/administración & dosificación , Interleucina-1beta/antagonistas & inhibidores , Interleucina-1beta/inmunología , Queratinocitos/efectos de los fármacos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Células TH1/efectos de los fármacos , Balance Th1 - Th2/efectos de los fármacos , Células Th2/efectos de los fármacos , Linfopoyetina del Estroma TímicoRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: The root bark of Dictamnus dasycarpus Turcz. is widely used as a medicinal herb for treatment of skin diseases such as eczema, pruritus and urticaria in China, Japan and Korea. MATERIALS AND METHODS: We investigated the effects of methanol extract of Dictamnus dasycarpus Turcz., root bark (MEDD) on ear thickness, ear weights, histopathological changes such as hyperplasia, edema, spongiosis and immune cell infiltration and cytokine productions in 1-fluoro-2,4-dinitrofluorobenzene (DNFB)-induced contact dermatitis (CD) mice. We also investigated its effects on degranulation of histamine and ß-hexosaminidase and related mechanisms using RBL-2H3 cells. RESULTS: Topical application of MEDD effectively inhibited enlargement of ear thickness and weight (P<0.05). MEDD treatment also inhibited hyperplasia, edema and spongiosis induced by DNFB. Treatment with 300 µg/ear of MEDD suppressed the increase in IFN-γ and TNF-α levels (P<0.05). In addition, treatment with >50 µg/mL MEDD reduced the level of ß-hexosaminidase release, while >100 µg/mL MEDD lowered the level of histamine release in a dose-dependent manner (P<0.05). Finally, MEDD treatment prevented phosphorylation of p38 MAPK induced by phorbol 12-myristate 13-acetate (PMA) and calcium ionophore A23187 in RBL-2H3 cells. CONCLUSIONS: These data indicate that root bark of Dictamnus dasycarpus Turcz. has the potential for use in the treatment of allergic skin diseases. Furthermore, they suggest that root bark of Dictamnus dasycarpus Turcz. is involved in decreasing degranulation of MCs via inhibition of the p38 MAPK pathway as well as in the inhibition of Th1 skewing reactions.