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Book chapterHuth M, 2019,
The merits of compositional abstraction: A case study in propositional logic
, Lecture Notes in Computer Science, Publisher: Springer International Publishing, Pages: 297-309, ISBN: 9783030223472We revisit a well-established and old topic in computational logic: algorithms – such as the one by Quine-McCluskey – that convert a formula of propositional logic into a semantically equivalent disjunctive normal form whose clauses are all prime implicants of that formula. This exercise in education is meant to honor Bernhard Steffen, who made important contributions in formal verification and its use of compositional abstraction, and who is a role model in transferring research insights into teaching addressed at students with varying skill levels. The algorithm we propose here is indeed compositional and can teach students about the value of compositional abstractions – making use of simple lattice-theoretic and semantic concepts.
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Journal articleShacklett BL, Blanco J, Hightow-Weidman L, et al., 2019,
HIV Research for Prevention 2018: From research to impact: Conference summary and highlights
, AIDS Research and Human Retroviruses, Vol: 35, Pages: 598-607, ISSN: 0889-2229The HIV Research for Prevention (HIVR4P) conference is dedicated to advancing HIV prevention research, responding to a growing consensus that effective and durable prevention will require a combination of approaches as well as unprecedented collaboration among scientists, practitioners, and community workers from different fields and geographic areas. The conference theme in 2018, “From Research to Impact,” acknowledged an increasing focus on translation of promising research findings into practical, accessible, and affordable HIV prevention options for those who need them worldwide. HIVR4P 2018 was held in Madrid, Spain, on 21–25 October, with >1,400 participants from 52 countries around the globe, representing all aspects of HIV prevention research and implementation. The program included 137 oral and 610 poster presentations. This article presents a brief summary of highlights from the conference. More detailed information, complete abstracts as well as webcasts and daily Rapporteur summaries may be found on the conference website.
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Journal articleSim MJW, Rajagopalan S, Altmann DM, et al., 2019,
Human NK cell receptor KIR2DS4 detects a conserved bacterial epitope presented by HLA-C.
, Proc Natl Acad Sci U S A, Vol: 116, Pages: 12964-12973Natural killer (NK) cells have an important role in immune defense against viruses and cancer. Activation of human NK cell cytotoxicity toward infected or tumor cells is regulated by killer cell immunoglobulin-like receptors (KIRs) that bind to human leukocyte antigen class I (HLA-I). Combinations of KIR with HLA-I are genetically associated with susceptibility to disease. KIR2DS4, an activating member of the KIR family with poorly defined ligands, is a receptor of unknown function. Here, we show that KIR2DS4 has a strong preference for rare peptides carrying a Trp at position 8 (p8) of 9-mer peptides bound to HLA-C*05:01. The complex of a peptide bound to HLA-C*05:01 with a Trp at p8 was sufficient for activation of primary KIR2DS4+ NK cells, independent of activation by other receptors and of prior NK cell licensing. HLA-C*05:01+ cells that expressed the peptide epitope triggered KIR2DS4+ NK cell degranulation. We show an inverse correlation of the worldwide allele frequency of functional KIR2DS4 with that of HLA-C*05:01, indicative of functional interaction and balancing selection. We found a highly conserved peptide sequence motif for HLA-C*05:01-restricted activation of human KIR2DS4+ NK cells in bacterial recombinase A (RecA). KIR2DS4+ NK cells were stimulated by RecA epitopes from multiple human pathogens, including Helicobacter, Chlamydia, Brucella, and Campylobacter. We predict that over 1,000 bacterial species could activate NK cells through KIR2DS4, and propose that human NK cells also contribute to immune defense against bacteria through recognition of a conserved RecA epitope presented by HLA-C*05:01.
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Journal articleCiano M, Mantellato G, Connolly M, et al., 2019,
EGF receptor (EGFR) inhibition promotes a slow-twitch oxidative, over a fast-twitch, muscle phenotype
, Scientific Reports, Vol: 9, ISSN: 2045-2322A low quadriceps slow-twitch (ST), oxidative (relative to fast-twitch) fiber proportion is prevalent in chronic diseases such Chronic Obstructive Pulmonary Disease (COPD) and is associated with exercise limitation and poor outcomes. Benefits of an increased ST fiber proportion are demonstrated in genetically modified animals. Pathway analysis of published data of differentially expressed genes in mouse ST and FT fibers, mining of our microarray data and a qPCR analysis of quadriceps specimens from COPD patients and controls were performed. ST markers were quantified in C2C12 myotubes with EGF-neutralizing antibody, EGFR inhibitor or an EGFR-silencing RNA added. A zebrafish egfra mutant was generated by genome editing and ST fibers counted. EGF signaling was (negatively) associated with the ST muscle phenotype in mice and humans, and muscle EGF transcript levels were raised in COPD. In C2C12 myotubes, EGFR inhibition/silencing increased ST, including mitochondrial, markers. In zebrafish, egfra depletion increased ST fibers and mitochondrial content. EGF is negatively associated with ST muscle phenotype in mice, healthy humans and COPD patients. EGFR blockade promotes the ST phenotype in myotubes and zebrafish embryos. EGF signaling suppresses the ST phenotype, therefore EGFR inhibitors may be potential treatments for COPD-related muscle ST fiber loss.
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Conference paperHunjan T, Abbara A, Patel A, et al., 2019,
FSH requirements for follicle growth during controlled ovarian stimulation in IVF cycles
, 35th Annual Meeting of the European Society of Human Reproduction and Embryology, Publisher: Oxford University Press, ISSN: 0268-1161 -
Journal articleFlack T, Romain C, White A, et al., 2019,
Design, synthesis and conformational analysis of oligobenzanilides as multi-facial alpha-helix mimetics
, Organic Letters, Vol: 21, Pages: 4433-4438, ISSN: 1523-7052The design, synthesis, and conformationalanalysis of an oligobenzanilide helix mimetic scaffold capableof simultaneous mimicry of two faces of an α-helix is reported.The synthetic methodology provides access to diversemonomer building blocks amenable to solid-phase assemblyin just four synthetic steps. The conformational flexibility ofmodel dimers was investigated using a combination of solidand solution state methodologies supplemented with DFTcalculations. The lack of noncovalent constraints allows forsignificant conformational plasticity in the scaffold, thuspermitting it to successfully mimic residues i, i+2, i+4, i+6, i+7, and i+9 of a canonical α-helix.
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Journal articleKallemeijn W, Lueg G, Faronato M, et al., 2019,
Validation and invalidation of chemical probes for the human N-myristoyltransferases
, Cell Chemical Biology, Vol: 26, Pages: 892-900, ISSN: 2451-9456On-target, cell-active chemical probes are of fundamental importance in both chemical and cell biology, whereas the application of poorly-characterised probes often leads to invalid conclusions.Human N-myristoyltransferase (NMT) has attracted increasing interest as a target in cancer and infectious diseases; here we report an in-depth comparison of five compounds widely applied as human NMT inhibitors, using a combination of quantitative whole-proteome N-myristoylation profiling, biochemical enzyme assays, cytotoxicity, in-cell protein synthesis and cell cycle assays. We find that N-myristoylation is unaffected by 2-hydroxymyristic acid (100 μM), D-NMAPPD (30 μM) or Tris-DBA palladium (10 μM), with the latter compounds causing cytotoxicity through mechanisms unrelated to NMT. In contrast, drug-like inhibitors IMP-366 (DDD85646) and IMP-1088 delivered complete and specific inhibition of N-myristoylation in a range of cell lines at 1 μM and 100 nM, respectively. This study enables the selection of appropriate on-target probes for future studies and suggests the need for reassessment of previous studies which used off-target compounds.
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Journal articleSonntag H-J, Filippi S, Pipis S, et al., 2019,
Blood biomarkers of sensitization and asthma
, Frontiers in Pediatrics, Vol: 7, ISSN: 2296-2360Biomarkers are essential to determine different phenotypes of childhood asthma, andfor the prediction of response to treatments. In young preschool children with asthma,aeroallergen sensitization, and blood eosinophil count of 300/µL or greater may identifythose who can benefit from the daily use of inhaled corticosteroids (ICS). We proposethat every preschool child who is considered for ICS treatment should have these twofeatures measured as a minimum before a decision is made on the commencementof long-term preventive treatment. In practice, IgE-mediated sensitization should beconsidered as a quantifiable variable, i.e., we should use the titer of sIgE antibodies orthe size of skin prick test response. A number of other blood biomarkers may proveuseful (e.g., allergen-specific IgG/IgE antibody ratios amongst sensitized individuals,component-resolved diagnostics which measures sIgE response to a large number ofallergenic molecules, assessment of immune responses to viruses, level of serum CC16,etc.), but it remains unclear whether these can be translated into clinically useful tests.Going forward, a more integrated approach which takes into account multiple domainsof asthma, from the pattern of symptoms and blood biomarkers to genetic risk andlung function measures, is needed if we are to move toward a stratified approach toasthma management.
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Journal articlePatel DF, Gaggar A, Blalock JE, et al., 2019,
Response to Comment on "An extracellular matrix fragment drives epithelial remodeling and airway hyperresponsiveness"
, SCIENCE TRANSLATIONAL MEDICINE, Vol: 11, ISSN: 1946-6234- Author Web Link
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Journal articleDharmage SC, Perret JL, Custovic A, 2019,
Epidemiology of asthma in children and adults
, Frontiers in Pediatrics, Vol: 7, ISSN: 2296-2360Asthma is a globally significant non-communicable disease with major public health consequences for both children and adults, including high morbidity, and mortality in severe cases. We have summarized the evidence on asthma trends, environmental determinants, and long-term impacts while comparing these epidemiological features across childhood asthma and adult asthma. While asthma incidence and prevalence are higher in children, morbidity, and mortality are higher in adults. Childhood asthma is more common in boys while adult asthma is more common in women, and the reversal of this sex difference in prevalence occurs around puberty suggesting sex hormones may play a role in the etiology of asthma. The global epidemic of asthma that has been observed in both children and adults is still continuing, especially in low to middle income countries, although it has subsided in some developed countries. As a heterogeneous disease, distinct asthma phenotypes, and endotypes need to be adequately characterized to develop more accurate and meaningful definitions for use in research and clinical settings. This may be facilitated by new clustering techniques such as latent class analysis, and computational phenotyping methods are being developed to retrieve information from electronic health records using natural language processing (NLP) algorithms to assist in the early diagnosis of asthma. While some important environmental determinants that trigger asthma are well-established, more work is needed to define the role of environmental exposures in the development of asthma in both children and adults. There is increasing evidence that investigation into possible gene-by-environment and environment-by-environment interactions may help to better uncover the determinants of asthma. Therefore, there is an urgent need to further investigate the interrelationship between environmental and genetic determinants to identify high risk groups and key modifiable exposures. For children, as
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