Host jumps shaped the diversity of extant rust fungi (Pucciniales)

* The aim of this study was to determine the evolutionary time line for rust fungi and date key speciation events using a molecular clock. Evidence is provided that supports a contemporary view for a recent origin of rust fungi, with a common ancestor on a flowering plant. * Divergence times for > 20 genera of rust fungi were studied with Bayesian evolutionary analyses. A relaxed molecular clock was applied to ribosomal and mitochondrial genes, calibrated against estimated divergence times for the hosts of rust fungi, such as Acacia (Fabaceae), angiosperms and the cupressophytes. * Results showed that rust fungi shared a most recent common ancestor with a mean age between 113 and 115 million yr. This dates rust fungi to the Cretaceous period, which is much younger than previous estimations. Host jumps, whether taxonomically large or between host genera in the same family, most probably shaped the diversity of rust genera. Likewise, species diversified by host shifts (through coevolution) or via subsequent host jumps. This is in contrast to strict coevolution with their hosts. * Puccinia psidii was recovered in Sphaerophragmiaceae, a family distinct from Raveneliaceae, which were regarded as confamilial in previous studies

The scale of population structure in Arabidopsis thaliana

The population structure of an organism reflects its evolutionary history and influences its evolutionary trajectory. It constrains the combination of genetic diversity and reveals patterns of past gene flow. Understanding it is a prerequisite for detecting genomic regions under selection, predicting the effect of population disturbances, or modeling gene flow. This paper examines the detailed global population structure of Arabidopsis thaliana. Using a set of 5,707 plants collected from around the globe and genotyped at 149 SNPs, we show that while A. thaliana as a species self-fertilizes 97% of the time, there is considerable variation among local groups. This level of outcrossing greatly limits observed heterozygosity but is sufficient to generate considerable local haplotypic diversity. We also find that in its native Eurasian range A. thaliana exhibits continuous isolation by distance at every geographic scale without natural breaks corresponding to classical notions of populations. By contrast, in North America, where it exists as an exotic species, A. thaliana exhibits little or no population structure at a continental scale but local isolation by distance that extends hundreds of km. This suggests a pattern for the development of isolation by distance that can establish itself shortly after an organism fills a new habitat range. It also raises questions about the general applicability of many standard population genetics models. Any model based on discrete clusters of interchangeable individuals will be an uneasy fit to organisms like A. thaliana which exhibit continuous isolation by distance on many scales

Efficacy of treatment for hyperglycemic crisis in elderly diabetic patients in a day hospital

The purpose of this prospective cohort study was to compare the costs of day hospital (DH) care for hyperglycemic crisis in elderly diabetic patients with those of conventional hospitalization (CH). Secondary objectives were to compare these two clinical scenarios in terms of glycemic control, number of emergency and outpatient visits, readmissions, hypoglycemic episodes, and nosocomial morbidity. The study population comprised diabetic patients aged >74 years consecutively admitted to a tertiary teaching hospital in Spain for hyperglycemic crisis (sustained hyperglycemia [>300 mg/dL] for at least 3 days with or without ketosis). The patients were assigned to DH or CH care according to time of admission and were followed for 6 months after discharge. Exclusion criteria were ketoacidosis, hyperosmolar crisis, hemodynamic instability, severe intercurrent illness, social deprivation, or Katz index >D. Sixty-four diabetic patients on DH care and 36 on CH care were included, with no differences in baseline characteristics. The average cost per patient was 1,345.1±793.6 € in the DH group and 2,212.4±982.5 € in the CH group (P <0.001). There were no differences in number of subjects with mild hypoglycemia during follow-up (45.3% DH versus 33.3% CH, P =0.24), nor in the percentage of patients achieving a glycated hemoglobin (HbA) <8% (67.2% DH versus 58.3% CH, P =0.375). Readmissions for hyperglycemic crisis and pressure ulcer rates were significantly higher in the CH group. DH care for hyperglycemic crises is more cost-effective than CH care, with a net saving of 1,418.4 € per case, lower number of readmissions and pressure ulcer rates, and similar short-term glycemic control and hypoglycemia rates

Impact of inhaled corticosteroids on growth in children with asthma: systematic review and meta-analysis

Background: Long-term inhaled corticosteroids (ICS) may reduce growth velocity and final height of children with asthma. We aimed to evaluate the association between ICS use of >12 months and growth. Methods: We initially searched MEDLINE and EMBASE in July 2013, followed by a PubMed search updated to December 2014. We selected RCTs and controlled observational studies of ICS use in patients with asthma. We conducted random effects meta-analysis of mean differences in growth velocity (cm/year) or final height (cm) between groups. Heterogeneity was assessed using the I2 statistic. Results: We found 23 relevant studies (twenty RCTs and three observational studies) after screening 1882 hits. Meta-analysis of 16 RCTs showed that ICS use significantly reduced growth velocity at one year follow-up (mean difference -0.48 cm/year (95% CI -0.66 to -0.29)). There was evidence of a dose-response effect in three RCTs. Final adult height showed a mean reduction of -1.20 cm (95% CI -1.90 cm to -0.50 cm) with budesonide versus placebo in a high quality RCT. Meta-analysis of two lower quality observational studies revealed uncertainty in the association between ICS use and final adult height, pooled mean difference -0.85 cm (95% CI -3.35 to 1.65). Conclusion: Use of ICS for >12 months in children with asthma has a limited impact on annual growth velocity. In ICS users, there is a slight reduction of about a centimeter in final adult height, which when interpreted in the context of average adult height in England (175 cm for men and 161 cm for women), represents a 0.7% reduction compared to non-ICS users

Neurospora from natural populations: Population genomics insights into the Life history of a model microbial Eukaryote

The ascomycete filamentous fungus Neurospora crassa played a historic role in experimental biology and became a model system for genetic research. Stimulated by a systematic effort to collect wild strains initiated by Stanford geneticist David Perkins, the genus Neurospora has also become a basic model for the study of evolutionary processes, speciation, and population biology. In this chapter, we will first trace the history that brought Neurospora into the era of population genomics. We will then cover the major contributions of population genomic investigations using Neurospora to our understanding of microbial biogeography and speciation, and review recent work using population genomics and genome-wide association mapping that illustrates the unique potential of Neurospora as a model for identifying the genetic basis of (potentially adaptive) phenotypes in filamentous fungi. The advent of population genomics has contributed to firmly establish Neurospora as a complete model system and we hope our review will entice biologists to include Neurospora in their research

Intravitreal Gene Therapy vs. Natural History in Patients With Leber Hereditary Optic Neuropathy Carrying the m.11778G&gt;A ND4 Mutation: Systematic Review and Indirect Comparison

Objective: This work aimed to compare the evolution of visual outcomes in Leber hereditary optic neuropathy (LHON) patients treated with intravitreal gene therapy to the spontaneous evolution in prior natural history (NH) studies. Design: A combined analysis of two phase three randomized, double-masked, sham-controlled studies (REVERSE and RESCUE) and their joint long-term extension trial (CLIN06) evaluated the efficacy of rAAV2/2-ND4 vs. 11 pooled NH studies used as an external control. Subjects: The LHON subjects carried the m.11778G>A ND4 mutation and were aged ≥15 years at onset of vision loss. Methods: A total of 76 subjects received a single intravitreal rAAV2/2-ND4 injection in one eye and sham injection in the fellow eye within 1 year after vision loss in REVERSE and RESCUE. Both eyes were considered as treated due to the rAAV2/2-ND4 treatment efficacy observed in the contralateral eyes. Best corrected visual acuity (BCVA) from REVERSE, RESCUE, and CLIN06 up to 4.3 years after vision loss was compared to the visual acuity of 208 NH subjects matched for age and ND4 genotype. The NH subjects were from a LHON registry (REALITY) and from 10 NH studies. A locally estimated scatterplot smoothing (LOESS), non-parametric, local regression model was used to modelize visual acuity curves over time, and linear mixed model was used for statistical inferences. Main Outcome Measures: The main outcome measure was evolution of visual acuity from 12 months after vision loss, when REVERSE and RESCUE patients had been treated with rAAV2/2-ND4. Results: The LOESS curves showed that the BCVA of the treated patients progressively improved from month 12 to 52 after vision loss. At month 48, there was a statistically and clinically relevant difference in visual acuity of −0.33 logarithm of the minimal angle of resolution (LogMAR) (16.5 ETDRS letters equivalent) in favor of treated eyes vs. NH eyes (p A LHON patients treated with rAAV2/2-ND4 exhibited an improvement of visual acuity over more than 4 years after vision loss to a degree not demonstrated in NH studies. Clinical Trial Registration: NCT02652767, NCT02652780, NCT03406104, and NCT03295071

Kinome rewiring reveals AURKA limits PI3K-pathway inhibitor efficacy in breast cancer.

Dysregulation of the PI3K-AKT-mTOR signaling network is a prominent feature of breast cancers. However, clinical responses to drugs targeting this pathway have been modest, possibly because of dynamic changes in cellular signaling that drive resistance and limit drug efficacy. Using a quantitative chemoproteomics approach, we mapped kinome dynamics in response to inhibitors of this pathway and identified signaling changes that correlate with drug sensitivity. Maintenance of AURKA after drug treatment was associated with resistance in breast cancer models. Incomplete inhibition of AURKA was a common source of therapy failure, and combinations of PI3K, AKT or mTOR inhibitors with the AURKA inhibitor MLN8237 were highly synergistic and durably suppressed mTOR signaling, resulting in apoptosis and tumor regression in vivo. This signaling map identifies survival factors whose presence limits the efficacy of targeted therapies and reveals new drug combinations that may unlock the full potential of PI3K-AKT-mTOR pathway inhibitors in breast cancer

Gradients versus Cycling in Genetic Selection Models

We review the hierarchy of (continuous time) selection models starting with the classical Fisher's viability selection model, and its generalizations when allowing mutations, recombination, sex-dependent viabilities, fertility selection and different mortality rates. We analyse the question in which way Fisher's "Fundamental Theorem of Natural Selection" and Kimura's Maximum Principle can be extended to these more general situations. It turns out that in many cases this is principally impossible since the dynamics becomes cycling or even chaotic

A cardinal role for cathepsin D in co-ordinating the host-mediated apoptosis of macrophages and killing of pneumococci

The bactericidal function of macrophages against pneumococci is enhanced by their apoptotic demise, which is controlled by the anti-apoptotic protein Mcl-1. Here, we show that lysosomal membrane permeabilization (LMP) and cytosolic translocation of activated cathepsin D occur prior to activation of a mitochondrial pathway of macrophage apoptosis. Pharmacological inhibition or knockout of cathepsin D during pneumococcal infection blocked macrophage apoptosis. As a result of cathepsin D activation, Mcl-1 interacted with its ubiquitin ligase Mule and expression declined. Inhibition of cathepsin D had no effect on early bacterial killing but inhibited the late phase of apoptosis-associated killing of pneumococci in vitro. Mice bearing a cathepsin D-/- hematopoietic system demonstrated reduced macrophage apoptosis in vivo, with decreased clearance of pneumococci and enhanced recruitment of neutrophils to control pulmonary infection. These findings establish an unexpected role for a cathepsin D-mediated lysosomal pathway of apoptosis in pulmonary host defense and underscore the importance of apoptosis-associated microbial killing to macrophage function

Transgenic expression of the dicotyledonous pattern recognition receptor EFR in rice leads to ligand-dependent activation of defense responses

Plant plasma membrane localized pattern recognition receptors (PRRs) detect extracellular pathogen-associated molecules. PRRs such as Arabidopsis EFR and rice XA21 are taxonomically restricted and are absent from most plant genomes. Here we show that rice plants expressing EFR or the chimeric receptor EFR::XA21, containing the EFR ectodomain and the XA21 intracellular domain, sense both Escherichia coli- and Xanthomonas oryzae pv. oryzae (Xoo)-derived elf18 peptides at sub-nanomolar concentrations. Treatment of EFR and EFR::XA21 rice leaf tissue with elf18 leads to MAP kinase activation, reactive oxygen production and defense gene expression. Although expression of EFR does not lead to robust enhanced resistance to fully virulent Xoo isolates, it does lead to quantitatively enhanced resistance to weakly virulent Xoo isolates. EFR interacts with OsSERK2 and the XA21 binding protein 24 (XB24), two key components of the rice XA21-mediated immune response. Rice-EFR plants silenced for OsSERK2, or overexpressing rice XB24 are compromised in elf18-induced reactive oxygen production and defense gene expression indicating that these proteins are also important for EFR-mediated signaling in transgenic rice. Taken together, our results demonstrate the potential feasibility of enhancing disease resistance in rice and possibly other monocotyledonous crop species by expression of dicotyledonous PRRs. Our results also suggest that Arabidopsis EFR utilizes at least a subset of the known endogenous rice XA21 signaling components