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101.
Lucia Reh Carsten Magnus Merle Schanz Jacqueline Weber Therese Uhr Peter Rusert Alexandra Trkola 《PLoS pathogens》2015,11(7)
An increasing number of broadly neutralizing antibodies (bnAbs) are considered leads for HIV-1 vaccine development and novel therapeutics. Here, we systematically explored the capacity of bnAbs to neutralize HIV-1 prior to and post-CD4 engagement and to block HIV-1 cell-cell transmission. Cell-cell spread is known to promote a highly efficient infection with HIV-1 which can inflict dramatic losses in neutralization potency compared to free virus infection. Selection of bnAbs that are capable of suppressing HIV irrespective of the transmission mode therefore needs to be considered to ascertain their in vivo activity in therapeutic use and vaccines. Employing assay systems that allow for unambiguous discrimination between free virus and cell-cell transmission to T cells, we probed a panel of 16 bnAbs for their activity against 11 viruses from subtypes A, B and C during both transmission modes. Over a wide range of bnAb-virus combinations tested, inhibitory activity against HIV-1 cell-cell transmission was strongly decreased compared to free virus transmission. Activity loss varied considerably between virus strains and was inversely associated with neutralization of free virus spread for V1V2- and V3-directed bnAbs. In rare bnAb-virus combinations, inhibition for both transmission modes was comparable but no bnAb potently blocked cell-cell transmission across all probed virus strains. Mathematical analysis indicated an increased probability of bnAb resistance mutations to arise in cell-cell rather than free virus spread, further highlighting the need to block this pathway. Importantly, the capacity to efficiently neutralize prior to CD4 engagement correlated with the inhibition efficacy against free virus but not cell-cell transmitted virus. Pre-CD4 attachment activity proved strongest amongst CD4bs bnAbs and varied substantially for V3 and V1V2 loop bnAbs in a strain-dependent manner. In summary, bnAb activity against divergent viruses varied depending on the transmission mode and differed depending on the window of action during the entry process, underscoring that powerful combinations of bnAbs are needed for in vivo application. 相似文献
102.
Jorge Esparza-Gordillo Anja Matanovic Ingo Marenholz Anja Bauerfeind Klaus Rohde Katja Nemat Min-Ae Lee-Kirsch Magnus Nordenskj?ld Marten C. G. Winge Thomas Keil Renate Krüger Susanne Lau Kirsten Beyer Birgit Kalb Bodo Niggemann Norbert Hübner Heather J. Cordell Maria Bradley Young-Ae Lee 《PLoS genetics》2015,11(3)
Epidemiological studies suggest that allergy risk is preferentially transmitted through mothers. This can be due to genomic imprinting, where the phenotype effect of an allele depends on its parental origin, or due to maternal effects reflecting the maternal genome''s influence on the child during prenatal development. Loss-of-function mutations in the filaggrin gene (FLG) cause skin barrier deficiency and strongly predispose to atopic dermatitis (AD). We investigated the 4 most prevalent European FLG mutations (c.2282del4, p.R501X, p.R2447X, and p.S3247X) in two samples including 759 and 450 AD families. We used the multinomial and maximum-likelihood approach implemented in the PREMIM/EMIM tool to model parent-of-origin effects. Beyond the known role of FLG inheritance in AD (R1meta-analysis = 2.4, P = 1.0 x 10−36), we observed a strong maternal FLG genotype effect that was consistent in both independent family sets and for all 4 mutations analysed. Overall, children of FLG-carrier mothers had a 1.5-fold increased AD risk (S1 = 1.50, Pmeta-analysis = 8.4 x 10−8). Our data point to two independent and additive effects of FLG mutations: i) carrying a mutation and ii) having a mutation carrier mother. The maternal genotype effect was independent of mutation inheritance and can be seen as a non-genetic transmission of a genetic effect. The FLG maternal effect was observed only when mothers had allergic sensitization (elevated allergen-specific IgE antibody plasma levels), suggesting that FLG mutation-induced systemic immune responses in the mother may influence AD risk in the child. Notably, the maternal effect reported here was stronger than most common genetic risk factors for AD recently identified through genome-wide association studies (GWAS). Our study highlights the power of family-based studies in the identification of new etiological mechanisms and reveals, for the first time, a direct influence of the maternal genotype on the offspring’s susceptibility to a common human disease. 相似文献
103.
Dongqing Xu Fang Lin Yan Jiang Junjie Ling Chamari Hettiarachchi Christian Tellgren-Roth Magnus Holm Ning Wei Xing Wang Deng 《PLoS genetics》2015,11(12)
CONSTITUTIVE PHOTOMORPHOGENIC 1 (COP1) functions as an E3 ubiquitin ligase and mediates a variety of developmental processes in Arabidopsis by targeting a number of key regulators for ubiquitination and degradation. Here, we identify a novel COP1 interacting protein, COP1 SUPPRESSOR 2 (CSU2). Loss of function mutations in CSU2 suppress the constitutive photomorphogenic phenotype of cop1-6 in darkness. CSU2 directly interacts with COP1 via their coiled-coil domains and is recruited by COP1 into nuclear speckles in living plant cells. Furthermore, CSU2 inhibits COP1 E3 ubiquitin ligase activity in vitro, and represses COP1 mediated turnover of HY5 in cell-free extracts. We propose that in csu2 cop1-6 mutants, the lack of CSU2’s repression of COP1 allows the low level of COP1 to exhibit higher activity that is sufficient to prevent accumulation of HY5 in the dark, thus restoring the etiolated phenotype. In addition, CSU2 is required for primary root development under normal light growth condition. 相似文献
104.
Lori Newman Jane Rowley Stephen Vander Hoorn Nalinka Saman Wijesooriya Magnus Unemo Nicola Low Gretchen Stevens Sami Gottlieb James Kiarie Marleen Temmerman 《PloS one》2015,10(12)
Background
Quantifying sexually transmitted infection (STI) prevalence and incidence is important for planning interventions and advocating for resources. The World Health Organization (WHO) periodically estimates global and regional prevalence and incidence of four curable STIs: chlamydia, gonorrhoea, trichomoniasis and syphilis.Methods and Findings
WHO’s 2012 estimates were based upon literature reviews of prevalence data from 2005 through 2012 among general populations for genitourinary infection with chlamydia, gonorrhoea, and trichomoniasis, and nationally reported data on syphilis seroprevalence among antenatal care attendees. Data were standardized for laboratory test type, geography, age, and high risk subpopulations, and combined using a Bayesian meta-analytic approach. Regional incidence estimates were generated from prevalence estimates by adjusting for average duration of infection. In 2012, among women aged 15–49 years, the estimated global prevalence of chlamydia was 4.2% (95% uncertainty interval (UI): 3.7–4.7%), gonorrhoea 0.8% (0.6–1.0%), trichomoniasis 5.0% (4.0–6.4%), and syphilis 0.5% (0.4–0.6%); among men, estimated chlamydia prevalence was 2.7% (2.0–3.6%), gonorrhoea 0.6% (0.4–0.9%), trichomoniasis 0.6% (0.4–0.8%), and syphilis 0.48% (0.3–0.7%). These figures correspond to an estimated 131 million new cases of chlamydia (100–166 million), 78 million of gonorrhoea (53–110 million), 143 million of trichomoniasis (98–202 million), and 6 million of syphilis (4–8 million). Prevalence and incidence estimates varied by region and sex.Conclusions
Estimates of the global prevalence and incidence of chlamydia, gonorrhoea, trichomoniasis, and syphilis in adult women and men remain high, with nearly one million new infections with curable STI each day. The estimates highlight the urgent need for the public health community to ensure that well-recognized effective interventions for STI prevention, screening, diagnosis, and treatment are made more widely available. Improved estimation methods are needed to allow use of more varied data and generation of estimates at the national level. 相似文献105.
Yasser Ahmed Hamed Hiroshi Yasuda Magnus Persson Ronny Berndtsson Xin-ping Wang 《PloS one》2015,10(3)
Arid soils in Egypt display large variability in solute transport properties, causing problems in soil management. To characterize this variability, dye infiltration experiments were conducted on four plots representing three main soil types in northeastern Egypt. The plots represented both cultivated and uncultivated land use. The observed dye patterns displayed a large variability and especially the clay soils indicated a high degree of preferential flow. The loamy sand and sandy soils displayed a more uniform dye distribution indicating more homogeneous soil properties. The observed dye patterns were modeled using a diffusion limited aggregation (DLA) model. The DLA is a random walk model where model parameters can be optimized using genetic algorithms (GA). The DLA model reproduced the observed dye patterns for all soils in an excellent way. The best fit was obtained with a specific combination of directional random walk probabilities Pu, Pd, Pr, and Pl for each plot (correlation 0.97–0.99). To account for soil layers with different hydraulic properties a two layer DLA model was developed. For all plots the Pu (upward random walk probability) was higher for the upper more homogeneous soil layer. The overall results showed that spatial variability resulting from solute transport for the investigated soils can be modeled using a DLA approach. 相似文献
106.
Yan Hou Michael D. Nowak Virginia Mirré Charlotte S. Bjor? Christian Brochmann Magnus Popp 《PloS one》2015,10(10)
Restriction-site associated DNA sequencing (RAD-seq) has recently become an important method to generate genome-wide molecular data for species delimitation, phylogeography, and population genetic studies. However, very few empirical studies have so far tested its applicability in phylogenetic reconstruction. The alpine-arctic genus Diapensia was selected to study the origin of the disjunction between the Arctic and the Himalayan-Hengduan Mountains (HHM). However, a previous phylogenetic analysis based on one nuclear and four plastid DNA regions failed to resolve the oldest divergences in Diapensia as well as the relationship between the two HHM species. Here we reconstruct a fully resolved phylogeny of Diapensia and address the conflict between the currently accepted taxonomy and the gene trees in the HHM species using RAD-seq. Based on a data set containing 2,650 loci selected to maximize the number of parsimony informative sites and allowing for a high level of missing data (51%), the phylogeny of Diapensia was fully resolved and each of the four species was reciprocally monophyletic. Whereas the arctic D. lapponica was inferred as sister to the HHM clade in the previous study, the RAD-seq data resolved the two arctic species as sisters to the HHM clade. Similar relationships were inferred from a differently filtered data set with far fewer loci (114) and less missing data (21%), but with lower support and with one of the two HHM species as non-monophyletic. Bayesian concordance analysis and Patterson’s D-statistic tests suggested that admixture has occurred between the two HHM species. 相似文献
107.
Rocio Acuna-Hidalgo Denny Schanze Ariana Kariminejad Ann Nordgren Mohamad Hasan Kariminejad Peter Conner Giedre Grigelioniene Daniel Nilsson Magnus Nordenskjöld Anna Wedell Christoph Freyer Anna Wredenberg Dagmar Wieczorek Gabriele Gillessen-Kaesbach Hülya Kayserili Nursel Elcioglu Siavash Ghaderi-Sohi Payman Goodarzi Hamidreza Setayesh Maartje van de Vorst Marloes Steehouwer Rolph Pfundt Birgit Krabichler Cynthia Curry Malcolm G. MacKenzie Kym M. Boycott Christian Gilissen Andreas R. Janecke Alexander Hoischen Martin Zenker 《American journal of human genetics》2014
108.
Georgios Tzelepis Akira Hosomi Tanim Jabid Hossain Hiroto Hirayama Mukesh Dubey Dan Funck Jensen Tadashi Suzuki Magnus Karlsson 《Biochemical and biophysical research communications》2014
N-Glycosylation is an important post-translational modification of proteins, which mainly occurs in the endoplasmic reticulum (ER). Glycoproteins that are unable to fold properly are exported to the cytosol for degradation by a cellular system called ER-associated degradation (ERAD). Once misfolded glycoproteins are exported to the cytosol, they are subjected to deglycosylation by peptide:N-glycanase (PNGase) to facilitate the efficient degradation of misfolded proteins by the proteasome. Interestingly, the ortholog of PNGase in some filamentous fungi was found to be an inactive deglycosylating enzyme. On the other hand, it has been shown that in filamentous fungi genomes, usually two different fungi-specific endo-β-N-acetylglucosamidases (ENGases) can be found; one is predicted to be localized in the cytosol and the other to have a signal sequence, while the functional importance of these enzymes remains to be clarified. In this study the ENGases of the filamentous fungus Trichoderma atroviride was characterized. By heterologous expression of the ENGases Eng18A and Eng18B in Saccharomyces cerevisiae, it was found that both ENGases are active deglycosylating enzymes. Interestingly, only Eng18B was able to enhance the efficient degradation of the RTL protein, a PNGase-dependent ERAD substrate, implying the involvement of this enzyme in the ERAD process. These results indicate that T. atroviride Eng18B may deglycosylate misfolded glycoproteins, substituting the function of the cytoplasmic PNGase in the ERAD process. 相似文献
109.
While contemporary philosophers have been content to declare the logical possibilities of sacrifice exhausted, to have finally ‘sacrificed sacrifice,’ for many people around the world the notion of sacrifice – whether religious, secular, or somewhere in between – remains absolutely central to their understanding of themselves, their relations with others, and their place in the world. From religion to economics, and from politics to the environment, sacrificial tropes frequently emerge as key means of mediating and propagating various forms of power, moral discourse, and cultural identity. This paper lays out reasons for retaining sacrifice as an analytical concept within anthropology, and argues for the importance of a renewed focus on the ‘other side of sacrifice’, as a means of understanding better how sacrifice emerges beyond ritual and enters into the full gamut of social life. 相似文献
110.
Christina ?hrmalm Magnus Jobs Ronnie Eriksson Sultan Golbob Amal Elfaitouri Farid Benachenhou Maria Str?mme Jonas Blomberg 《Nucleic acids research》2010,38(21):e195
One of the main problems in nucleic acid-based techniques for detection of infectious agents, such as influenza viruses, is that of nucleic acid sequence variation. DNA probes, 70-nt long, some including the nucleotide analog deoxyribose-Inosine (dInosine), were analyzed for hybridization tolerance to different amounts and distributions of mismatching bases, e.g. synonymous mutations, in target DNA. Microsphere-linked 70-mer probes were hybridized in 3M TMAC buffer to biotinylated single-stranded (ss) DNA for subsequent analysis in a Luminex® system. When mismatches interrupted contiguous matching stretches of 6 nt or longer, it had a strong impact on hybridization. Contiguous matching stretches are more important than the same number of matching nucleotides separated by mismatches into several regions. dInosine, but not 5-nitroindole, substitutions at mismatching positions stabilized hybridization remarkably well, comparable to N (4-fold) wobbles in the same positions. In contrast to shorter probes, 70-nt probes with judiciously placed dInosine substitutions and/or wobble positions were remarkably mismatch tolerant, with preserved specificity. An algorithm, NucZip, was constructed to model the nucleation and zipping phases of hybridization, integrating both local and distant binding contributions. It predicted hybridization more exactly than previous algorithms, and has the potential to guide the design of variation-tolerant yet specific probes. 相似文献