26 research outputs found
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Fluoroquinolone Efficacy against Tuberculosis Is Driven by Penetration into Lesions and Activity against Resident Bacterial Populations.
Fluoroquinolones represent the pillar of multidrug-resistant tuberculosis (MDR-TB) treatment, with moxifloxacin, levofloxacin, or gatifloxacin being prescribed to MDR-TB patients. Recently, several clinical trials of "universal" drug regimens, aiming to treat drug-susceptible and drug-resistant TB, have included a fluoroquinolone. In the absence of clinical data comparing their side-by-side efficacies in controlled MDR-TB trials, a pharmacological rationale is needed to guide the selection of the most efficacious fluoroquinolone. The present studies were designed to test the hypothesis that fluoroquinolone concentrations (pharmacokinetics) and activity (pharmacodynamics) at the site of infection are better predictors of efficacy than the plasma concentrations and potency measured in standard growth inhibition assays and are better suited to determinations of whether one of the fluoroquinolones outperforms the others in rabbits with active TB. We first measured the penetration of these fluoroquinolones in lung lesion compartments, and their potency against bacterial populations that reside in each compartment, to compute lesion-centric pharmacokinetic-pharmacodynamic (PK/PD) parameters. PK modeling methods were used to quantify drug penetration from plasma to tissues at human-equivalent doses. On the basis of these metrics, moxifloxacin emerged with a clear advantage, whereas plasma-based PK/PD favored levofloxacin (the ranges of the plasma AUC/MIC ratio [i.e., the area under the concentration-time curve over 24 h in the steady state divided by the MIC] are 46 to 86 for moxifloxacin and 74 to 258 for levofloxacin). A comparative efficacy trial in the rabbit model of active TB demonstrated the superiority of moxifloxacin in reducing bacterial burden at the lesion level and in sterilizing cellular and necrotic lesions. Collectively, these results show that PK/PD data obtained at the site of infection represent an adequate predictor of drug efficacy against TB and constitute the baseline required to explore synergies, antagonism, and drug-drug interactions in fluoroquinolone-containing regimens
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Population genetic structure and habitat connectivity for jaguar (Panthera onca) conservation in Central Belize
Background
Connectivity among jaguar (Panthera onca) populations will ensure natural gene flow and the long-term survival of the species throughout its range. Jaguar conservation efforts have focused primarily on connecting suitable habitat in a broad-scale. Accelerated habitat reduction, human-wildlife conflict, limited funding, and the complexity of jaguar behaviour have proven challenging to maintain connectivity between populations effectively. Here, we used non-invasive genetic sampling and individual-based conservation genetic analyses to assess genetic diversity and levels of genetic connectivity between individuals in the Cockscomb Basin Wildlife Sanctuary and the Maya Forest Corridor. We used expert knowledge and scientific literature to develop models of landscape permeability based on circuit theory with fine-scale landscape features as ecosystem types, distance to human settlements and roads to predict the most probable jaguar movement across central Belize.
Results
We used 12 highly polymorphic microsatellite loci to identify 50 individual jaguars. We detected high levels of genetic diversity across loci (HE = 0.61, HO = 0.55, and NA = 9.33). Using Bayesian clustering and multivariate models to assess gene flow and genetic structure, we identified one single group of jaguars (K = 1). We identified critical areas for jaguar movement that fall outside the boundaries of current protected areas in central Belize. We detected two main areas of high landscape permeability in a stretch of approximately 18 km between Sittee River Forest Reserve and Manatee Forest Reserve that may increase functional connectivity and facilitate jaguar dispersal from and to Cockscomb Basin Wildlife Sanctuary. Our analysis provides important insights on fine-scale genetic and landscape connectivity of jaguars in central Belize, an area of conservation concern.
Conclusions
The results of our study demonstrate high levels of relatively recent gene flow for jaguars between two study sites in central Belize. Our landscape analysis detected corridors of expected jaguar movement between the Cockscomb Basin Wildlife Sanctuary and the Maya Forest Corridor. We highlight the importance of maintaining already established corridors and consolidating new areas that further promote jaguar movement across suitable habitat beyond the boundaries of currently protected areas. Continued conservation efforts within identified corridors will further maintain and increase genetic connectivity in central Belize
Data from: Genetic diversity and population structure of Mesoamerican jaguars (Panthera onca): implications for conservation and management
Mesoamerican jaguars (Panthera onca) have been extirpated from over 77% of their historic range, inhabiting fragmented landscapes at potentially reduced population sizes. Maintaining and restoring genetic diversity and connectivity across human-altered landscapes has become a major conservation priority; nonetheless large-scale genetic monitoring of natural populations is rare. This is the first regional conservation genetic study of jaguars to primarily use fecal samples collected in the wild across five Mesoamerican countries: Belize, Costa Rica, Guatemala, Honduras, and Mexico. We genotyped 445 jaguar fecal samples and examined patterns of genetic diversity and connectivity among 115 individual jaguars using data from 12 microsatellite loci. Overall, moderate levels of genetic variation were detected (NA = 4.50 ± 1.05, AR = 3.43 ± 0.22, HE = 0.59 ± 0.04), with Mexico having the lowest genetic diversity, followed by Honduras, Guatemala, Belize, and Costa Rica. Population-based gene flow measures (FST = 0.09 to 0.15, Dest = 0.09 to 0.21), principal component analysis, and Bayesian clustering applied in a hierarchical framework revealed significant genetic structure in Mesoamerican jaguars, roughly grouping individuals into four genetic clusters with varying levels of admixture. Gene flow was highest among Selva Maya jaguars (northern Guatemala and central Belize), whereas genetic differentiation among all other sampling sites was moderate. Genetic subdivision was most pronounced between Selva Maya and Honduran jaguars, suggesting limited jaguar movement between these close geographic regions and ultimately refuting the hypothesis of contemporary panmixia. To maintain a critical linkage for jaguars dispersing through the Mesoamerican landscape and ensure long-term viability of this near threatened species, we recommend continued management and maintenance of jaguar corridors. The baseline genetic data provided by this study underscores the importance of understanding levels of genetic diversity and connectivity to making informed management and conservation decisions with the goal to maintain functional connectivity across the region
Genetic structure in Mesoamerican jaguars.
<p>Results were obtained from Bayesian clustering analysis (<i>K</i> = 3) using STRUCTURE, version 2.3.4 [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0162377#pone.0162377.ref047" target="_blank">47</a>] and genotype data from 12 microsatellite loci for jaguars (<i>n</i> = 115) sampled across five Mesoamerican countries (Belize, Costa Rica, Guatemala, Honduras, Mexico). (a) STRUCTURE barplot—vertical bars represent individuals and the color of each bar visualizes the % of membership (<i>Q</i>) the individual belongs to the genetic clusters (<i>K</i>) identified. (b) Pie charts represent fractions of <i>Q</i> for groups of jaguar individuals studied across different sampling sites (A, Sierra del Abra Tanchipa Biosphere Reserve, Mexico; B, Sierra Mixe, Oaxaca, Mexico; C, northern Guatemala [Laguna del Tigre National Park, Maya Biosphere Reserve, Mirador R<b>Ă</b>o-Azul National Park]; D, Central Belize Corridor Area, Belize; E, Cockscomb Basin Wildlife Sanctuary, Belize; F, Jeanette Kawas National Park, Honduras; G, Pico Bonito National Park, Honduras; H, RĂo Plátano Biosphere Reserve, Honduras; I, northeastern Costa Rica [Tortuguero National Park, Barra del Colorado Wildlife Refuge, and Barbilla National Park]; J, several sites across northern and northwestern Costa Rica; K, Corcovado National Park, Costa Rica.</p
Regional and fine-scale isolation-by-distance patterns in Mesoamerican jaguars.
<p>Isolation-by-distance in Mesoamerican jaguars was assessed by plotting pairwise codominant genotypic distance calculated in GenAlEx, version 6.41 [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0162377#pone.0162377.ref039" target="_blank">39</a>] versus pairwise Euclidean distances (km) across (A) all sampling sites, (B) Mexico, Guatemala, and Belize, (C) Guatemala, Belize, and Honduras, and (D) Honduras and Costa Rica. Statistical significance was assessed using simple Mantel tests in <i>ecodist</i>, version 1.2.9 [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0162377#pone.0162377.ref062" target="_blank">62</a>] in R, version 3.1.3 [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0162377#pone.0162377.ref041" target="_blank">41</a>]. Each point represents a pairwise comparison among individual jaguars.</p
Spatial autocorrelation in Mesoamerican jaguars.
<p>Spatial correlogram for jaguars (<i>n</i> = 99) showing the genetic correlation coefficient (<i>r</i>) as a function of geographic distance across defined spatial distance classes. Dashed red lines represent upper (U) and lower (L) bounds of the null hypothesis of no spatial structure based on 10,000 random permutations. Error bars represent 95% confidence intervals about <i>r</i> based on 1,000 bootstraps.</p
Results of the global STRUCTURE analysis in Mesoamerican jaguars.
<p>The optimal number of genetic clusters (<i>K</i>) in Mesoamerican jaguars (<i>n</i> = 115) applying Bayesian clustering methods in STRUCTURE, version 2.3.4 [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0162377#pone.0162377.ref047" target="_blank">47</a>] was chosen based on posterior probabilities (mean L(<i>K</i>); A) and delta <i>K</i> (Δ<i>K</i>, mean (|L”(<i>K</i>)|)/SD(L(<i>K</i>)); D) for each <i>K</i> value. SD, standard deviation; L’(<i>K</i>), mean rate of change of the likelihood distribution (B); |L”(<i>K</i>)|, absolute value of the 2<sup>nd</sup> order rate of change of the likelihood distribution (C).</p
DNA sample summary.
<p>Number of individual jaguars (<i>n</i>) and number of males and females detected across five Mesoamerican countries (Belize, Costa Rica, Guatemala, Honduras, Mexico).</p