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  • 1
    Language: English
    In: 2015, Vol.11(4), p.e1004150
    Description: The sequences that were chosen had recently been solved by X-ray crystallography but had not been not published or released until after the predictions from the community were made. Since the first CASP, we have seen many successful challenges, including Critical Assessment of Function Annotation (CAFA)...
    Keywords: Editorial
    ISSN: 1553-734X
    E-ISSN: 1553-7358
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  • 2
    Language: English
    In: Frontiers in Immunology, May 9, 2018
    Description: The recent West African Ebola virus pandemic, which affected 〉28,000 individuals increased interest in anti-Ebolavirus vaccination programs. Here, we systematically analyzed the requirements for a prophylactic vaccination program based on the basic reproductive number ( R 0 , i.e., the number of secondary cases that result from an individual infection). Published R 0 values were determined by systematic literature research and ranged from 0.37 to 20. R 0 s ≥ 4 realistically reflected the critical early outbreak phases and superspreading events. Based on the R 0 , the herd immunity threshold ( I c ) was calculated using the equation I c  = 1 − (1/ R 0 ). The critical vaccination coverage ( V c ) needed to provide herd immunity was determined by including the vaccine effectiveness ( E ) using the equation V c  =  I c / E . At an R 0 of 4, the I c is 75% and at an E of 90%, more than 80% of a population need to be vaccinated to establish herd immunity. Such vaccination rates are currently unrealistic because of resistance against vaccinations, financial/logistical challenges, and a lack of vaccines that provide long-term protection against all human-pathogenic Ebolaviruses. Hence, outbreak management will for the foreseeable future depend on surveillance and case isolation. Clinical vaccine candidates are only available for Ebola viruses. Their use will need to be focused on health-care workers, potentially in combination with ring vaccination approaches.
    Keywords: Herd Immunity -- Research ; Ebola Hemorrhagic Fever -- Prevention ; Ebola Hemorrhagic Fever -- Risk Factors ; Vaccination -- Usage
    ISSN: 1664-3224
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  • 3
    Language: English
    In: BMC genomics, 11 August 2017, Vol.18(Suppl 5), pp.550
    Description: Cystinuria is an inherited disease that results in the formation of cystine stones in the kidney, which can have serious health complications. Two genes (SLC7A9 and SLC3A1) that form an amino acid transporter are known to be responsible for the disease. Variants that cause the disease disrupt amino acid transport across the cell membrane, leading to the build-up of relatively insoluble cystine, resulting in formation of stones. Assessing the effects of each mutation is critical in order to provide tailored treatment options for patients. We used various computational methods to assess the effects of cystinuria associated mutations, utilising information on protein function, evolutionary conservation and natural population variation of the two genes. We also analysed the ability of some methods to predict the phenotypes of individuals with cystinuria, based on their genotypes, and compared this to clinical data. Using a literature search, we collated a set of 94 SLC3A1 and 58 SLC7A9 point mutations known to be associated with cystinuria. There are differences in sequence location, evolutionary conservation, allele frequency, and predicted effect on protein function between these mutations and other genetic variants of the same genes that occur in a large population. Structural analysis considered how these mutations might lead to cystinuria. For SLC7A9, many mutations swap hydrophobic amino acids for charged amino acids or vice versa, while others affect known functional sites. For SLC3A1, functional information is currently insufficient to make confident predictions but mutations often result in the loss of hydrogen bonds and largely appear to affect protein stability. Finally, we showed that computational predictions of mutation severity were significantly correlated with the disease phenotypes of patients from a clinical study, despite different methods disagreeing for some of their predictions. The results of this study are promising and highlight the areas of research which must now be pursued to better understand how mutations in SLC3A1 and SLC7A9 cause cystinuria. The application of our approach to a larger data set is essential, but we have shown that computational methods could play an important role in designing more effective personalised treatment options for patients with cystinuria.
    Keywords: Computational Predictions ; Cystinuria ; Exac ; Personalised Medicine ; Structural Modelling ; Models, Molecular ; Point Mutation ; Severity of Illness Index ; Amino Acid Transport Systems, Basic -- Chemistry ; Amino Acid Transport Systems, Neutral -- Chemistry ; Cystinuria -- Genetics
    E-ISSN: 1471-2164
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  • 4
    Language: English
    In: mSphere, 2016, Vol.1(6)
    Description: Out of the five members of the family, four cause life-threatening disease, whereas the fifth, Reston virus (RESTV), is nonpathogenic in humans. The reasons for this discrepancy remain unclear. In this review, we analyze the currently available information to provide a state-of-the-art summary of the factors that determine the human pathogenicity of Ebolaviruses. RESTV causes sporadic infections in cynomolgus monkeys and is found in domestic pigs throughout the Philippines and China. Phylogenetic analyses revealed that RESTV is most closely related to the Sudan virus, which causes a high mortality rate in humans. Amino acid sequence differences between RESTV and the other Ebolaviruses are found in all nine Ebolavirus proteins, though no one residue appears sufficient to confer pathogenicity. Changes in the glycoprotein contribute to differences in Ebolavirus pathogenicity but are not sufficient to confer pathogenicity on their own. Similarly, differences in VP24 and VP35 affect viral immune evasion and are associated with changes in human pathogenicity. A recent analysis systematically determined the functional consequences of sequence variations between RESTV and human-pathogenic Ebolaviruses. Multiple positions in VP24 were differently conserved between RESTV and the other Ebolaviruses and may alter human pathogenicity. In conclusion, the factors that determine the pathogenicity of Ebolaviruses in humans remain insufficiently understood. An improved understanding of these pathogenicity-determining factors is of crucial importance for disease prevention and for the early detection of emergent and potentially human-pathogenic RESTVs.
    Keywords: Ebolavirus ; Reston ; Pathogenicity
    ISSN: 2379-5042
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  • 5
    Language: English
    In: BMC genomics, 11 August 2017, Vol.18(Suppl 5), pp.566
    Description: Ebolaviruses have been known to cause deadly disease in humans for 40 years and have recently been demonstrated in West Africa to be able to cause large outbreaks. Four Ebolavirus species cause severe disease associated with high mortality in humans. Reston viruses are the only Ebolaviruses that do not cause disease in humans. Conserved amino acid changes in the Reston virus protein VP24 compared to VP24 of other Ebolaviruses have been suggested to alter VP24 binding to host cell karyopherins resulting in impaired inhibition of interferon signalling, which may explain the difference in human pathogenicity. Here we used protein structural analysis and molecular dynamics to further elucidate the interaction between VP24 and KPNA5. As a control experiment, we compared the interaction of wild-type and R137A-mutant (known to affect KPNA5 binding) Ebola virus VP24 with KPNA5. Results confirmed that the R137A mutation weakens direct VP24-KPNA5 binding and enables water molecules to penetrate at the interface. Similarly, Reston virus VP24 displayed a weaker interaction with KPNA5 than Ebola virus VP24, which is likely to reduce the ability of Reston virus VP24 to prevent host cell interferon signalling. Our results provide novel molecular detail on the interaction of Reston virus VP24 and Ebola virus VP24 with human KPNA5. The results indicate a weaker interaction of Reston virus VP24 with KPNA5 than Ebola virus VP24, which is probably associated with a decreased ability to interfere with the host cell interferon response. Hence, our study provides further evidence that VP24 is a key player in determining Ebolavirus pathogenicity.
    Keywords: Ebola ; Molecular Dynamics ; Pathogenicity ; Protein Structure ; Virology ; Molecular Dynamics Simulation ; Ebolavirus -- Pathogenicity ; Viral Proteins -- Metabolism
    E-ISSN: 1471-2164
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  • 6
    Language: English
    In: PloS one, 2014, Vol.9(8), pp.e102645
    Description: The genetic sequence variation of people from the Indian subcontinent who comprise one-quarter of the world's population, is not well described. We carried out whole genome sequencing of 168 South Asians, along with whole-exome sequencing of 147 South Asians to provide deeper characterisation of coding regions. We identify 12,962,155 autosomal sequence variants, including 2,946,861 new SNPs and 312,738 novel indels. This catalogue of SNPs and indels amongst South Asians provides the first comprehensive map of genetic variation in this major human population, and reveals evidence for selective pressures on genes involved in skin biology, metabolism, infection and immunity. Our results will accelerate the search for the genetic variants underlying susceptibility to disorders such as type-2 diabetes and cardiovascular disease which are highly prevalent amongst South Asians.
    Keywords: Genetic Variation ; Genome, Human ; Asian Continental Ancestry Group -- Genetics ; European Continental Ancestry Group -- Genetics
    E-ISSN: 1932-6203
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  • 7
    Language: English
    In: Nucleic acids research, July 2014, Vol.42(Web Server issue), pp.W331-6
    Description: Unravelling the genotype-phenotype relationship in humans remains a challenging task in genomics studies. Recent advances in sequencing technologies mean there are now thousands of sequenced human genomes, revealing millions of single nucleotide variants (SNVs). For non-synonymous SNVs present in proteins the difficulties of the problem lie in first identifying those nsSNVs that result in a functional change in the protein among the many non-functional variants and in turn linking this functional change to phenotype. Here we present VarMod (Variant Modeller) a method that utilises both protein sequence and structural features to predict nsSNVs that alter protein function. VarMod develops recent observations that functional nsSNVs are enriched at protein-protein interfaces and protein-ligand binding sites and uses these characteristics to make predictions. In benchmarking on a set of nearly 3000 nsSNVs VarMod performance is comparable to an existing state of the art method. The VarMod web server provides extensive resources to investigate the sequence and structural features associated with the predictions including visualisation of protein models and complexes via an interactive JSmol molecular viewer. VarMod is available for use at http://www.wasslab.org/varmod.
    Keywords: Genetic Variation ; Models, Molecular ; Software ; Proteins -- Genetics
    ISSN: 03051048
    E-ISSN: 1362-4962
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  • 8
    Language: English
    In: Sci Rep, 2016, Vol.6(1), pp.23743-23743
    Description: Reston viruses are the only Ebolaviruses that are not pathogenic in humans. We analyzed 196 Ebolavirus genomes and identified specificity determining positions (SDPs) in all nine Ebolavirus proteins that distinguish Reston viruses from the four human pathogenic Ebolaviruses. A subset of these SDPs will explain the differences in human pathogenicity between Reston and the other four ebolavirus species. Structural analysis was performed to identify those SDPs that are likely to have a functional effect. This analysis revealed novel functional insights in particular for Ebolavirus proteins VP40 and VP24. The VP40 SDP P85T interferes with VP40 function by altering octamer formation. The VP40 SDP Q245P affects the structure and hydrophobic core of the protein and consequently protein function. Three VP24 SDPs (T131S, M136L, Q139R) are likely to impair VP24 binding to human karyopherin alpha5 (KPNA5) and therefore inhibition of interferon signaling. Since VP24 is critical for Ebolavirus adaptation to novel hosts and only a few SDPs distinguish Reston virus VP24 from VP24 of other Ebolaviruses, human pathogenic Reston viruses may emerge. This is of concern since Reston viruses circulate in domestic pigs and can infect humans, possibly via airborne transmission.
    Keywords: Airborne Infection ; Disease Transmission ; Genomes ; Human Diseases ; Inhibition ; Interferon ; Pathogenesis ; Pathogenicity ; Hogs ; Swine ; Man ; Pigs ; Viruses ; Sus Scrofa ; Sus ; Suidae ; Suiformes ; Artiodactyla ; Mammals ; Vertebrates ; Chordata ; Animals ; Eukaryotes ; Homo ; Hominidae ; Primates;
    ISSN: 2045-2322
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  • 9
    In: Nature Genetics, 2010, Vol.42(2), p.149
    Description: To identify genetic factors influencing cardiac conduction, we carried out a genome-wide association study of electrocardiographic time intervals in 6,543 Indian Asians. We identified association of a nonsynonymous SNP, rs6795970, in SCN10A (P = 2.8 10 super(-15)) with PR interval, a marker of cardiac atrioventricular conduction. Replication testing among 6,243 Indian Asians and 5,370 Europeans confirmed that rs6795970 (G〉A) is associated with prolonged cardiac conduction (longer P-wave duration, PR interval and QRS duration, P = 10 super(-5) to 10 super(-20)). SCN10A encodes Na sub(V)1.8, a sodium channel. We show that SCN10A is expressed in mouse and human heart tissue and that PR interval is shorter in Scn10a super(-/-) mice than in wild-type mice. We also find that rs6795970 is associated with a higher risk of heart block (P 〈 0.05) and a lower risk of ventricular fibrillation (P = 0.01). Our findings provide new insight into the pathogenesis of cardiac conduction, heart block and ventricular fibrillation.
    Keywords: Heart ; Genetic Factors ; Sodium Channels (Voltage-Gated) ; Single-Nucleotide Polymorphism ; Replication ; Fibrillation ; Risk Factors ; Genetic Diversity ; Nerve Conduction ; Conduction ; Mammals ; Miscellaneous;
    ISSN: 1061-4036
    E-ISSN: 15461718
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  • 10
    Language: English
    In: PloS one, 2017, Vol.12(2), pp.e0172140
    Description: The formation of acquired drug resistance is a major reason for the failure of anti-cancer therapies after initial response. Here, we introduce a novel model of acquired oxaliplatin resistance, a sub-line of the non-MYCN-amplified neuroblastoma cell line SK-N-AS that was adapted to growth in the presence of 4000 ng/mL oxaliplatin (SK-N-ASrOXALI4000). SK-N-ASrOXALI4000 cells displayed enhanced chromosomal aberrations compared to SK-N-AS, as indicated by 24-chromosome fluorescence in situ hybridisation. Moreover, SK-N-ASrOXALI4000 cells were resistant not only to oxaliplatin but also to the two other commonly used anti-cancer platinum agents cisplatin and carboplatin. SK-N-ASrOXALI4000 cells exhibited a stable resistance phenotype that was not affected by culturing the cells for 10 weeks in the absence of oxaliplatin. Interestingly, SK-N-ASrOXALI4000 cells showed no cross resistance to gemcitabine and increased sensitivity to doxorubicin and UVC radiation, alternative treatments that like platinum drugs target DNA integrity. Notably, UVC-induced DNA damage is thought to be predominantly repaired by nucleotide excision repair and nucleotide excision repair has been described as the main oxaliplatin-induced DNA damage repair system. SK-N-ASrOXALI4000 cells were also more sensitive to lysis by influenza A virus, a candidate for oncolytic therapy, than SK-N-AS cells. In conclusion, we introduce a novel oxaliplatin resistance model. The oxaliplatin resistance mechanisms in SK-N-ASrOXALI4000 cells appear to be complex and not to directly depend on enhanced DNA repair capacity. Models of oxaliplatin resistance are of particular relevance since research on platinum drugs has so far predominantly focused on cisplatin and carboplatin.
    Keywords: DNA Damage ; Drug Resistance, Multiple -- Genetics ; Drug Resistance, Neoplasm -- Genetics ; Organoplatinum Compounds -- Pharmacology
    E-ISSN: 1932-6203
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