3,5-Dimethylisoxazoles Act As Acetyl-lysine-mimetic Bromodomain Ligands

Histone-lysine acetylation is a vital chromatin post-translational modification involved in the epigenetic regulation of gene transcription. Bromodomains bind acetylated lysines, acting as readers of the histone-acetylation code. Competitive inhibitors of this interaction have antiproliferative and anti-inflammatory properties. With 57 distinct bromodomains known, the discovery of subtype-selective inhibitors of the histone-bromodomain interaction is of great importance. We have identified the 3,5 dimethylisoxazole moiety as a novel acetyl-lysine bioisostere, which displaces acetylated histone-mimicking peptides from bromodomains. Using X-ray crystallographic analysis, we have determined the interactions responsible for the activity and selectivity of 4-substituted 3,5-dimethylisoxazoles against a selection of phylogenetically diverse bromodomains. By exploiting these interactions, we have developed compound 4d, which has IC50 values of <5 μM for the bromodomain-containing proteins BRD2(1) and BRD4(1). These compounds are promising leads for the further development of selective probes for the bromodomain and extra C-terminal domain (BET) family and CREBBP bromodomains

Prevalence, Outcome, and Prevention of Congenital Cytomegalovirus Infection in Neonates Born to Women With Preconception Immunity (CHILd Study)

Background. Human cytomegalovirus (HCMV) is the leading infectious cause of congenital disabilities. We designed a prospective study to investigate the rate, outcome, and risk factors of congenital CMV (cCMV) infection in neonates born to immune women, and the potential need and effectiveness of hygiene recommendations in this population.Methods. The study was composed of 2 sequential parts: an epidemiology (part 1) and a prevention (part 2) study. Performance of part 2 depended upon a cCMV rate >0.4%. Women enrolled in part 1 did not receive hygiene recommendations. Newborns were screened by HCMV DNA testing in saliva and cCMV was confirmed by urine testing.Results. Saliva swabs were positive for HCMV DNA in 45/9661 newborns and cCMV was confirmed in 18 cases. The rate of cCMV was .19% (95% confidence interval [CI]: .11-.29%), and 3 out of 18 infants with cCMV had symptoms of CMV at birth. Age, nationality, occupation, and contact with children were similar between mothers of infected and noninfected newborns. Twin pregnancy (odds ratio [OR]: 7.2; 95% CI: 1.7-32.2; P=.037) and maternal medical conditions (OR: 3.9; 95% CI: 1.5-10.1; P= .003) appeared associated with cCMV. Given the rate of cCMV was lower than expected, the prevention part of the study was cancelled.Conclusions. Newborns from women with preconception immunity have a low rate of cCMV, which appears to be mostly due to reactivation of the latent virus. Therefore, serological screening in childbearing age would be pivotal to identify HCMV-seropositive women, whose newborns have a low risk of cCMV

European Electricity Market Reforms: Any Signs of Efficiency Improvements?

This paper investigates whether European electricity market refirms have induced any changes infirm efficiency either through productive, allocative or dynamic efficiency improve- ments. In particular, this ex-post analysis looks closely at productivity e ects of changing industry structure, ownership structure and regulation with respect to barriers to entry and access to wholesale and retail markets. Based on the Europeanfirm-level data for the period 1996-2007, the results indicate sluggish productivity improvements of European electricityfirms due to refirms implemented in the last decade. In particular, productivity gains are associated with high-productivityfirms close to the technology frontier, while no signi cant impact is found for the laggards. Looking from a dynamic perspective, it seems that the clos- est are thefirms to the frontier the more they are able to improve productivity in response to liberalization e orts stimulating competition

Prevalence, Outcome, and Prevention of Congenital Cytomegalovirus Infection in Neonates Born to Women with Preconception Immunity (CHILd Study)

Background: Human cytomegalovirus (HCMV) is the leading infectious cause of congenital disabilities. We designed a prospective study to investigate the rate, outcome, and risk factors of congenital CMV (cCMV) infection in neonates born to immune women, and the potential need and effectiveness of hygiene recommendations in this population. Methods: The study was composed of 2 sequential parts: an epidemiology (part 1) and a prevention (part 2) study. Performance of part 2 depended upon a cCMV rate >0.4%. Women enrolled in part 1 did not receive hygiene recommendations. Newborns were screened by HCMV DNA testing in saliva and cCMV was confirmed by urine testing. Results: Saliva swabs were positive for HCMV DNA in 45/9661 newborns and cCMV was confirmed in 18 cases. The rate of cCMV was. 19% (95% confidence interval [CI]:. 11-.29%), and 3 out of 18 infants with cCMV had symptoms of CMV at birth. Age, nationality, occupation, and contact with children were similar between mothers of infected and noninfected newborns. Twin pregnancy (odds ratio [OR]: 7.2; 95% CI: 1.7-32.2; P =. 037) and maternal medical conditions (OR: 3.9; 95% CI: 1.5-10.1; P =. 003) appeared associated with cCMV. Given the rate of cCMV was lower than expected, the prevention part of the study was cancelled. Conclusions: Newborns from women with preconception immunity have a low rate of cCMV, which appears to be mostly due to reactivation of the latent virus. Therefore, serological screening in childbearing age would be pivotal to identify HCMV-seropositive women, whose newborns have a low risk of cCMV. Clinical trials registration: www.clinicaltrials.gov (NCT03973359)

Abundance and Species Richness of Leafhoppers and Planthoppers (Hemiptera: Cicadellidae and Delphacidae) in Brazilian Maize Crops

Fil: De Oliveira, Charles Martins. Embrapa Cerrados. Planaltina. Brasília/DF; BrazilFil: De Oliveira, Elizabeth. Embrapa Milho e Sorgo. Sete Lagoas/MG; BrazilFil: Prazeres De Souza, Isabel Regina. Embrapa Milho e Sorgo. Sete Lagoas/MG; BrazilFil: Alves, Elcio. DuPont do Brazil S.A. DivisÆo Pioneer Sementes. Itumbiara/GO; BrazilFil: Dolezal, William. Pioneer Hi-Bred International. Itumbiara/GO; BrazilFil: Paradell, Susana Liria. División Entomología. Facultad de Ciencias Naturales y Museo. Universidad Nacional de La Plata; ArgentinaFil: Marino de Remes Lenicov, Ana María. División Entomología. Facultad de Ciencias Naturales y Museo. Universidad Nacional de La Plata; ArgentinaFil: Frizzas, Marina Regina. Universidade de Brasília. Departamento de Zoologia. Instituto de Ciências Biológicas. Brasília/DF; Brazi

Neuregulin 1 type III reduces severity in a mouse model of Congenital Hypomyelinating Neuropathy

Myelin sheath thickness is precisely regulated and essential for rapid propagation of action potentials along myelinated axons. In the peripheral nervous system, extrinsic signals from the axonal protein neuregulin 1 type III regulate Schwann cell fate and myelination. Here we ask if modulating neuregulin 1 type III levels in neurons would restore myelination in a model of congenital hypomyelinating neuropathy (CHN). Using a mouse model of CHN, we rescued the myelination defects by early overexpression of neuregulin 1 type III. Surprisingly, the rescue was independent from the upregulation of Egr2 or essential myelin genes. Rather, we observed the activation of MAPK/ERK and other myelin genes such as peripheral myelin protein 2 (Pmp2) and oligodendrocyte myelin glycoprotein (Omg). We also confirmed that the permanent activation of MAPK/ERK in Schwann cells has detrimental effects on myelination. Our findings demonstrate that the modulation of axon-to-glial neuregulin 1 type III signaling has beneficial effects and restores myelination defects during development in a model of CHN

Competition, Innovation, and Competition Law: Dissecting the Interplay

The digital revolution has reinvigorated the discussion about the problem how to consider innovation in the application of competition law. This raises difficult questions about the relationship between competition and innovation as well as what kind of assessment concepts competition authorities should use for investigating innovation effects, e.g., in merger cases. This paper, on one hand, reviews briefly our economic knowledge about competition and innovation, and claims that it is necessary to go beyond the limited insights that can be gained from industrial economics research about innovation (Schumpeter vs. Arrow discussion), and take into account much more insights from innovation research, evolutionary innovation economics, and business and management studies. On the other hand, it is also necessary to develop much more innovation-specific assessment concepts in competition law (beyond the traditional product market concept). Using the example of assessing innovation competition in merger cases, this article suggests to analyze much more systematically the resources (specialized assets) that are necessary for innovation. This concept is directly linked to the new discussion about the Dow/DuPont case in the EU and about data as necessary resource for (data-driven) innovation

European Competitiveness: A Semi-Parametric Stochastic Metafrontier Analysis at the Firm Level

In this paper a semiparametric stochastic metafrontier approach is used to obtain insight into firm-level competitiveness in Europe. We divert from standard TFP studies at the firm level as we simultaneously allow for inefficiency, noise and do not impose a functional form on the input-output relation. Using AMADEUS firm-level data covering 10 manufacturing sectors from seven EU15 countries, (i) we document substantial, persistent divergences in competitiveness (with Belgium and Germany as benchmark countries and Spain lagging behind) and a wide technology gap, (ii) we confirm the absence of convergence in TFP between the seven selected countries, (iii) we confirm that the technology gap is more pronounced for smaller firms, (iv) we highlight the role of post-entry growth for competitiveness