Estimating Variable Effective Population Sizes from Multiple Genomes: A Sequentially Markov Conditional Sampling Distribution Approach

Throughout history, the population size of modern humans has varied considerably due to changes in environment, culture, and technology. More accurate estimates of population size changes, and when they occurred, should provide a clearer picture of human colonization history and help remove confounding effects from natural selection inference. Demography influences the pattern of genetic variation in a population, and thus genomic data of multiple individuals sampled from one or more present-day populations contain valuable information about the past demographic history. Recently, Li and Durbin developed a coalescent-based hidden Markov model, called the pairwise sequentially Markovian coalescent (PSMC), for a pair of chromosomes (or one diploid individual) to estimate past population sizes. This is an efficient, useful approach, but its accuracy in the very recent past is hampered by the fact that, because of the small sample size, only few coalescence events occur in that period. Multiple genomes from the same population contain more information about the recent past, but are also more computationally challenging to study jointly in a coalescent framework. Here, we present a new coalescent-based method that can efficiently infer population size changes from multiple genomes, providing access to a new store of information about the recent past. Our work generalizes the recently developed sequentially Markov conditional sampling distribution framework, which provides an accurate approximation of the probability of observing a newly sampled haplotype given a set of previously sampled haplotypes. Simulation results demonstrate that we can accurately reconstruct the true population histories, with a significant improvement over the PSMC in the recent past. We apply our method, called diCal, to the genomes of multiple human individuals of European and African ancestry to obtain a detailed population size change history during recent times.     

Tumor Necrosis Factor Receptor-associated Factor 6 (TRAF6) and TGFβ-activated Kinase 1 (TAK1) Play Essential Roles in the C-type Lectin Receptor Signaling in Response to Candida albicans Infection

Tumor necrosis factor receptor-associated factor 6 (TRAF6) and TGFβ-activated kinase 1 (TAK1) are considered as key intermediates in Toll-like receptor (TLR) signaling. However, the role of TRAF6 and TAK1 in C-type lectin receptors (CLRs) in response to fungal infection has not been studied. In this study, we have utilized macrophages derived from TRAF6 knock-out mice and myeloid-specific TAK1-deficient mice and determined the role of TRAF6 and TAK1 in CLR-induced signal transduction events. We demonstrate that TRAF6 and TAK1 are required for NF-κB and JNK activation, and expression of proinflammatory cytokines in response to Candida albicans infection. Our results highlight TRAF6 and TAK1 as key components in the signaling cascade downstream of C-type lectin receptors and as critical mediators of the anti-fungal immune response. Therefore, our studies provide a mechanistic understanding of the host immune response to C. albicans, which has a significant impact for the development of anti-fungal therapeutics and in understanding risk-factors and determining susceptibility to C. albicans infection.     

13- and 14-membered macrocyclic ligands containing methylcarboxylate or methylphosphonate pendant arms: chemical and biological evaluation of their (153)Sm and (166)Ho complexes as potential agents for therapy or bone pain palliation

The stability constants of La(3+), Sm(3+) and Ho(3+) complexes with 13- and 14-membered macrocycles having methylcarboxylate (trita and teta) or methylphosphonate (tritp and tetp) arms were determined. All the ligands were labelled with (153)Sm and (166)Ho in order to evaluate the effect of the macrocyclic cavity size and type of appended arms on their in vitro and in vivo behaviour. The radiolabelling efficiency was found to be higher than 98% for all the complexes, except for those of tetp. All radiocomplexes studied are hydrophilic with an overall negative charge and low plasmatic protein binding. Good in vitro stability in physiological media and human serum was found for all complexes, except the (153)Sm/(166)Ho-teta, which are unstable in phosphate buffer (pH 7.4). In vitro hydroxyapatite (HA) adsorption studies indicated that (153)Sm/(166)Ho-tritp complexes bind to HA having the (166)Ho complex the highest degree of adsorption (>80%, 10 mg). Biodistribution studies in mice demonstrated that (153)Sm/(166)Ho-trita complexes have a fast tissue clearance with more than 95% of the injected activity excreted after 2 h, value that is comparable to the corresponding dota complexes. In contrast, the (153)Sm-teta complex has a significantly lower total excretion. (153)Sm/(166)Ho-tritp complexes are retained by the bone, particularly (166)Ho-tritp that has 5-6% (% I.D./g) bone uptake and also a high rate of total excretion. Thus, these studies support the potential interest of (153)Sm/(166)Ho-trita complexes for therapy when conjugated to a biomolecule and the potential usefulness of the (166)Ho-tritp complex in bone pain palliation.     

Development of a RNA extraction method from milk for gene expression study in the mammary gland of sheep

The aim of the study was to develop a reliable method for the RNA extraction from milk of Sarda sheep breed and to highlight if the extracted RNA can be used for expression study on mammary genes involved in milk fat synthesis using RT-qPCR. The main result is that a sample of 150 ml of milk provides an optimal amount of RNA (73.5 μg/ml). The highest RNA concentration has been found in the samples analysed within 4 h after collection. The RNA extracted was positively correlated to the number of somatic cells (P < 0.001). The efficiency of the extraction method was confirmed by the results obtained from qPCR which showed a Ct value, for SREBPF1 gene of 26.8 ± 0.15. This research demonstrated that the high-quality of the RNA obtained is suited to use for studies of mammary genes expression in sheep, avoiding any damage caused by mammary gland biopsy.     

E. coli outbreak in a neonate intensive care unit in a general hospital in Mexico City

Nosocomial infections are a major cause of morbidity and mortality among neonates admitted to neonatal intensive care units (NICUs). The aim of this paper was to describe an outbreak of Escherichia coli among infants admitted to the NICU of the General Hospital “Dr. Manuel Gea Gonzalez” in May of 2008. The isolated E. coli strains were identified using standard biochemical methods. The susceptibilities of these strains were analysed by determining their minimal inhibitory concentrations. Following this, their molecular relationships to each other were assessed by pulsed field gel electrophoresis (PFGE) analysis and corroborated by serology. Twelve E. coli strains were isolated from blood, urine, or indwelling catheter samples from five cases of preterm infants within a 3-day period. Patients were admitted to the NICU of the general hospital and, during the outbreak, developed sepsis caused by E. coli. For four of the patients, the average age was 23 days, while one patient was a 3-month-old infant. Prior to sepsis, the infants had received assisted ventilation and hyperalimentation through a central venous catheter. Two profiles were observed by PFGE; profile A was identified as the outbreak’s cause and an outcome of cross-infection, while profile B showed genetic differences but serologically it was identified as part of the same serotype. We conclude that E. coli colonised the patients through horizontal transmission. A focal source of the microorganism in this outbreak was not identified, but cross-transmission through handling was the most probable route.     

Consequences of dispersal limitation and habitat fragmentation for the Brazilian heart‐tongued frogs (Phyllodytes spp.)

Poorly known species may be cryptically endangered, especially when they inhabit fragmented and threatened habitats. Heart‐tongued frogs (genus Phyllodytes, family Hylidae, Lophyohylinae) comprise 17 species of poorly known frogs that have obligatory associations with tank bromeliads. The distributions of all species are restricted to a small, extremely fragmented, region of Atlantic Forest in eastern Brazil. We model climate and tank bromeliad distributions to better understand frog distribution limits. Using records from several sources for frogs and bromeliads with climate data from WorldClim, we modelled the distribution of Phyllodytes using maximum entropy. We compared climate and altitude within the distribution and nearby to test how climate may limit distribution. Climate together with bromeliad distributions provided the best model and predicted the smallest suitable area for Phyllodytes that was larger than that occupied, from the state of Paraíba in the north to Rio Grande do Sul in the south. Phyllodytes occurs in lower elevations that are warmer, wetter and less variable than the surrounding regions where it does not occur, and dispersal is apparently limited by the surrounding, inhospitable, region. Dispersal limitation and habitat fragmentation have relegated Phyllodytes to many very small habitat fragments. With many species in this genus being known from a single or few samples, this unfortunate combination of limitation and fragmentation suggests that some or all species of Phyllodytes may be threatened with extinction, especially if habitat fragmentation continues at its present pace in eastern Brazil.     

Peroxisome proliferator-activated receptor β/δ agonism protects the kidney against ischemia/reperfusion injury in diabetic rats

Diabetes is an important risk factor for ischemic acute kidney injury, whose pharmacological treatment remains an unmet medical need. The peroxisome proliferator-activated receptor (PPAR) β/δ is highly expressed in the kidney, although its role has not yet been elucidated. Here, we used an in vivo model of renal ischemia/reperfusion (I/R) in streptozotocin-induced diabetic rats (i) to evaluate whether diabetes increases kidney susceptibility to I/R injury and (ii) to investigate the effects of PPARβ/δ activation. The degree of renal injury (1h ischemia/6h reperfusion) was significantly increased in diabetic rats compared with nondiabetic littermates. PPARβ/δ expression was increased after I/R, with the highest levels in diabetic rats. Administration of the selective PPARβ/δ agonist GW0742 attenuated the renal dysfunction, leukocyte infiltration, and formation of interleukin-6 and tumor necrosis factor-α. These effects were accompanied by an increased expression of the suppressor of cytokine signaling (SOCS)-3, which plays a critical role in the cytokine-activated signaling pathway. The beneficial effects of GW0742 were attenuated by the selective PPARβ/δ antagonist GSK0660. Thus, we report herein that PPARβ/δ activation protects the diabetic kidney against I/R injury by a mechanism that may involve changes in renal expression of SOCS-3 resulting in a reduced local inflammatory response.     

Genetic consequences of trumpeter swan (Cygnus buccinator) reintroductions

Relocation programs are often initiated to restore threatened species to previously occupied portions of their range. A primary challenge of restoration efforts is to translocate individuals in a way that prevents loss of genetic diversity and decreases differentiation relative to source populations—a challenge that becomes increasingly difficult when remnant populations of the species are already genetically depauperate. Trumpeter swans were previously extirpated in the entire eastern half of their range. Physical translocations of birds over the last 70 years have restored the species to portions of its historical range. Despite the long history of management, there has been little monitoring of the genetic outcomes of these restoration attempts. We assessed the consequences of this reintroduction program by comparing patterns of genetic variation at 17 microsatellite loci across four restoration flocks (three wild-released, one captive) and their source populations. We found that a wild-released population established from a single source displayed a trend toward reduced genetic diversity relative to and significant genetic differentiation from its source population, though small founder population effects may also explain this pattern. Wild-released flocks restored from multiple populations maintained source levels of genetic variation and lacked significant differentiation from at least one of their sources. Further, the flock originating from a single source revealed significantly lower levels of genetic variation than those established from multiple sources. The distribution of genetic variation in the captive flock was similar to its source. While the case of trumpeter swans provides evidence that restorations from multiple versus single source populations may better preserve natural levels of genetic diversity, more studies are needed to understand the general applicability of this management strategy.