LIN28B affects gene expression at the hypothalamic-pituitary axis and serum testosterone levels.

Genome-wide association studies (GWAS) have recurrently associated sequence variation nearby LIN28B with pubertal timing, growth and disease. However, the biology linking LIN28B with these traits is still poorly understood. With our study, we sought to elucidate the mechanisms behind the LIN28B associations, with a special focus on studying LIN28B function at the hypothalamic-pituitary (HP) axis that is ultimately responsible for pubertal onset.

Genetic Associations with Gestational Duration and Spontaneous Preterm Birth.

Background: Despite evidence that genetic factors contribute to the duration of gestation and the risk of preterm birth, robust associations with genetic variants have not been identified. We used large data sets that included the gestational duration to determine possible genetic associations.

Methods: We performed a genomewide association study in a discovery set of samples obtained from 43,568 women of European ancestry using gestational duration as a continuous trait and term or preterm (<37 weeks) birth as a dichotomous outcome.

Matched preclinical designs for improved translatability.

A more stratified preclinical design strategy will increase the statistical power and reproducibility of animal studies and their translatability.

RNA sequencing of chorionic villi from recurrent pregnancy loss patients reveals impaired function of basic nuclear and cellular machinery.

Recurrent pregnancy loss (RPL) concerns ~3% of couples aiming at childbirth. In the current study, transcriptomes and miRNomes of 1 trimester placental chorionic villi were analysed for 2 RPL cases (≥6 miscarriages) and normal, but electively terminated pregnancies (ETP; n = 8). Sequencing was performed on Illumina HiSeq 2000 platform.

Screening out irrelevant cell-based models of disease.

The common and persistent failures to translate promising preclinical drug candidates into clinical success highlight the limited effectiveness of disease models currently used in drug discovery. An apparent reluctance to explore and adopt alternative cell- and tissue-based model systems, coupled with a detachment from clinical practice during assay validation, contributes to ineffective translational research. To help address these issues and stimulate debate, here we propose a set of principles to facilitate the definition and development of disease-relevant assays, and we discuss new opportunities for exploiting the latest advances in cell-based assay technologies in drug discovery, including induced pluripotent stem cells, three-dimensional (3D) co-culture and organ-on-a-chip systems, complemented by advances in single-cell imaging and gene editing technologies.

JNJ872 inhibits influenza A virus replication without altering cellular antiviral responses.

JNJ-63623872 (formally known as VX-787; referred to here as JNJ872) is an orally bioavailable compound, which is in phase II clinical trials for the treatment of influenza A virus (IAV) infections. Here we show that JNJ872 inhibits at nanomolar concentrations the transcription of viral RNA in IAV-infected human macrophages by targeting a highly conserved site on the cap-snatching domain of influenza polymerase basic 2 protein (PB2). Furthermore, even lower concentrations of JNJ872 protected macrophages from IAV-mediated death when given in combination with 100 nM gemcitabine, which also attenuated transcription and replication of viral RNA.

Protein profiling of nasopharyngeal aspirates of hospitalized and outpatients revealed cytokines associated with severe influenza A(H1N1)pdm09 virus infections: A pilot study.

Influenza A viruses (IAV) mutate rapidly and cause seasonal epidemics and occasional pandemics, which result in substantial number of patient visits to the doctors and even hospitalizations. We aimed here to identify inflammatory proteins, which levels correlated to clinical severity of the disease. For this we analysed 102 cytokines and growth factors in human nasopharyngeal aspirate (NPA) samples of 27 hospitalized and 27 outpatients diagnosed with influenza A(H1N1)pdm09 virus infection.

Immuno-modulating properties of saliphenylhalamide, SNS-032, obatoclax, and gemcitabine.

Influenza A viruses (IAVs) impact the public health and global economy by causing yearly epidemics and occasional pandemics. Several anti-IAV drugs are available and many are in development. However, the question remains which of these antiviral agents may allow activation of immune responses and protect patients against co- and re-infections.

Relevance Rank Platform (RRP) for Functional Filtering of High Content Protein-Protein Interaction Data.

High content protein interaction screens have revolutionized our understanding of protein complex assembly. However, one of the major challenges in translation of high content protein interaction data is identification of those interactions that are functionally relevant for a particular biological question. To address this challenge, we developed a relevance ranking platform (RRP), which consist of modular functional and bioinformatic filters to provide relevance rank among the interactome proteins.

Comparative Analysis of Whole-Genome Sequences of Influenza A(H1N1)pdm09 Viruses Isolated from Hospitalized and Nonhospitalized Patients Identifies Missense Mutations That Might Be Associated with Patient Hospital Admissions in Finland during 2009 to 2014.

Here, we report 40 new whole-genome sequences of influenza A(H1N1)pdm09 viruses isolated from Finnish patients during 2009 to 2014. A preliminary analysis of these and 186 other whole genomes of influenza A(H1N1)pdm09 viruses isolated from hospitalized and nonhospitalized patients during 2009 to 2014 in Finland revealed several viral mutations that might be associated with patient hospitalizations.

Meta-Analysis of Placental Transcriptome Data Identifies a Novel Molecular Pathway Related to Preeclampsia.

Studies using the placental transcriptome to identify key molecules relevant for preeclampsia are hampered by a relatively small sample size. In addition, they use a variety of bioinformatics and statistical methods, making comparison of findings challenging. To generate a more robust preeclampsia gene expression signature, we performed a meta-analysis on the original data of 11 placenta RNA microarray experiments, representing 139 normotensive and 116 preeclamptic pregnancies.

Complete Genome Sequences of Influenza A/H1N1 Strains Isolated from Patients during the 2013-2014 Epidemic Season in Finland.

Here, we report 40 complete genome sequences of influenza A/H1N1 strains isolated from 33 nonhospitalized and 7 hospitalized patients during the 2013-2014 epidemic season in Finland. An analysis of the aligned sequences revealed no oseltamivir-resistant genotypes. As a whole, the recent viruses have drifted from the prototype A/California/7/2009 virus by ca.

Influenza pH1N1 Virus Accumulated H275Y Mutation in Neuraminidase during Propagation in MDCK Cells.

Here, we sequenced the genome of the influenza A/Finland/741 M/2014(H1N1) virus and found that the virus accumulated oseltamivir resistance mutation H275Y in its neuraminidase during propagation in cell culture. This indicates that propagation in cell culture modifies virus genomes. The instability of influenza genomes should be taken into consideration during drug-sensitivity studies.

Interactions between genetic variants and dietary lipid composition: effects on circulating LDL cholesterol in children.

Background: Elevated serum low-density lipoprotein (LDL) cholesterol is a predictor of cardiovascular disease events, and the quality of dietary fat is known to influence serum concentrations of LDL cholesterol in children. Interindividual differences in response to diet exist, but the underlying genetic factors remain largely unknown.

Objective: We aimed to identify genetic variants that modify the variation in serum lipid response to dietary fat quality.

Genetic Instability of Influenza pH1N1 Viruses.

Here, we report full-length genome sequences of influenza pH1N1 viruses obtained prior to and after propagation in MDCK cells. Paired comparisons of the genomes showed that each strain acquired 1.0 to 18.

Neolithic dairy farming at the extreme of agriculture in northern Europe.

The conventional 'Neolithic package' comprised animals and plants originally domesticated in the Near East. As farming spread on a generally northwest trajectory across Europe, early pastoralists would have been faced with the challenge of making farming viable in regions in which the organisms were poorly adapted to providing optimal yields or even surviving. Hence, it has long been debated whether Neolithic economies were ever established at the modern limits of agriculture.

Full-Genome Sequences of Influenza H3N2 Virus Strains Isolated from Finnish Patients during the 2012-2013 Epidemic Season.

Here, we sequenced 10 influenza A(H3N2) virus genomes isolated from Finnish patients diagnosed with flu-like illness during the 2012-2013 influenza season. The alignment showed a high number of amino acid substitutions (238 in total) in only 10 samples, proving that a high mutation rate exists in seasonal influenza A viruses.

Global Human-Kinase Screening Identifies Therapeutic Host Targets against Influenza.

During viral infection of human cells, host kinases mediate signaling activities that are used by all viruses for replication; therefore, targeting of host kinases is of broad therapeutic interest. Here, host kinases were globally screened during human influenza virus (H1N1) infection to determine the time-dependent effects of virus infection and replication on kinase function. Desthiobiotin-labeled analogs of adenosine triphosphate and adenosine diphosphate were used to probe and covalently label host kinases in infected cell lysates, and probe affinity was determined.

Full-Genome Sequences of Influenza A(H1N1)pdm09 Viruses Isolated from Finnish Patients from 2009 to 2013.

Here we report full-length sequencing of the first large set of influenza A(H1N1)pdm09 virus genomes isolated in Finland between the years 2009 and 2013 and discuss the advantages and needs of influenza virus sequencing efforts.

The Finnish disease heritage database (FinDis) update-a database for the genes mutated in the Finnish disease heritage brought to the next-generation sequencing era.

The Finnish Disease Heritage Database (FinDis) (http://findis.org) was originally published in 2004 as a centralized information resource for rare monogenic diseases enriched in the Finnish population. The FinDis database originally contained 405 causative variants for 30 diseases.

Anticancer compound ABT-263 accelerates apoptosis in virus-infected cells and imbalances cytokine production and lowers survival rates of infected mice.

ABT-263 and its structural analogues ABT-199 and ABT-737 inhibit B-cell lymphoma 2 (Bcl-2), BCL2L1 long isoform (Bcl-xL) and BCL2L2 (Bcl-w) proteins and promote cancer cell death. Here, we show that at non-cytotoxic concentrations, these small molecules accelerate the deaths of non-cancerous cells infected with influenza A virus (IAV) or other viruses. In particular, we demonstrate that ABT-263 altered Bcl-xL interactions with Bcl-2 antagonist of cell death (Bad), Bcl-2-associated X protein (Bax), uveal autoantigen with coiled-coil domains and ankyrin repeats protein (UACA).