GPRA and the asthma locus on chromosome 7p14-p15

The basis of this work was the identification of a genomic region on chromosome 7p14-p15 that strongly associated with asthma and high serum total immunoglobulin E in a Finnish founder population from Kainuu. Using a hierarchical genotyping approach the linkage region was narrowed down until an evolutionary collectively inherited 133-kb haplotype block was discovered. The results were confirmed in two independent data sets: Asthma families from Quebec and allergy families from North-Karelia. In all the three cohorts studied, single nucleotide polymorphisms tagging seven common gene variants (haplotypes) were identified. Over half of the asthma patients carried three evolutionary closely related susceptibility haplotypes as opposed to approximately one third of the healthy controls. The risk effects of the gene variants varied from 1.4 to 2.5. In the disease-associated region, there was one protein-coding gene named GPRA (G Protein-coupled Receptor for Asthma susceptibility also known as NPSR1) which displayed extensive alternative splicing. Only the two isoforms with distinct intracellular tail sequences, GPRA-A and -B, encoded a full-length G protein-coupled receptor with seven transmembrane regions. Using various techniques, we showed that GPRA is expressed in multiple mucosal surfaces including epithelial cells throughout the respiratory tract. GPRA-A has additional expression in respiratory smooth muscle cells. However, in bronchial biopsies with unknown haplotypes, GPRA-B was upregulated in airways of all patient samples in contrast to the lack of expression in controls. Further support for GPRA as a common mediator of inflammation was obtained from a mouse model of ovalbumin-induced inflammation, where metacholine-induced airway hyperresponsiveness correlated with elevated GPRA mRNA levels in the lung and increased GPRA immunostaining in pulmonary macrophages. A novel GPRA agonist, Neuropeptide S (NPS), stimulated phagocytosis of Esterichia coli bacteria in a mouse macrophage cell line indicating a role for GPRA in the removal of inhaled allergens. The suggested GPRA functions prompted us to study, whether GPRA haplotypes associate with respiratory distress syndrome (RDS) and bronchopulmonary dysplasia (BPD) in infants sharing clinical symptoms with asthma. According to the results, near-term RDS and asthma may also share the same susceptibility and protective GPRA haplotypes. As in asthma, GPRA-B isoform expression was induced in bronchial smooth muscle cells in RDS and BPD suggesting a role for GPRA in bronchial hyperresponsiveness. In conclusion, the results of the present study suggest that the dysregulation of the GPRA/NPS pathway may not only be limited to the individuals carrying the risk variants of the gene but is also involved in the regulation of immune functions of asthma.Astma määritellään keuhkoputkien tulehdukselliseksi sairaudeksi, jonka oireisiin kuuluu vaihteleva ja itsestään tai hoidon vaikutuksesta laukeava keuhkoputkien ahtautuminen sekä lisääntynyt supistumisherkkyys. Suomessa astma on yleisin lasten ja kolmanneksi yleisin aikuisten pitkäaikaissairaus. Perintötekijät eivät yksinään aiheuta monitekijäisiin tauteihin sairastumista, mutta elintapojen ja -ympäristön vaikutuksesta ne kuitenkin lisäävät sairastumisriskiä. Tutkimalla yli kymmenen vuoden ajan astman periytymisen mekanismeja suomalaisperheissä ryhmämme on koko genomin kattavilla geenimerkkien hauilla paikantanut astmaan ja allergioihin kytkeytyvän alueen. Väitöskirjatutkimuksen ensimmäisessä osatyössä hienokartoitimme tämän kromosomissa 7 sijaitsevan geenialueen 133 000 emäksen kokoiseksi. Tietyt evoluutiossa säilyneet emäsmuutokset nostivat sairastumisriskiä jopa 2,5-kertaiseksi muuhun väestöön verrattuna selittäen astmaa 20-25 %:lla potilaista. Alkuperäiseen tutkimukseen osallistui 250 kainuulaisperhettä, mutta tulokset varmistettiin myös kanadan-ranskalaisilla ja pohjois-karjalaisilla perheillä. Geenien ennustusohjelmien avulla löysimme alueelta kaksi aikaisemmin heikosti tunnettua geeniä, jotka nimesimme AAA1:ksi ja GPRA:ksi. AAA1 geenin luenta ei johda proteiinisynteesiin, mutta solukalvon G-proteiinireseptori GPRA (tunnetaan myös nimellä NPSR1) sopii rakenteensa vuoksi uudeksi lääkekohdemolekyyliksi. Tämän väitöskirjatyön tulosten perusteella GPRA:ta tuotetaan mm. hengitysteiden ja ruoansulatuskanavan limakalvoilla sekä puolustusjärjestelmän soluissa. Hiiren soluviljelmä- ja astmamallista saatujen tulosten perusteella GPRA näyttäisi osallistuvan elimistön synnynnäisiin suojamekanismeihin ja hengitettyjen partikkelien poistoon. GPRA:ta tuotetaan astmaatikkojen hengitysteiden lihassolukerroksessa, joten reseptori voisi siten osallistua keuhkoputkien supistumisherkkyyden säätelyyn. Ennenaikaisesti syntyneiden keskosten kehittyneet hoitomuodot ovat vähentäneet kuolleisuutta tehokkaasti, mutta samalla vastasyntyneen hengitysvaikeusoireyhtymän RDS:n ja kroonisen keuhkotaudin BPD:n esiintyvyys on noussut. Koska RDS ja BPD nostavat astmariskiä, tutkimme GPRA:n ja lasten kroonisten keuhkosairauksien välistä geneettistä yhteyttä suomalaisissa vastasyntyneissä. Havaitsimme osan astmatutkimuksen yhteydessä havaituista GPRA:n emäsmuutoksista liittyvän myös RDS:n sairastumisalttiuteen. Lisäksi GPRA:n vasta-ainevärjäysten päälöydös RDS- ja BPD -potilaissa muistutti astmaatikkojen ilmatiehyissä nähtyjä muutoksia. G-proteiinireseptorit ovat modernin lääkekehityksen parhaiten tunnettuja kohdemolekyylejä, joten GPRA on lupaava uusi reseptori astman ja muiden allergisten tautien mekanismien selvittämisessä ja niiden estämisessä

Synthesizing Perceived Challenges in Continuous Delivery : A Systematic Literature Review

Continuous delivery is an approach to software development which incorporates the practices, technologies and processes in order to achieve frequent delivery of valuable software to customers. Even though the continuous delivery approach has not existed very long yet, there has been quite a lot of a buzz around it and terms related to it (continuous deployment, deployment pipeline, and DevOps). Practices and benefits of the approach are presented in the literature, and organizations have been adopting it to a varying extent. However, as easy as the advocates of continuous delivery make the adoption look like, there have been reported challenges along the way. In order to focus research on finding the causes and creating solutions to these challenges, we must first identify them. To address this, we conducted a systematic literature review in order to collect perceived challenges related to the adoption of continuous delivery practices in software development projects, and analyzed the findings in order to provide synthesized information about these challenges. From among 13 publications 59 different challenges were identified which we categorized either as a social (procedural or organizational) or as a technical type of a challenge based on the evaluation of the findings. Among these challenges we found 14 more frequently occurring ones which also spanned across multiple software domains. We described these as common challenges. We also analyzed the reasons behind these challenges and identified five different themes (main reasons) that were immaturity, unsuitability, complexity, dependency, and security. We also analyzed how the software domain affected these reasons. Based on the observed mitigation strategies and research proposals, and our analysis, we proposed suggestions for future research directions. This study can be used as a support for finding future research directions regarding the challenges in the area of adopting continuous delivery practices in software development projects

Multiobjective optimization identifies cancer-selective combination therapies

Author summary Cancer is diagnosed in nearly 40% of people in the U.S at some point during their lifetimes. Despite decades of research to lower cancer incidence and mortality, cancer remains a leading cause of deaths worldwide. Therefore, new targeted therapies are required to further reduce the death rates and toxic effects of treatments. Here we developed a mathematical optimization framework for finding cancer-selective treatments that optimally use drugs and their combinations. The method uses multiobjective optimization to identify drug combinations that simultaneously show maximal therapeutic potential and minimal non-selectivity, to avoid severe side effects. Our systematic search approach is applicable to various cancer types and it enables optimization of combinations involving both targeted therapies as well as standard chemotherapies. Combinatorial therapies are required to treat patients with advanced cancers that have become resistant to monotherapies through rewiring of redundant pathways. Due to a massive number of potential drug combinations, there is a need for systematic approaches to identify safe and effective combinations for each patient, using cost-effective methods. Here, we developed an exact multiobjective optimization method for identifying pairwise or higher-order combinations that show maximal cancer-selectivity. The prioritization of patient-specific combinations is based on Pareto-optimization in the search space spanned by the therapeutic and nonselective effects of combinations. We demonstrate the performance of the method in the context of BRAF-V600E melanoma treatment, where the optimal solutions predicted a number of co-inhibition partners for vemurafenib, a selective BRAF-V600E inhibitor, approved for advanced melanoma. We experimentally validated many of the predictions in BRAF-V600E melanoma cell line, and the results suggest that one can improve selective inhibition of BRAF-V600E melanoma cells by combinatorial targeting of MAPK/ERK and other compensatory pathways using pairwise and third-order drug combinations. Our mechanism-agnostic optimization method is widely applicable to various cancer types, and it takes as input only measurements of a subset of pairwise drug combinations, without requiring target information or genomic profiles. Such data-driven approaches may become useful for functional precision oncology applications that go beyond the cancer genetic dependency paradigm to optimize cancer-selective combinatorial treatments.Peer reviewe

Prenatal programming of child neurocognitive abilities and maternal mental health : Fetal Programming

Maternal mental health problems during pregnancy, especially mood and anxiety disorders and symptoms, are common. They not only hinder maternal well-being and health during pregnancy but also are associated with physical and mental health adversities in the offspring. We provide here a review of the studies published between 2017 and 2019, which reported on the associations between maternal mental health problems during pregnancy and child neurocognitive outcomes. We identified eight studies, which reported a mixed pattern of findings. While the balance of evidence favors lack of associations, small sample sizes and heterogeneity in study designs, exposures, outcomes, and covariate adjustments between the studies preclude firm conclusions. The reviewed studies encourage further research filling in the knowledge gaps we identified.Peer reviewe