The relations between recombination rate and patterns of molecular variation and evolution in Drosophila.

Genetic recombination affects levels of variability and the efficacy of selection because natural selection acting at one site affects evolutionary processes at linked sites. The variation in local recombination rates across the Drosophila genome provides excellent material for testing hypotheses concerning the evolutionary consequences of recombination. The current state of knowledge from studies of Drosophila genomics and population genetics is reviewed here. Selection at linked sites has influenced the relations between recombination rates and patterns of molecular variation and evolution, such that higher rates of recombination are associated with both higher levels of variability and a greater efficacy of selection. It seems likely that background selection against deleterious mutations is a major factor contributing to these patterns in genome regions in which crossing over is rare or absent, whereas selective sweeps of positively selected mutations probably play an important role in regions with crossing over.

Faster-X evolution: Theory and evidence from Drosophila.

A faster rate of adaptive evolution of X-linked genes compared with autosomal genes can be caused by the fixation of recessive or partially recessive advantageous mutations, due to the full expression of X-linked mutations in hemizygous males. Other processes, including recombination rate and mutation rate differences between X chromosomes and autosomes, may also cause faster evolution of X-linked genes. We review population genetics theory concerning the expected relative values of variability and rates of evolution of X-linked and autosomal DNA sequences. The theoretical predictions are compared with data from population genomic studies of several species of Drosophila. We conclude that there is evidence for adaptive faster-X evolution of several classes of functionally significant nucleotides. We also find evidence for potential differences in mutation rates between X-linked and autosomal genes, due to differences in mutational bias towards GC to AT mutations. Many aspects of the data are consistent with the male hemizygosity model, although not all possible confounding factors can be excluded.

Cardiovascular Studies in Patients with Chronic Obstructive Pulmonary Disease Due to Biomass Smoke or Tobacco.

BACKGROUND AND OBJECTIVE: The cardiovascular effects of biomass smoke exposure in patients with chronic obstructive pulmonary disease are not well characterized, and few studies have assessed the possible differences between patients with disease caused by biomass smoke and tobacco. The aim of this study was to search for differences in cardiovascular variables between both types of the disease. METHODS: Twenty subjects (15 men, 5 women) with chronic obstructive pulmonary disease caused by tobacco were matched one to one for sex, age, and forced expiratory volume in 1 s to 20 patients with biomass-related disease. Echocardiography and carotid ultrasound studies were performed. Flow-mediated endothelium-dependent vasodilatation and endothelium-independent vasodilatation were also measured. RESULTS: There were no significant differences between groups in any of the echocardiographic variables, nor in the intima-media carotid thickness, the number of carotid plaques, or the percentage of endothelium-dependent or endothelium-independent vasodilation. A high percentage of patients in both groups showed an abnormal flow-mediated endothelium-dependent vasodilatation pattern. CONCLUSION: The study does not support the hypothesis of a different cardiovascular effect of biomass or tobacco smoke exposure in patients with chronic obstructive pulmonary disease. Cardiovascular comorbidity should be assessed in patients with biomass-associated disease, similarly to subjects with tobacco-related disease.

Adaptive Evolution Is Substantially Impeded by Hill-Robertson Interference in Drosophila.

Hill-Robertson interference (HRi) is expected to reduce the efficiency of natural selection when two or more linked selected sites do not segregate freely, but no attempt has been done so far to quantify the overall impact of HRi on the rate of adaptive evolution for any given genome. In this work, we estimate how much HRi impedes the rate of adaptive evolution in the coding genome of Drosophila melanogaster. We compiled a data set of 6,141 autosomal protein-coding genes from Drosophila, from which polymorphism levels in D. melanogaster and divergence out to D. yakuba were estimated. The rate of adaptive evolution was calculated using a derivative of the McDonald-Kreitman test that controls for slightly deleterious mutations. We find that the rate of adaptive amino acid substitution at a given position of the genome is positively correlated to both the rate of recombination and the mutation rate, and negatively correlated to the gene density of the region. These correlations are robust to controlling for each other, for synonymous codon bias and for gene functions related to immune response and testes. We show that HRi diminishes the rate of adaptive evolution by approximately 27%. Interestingly, genes with low mutation rates embedded in gene poor regions lose approximately 17% of their adaptive substitutions whereas genes with high mutation rates embedded in gene rich regions lose approximately 60%. We conclude that HRi hampers the rate of adaptive evolution in Drosophila and that the variation in recombination, mutation, and gene density along the genome affects the HRi effect.

The relation between recombination rate and patterns of molecular evolution and variation in Drosophila melanogaster.

Genetic recombination associated with sexual reproduction increases the efficiency of natural selection by reducing the strength of Hill-Robertson interference. Such interference can be caused either by selective sweeps of positively selected alleles or by background selection (BGS) against deleterious mutations. Its consequences can be studied by comparing patterns of molecular evolution and variation in genomic regions with different rates of crossing over. We carried out a comprehensive study of the benefits of recombination in Drosophila melanogaster, both by contrasting five independent genomic regions that lack crossing over with the rest of the genome and by comparing regions with different rates of crossing over, using data on DNA sequence polymorphisms from an African population that is geographically close to the putatively ancestral population for the species, and on sequence divergence from a related species. We observed reductions in sequence diversity in noncrossover (NC) regions that are inconsistent with the effects of hard selective sweeps in the absence of recombination. Overall, the observed patterns suggest that the recombination rate experienced by a gene is positively related to an increase in the efficiency of both positive and purifying selection. The results are consistent with a BGS model with interference among selected sites in NC regions, and joint effects of BGS, selective sweeps, and a past population expansion on variability in regions of the genome that experience crossing over. In such crossover regions, the X chromosome exhibits a higher rate of adaptive protein sequence evolution than the autosomes, implying a Faster-X effect.

The effects of sex-biased gene expression and X-linkage on rates of adaptive protein sequence evolution in Drosophila.

A faster rate of adaptive evolution of X-linked genes compared with autosomal genes may be caused by the fixation of new recessive or partially recessive advantageous mutations (the Faster-X effect). This effect is expected to be largest for mutations that affect only male fitness and absent for mutations that affect only female fitness. We tested these predictions in Drosophila melanogaster by using genes with different levels of sex-biased expression and by estimating the extent of adaptive evolution of non-synonymous mutations from polymorphism and divergence data. We detected both a Faster-X effect and an effect of male-biased gene expression. There was no evidence for a strong association between the two effects--modest levels of male-biased gene expression increased the rate of adaptive evolution on both the autosomes and the X chromosome, but a Faster-X effect occurred for both unbiased genes and female-biased genes. The rate of genetic recombination did not influence the magnitude of the Faster-X effect, ruling out the possibility that it reflects less Hill-Robertson interference for X-linked genes.

Codon usage bias and effective population sizes on the X chromosome versus the autosomes in Drosophila melanogaster.

Codon usage bias (CUB) in Drosophila is higher for X-linked genes than for autosomal genes. One possible explanation is that the higher effective recombination rate for genes on the X chromosome compared with the autosomes reduces their susceptibility to Hill-Robertson effects, and thus enhances the efficacy of selection on codon usage. The genome sequence of D. melanogaster was used to test this hypothesis. Contrary to expectation, it was found that, after correcting for the effective recombination rate, CUB remained higher on the X than on the autosomes. In contrast, an analysis of polymorphism data from a Rwandan population showed that mean nucleotide site diversity at 4-fold degenerate sites for genes on the X is approximately three-quarters of the autosomal value after correcting for the effective recombination rate, compared with approximate equality before correction. In addition, these data show that selection for preferred versus unpreferred synonymous variants is stronger on the X than the autosomes, which accounts for the higher CUB of genes on the X chromosome. This difference in the strength of selection does not appear to reflect the effects of dominance of mutations affecting codon usage, differences in gene expression levels between X and autosomes, or differences in mutational bias. Its cause therefore remains unexplained. The stronger selection on CUB on the X chromosome leads to a lower rate of synonymous site divergence compared with the autosomes; this will cause a stronger upward bias for X than A in estimates of the proportion of nonsynonymous mutations fixed by positive selection, for methods based on the McDonald-Kreitman test.

Lymphaticovenous anastomosis in rabbits: A novel live experimental animal model for supermicrosurgical training.

BACKGROUND: Lymphaticovenous anastomosis is widely used in lymphedema management. Although its effectiveness in reducing edema in patients can be clinically observed, evaluating the long-term outcomes of this technique can be complex. This study established an animal model to assess the outcomes of lymphaticovenous anastomosis technique at 15 and 30-days post-surgery using indocyanine green lymphography, Patent Blue V dye injection, and histopathological examination. METHODS: An experimental model was established in the hindlimbs of 10 rabbits using the popliteal vein and afferent lymphatic vessels in the popliteal area. The subjects were divided into two groups: the first group (n = 5) underwent patency assessment at 0 and 15 days, and the second group (n = 5) at 0 and 30-days, resulting in 20 anastomoses. Patency was verified at 0, 15, and 30-days using indocyanine green lymphography and Patent Blue V injection. Histopathological examinations were performed on the collected anastomosis samples. RESULTS: The patency rate was 90% (19/20) initially, 60% (6/10) at 15 days post-surgery, and 80% (8/10) at 30-days. The average diameter of lymphatic vessels and veins was 1.0 mm and 0.8 mm, respectively. The median number of collateral veins was 3; the median surgical time was 65.8 min. Histopathology revealed minimal endothelial damage and inflammatory responses due to the surgical sutures, with vascular inflammation and thrombosis in a single case. Local vascular neoformations were observed. CONCLUSION: This study highlights the reliability and reproducibility of using rabbits as experimental models for training in lymphaticovenous anastomosis technique owing to the accessibility of the surgical site and dimensions of their popliteal vasculature.

Identification of oxidative stress related proteins as biomarkers for lung cancer and chronic obstructive pulmonary disease in bronchoalveolar lavage.

Lung cancer (LC) and chronic obstructive pulmonary disease (COPD) commonly coexist in smokers, and the presence of COPD increases the risk of developing LC. Cigarette smoke causes oxidative stress and an inflammatory response in lung cells, which in turn may be involved in COPD and lung cancer development. The aim of this study was to identify differential proteomic profiles related to oxidative stress response that were potentially involved in these two pathological entities. Protein content was assessed in the bronchoalveolar lavage (BAL) of 60 patients classified in four groups: COPD, COPD and LC, LC, and control (neither COPD nor LC). Proteins were separated into spots by two dimensional polyacrylamide gel electrophoresis (2D-PAGE) and examined by matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF/TOF). A total of 16 oxidative stress regulatory proteins were differentially expressed in BAL samples from LC and/or COPD patients as compared with the control group. A distinct proteomic reactive oxygen species (ROS) protein signature emerged that characterized lung cancer and COPD. In conclusion, our findings highlight the role of the oxidative stress response proteins in the pathogenic pathways of both diseases, and provide new candidate biomarkers and predictive tools for LC and COPD diagnosis.

Determination of inflammatory biomarkers in patients with COPD: a comparison of different assays.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is an inflammatory pulmonary disorder with systemic inflammatory manifestations that are mediated by circulating acute-phase reactants. This study compared an enzyme-linked immunosorbent assay (ELISA) to a nephelometric technique for the measurement of serum C-reactive protein (CRP) and serum amyloid A (SAA) and investigated how the choice of assay influenced the estimation of inflammation in patients with stable COPD. METHODS: CRP and SAA concentrations measured by ELISA and nephelometry in 88 patients with COPD and 45 control subjects were used to evaluate the performance of these methods in a clinical setting. RESULTS: With both assays, the concentrations of CRP and SAA were higher in COPD patients than in controls after adjustment for age and sex. There was a moderate correlation between the values measured by ELISA and those measured by nephelometry (logCRP: r = 0.55, p < 0.001; logSAA: r = 0.40, p < 0.001). However, the concentrations of biomarkers determined by nephelometry were significantly higher than those obtained with ELISA for CRP (mean difference = 2.7 (9.4) mg/L) and SAA (mean difference = 0.31 (14.3) mg/L). CONCLUSION: Although the serum CRP and SAA concentrations measured by ELISA and nephelometry correlated well in COPD patients, the ELISA values tended to be lower for CRP and SAA when compared with nephelometric measurements. International standardization of commercial kits is required before the predictive validity of inflammatory markers for patients with COPD can be effectively assessed in clinical practice.

South American precipitation dipole forced by interhemispheric temperature gradient.

Tropical South American hydroclimate sustains the world's highest biodiversity and hundreds of millions of people. Whitin this region, Amazonia and northeastern Brazil have attracted much attention due to their high biological and social vulnerabilities to climate change (i.e. considered climate change hotspots). Still, their future response to climate change remains uncertain. On precession timescale, it has been suggested that periods of decreased western Amazonian precipitation were accompanied by increased northeastern Brazilian precipitation and vice-versa, setting an east-west tropical South American precipitation dipole. However, the very existence of this precession-driven precipitation dipole remains unsettled given the scarcity of long and appropriate northeastern Brazilian records. Here we show that the precession-driven South American precipitation dipole has persisted over the last 113 ka as revealed by a northern northeastern Brazilian precipitation record obtained from quartz thermoluminescence sensitivity measured in marine sediment cores. Precession-induced austral summer insolation changes drove the precipitation dipole through the interhemispheric temperature gradient control over the regional Walker circulation and the Intertropical Convergence Zone seasonal migration range. Since modern global warming affects the interhemispheric temperature gradient, our study provides insights about possible future tropical South American hydroclimate responses.

Retrospective Study of the Analgesic Effect of Sacroiliac Joint Radiofrequency Denervation.

BACKGROUND: Interventional radiofrequency (RF) ablation techniques are indicated when an adequate effect is not obtained with conservative measures. OBJECTIVES: The primary objective of this study was to evaluate pain relief after RF denervation of the sacroiliac joint. The secondary objective was to evaluate pain intensity and relief duration. STUDY DESIGN: The study was retrospective. SETTING: The study was conducted at Vera Cruz Hospital, Campinas, Brazil. METHODS: Data were collected from the medical records of patients undergoing RF denervation for low back pain originating in the sacroiliac joint, from January 2015 to December 2017. There were 78 patients studied, between 18 and 65 years old, of both genders, ASA I or II, who underwent knee arthroscopic meniscectomy. The patients were submitted to denervation of sacroiliac joint by 3 types of RF (conventional, pulsed, and cooled). The following parameters were evaluated, number of patients who obtained ? 50% pain relief; pain intensity, measured using the visual analog scale (before the procedure and 15, 30, 90 and 180 days after, performed by the same evaluator); and the use of complementary analgesic for 2 weeks. RESULTS: Of the 78 included patients, 56 (71.8%) underwent conventional RF, 9 (11.5%) underwent pulsed RF, and 13 (16.7%) underwent cooled RF. There were losses to follow-up including 40 patients who underwent conventional RF, 5 who underwent pulsed RF, and 12 who underwent cooled RF, who were retained for 6 months. There was significant pain relief with the three types of RF for up to 6 months of follow-up, with no difference among the types. After 6 months, 90.2% of patients who underwent conventional RF, 100% who underwent pulsed RF, and 91.7% who underwent cooled RF maintained ≥ 50% pain relief. Complementary analgesics were used by 95% of the patients who underwent conventional RF, 80% who underwent pulsed RF, and 91% who underwent cooled RF 2 weeks after the procedure. There were mild adverse effects, such as edema, hematoma, and local pain, without complications. LIMITATIONS: As for limitations, the number of pulsed and cooled RF is low and in a retrospective study some data may be missing, especially from follow-up. CONCLUSIONS: RF denervation of the sacroiliac joint is effective and promotes a long-lasting analgesic effect.

Waveguide Manufacturing Technologies for Next-Generation Millimeter-Wave Antennas.

Some recent waveguide-based antennas are presented in this paper, designed for the next generation of communication systems operating at the millimeter-wave band. The presented prototypes have been conceived to be manufactured using different state-of-the-art techniques, involving subtractive and additive approaches. All the designs have used the latest developments in the field of manufacturing to guarantee the required accuracy for operation at millimeter-wave frequencies, where tolerances are extremely tight. Different designs will be presented, including a monopulse antenna combining a comparator network, a mode converter, and a spline profile horn; a tunable phase shifter that is integrated into an array to implement reconfigurability of the main lobe direction; and a conformal array antenna. These prototypes were manufactured by diverse approaches taking into account the waveguide configuration, combining parts with high-precision milling, electrical discharge machining, direct metal laser sintering, or stereolithography with spray metallization, showing very competitive performances at the millimeter-wave band till 40 GHz.

Research priorities to address the global burden of chronic obstructive pulmonary disease (COPD) in the next decade.

BACKGROUND: The global prevalence of chronic obstructive pulmonary disease (COPD) has increased markedly in recent decades. Given the scarcity of resources available to address global health challenges and respiratory medicine being relatively under-invested in, it is important to define research priorities for COPD globally. In this paper, we aim to identify a ranked set of COPD research priorities that need to be addressed in the next 10 years to substantially reduce the global impact of COPD. METHODS: We adapted the Child Health and Nutrition Research Initiative (CHNRI) methodology to identify global COPD research priorities. RESULTS: 62 experts contributed 230 research ideas, which were scored by 34 researchers according to six pre-defined criteria: answerability, effectiveness, feasibility, deliverability, burden reduction, and equity. The top-ranked research priority was the need for new effective strategies to support smoking cessation. Of the top 20 overall research priorities, six were focused on feasible and cost-effective pulmonary rehabilitation delivery and access, particularly in primary/community care and low-resource settings. Three of the top 10 overall priorities called for research on improved screening and accurate diagnostic methods for COPD in low-resource primary care settings. Further ideas that drew support involved a better understanding of risk factors for COPD, development of effective training programmes for health workers and physicians in low resource settings, and evaluation of novel interventions to encourage physical activity. CONCLUSIONS: The experts agreed that the most pressing feasible research questions to address in the next decade for COPD reduction were on prevention, diagnosis and rehabilitation of COPD, especially in low resource settings. The largest gains should be expected in low- and middle-income countries (LMIC) settings, as the large majority of COPD deaths occur in those settings. Research priorities identified by this systematic international process should inform and motivate policymakers, funders, and researchers to support and conduct research to reduce the global burden of COPD.

Sex differences between women and men with COPD: A new analysis of the 3CIA study.

BACKGROUND: There is partial evidence that COPD is expressed differently in women than in men, namely on symptoms, pulmonary function, exacerbations, comorbidities or prognosis. There is a need to improve the characterization of COPD in females. METHODS: We obtained and pooled data of 17 139 patients from 22 COPD cohorts and analysed the clinical differences by sex, establishing the relationship between these characteristics in women and the prognosis and severity of the disease. Comparisons were established with standard statistics and survival analysis, including crude and multivariate Cox-regression analysis. RESULTS: Overall, 5355 (31.2%) women were compared with men with COPD. Women were younger, had lower pack-years, greater FEV1%, lower BMI and a greater number of exacerbations (all p < 0.05). On symptoms, women reported more dyspnea, equal cough but less expectoration (p < 0.001). There were no differences in the BODE index score in women (2.4) versus men (2.4) (p = 0.5), but the distribution of all BODE components was highly variable by sex within different thresholds of BODE. On prognosis, 5-year survival was higher in COPD females (86.9%) than in males (76.3%), p < 0.001, in all patients and within each of the specific comorbidities that we assessed. The crude and adjusted RR and 95% C.I. for death in males was 1.82 (1.69-1.96) and 1.73 (1.50-2.00), respectively. CONCLUSIONS: COPD in women has some characteristic traits expressed differently than compared to men, mainly with more dyspnea and COPD exacerbations and less phlegm, among others, although long-term survival appears better in female COPD patients.

Incidence of osteonecrosis of the jaw by the use of osteoclast inhibitors in patients with bone metastases: a retrospective cohort study.

BACKGROUND: The use of osteoclast inhibitors in metastatic bone disease, increase bone mineral density and reduce the risk of fracture, patients with osteonecrosis have been reported after the chronic use of these inhibitors. In our country, the use of osteoclast inhibitors is in the context of osteoporosis and bone metastases, so it is important to describe the incidence of this complication in Mexican population. OBJECTIVE: To describe the incidence of osteonecrosis of the jaws at the Centro Médico Nacional 20 de Noviembre, during the period from January 1st, 2010 to June 1st, 2016. METHODS: This is a retrospective cohort study developed at the Centro Medico Nacional 20 Noviembre, ISSSTE, Mexico. We included all patients who received bisphosphonates or denosumab in the context of metastatic bone disease due to solid tumors and who had osteonecrosis of the jaw. RESULTS: A 802 patients who used bisphosphonates or denosumab in metastatic bone disease (699 bisphosphonates and 103 denosumab). Of these, 28 (3.5%) patients presented osteonecrosis. The median use of zoledronic acid for the presence of osteonecrosis was 25 months (15-49 months) and for Denosumab it was 16 months (11-35 months), without finding significant differences between the use of drugs p = 0.511 and the risk of osteonecrosis. CONCLUSIONS: Drug-induced osteonecrosis has a low incidence in Mexican population, denosumab does not show a greater number of cases of osteonecrosis compared to bisphosphonates; no association was found between functional status, number of metastatic bone sites, nor use of antigenic or tyrosine kinase inhibitors as factor associated with osteonecrosis of the jaws.

ANTECEDENTES: El uso de inhibidores de osteoclastos en la enfermedad metastasica ósea tiene como objetivo aumentar la densidad mineral ósea y reducir el riesgo de fractura. Se han reportado pacientes con osteonecrosis de los maxilares tras el uso crónico de estos inhibidores. En nuestro país, los inhibidores de osteoclastos se usan en el contexto de osteoporosis y de metástasis óseas, por lo que es importante describir la incidencia de esta complicación en población mexicana. OBJETIVO: Describir la incidencia de osteonecrosis de los maxilares en el Centro Médico Nacional 20 de Noviembre, durante el periodo del 1 de enero del 2010 al 1 de junio de 2016. MÉTODO: Estudio de cohorte retrospectiva desarrollado en el Centro Médico Nacional 20 de Noviembre, del Instituto de Seguridad y Servicios Sociales de los Trabajadores del Estado, en Ciudad de México. Se incluyeron todos los pacientes que recibieron bisfosfonatos o denosumab con enfermedad metastasica ósea por tumores sólidos, y que presentaron osteonecrosis de mandíbula. RESULTADOS: Se analizaron 802 pacientes que recibieron bisfosfonatos o denosumab en enfermedad metastasica ósea (699 bifosfonatos y 103 denosumab). De ellos, 28 (3.5%) presentaron osteonecrosis. La mediana de uso de ácido zoledrónico para la presencia de osteonecrosis fue de 25 meses (15-49 meses), y para denosumab fue de 16 meses (11-35 meses), sin encontrar diferencias significativas entre ellos (p = 0.511) y el riesgo de osteonecrosis. CONCLUSIONES: La osteonecrosis inducida por medicamentos tiene una baja incidencia en población mexicana. El denosumab no muestra un mayor número de casos de osteonecrosis en comparación con los bisfosfonatos. No se encontró asociación entre el estado funcional, el número de sitios óseos metastásicos ni el uso de antiangiogénicos o de inhibidores de la tirosina cinasa como factor asociado a osteonecrosis de los maxilares.

Recent lung cancer mortality trends in Europe: effect of national smoke-free legislation strengthening.

The impact of smoke-free legislation within European Union (EU) countries on lung cancer mortality has not been evaluated to date. We aimed to determine lung cancer mortality trends in the EU-27 by sex, age, and calendar year for the period of 1994 and 2012, and relate them with changes in tobacco legislation at the national level. Deaths by Eurostat in each European country were analyzed, focusing on ICD-10 codes C33 and C34 from the years 1994 to 2012. Age-standardized mortality rates (ASR) were estimated separately for women and men in the EU-27 total and within country for each one of the years studied, and the significance of changing trends was estimated by joinpoint regression analysis, exploring lag times after initiation of smoke-free legislation in every country, if any. From 1994 to 2012, there were 4 681 877 deaths from lung cancer in Europe (3 491 607 in men and 1 190 180 in women) and a nearly linear decrease in mortality rates because of lung cancer in men from was observed1994 to 2012, mirrored in women by an upward trend, narrowing the sex gap during the study period from 5.1 in 1994 to 2.8 in 2012. Joinpoint regression analysis identified a number of trend changes over time, but it appears that they were unrelated to the implementation of smoke-free legislations. A few years after the introduction of smoke-free legislations across Europe, trends of lung cancer mortality trends have not changed.

Paclitaxel coated-stent for early-onset thrombosis after liver transplantation.

Hepatic artery thrombosis (HAT) is the most common vascular complication of orthotopic liver transplantation (OLT) and constitutes a potential emergency during the postoperative period. Surgical revascularization and retransplantation are the treatments of choice for this condition. The aim of this report is to present long-term follow-up on survival and graft function of three patients with paclitaxel-coated hepatic artery stents placed percutaneously after earlyonset HAT. Three patients developed early onset HAT after cadaveric-donor OLT in a tertiary care center in Mexico. These patients were treated percutaneously with balloon angioplasty and paclitaxel-coated stents. After 24 months or more of follow-up, 2 patients present total occlusion of the stent and one patient, intra-stent stenosis; interestingly, all patients have normal graft function and excellent quality of life. In conclusion, although balloon angioplasty and stent placement may be a therapeutic option for suitable patients with early-onset HAT after OLT, longterm patency is unlikely even with the use of paclitaxel- coated materials.

Variation in the Intensity of Selection on Codon Bias over Time Causes Contrasting Patterns of Base Composition Evolution in Drosophila.

Four-fold degenerate coding sites form a major component of the genome, and are often used to make inferences about selection and demography, so that understanding their evolution is important. Despite previous efforts, many questions regarding the causes of base composition changes at these sites in Drosophila remain unanswered. To shed further light on this issue, we obtained a new whole-genome polymorphism data set from D. simulans. We analyzed samples from the putatively ancestral range of D. simulans, as well as an existing polymorphism data set from an African population of D. melanogaster. By using D. yakuba as an outgroup, we found clear evidence for selection on 4-fold sites along both lineages over a substantial period, with the intensity of selection increasing with GC content. Based on an explicit model of base composition evolution, we suggest that the observed AT-biased substitution pattern in both lineages is probably due to an ancestral reduction in selection intensity, and is unlikely to be the result of an increase in mutational bias towards AT alone. By using two polymorphism-based methods for estimating selection coefficients over different timescales, we show that the selection intensity on codon usage has been rather stable in D. simulans in the recent past, but the long-term estimates in D. melanogaster are much higher than the short-term ones, indicating a continuing decline in selection intensity, to such an extent that the short-term estimates suggest that selection is only active in the most GC-rich parts of the genome. Finally, we provide evidence for complex evolutionary patterns in the putatively neutral short introns, which cannot be explained by the standard GC-biased gene conversion model. These results reveal a dynamic picture of base composition evolution.