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  • 1
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    Public Library of Science (PLoS)
    Publication Date: 2018-05-03
    Description: by The PLOS Neglected Tropical Diseases Staff
    Print ISSN: 1935-2727
    Electronic ISSN: 1935-2735
    Topics: Medicine
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  • 2
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    Public Library of Science (PLoS)
    Publication Date: 2018-05-03
    Description: by Ari Prayitno, Anne-Frieda Taurel, Joshua Nealon, Hindra Irawan Satari, Mulya Rahma Karyanti, Rini Sekartini, Soedjatmiko Soedjatmiko, Hartono Gunardi, Bernie Endyarni Medise, R. Tedjo Sasmono, James Mark Simmerman, Alain Bouckenooghe, Sri Rezeki Hadinegoro
    Print ISSN: 1935-2727
    Electronic ISSN: 1935-2735
    Topics: Medicine
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  • 3
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    Public Library of Science (PLoS)
    Publication Date: 2018-05-03
    Description: by Kohei Kitami, Megumi Kitami, Masaru Kaku, Bin Wang, Yoshihiro Komatsu Craniofacial abnormalities, including facial skeletal defects, comprise approximately one-third of all birth defects in humans. Since most bones in the face derive from cranial neural crest cells (CNCCs), which are multipotent stem cells, craniofacial bone disorders are largely attributed to defects in CNCCs. However, it remains unclear how the niche of CNCCs is coordinated by multiple gene regulatory networks essential for craniofacial bone development. Here we report that tumor suppressors breast cancer 1 (BRCA1) and breast cancer 2 (BRCA2) are required for craniofacial bone development in mice. Disruption of Brca1 in CNCC-derived mesenchymal cells, but not in epithelial-derived cells, resulted in craniofacial skeletal defects. Whereas osteogenic differentiation was normal, both osteogenic proliferation and survival were severely attenuated in Brca1 mutants. Brca1 -deficient craniofacial skeletogenic precursors displayed increased DNA damage and enhanced cell apoptosis. Importantly, the craniofacial skeletal defects were sufficiently rescued by superimposing p53 null alleles in a neural crest-specific manner in vivo , indicating that BRCA1 deficiency induced DNA damage, cell apoptosis, and that the pathogenesis of craniofacial bone defects can be compensated by inactivation of p53. Mice lacking Brca2 in CNCCs, but not in epithelial-derived cells, also displayed abnormalities resembling the craniofacial skeletal malformations observed in Brca1 mutants. Our data shed light on the importance of BRCA1/BRCA2 function in CNCCs during craniofacial skeletal formation.
    Print ISSN: 1553-7390
    Electronic ISSN: 1553-7404
    Topics: Biology
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  • 4
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    Public Library of Science (PLoS)
    Publication Date: 2018-05-03
    Description: by Shoichiro Yamaguchi, Honda Naoki, Muneki Ikeda, Yuki Tsukada, Shunji Nakano, Ikue Mori, Shin Ishii Animals are able to reach a desired state in an environment by controlling various behavioral patterns. Identification of the behavioral strategy used for this control is important for understanding animals’ decision-making and is fundamental to dissect information processing done by the nervous system. However, methods for quantifying such behavioral strategies have not been fully established. In this study, we developed an inverse reinforcement-learning (IRL) framework to identify an animal’s behavioral strategy from behavioral time-series data. We applied this framework to C . elegans thermotactic behavior; after cultivation at a constant temperature with or without food, fed worms prefer, while starved worms avoid the cultivation temperature on a thermal gradient. Our IRL approach revealed that the fed worms used both the absolute temperature and its temporal derivative and that their behavior involved two strategies: directed migration (DM) and isothermal migration (IM). With DM, worms efficiently reached specific temperatures, which explains their thermotactic behavior when fed. With IM, worms moved along a constant temperature, which reflects isothermal tracking, well-observed in previous studies. In contrast to fed animals, starved worms escaped the cultivation temperature using only the absolute, but not the temporal derivative of temperature. We also investigated the neural basis underlying these strategies, by applying our method to thermosensory neuron-deficient worms. Thus, our IRL-based approach is useful in identifying animal strategies from behavioral time-series data and could be applied to a wide range of behavioral studies, including decision-making, in other organisms.
    Print ISSN: 1553-734X
    Electronic ISSN: 1553-7358
    Topics: Biology , Computer Science
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  • 5
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    Public Library of Science (PLoS)
    Publication Date: 2018-05-03
    Description: by Magdalena Circu, James Cardelli, Martin P. Barr, Kenneth O’Byrne, Glenn Mills, Hazem El-Osta
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 6
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    Public Library of Science (PLoS)
    Publication Date: 2018-05-03
    Description: by Xinyu Feng, Shuisen Zhou, Jingwen Wang, Wei Hu Mosquitoes are incriminated as vectors for many crippling diseases, including malaria, West Nile fever, Dengue fever, and other neglected tropical diseases (NTDs). microRNAs (miRNAs) can interact with multiple target genes to elicit biological functions in the mosquitoes. However, characterization and function of individual miRNAs and their potential targets have not been fully determined to date. We conducted a systematic review of published literature following PRISMA guidelines. We summarize the information about miRNAs in mosquitoes to better understand their metabolism, development, and responses to microorganisms. Depending on the study, we found that miRNAs were dysregulated in a species-, sex-, stage-, and tissue/organ-specific manner. Aberrant miRNA expressions were observed in development, metabolism, host-pathogen interactions, and insecticide resistance. Of note, many miRNAs were down-regulated upon pathogen infection. The experimental studies have expanded the identification of miRNA target from the 3′ untranslated regions (UTRs) of mRNAs of mosquitoes to the 5′ UTRs of mRNAs of the virus. In addition, we discuss current trends in mosquito miRNA research and offer suggestions for future studies.
    Print ISSN: 1935-2727
    Electronic ISSN: 1935-2735
    Topics: Medicine
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  • 7
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    Public Library of Science (PLoS)
    Publication Date: 2018-05-03
    Description: by Elisa Sicuri, Azucena Bardají, Sergi Sanz, Sergi Alonso, Silke Fernandes, Kara Hanson, Myriam Arevalo-Herrera, Clara Menendez Malaria in pregnancy threatens birth outcomes and the health of women and their newborns. This is also the case in low transmission areas, such as Colombia, where Plasmodium vivax is the dominant parasite species. Within the Colombian health system, which underwent major reforms in the ‘90s, malaria treatment is provided free of charge to patients. However, patients still incur costs, such as transportation and value of time lost due to the disease. We estimated such costs among 40 pregnant women with clinical malaria (30% Plasmodium falciparum , 70% Plasmodium vivax ) in the municipality of Tierralta, Northern Colombia. In a cross-sectional study, women were interviewed after an outpatient or inpatient laboratory confirmed malaria episode. Women were asked to report all types of cost incurred before (including prevention), during and immediately after the contact with the health facility. Median total cost was over 16US$ for an outpatient visit, rising to nearly 30US$ if other treatments were sought before reaching the health facility. Median total inpatient cost was 26US$ or 54US$ depending on whether costs incurred prior to admission were excluded or included. For both outpatients and inpatients, direct costs were largely due to transportation and indirect costs constituted the largest share of total costs. Estimated costs are likely to represent only one of the constraints that women face when seeking treatment in an area characterized, at the time of the study, by armed conflict, displacement, and high vulnerability of indigenous women, the group at highest risk of malaria. Importantly, the Colombian peace process, which culminated with the cease-fire in August 2016, may have a positive impact on achieving universal access to healthcare in conflict areas. The current study can inform malaria elimination initiatives in Colombia.
    Print ISSN: 1935-2727
    Electronic ISSN: 1935-2735
    Topics: Medicine
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  • 8
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    Public Library of Science (PLoS)
    Publication Date: 2018-05-03
    Description: by Ling Lu, Derrick A. Bennett, Iona Y. Millwood, Sarah Parish, Mark I. McCarthy, Anubha Mahajan, Xu Lin, Fiona Bragg, Yu Guo, Michael V. Holmes, Shoaib Afzal, Børge G. Nordestgaard, Zheng Bian, Michael Hill, Robin G. Walters, Liming Li, Zhengming Chen, Robert Clarke Background Observational studies have reported that higher plasma 25-hydroxyvitamin D (25[OH]D) concentrations are associated with lower risks of diabetes, but it is unclear if these associations are causal. The aim of this study was to test the relevance of 25(OH)D for type 2 diabetes using genetically instrumented differences in plasma 25(OH)D concentrations. Methods and findings Data were available on four 25(OH)D single nucleotide polymorphisms (SNPs; n = 82,464), plasma 25(OH)D concentrations ( n = 13,565), and cases with diabetes ( n = 5,565) in the China Kadoorie Biobank (CKB). The effects on risk of diabetes were assessed by a genetic score using two 25(OH)D synthesis SNPs ( DHCR7 -rs12785878 and CYP2R1 -rs10741657), with and without the addition of SNPs affecting the transport ( GC/DBP -rs2282679) and catabolism ( CYP24A1 -rs6013897) of 25(OH)D. The CKB results were combined in a meta-analysis of 10 studies for the 2 synthesis SNPs ( n = 58,312 cases) and 7 studies for all 4 SNPs ( n = 32,796 cases). Mean (SD) 25(OH)D concentration was 62 (20) nmol/l in CKB, and the per allele effects of genetic scores on 25(OH)D were 2.87 (SE 0.39) for the synthesis SNPs and 3.54 (SE 0.32) for all SNPs. A 25-nmol/l higher biochemically measured 25(OH)D was associated with a 9% (95% CI: 0%–18%) lower risk of diabetes in CKB. In a meta-analysis of all studies, a 25-nmol/l higher genetically instrumented 25(OH)D concentration was associated with a 14% (95% CI: 3%–23%) lower risk of diabetes ( p = 0.01) using the 2 synthesis SNPs. An equivalent difference in 25(OH)D using a genetic score with 4 SNPs was not significantly associated with diabetes (odds ratio 8%, 95% CI: −1% to 16%, lower risk, p = 0.07), but had some evidence of pleiotropy. A limitation of the meta-analysis was the access only to study level rather than individual level data. Conclusions The concordant risks of diabetes for biochemically measured and genetically instrumented differences in 25(OH)D using synthesis SNPs provide evidence for a causal effect of higher 25(OH)D for prevention of diabetes.
    Print ISSN: 1549-1277
    Electronic ISSN: 1549-1676
    Topics: Medicine
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  • 9
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    Public Library of Science (PLoS)
    Publication Date: 2018-05-03
    Description: by Inês Bártolo, Ana Rita Diniz, Pedro Borrego, João Pedro Ferreira, Maria Rosário Bronze, Helena Barroso, Rui Pinto, Carlos Cardoso, João F. Pinto, Rafael Ceña Diaz, Pilar Garcia Broncano, Maria Angel Muñoz-Fernández, Nuno Taveira
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 10
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    Public Library of Science (PLoS)
    Publication Date: 2018-05-03
    Description: by The PLOS ONE Staff
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 11
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    Public Library of Science (PLoS)
    Publication Date: 2018-05-03
    Description: by The PLOS ONE Staff
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 12
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    Public Library of Science (PLoS)
    Publication Date: 2018-05-03
    Description: by Folashade Otegbeye, Evelyn Ojo, Stephen Moreton, Nathan Mackowski, Dean A. Lee, Marcos de Lima, David N. Wald
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 13
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    Public Library of Science (PLoS)
    Publication Date: 2018-05-03
    Description: by Ana Kasradze, Diana Echeverria, Khatuna Zakhashvili, Christian Bautista, Nicholas Heyer, Paata Imnadze, Veriko Mirtskhulava
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 14
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    Public Library of Science (PLoS)
    Publication Date: 2018-05-03
    Description: by Ahmed S. Abdel-Moneim, Mohammad E. Mahfouz, Dalia M. Zytouni
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 15
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    Public Library of Science (PLoS)
    Publication Date: 2018-05-03
    Description: by Naoto Fujita, Saki Aono, Kohei Karasaki, Fumi Sera, Tomoyuki Kurose, Hidemi Fujino, Susumu Urakawa Although exercise is effective in improving obesity and hyperinsulinemia, the exact influence of exercise on the capillary density of skeletal muscles remains unknown. The aim of this study was to investigate the effects of low-intensity exercise training on metabolism in obesity with hyperinsulinemia, focusing specifically on the capillary density within the skeletal muscle. Otsuka Long-Evans Tokushima fatty (OLETF) rats were used as animal models of obesity with hyperinsulinemia, whereas Long-Evans Tokushima Otsuka (LETO) rats served as controls (no obesity, no hyperinsulinemia). The animals were randomly assigned to either non-exercise or exercise groups (treadmill running for 60 min/day, for 4 weeks). The exercise groups were further divided into subgroups according to training mode: single bout (60 min, daily) vs. multiple bout (three bouts of 20 min, daily). Fasting insulin levels were significantly higher in OLETF than in LETO rats. Among OLETF rats, there were no significant differences in fasting glucose levels between the exercise and the non-exercise groups, but the fasting insulin levels were significantly lower in the exercise group. Body weight and triacylglycerol levels in the liver were significantly higher in OLETF than in LETO rats; however, among OLETF rats, these levels were significantly lower in the exercise than in the non-exercise group. The capillary-to-fiber ratio of the soleus muscle was significantly higher in OLETF than in LETO rats; however, among OLETF rats, the ratio was lower in the exercise group than in the non-exercise group. No significant differences in any of the studied parameters were noted between the single-bout and multiple-bout exercise training modes among either OLETF or LETO rats. These results suggest that low-intensity exercise training improves insulin sensitivity and fatty liver. Additionally, the fact that attenuation of excessive capillarization in the skeletal muscle of OLETF rats was accompanied by improvement in increased body weight.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 16
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    Public Library of Science (PLoS)
    Publication Date: 2018-04-04
    Description: by Michael A. Johansson, Nicholas G. Reich, Lauren Ancel Meyers, Marc Lipsitch In an Essay, Michael Johansson and colleagues advocate the posting of research studies addressing infectious disease outbreaks as preprints.
    Print ISSN: 1549-1277
    Electronic ISSN: 1549-1676
    Topics: Medicine
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  • 17
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    Public Library of Science (PLoS)
    Publication Date: 2018-04-04
    Description: by Javier A. Caballero, Mark D. Humphries, Kevin N. Gurney Decision formation recruits many brain regions, but the procedure they jointly execute is unknown. Here we characterize its essential composition, using as a framework a novel recursive Bayesian algorithm that makes decisions based on spike-trains with the statistics of those in sensory cortex (MT). Using it to simulate the random-dot-motion task, we demonstrate it quantitatively replicates the choice behaviour of monkeys, whilst predicting losses of otherwise usable information from MT. Its architecture maps to the recurrent cortico-basal-ganglia-thalamo-cortical loops, whose components are all implicated in decision-making. We show that the dynamics of its mapped computations match those of neural activity in the sensorimotor cortex and striatum during decisions, and forecast those of basal ganglia output and thalamus. This also predicts which aspects of neural dynamics are and are not part of inference. Our single-equation algorithm is probabilistic, distributed, recursive, and parallel. Its success at capturing anatomy, behaviour, and electrophysiology suggests that the mechanism implemented by the brain has these same characteristics.
    Print ISSN: 1553-734X
    Electronic ISSN: 1553-7358
    Topics: Biology , Computer Science
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  • 18
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    Public Library of Science (PLoS)
    Publication Date: 2018-04-04
    Description: by Shisheng Chen, Wenjun Zhang, Stephen Bolus, Matthew N. Rouse, Jorge Dubcovsky Wheat stem rust, caused by Puccinia graminis f. sp. tritici ( Pgt ), is a devastating foliar disease. The Ug99 race group has combined virulence to most stem rust ( Sr ) resistance genes deployed in wheat and is a threat to global wheat production. Here we identified a coiled-coil, nucleotide-binding leucine-rich repeat protein (NLR) completely linked to the Ug99 resistance gene Sr21 from Triticum monococcum . Loss-of-function mutations and transgenic complementation confirmed that this gene is Sr21 . Sr21 transcripts were significantly higher at high temperatures, and this was associated with significant upregulation of pathogenesis related ( PR ) genes and increased levels of resistance at those temperatures. Introgression of Sr21 into hexaploid wheat resulted in lower levels of resistance than in diploid wheat, but transgenic hexaploid wheat lines with high levels of Sr21 expression showed high levels of resistance. Sr21 can be a valuable component of transgenic cassettes or gene pyramids combining multiple resistance genes against Ug99.
    Print ISSN: 1553-7390
    Electronic ISSN: 1553-7404
    Topics: Biology
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  • 19
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    Public Library of Science (PLoS)
    Publication Date: 2018-04-04
    Description: by Tyler C. Moore, Ronald J. Messer, Kim J. Hasenkrug Recent vaccine studies with experimental antigens have shown that regulatory T cells (Tregs) constrain the magnitude of B cell responses. This homeostatic Treg-mediated suppression is thought to reduce the potential of germinal center (GC) responses to generate autoreactive antibodies. However, essentially opposite results were observed in live influenza infections where Tregs promoted B cell and antibody responses. Thus, it remains unclear whether Tregs dampen or enhance B cell responses, especially during live viral infections. Here, we use mice infected with Friend retrovirus (FV), which induces a robust expansion of Tregs. Depletion of Tregs led to elevated activation, proliferation, and class switching of B cells. In addition, Treg depletion enhanced the production of virus-specific and virus-neutralizing antibodies and reduced FV viremia. Thus, in contrast to influenza infection, Tregs either directly or indirectly suppress B cells during mouse retroviral infection indicating that the ultimate effect of Tregs on B cell responses is specific to the particular infectious agent.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 20
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    Publication Date: 2018-04-04
    Description: by Daniel Weiss, Håvard T. Rydland, Emil Øversveen, Magnus Rom Jensen, Solvor Solhaug, Steinar Krokstad The aim of this study was to systematically review the range, nature, and extent of current research activity exploring the influence of innovative health-related technologies on social inequalities in health, with specific focus on a deeper understanding of the variables used to measure this connection and the pathways leading to the (re)production of inequalities. A review process was conducted, based on scoping review techniques, searching literature published from January 1, 1996 to November 25, 2016 using MEDLINE, Scopus, and ISI web of science. Search, sorting, and data extraction processes were conducted by a team of researchers and experts using a dynamic, reflexive examination process. Of 4139 studies collected from the search process, a total of 33 were included in the final analysis. Results of this study include the classification of technologies based on how these technologies are accessed and used by end users. In addition to the factors and mechanisms that influence unequal access to technologies, the results of this study highlight the importance of variations in use that importantly shape social inequalities in health. Additionally, focus on health care services technologies must be accompanied by investigating emerging technologies influencing healthy lifestyle, genomics, and personalized devices in health. Findings also suggest that choosing one measure of social position over another has important implications for the interpretation of research results. Furthermore, understanding the pathways through which various innovative health technologies reduce or (re)produce social inequalities in health is context dependent. In order to better understand social inequalities in health, these contextual variations draw attention to the need for critical distinctions between technologies based on how these various technologies are accessed and used. The results of this study provide a comprehensive starting point for future research to further investigate how innovative technologies may influence the unequal distribution of health as a human right.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 21
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    Publication Date: 2018-04-04
    Description: by Ezio Bonifacio, Andreas Beyerlein, Markus Hippich, Christiane Winkler, Kendra Vehik, Michael N. Weedon, Michael Laimighofer, Andrew T. Hattersley, Jan Krumsiek, Brigitte I. Frohnert, Andrea K. Steck, William A. Hagopian, Jeffrey P. Krischer, Åke Lernmark, Marian J. Rewers, Jin-Xiong She, Jorma Toppari, Beena Akolkar, Richard A. Oram, Stephen S. Rich, Anette-G. Ziegler, for the TEDDY Study Group Background Around 0.3% of newborns will develop autoimmunity to pancreatic beta cells in childhood and subsequently develop type 1 diabetes before adulthood. Primary prevention of type 1 diabetes will require early intervention in genetically at-risk infants. The objective of this study was to determine to what extent genetic scores (two previous genetic scores and a merged genetic score) can improve the prediction of type 1 diabetes. Methods and findings The Environmental Determinants of Diabetes in the Young (TEDDY) study followed genetically at-risk children at 3- to 6-monthly intervals from birth for the development of islet autoantibodies and type 1 diabetes. Infants were enrolled between 1 September 2004 and 28 February 2010 and monitored until 31 May 2016. The risk (positive predictive value) for developing multiple islet autoantibodies (pre-symptomatic type 1 diabetes) and type 1 diabetes was determined in 4,543 children who had no first-degree relatives with type 1 diabetes and either a heterozygous HLA DR3 and DR4-DQ8 risk genotype or a homozygous DR4-DQ8 genotype, and in 3,498 of these children in whom genetic scores were calculated from 41 single nucleotide polymorphisms. In the children with the HLA risk genotypes, risk for developing multiple islet autoantibodies was 5.8% (95% CI 5.0%–6.6%) by age 6 years, and risk for diabetes by age 10 years was 3.7% (95% CI 3.0%–4.4%). Risk for developing multiple islet autoantibodies was 11.0% (95% CI 8.7%–13.3%) in children with a merged genetic score of 〉14.4 (upper quartile; n = 907) compared to 4.1% (95% CI 3.3%–4.9%, P 〈 0.001) in children with a genetic score of ≤14.4 ( n = 2,591). Risk for developing diabetes by age 10 years was 7.6% (95% CI 5.3%–9.9%) in children with a merged score of 〉14.4 compared with 2.7% (95% CI 1.9%–3.6%) in children with a score of ≤14.4 ( P 〈 0.001). Of 173 children with multiple islet autoantibodies by age 6 years and 107 children with diabetes by age 10 years, 82 (sensitivity, 47.4%; 95% CI 40.1%–54.8%) and 52 (sensitivity, 48.6%, 95% CI 39.3%–60.0%), respectively, had a score 〉14.4. Scores were higher in European versus US children ( P = 0.003). In children with a merged score of 〉14.4, risk for multiple islet autoantibodies was similar and consistently 〉10% in Europe and in the US; risk was greater in males than in females ( P = 0.01). Limitations of the study include that the genetic scores were originally developed from case–control studies of clinical diabetes in individuals of mainly European decent. It is, therefore, possible that it may not be suitable to all populations. Conclusions A type 1 diabetes genetic score identified infants without family history of type 1 diabetes who had a greater than 10% risk for pre-symptomatic type 1 diabetes, and a nearly 2-fold higher risk than children identified by high-risk HLA genotypes alone. This finding extends the possibilities for enrolling children into type 1 diabetes primary prevention trials.
    Print ISSN: 1549-1277
    Electronic ISSN: 1549-1676
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  • 22
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    Public Library of Science (PLoS)
    Publication Date: 2018-04-04
    Description: by Inam Yekwayo, James S. Pryke, René Gaigher, Michael J. Samways Fire is a major driver in many ecosystems. Yet, little is known about how different ground-living arthropods survive fire. Using three sampling methods, and time-since-fire (last fire event: 3 months, 1 year, and 7 years), we investigate how ground-living arthropod diversity responds to fire, and how species richness, diversity, abundance, and composition of the four dominant taxa: ants, beetles, cockroaches and mites, respond. We did this in the naturally fire-prone Mediterranean-type scrubland vegetation (fynbos) of the Cape Floristic Region. Surprisingly, overall species richness and diversity was the same for all time-since-fire categories. However, when each dominant taxon was analysed separately, effect of fire on species richness and abundance varied among taxa. This emphasizes that many taxa must be investigated to really understand fire-driven events. We also highlight the importance of using different diversity measures, as fire did not influence species richness and abundance of particular taxa, while it affected others, overall greatly affecting assemblages of all taxa. Rockiness affected species richness, abundance and composition of a few taxa. We found that all time-since-fire categories supported distinctive assemblages. Some indicator species occurred across all time-since-fire categories, while others were restricted to a single time-since-fire category, showing that there is a wide range of responses to fire between taxa. Details of local landscape structure, abiotic and biotic, and frequency and intensity of fire add complexity to the fire-arthropod interaction. Overall, we show that the relationship between fire and arthropods is phylogenetically constrained, having been honed by many millennia of fire events, and highly complex. Present-day species manifest a variety of adaptations for surviving the great natural selective force of fire.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 23
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    Publication Date: 2018-04-04
    Description: by Sylvie Droit-Volet, Sophie Monceau, Mickaël Berthon, Panos Trahanias, Michail Maniadakis In this study, individuals estimated interval times of several minutes (from 2 to 32 minutes) during their everyday lives using a cell phone they kept with them. Their emotional state, the difficulty of the activity performed during this interval, and the attention that it required were also assessed, together with their subjective experience of the passage of time. The results showed that the mean time estimates and their variability increased linearly with increasing interval duration, indicating that the fundamental scalar property of time found for short durations also applies to very long durations of several minutes. In addition, the emotional state and difficulty of the activity were significant predictors of the judgment of long durations. However, the awareness of the passage of time appeared to play a crucial role in the judgment of very long duration in humans. A theory on the emergence of the awareness of the passage of time and how it affects the judgment of interval durations lasting several minutes is therefore discussed.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 24
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    Publication Date: 2018-04-04
    Description: by Charlotte Luchsinger, Marcelo Aguilar, Patricia V. Burgos, Pamela Ehrenfeld, Gonzalo A. Mardones Increasing evidence indicates that the Golgi apparatus plays active roles in cancer, but a comprehensive understanding of its functions in the oncogenic transformation has not yet emerged. At the same time, the Golgi is becoming well recognized as a hub that integrates its functions of protein and lipid biosynthesis to signal transduction for cell proliferation and migration in cancer cells. Nevertheless, the active function of the Golgi apparatus in cancer cells has not been fully evaluated as a target for combined treatment. Here, we analyzed the effect of perturbing the Golgi apparatus on the sensitivity of the MDA-MB-231 breast cancer cell line to the drugs Actinomycin D and Vinblastine. We disrupted the function of ARF1, a protein necessary for the homeostasis of the Golgi apparatus. We found that the expression of the ARF1-Q71L mutant increased the sensitivity of MDA-MB-231 cells to both Actinomycin D and Vinblastine, resulting in decreased cell proliferation and cell migration, as well as in increased apoptosis. Likewise, the combined treatment of cells with Actinomycin D or Vinblastine and Brefeldin A or Golgicide A, two disrupting agents of the ARF1 function, resulted in similar effects on cell proliferation, cell migration and apoptosis. Interestingly, each combined treatment had distinct effects on ERK1/2 and AKT signaling, as indicated by the decreased levels of either phospho-ERK1/2 or phospho-AKT. Our results suggest that disruption of Golgi function could be used as a strategy for the sensitization of cancer cells to chemotherapy.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 25
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    Public Library of Science (PLoS)
    Publication Date: 2018-04-04
    Description: by Fabiana Araújo, Frank van Oosterhout, Vanessa Becker, José Luiz Attayde, Miquel Lürling In tropical and subtropical lakes, eutrophication often leads to nuisance blooms of Cylindrospermopsis raciborskii . In laboratory experiments, we tested the combined effects of flocculant polyaluminum chloride (PAC) and lanthanum-modified bentonite (LMB) on the sinking and growth rates of three C . raciborskii strains. We tested the hypothesis that the combination of PAC and LMB would (1) effectively sink C . raciborskii in a test tube experiment and (2) impair C . raciborskii growth, irrespective of the biomass of the inoculum (bloom) and the strain in the growth experiment. We tested the recommended (LMB1) and a three-times higher dose of LMB (LMB3). The combined addition of PAC and LMB enhanced the sedimentation of all C . raciborskii strains. Moreover, both the PAC and LMB doses decreased the phosphate concentration. PAC and LMB1 decreased the growth rate of all strains, but the efficacy depended on the biomass and strain. The combined addition of PAC and LMB3 inhibited the growth of all strains independently of the biomass and strain. We conclude that a low dose of PAC in combination with the recommended dose of LMB decreases C . raciborskii blooms and that the efficiency of the technique depends on the biomass of the bloom. A higher dose of LMB is needed to obtain a more efficient control of C . raciborskii blooms.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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    Publication Date: 2018-04-04
    Description: by Nichole E. Brinkman, Eric N. Villegas, Jay L. Garland, Scott P. Keely Metagenomics is a powerful tool for characterizing viral composition within environmental samples, but sample and molecular processing steps can bias the estimation of viral community structure. The objective of this study is to understand the inherent variability introduced when conducting viral metagenomic analyses of wastewater and provide a bioinformatic strategy to accurately analyze sequences for viral community analyses. A standard approach using a combination of ultrafiltration, membrane filtration, and DNase treatment, and multiple displacement amplification (MDA) produced DNA preparations without any bacterial derived genes. Results showed recoveries in wastewater matrix ranged between 60–100%. A bias towards small single stranded DNA (ssDNA; polyomavirus) virus types vs larger double stranded DNA (dsDNA; adenovirus) viruses was also observed with a total estimated recovery of small circular viruses to be as much as 173-fold higher. Notably, ssDNA abundance decreased with sample dilution while large dsDNA genomes (e.g., Caudovirales ) initially increased in abundance with dilution before gradually decreasing with further dilution in wastewater samples. The present study revealed the inherent biases associated with different components of viral metagenomic methods applied to wastewater. Overall, these results provide a well-characterized approach for effectively conducting viral metagenomics analysis of wastewater and reveal that dilution can effectively mitigate MDA bias.
    Electronic ISSN: 1932-6203
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  • 27
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    Publication Date: 2018-04-04
    Description: by Yuan Guan, Jiamei He The present study aimed to explore how state self-control influences the intertemporal decisions made by individuals with high and low trait self-control. State self-control, represented by the degree of depletion, was manipulated by conducting Stroop tasks with different levels of difficulty, and the intertemporal decision task was used as a self-control task. Compared with participants with high trait self-control, the preferences of participants with low trait self-control for immediate rewards were more vulnerable to the difficulty of depletion tasks. Throughout the experimental stages, the heart rate variability (HRV) of participants with high trait self-control was significantly higher than that of participants with low trait self-control, indicating that individuals with high trait self-control may have stronger and more stable self-control abilities.
    Electronic ISSN: 1932-6203
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  • 28
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    Publication Date: 2018-04-04
    Description: by Xueying Han, Richard P. Appelbaum In keeping with China’s President Xi Jinping’s “Chinese Dream,” China has set a goal of becoming a world-class innovator by 2050. China’s higher education Science, Technology, Engineering, and Math (STEM) research environment will play a pivotal role in influencing whether China is successful in transitioning from a manufacturing-based economy to an innovation-driven, knowledge-based economy. Past studies on China’s research environment have been primarily qualitative in nature or based on anecdotal evidence. In this study, we surveyed STEM faculty from China’s top 25 universities to get a clearer understanding of how faculty members view China’s overall research environment. We received 731 completed survey responses, 17% of which were from individuals who received terminal degrees from abroad and 83% of which were from individuals who received terminal degrees from domestic institutions of higher education. We present results on why returnees decided to study abroad, returnees’ decisions to return to China, and differences in perceptions between returnees and domestic degree holders on the advantages of having a foreign degree. The top five challenges to China’s research environment identified by survey respondents were: a promotion of short-term thinking and instant success (37% of all respondents); research funding (33%); too much bureaucratic or governmental intervention (31%); the evaluation system (27%); and a reliance on human relations (26%). Results indicated that while China has clearly made strides in its higher education system, there are numerous challenges that must be overcome before China can hope to effectively produce the kinds of innovative thinkers that are required if it is to achieve its ambitious goals. We also raise questions about the current direction of education and inquiry in China, particularly indications that government policy is turning inward, away from openness that is central to innovative thinking.
    Electronic ISSN: 1932-6203
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  • 29
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    Publication Date: 2018-04-04
    Description: by Takehisa Kawata, Shin Tokunaga, Miki Murai, Nami Masuda, Waka Haruyama, Youji Shoukei, Yutaka Hisada, Tetsuya Yanagida, Hiroshi Miyazaki, Michihito Wada, Tadao Akizawa, Masafumi Fukagawa Cinacalcet hydrochloride (cinacalcet), an oral calcimimetic agent has been widely used for the management of secondary hyperparathyroidism (SHPT) in chronic kidney disease (CKD). In sharp contrast to vitamin D receptor activators, cinacalcet suppresses SHPT without inducing hypercalcemia or hyperphosphatemia. Nevertheless, some patients remain refractory to SHPT with this agent, as the dose cannot be sufficiently increased due to gastrointestinal symptoms. In order to resolve this issue, we have developed a newly synthesized calcimimetic agent, evocalcet (MT-4580/KHK7580). In a rat model of CKD induced by 5/6 nephrectomy, oral administration of evocalcet efficiently suppressed the secretion of parathyroid hormone (PTH). With regard to the gastro-intestinal effects, cinacalcet induced a significant delay in gastric emptying in rats, while evocalcet did no marked effects on it. Evocalcet also demonstrated the less induction of emesis compared to cinacalcet in common marmosets. The pharmacological effects of evocalcet were observed at lower doses because of its higher bioavailability than cinacalcet, which may have contributed to the reduced GI tract symptoms. In addition, evocalcet showed no substantial direct inhibition of any CYP isozymes in in vitro liver microsome assay, suggesting a better profile in drug interactions than cinacalcet that inhibits cytochrome P450 (CYP) 2D6. These findings suggest that evocalcet can be a better alternative to cinacalcet, an oral calcimimetic agent, with a wider safety margin.
    Electronic ISSN: 1932-6203
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    Publication Date: 2018-04-04
    Description: by Kaja Zupanc, Erik Štrumbelj We propose a novel approach to modelling rater effects in scoring-based assessment. The approach is based on a Bayesian hierarchical model and simulations from the posterior distribution. We apply it to large-scale essay assessment data over a period of 5 years. Empirical results suggest that the model provides a good fit for both the total scores and when applied to individual rubrics. We estimate the median impact of rater effects on the final grade to be ± 2 points on a 50 point scale, while 10% of essays would receive a score at least ± 5 different from their actual quality. Most of the impact is due to rater unreliability, not rater bias.
    Electronic ISSN: 1932-6203
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    Publication Date: 2018-04-04
    Description: by Maria Paola Bertone, Jean-Benoît Falisse, Giuliano Russo, Sophie Witter Performance-based financing (PBF) schemes have been expanding rapidly across low and middle income countries in the past decade, with considerable external financing from multilateral, bilateral and global health initiatives. Many of these countries have been fragile and conflict-affected (FCAS), but while the influence of context is acknowledged to be important to the operation of PBF, there has been little examination of how it affects adoption and implementation of PBF. This article lays out initial hypotheses about how FCAS contexts may influence the adoption, adaption, implementation and health system effects of PBF. These are then interrogated through a review of available grey and published literature (140 documents in total, covering 23 PBF schemes). We find that PBF has been more common in FCAS contexts, which were also more commonly early adopters. Very little explanation of the rationale for its adoption, in particular in relation with the contextual features, is given in programme documents. However, there are a number of factors which could explain this, including the greater role of external actors and donors, a greater openness to institutional reform, and lower levels of trust within the public system and between government and donors, all of which favour more contractual approaches. These suggest that rather than emerging despite fragility, conditions of fragility may favour the rapid emergence of PBF. We also document few emerging adaptations of PBF to humanitarian settings and limited evidence of health system effects which may be contextually driven, but these require more in-depth analysis. Another area meriting more study is the political economy of PBF and its diffusion across contexts.
    Electronic ISSN: 1932-6203
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    Publication Date: 2018-04-04
    Description: by Andréia Gonçalves Arruda, Carles Vilalta, Pere Puig, Andres Perez, Anna Alba Industry-driven voluntary disease control programs for swine diseases emerged in North America in the early 2000’s, and, since then, those programs have been used for monitoring diseases of economic importance to swine producers. One example of such initiatives is Dr. Morrison’s Swine Health Monitoring Project, a nation-wide monitoring program for swine diseases including the porcine reproductive and respiratory syndrome (PRRS). PRRS has been extensively reported as a seasonal disease in the U.S., with predictable peaks that start in fall and are extended through the winter season. However, formal time series analysis stratified by geographic region has never been conducted for this important disease across the U.S. The main objective of this study was to use approximately seven years of PRRS incidence data in breeding swine herds to conduct time-series analysis in order to describe the temporal patterns of PRRS outbreaks at the farm level for five major swine-producing states across the U.S. including the states of Minnesota, Iowa, North Carolina, Nebraska and Illinois. Data was aggregated retrospectively at the week level for the number of herds containing animals actively shedding PRRS virus. Basic descriptive statistics were conducted followed by autoregressive integrated moving average (ARIMA) modelling, conducted separately for each of the above-mentioned states. Results showed that there was a difference in the nature of PRRS seasonality among states. Of note, when comparing states, the typical seasonal pattern previously described for PRRS could only be detected for farms located in the states of Minnesota, North Carolina and Nebraska. For the other two states, seasonal peaks every six months were detected within a year. In conclusion, we showed that epidemic patterns are not homogeneous across the U.S, with major peaks of disease occurring through the year. These findings highlight the importance of coordinating alternative control strategies in different regions considering the prevailing epidemiological patterns.
    Electronic ISSN: 1932-6203
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  • 33
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    Publication Date: 2018-04-04
    Description: by Daniel Lüdecke, Barbara Bien, Kevin McKee, Barbro Krevers, Elizabeth Mestheneos, Mirko Di Rosa, Olaf von dem Knesebeck, Christopher Kofahl Objectives Demographic change has led to an increase of older people in need of long-term care in nearly all European countries. Informal carers primarily provide the care and support needed by dependent people. The supply and willingness of individuals to act as carers are critical to sustain informal care resources as part of the home health care provision. This paper describes a longitudinal study of informal care in six European countries and reports analyses that determine those factors predicting the outcomes of family care over a one-year period. Methods Analyses are based on data from the EUROFAMCARE project, a longitudinal survey study of family carers of older people with baseline data collection in 2004 and follow-up data collection a year later in six European countries (Germany, Greece, Italy, Poland, Sweden, and the United Kingdom), N = 3,348. Descriptive statistics of the sample characteristics are reported. Binary logistic random-intercept regressions were computed, predicting the outcome of change of the care dyad’s status at follow-up. Results Where care is provided by a more distant family member or by a friend or neighbour, the care-recipient is significantly more likely to be cared for by someone else (OR 1.62) or to be in residential care (OR 3.37) after one year. The same holds true if the care-recipient has memory problems with a dementia diagnosis (OR 1.79/OR 1.84). Higher dependency (OR 1.22) and behavioural problems (OR 1.76) in the care-recipient also lead to a change of care dyad status. Country of residence explained a relatively small amount of variance (8%) in whether a care-recipient was cared for by someone else after one year, but explained a substantial amount of variance (52%) in whether a care-recipient was in residential care. Particularly in Sweden, care-recipients are much more likely to be cared for by another family or professional carer or to be in residential care, whereas in Greece the status of the care dyad is much less likely to change. Discussion The majority of family carers continued to provide care to their respective older relatives over a one-year period, despite often high levels of functional, cognitive and behavioural problems in the care-recipient. Those family carers could benefit most from appropriate support. The carer/care-recipient relationship plays an important role in whether or not a family care dyad remains intact over a one-year period. The support of health and social care services should be particularly targeted toward those care dyads where there is no partner or spouse acting as carer, or no extended family network that might absorb the caring role when required. Distant relatives, friends or acquaintances who are acting as carers might need substantial intervention if their caregiving role is to be maintained.
    Electronic ISSN: 1932-6203
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    Publication Date: 2018-04-04
    Description: by Jong Seo Yoon, Cheol Hwan So, Hae Sang Lee, Jung Sub Lim, Jin Soon Hwang Brain magnetic resonance imaging (MRI) is routinely performed to identify brain lesions in boys with central precocious puberty (CPP). We investigated the prevalence of CPP in Korean boys and the necessity for routine brain MRI examinations. This retrospective cross-sectional study was conducted from April 2003 to December 2016 at a Korean university hospital. Among 151 boys who were diagnosed with CPP, the data of 138 boys who underwent sellar MRI were evaluated. The mean age of the study subjects was 9.51 ± 0.56 years (
    Electronic ISSN: 1932-6203
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    Publication Date: 2018-04-04
    Description: by Farah Rahman, Jun Guan, Richard H. Glazier, Adalsteinn Brown, Arlene S. Bierman, Ruth Croxford, Therese A. Stukel One of the more fundamental health policy questions is the relationship between health care quality and spending. A better understanding of these relationships is needed to inform health systems interventions aimed at increasing quality and efficiency of care. We measured 65 validated quality indicators (QI) across Ontario physician networks. QIs were aggregated into domains representing six dimensions of care: screening and prevention, evidence-based medications, hospital-community transitions (7-day post-discharge visit with a primary care physician; 30-day post-discharge visit with a primary care physician and specialist), potentially avoidable hospitalizations and emergency department (ED) visits, potentially avoidable readmissions and unplanned returns to the ED, and poor cancer end of life care. Each domain rate was computed as a weighted average of QI rates, weighting by network population at risk. We also measured overall and sector-specific per capita healthcare network spending. We evaluated the associations between domain rates, and between domain rates and spending using weighted correlations, weighting by network population at risk, using an ecological design. All indicators were measured using Ontario health administrative databases. Large variations were seen in timely hospital-community transitions and potentially avoidable hospitalizations. Networks with timely hospital-community transitions had lower rates of avoidable admissions and readmissions (r = -0.89, -0.58, respectively). Higher physician spending, especially outpatient primary care spending, was associated with lower rates of avoidable hospitalizations (r = -0.83) and higher rates of timely hospital-community transitions (r = 0.81) and moderately associated with lower readmission rates (r = -0.46). Investment in effective primary care services may help reduce burden on the acute care sector and associated expenditures.
    Electronic ISSN: 1932-6203
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    Publication Date: 2018-05-04
    Description: by Aiko Yoshida, Nobuaki Sakai, Yoshitsugu Uekusa, Yuka Imaoka, Yoshitsuna Itagaki, Yuki Suzuki, Shige H. Yoshimura Clathrin-mediated endocytosis (CME) proceeds through a series of morphological changes of the plasma membrane induced by a number of protein components. Although the spatiotemporal assembly of these proteins has been elucidated by fluorescence-based techniques, the protein-induced morphological changes of the plasma membrane have not been fully clarified in living cells. Here, we visualize membrane morphology together with protein localizations during CME by utilizing high-speed atomic force microscopy (HS-AFM) combined with a confocal laser scanning unit. The plasma membrane starts to invaginate approximately 30 s after clathrin starts to assemble, and the aperture diameter increases as clathrin accumulates. Actin rapidly accumulates around the pit and induces a small membrane swelling, which, within 30 s, rapidly covers the pit irreversibly. Inhibition of actin turnover abolishes the swelling and induces a reversible open–close motion of the pit, indicating that actin dynamics are necessary for efficient and irreversible pit closure at the end of CME.
    Print ISSN: 1544-9173
    Electronic ISSN: 1545-7885
    Topics: Biology
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    Publication Date: 2018-05-04
    Description: by Melissa L. Harris, Temesgen D. Fufa, Joseph W. Palmer, Sandeep S. Joshi, Denise M. Larson, Arturo Incao, Derek E. Gildea, Niraj S. Trivedi, Autumne N. Lee, Chi-Ping Day, Helen T. Michael, Thomas J. Hornyak, Glenn Merlino, NISC Comparative Sequencing Program , William J. Pavan Melanocyte stem cells (McSCs) and mouse models of hair graying serve as useful systems to uncover mechanisms involved in stem cell self-renewal and the maintenance of regenerating tissues. Interested in assessing genetic variants that influence McSC maintenance, we found previously that heterozygosity for the melanogenesis associated transcription factor, Mitf , exacerbates McSC differentiation and hair graying in mice that are predisposed for this phenotype. Based on transcriptome and molecular analyses of Mitf mi-vga9/+ mice, we report a novel role for MITF in the regulation of systemic innate immune gene expression. We also demonstrate that the viral mimic poly(I:C) is sufficient to expose genetic susceptibility to hair graying. These observations point to a critical suppressor of innate immunity, the consequences of innate immune dysregulation on pigmentation, both of which may have implications in the autoimmune, depigmenting disease, vitiligo.
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    Publication Date: 2018-05-04
    Description: by Jianbin Su, Liuyi Yang, Qiankun Zhu, Hongjiao Wu, Yi He, Yidong Liu, Juan Xu, Dean Jiang, Shuqun Zhang Extensive research revealed tremendous details about how plants sense pathogen effectors during effector-triggered immunity (ETI). However, less is known about downstream signaling events. In this report, we demonstrate that prolonged activation of MPK3 and MPK6, two Arabidopsis pathogen-responsive mitogen-activated protein kinases (MPKs), is essential to ETI mediated by both coiled coil-nucleotide binding site-leucine rich repeats (CNLs) and toll/interleukin-1 receptor nucleotide binding site-leucine rich repeats (TNLs) types of R proteins. MPK3/MK6 activation rapidly alters the expression of photosynthesis-related genes and inhibits photosynthesis, which promotes the accumulation of superoxide and hydrogen peroxide (H 2 O 2 ), two major reactive oxygen species (ROS), in chloroplasts under light. In the chemical-genetically rescued mpk3 mpk6 double mutants, ETI-induced photosynthetic inhibition and chloroplastic ROS accumulation are compromised, which correlates with delayed hypersensitive response (HR) cell death and compromised resistance. Furthermore, protection of chloroplasts by expressing a plastid-targeted cyanobacterial flavodoxin (pFLD) delays photosynthetic inhibition and compromises ETI. Collectively, this study highlights a critical role of MPK3/MPK6 in manipulating plant photosynthetic activities to promote ROS accumulation in chloroplasts and HR cell death, which contributes to the robustness of ETI. Furthermore, the dual functionality of MPK3/MPK6 cascade in promoting defense and inhibiting photosynthesis potentially allow it to orchestrate the trade-off between plant growth and defense in plant immunity.
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    Publication Date: 2018-05-04
    Description: by Aaron T. L. Lun, Hervé Pagès, Mike L. Smith Biological experiments involving genomics or other high-throughput assays typically yield a data matrix that can be explored and analyzed using the R programming language with packages from the Bioconductor project. Improvements in the throughput of these assays have resulted in an explosion of data even from routine experiments, which poses a challenge to the existing computational infrastructure for statistical data analysis. For example, single-cell RNA sequencing (scRNA-seq) experiments frequently generate large matrices containing expression values for each gene in each cell, requiring sparse or file-backed representations for memory-efficient manipulation in R. These alternative representations are not easily compatible with high-performance C++ code used for computationally intensive tasks in existing R/Bioconductor packages. Here, we describe a C++ interface named beachmat , which enables agnostic data access from various matrix representations. This allows package developers to write efficient C++ code that is interoperable with dense, sparse and file-backed matrices, amongst others. We evaluated the performance of beachmat for accessing data from each matrix representation using both simulated and real scRNA-seq data, and defined a clear memory/speed trade-off to motivate the choice of an appropriate representation. We also demonstrate how beachmat can be incorporated into the code of other packages to drive analyses of a very large scRNA-seq data set.
    Print ISSN: 1553-734X
    Electronic ISSN: 1553-7358
    Topics: Biology , Computer Science
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    Publication Date: 2018-05-04
    Description: by Xunwei Wu, Alice Tommasi di Vignano, Qian Zhou, Piotr J. Michel-Dziunycz, Fuxiang Bai, Jun Mi, Jing Qin, Tingjian Zu, Günther F. L. Hofbauer An increased incidence of skin inflammatory diseases is frequently observed in organtransplanted patients being treated with calcineurin inhibitor-based immunosuppressive agents. The mechanism of increased skin inflammation in this context has however not yet been clarified. Here we report an increased inflammation following inhibition of calcineurin signaling seen in both chemically induced mouse skin tumors and in tumors grafted from H-ras V12 expressing primary human keratinocytes (HKCs). Following UVB or TPA treatment, we specifically found that deletion of the calcineurin gene in mouse keratinocytes (MKCs) resulted in increased inflammation, and this was accompanied by the enhanced production of pro-inflammatory cytokines, such as TNFα, IL-8 and CXCL1. Furthermore, expression of the RNA-binding protein, tristetraprolin (TTP) was down-regulated in response to calcineurin inhibition, wherein TTP was shown to negatively regulate the production of pro-inflammatory cytokines in keratinocytes. The induction of TTP following TPA or UVB treatment was attenuated by calcineurin inhibition in keratinocytes, and correspondingly, disruption of calcineurin signaling down-regulated the amounts of TTP in both clinical and H-ras V12 -transformed keratinocyte tumor models. Our results further demonstrated that calcineurin positively controls the stabilization of TTP in keratinocytes through a proteasome-dependent mechanism. Reducing the expression of TTP functionally promoted tumor growth of H-ras V12 expressing HKCs, while stabilizing TTP expression counteracted the tumor-promoting effects of calcineurin inhibition. Collectively these results suggest that calcineurin signaling, acting through TTP protein level stabilization, suppresses keratinocyte tumors by downregulating skin inflammation.
    Print ISSN: 1553-7390
    Electronic ISSN: 1553-7404
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  • 41
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    Publication Date: 2018-05-04
    Description: by Sebastian Kittelmann, Alexandra D. Buffry, Franziska A. Franke, Isabel Almudi, Marianne Yoth, Gonzalo Sabaris, Juan Pablo Couso, Maria D. S. Nunes, Nicolás Frankel, José Luis Gómez-Skarmeta, Jose Pueyo-Marques, Saad Arif, Alistair P. McGregor Convergent phenotypic evolution is often caused by recurrent changes at particular nodes in the underlying gene regulatory networks (GRNs). The genes at such evolutionary ‘hotspots’ are thought to maximally affect the phenotype with minimal pleiotropic consequences. This has led to the suggestion that if a GRN is understood in sufficient detail, the path of evolution may be predictable. The repeated evolutionary loss of larval trichomes among Drosophila species is caused by the loss of shavenbaby ( svb ) expression. svb is also required for development of leg trichomes, but the evolutionary gain of trichomes in the ‘naked valley’ on T2 femurs in Drosophila melanogaster is caused by reduced microRNA-92a ( miR-92a ) expression rather than changes in svb . We compared the expression and function of components between the larval and leg trichome GRNs to investigate why the genetic basis of trichome pattern evolution differs in these developmental contexts. We found key differences between the two networks in both the genes employed, and in the regulation and function of common genes. These differences in the GRNs reveal why mutations in svb are unlikely to contribute to leg trichome evolution and how instead miR-92a represents the key evolutionary switch in this context. Our work shows that variability in GRNs across different developmental contexts, as well as whether a morphological feature is lost versus gained, influence the nodes at which a GRN evolves to cause morphological change. Therefore, our findings have important implications for understanding the pathways and predictability of evolution.
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  • 42
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    Publication Date: 2018-04-04
    Description: by Wei Wang, Florian Duclot, Bradley R. Groveman, Nicole Carrier, Haifa Qiao, Xiao-Qian Fang, Hui Wang, Wenkuan Xin, Xing-Hong Jiang, Michael W. Salter, Xin-Sheng Ding, Mohamed Kabbaj, Xian-Min Yu Background Understanding molecular mechanisms underlying the induction of learning and memory impairments remains a challenge. Recent investigations have shown that the activation of group I mGluRs (mGluR1 and mGluR5) in cultured hippocampal neurons by application of ( S )-3,5-Dihydroxyphenylglycine (DHPG) causes the regulated internalization of N-methyl-D-aspartate receptors (NMDARs), which subsequently activates protein kinase D1 (PKD1). Through phosphorylating the C-terminals of the NMDAR GluN2 subunits, PKD1 down-regulates the activity of remaining (non-internalized) surface NMDARs. The knockdown of PKD1 does not affect the DHPG-induced inhibition of AMPA receptor-mediated miniature excitatory post-synaptic currents (mEPSCs) but prevents the DHPG-induced inhibition of NMDAR-mediated mEPSCs in vitro . Thus, we investigated the in vivo effects of bilateral infusions of DHPG into the hippocampal CA1 area of rats in the Morris water maze (MWM) and the novel object discrimination (NOD) tests. Methods A total of 300 adult male Sprague Dawley rats (250–280 g) were used for behavioral tests. One hundred ninety four were used in MWM test and the other 106 rats in the NOD test. Following one week of habituation to the vivarium, rats were bilaterally implanted under deep anesthesia with cannulas aimed at the CA1 area of the hippocampus (CA1 coordinates in mm from Bregma: AP -3.14; lateral +/-2; DV -3.0). Through implanted cannulas artificial cerebrospinal fluid (ACSF), the group1 mGluR antagonist 6-Methyl-2-(phenylethynyl)pyridine (MPEP), the dynamin-dependent internalization inhibitor Dynasore, or the PKD1 inhibitor CID755673 were infused into the bilateral hippocampal CA1 areas (2 μL per side, over 5 min). The effects of these infusions and the effects of PKD1 knockdown were examined in MWM or NOD test. Results DHPG infusion increased the latency to reach the platform in the MWM test and reduced the preference for the novel object in the NOD task. We found that the DHPG effects were dose-dependent and could be maintained for up to 2 days. Notably, these effects could be prevented by pre-infusion of the group1 mGluR antagonist MPEP, the dynamin-dependent internalization inhibitor Dynasore, the PKD1 inhibitor CID755673, or by PKD1 knockdown in the hippocampal CA1 area. Conclusion Altogether, these findings provide direct evidence that PKD1-mediated signaling may play a critical role in the induction of learning and memory impairments by DHPG infusion into the hippocampal CA1 area.
    Electronic ISSN: 1932-6203
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    Publication Date: 2018-05-04
    Description: by Zaida Herrador, Belén Garcia, Policarpo Ncogo, Maria Jesus Perteguer, Jose Miguel Rubio, Eva Rivas, Marta Cimas, Guillermo Ordoñez, Silvia de Pablos, Ana Hernández-González, Rufino Nguema, Laura Moya, María Romay-Barja, Teresa Garate, Kira Barbre, Agustín Benito Background Onchocerciasis, also known as river blindness, is a parasitic disease. More than 99 percent of all cases occur in Africa. Bioko Island (Equatorial Guinea) is the only island endemic for onchocerciasis in the world. Since 2005, when vector Simulium yahense was eliminated, there have not been any reported cases of infection. This study aimed to demonstrate that updated WHO criteria for stopping mass drug administration (MDA) have been met. Methodology/Principal findings A cross-sectional study was conducted from September 2016 to January 2017. Participants were 5- to 9-year-old school children. Onchocerciasis/lymphatic Filariasis (LF, only in endemic districts) rapid diagnostic tests (RDTs) were performed. Blood spots were collected from RDT positive children and 10 percent of the RDT negatives to determine Ov16 and Wb123 IgG4 antibodies through enzyme-linked immunosorbent assay (ELISA). Skin snips were collected from RDT positives. Filarial detection was performed by PCR in positives and indeterminate sera. Black fly collection was carried out in traditional breeding sites. A total of 7,052 children, ranging from 5 to 9 years of age, were included in the study. Four children (0.06%) were Ov16 IgG4 RDT positives, but negative by ELISA Ov16, while 6 RDT negative children tested positive by ELISA. A total of 1,230 children from the Riaba and Baney districts were tested for LF. One child was Wb123 RDT positive (0.08%), but ELISA negative, while 3 RDT negative children were positive by Wb123 ELISA. All positive samples were negative by PCR for onchocerciasis and LF (in blood spot and skin snip). All fly collections and larval prospections in the traditional catching and prospection sites were negative. Conclusions/Significance WHO criteria have been met, therefore MDA in Bioko Island can be stopped. Three years of post-treatment surveillance should be implemented to identify any new occurrences of exposure or infection.
    Print ISSN: 1935-2727
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    Publication Date: 2018-05-04
    Description: by Liviu Badea, Mihaela Onu, Tao Wu, Adina Roceanu, Ovidiu Bajenaru
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 45
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    Publication Date: 2018-05-04
    Description: by The PLOS ONE Editors
    Electronic ISSN: 1932-6203
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  • 46
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    Publication Date: 2018-05-04
    Description: by Doris Haas, Herbert Galler, Carola Fritz, Christina Hasler, Juliana Habib, Franz F. Reinthaler
    Electronic ISSN: 1932-6203
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  • 47
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    Publication Date: 2018-05-04
    Description: by Adugna Abdi Woldesemayat, David M. Modise, Junaid Gamieldien, Bongani K. Ndimba, Alan Christoffels
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  • 48
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    Publication Date: 2018-05-04
    Description: by Ami B. Shah, Isaac Nivar, Diana L. Speelman Background Elevated testosterone (T) is routinely reported as a marker of hyperandrogenemia in rodent models for polycystic ovary syndrome (PCOS). In women with PCOS, elevated serum androstenedione (A4) is associated with more severe phenotypes, including a positive correlation with serum T, DHEAS, free androgen index (FAI), LH, and LH/FSH ratio. Furthermore, A4, along with calculated free T and FAI, was identified as one of the best predictors of PCOS in adult women of all ages (18 to 〉 50 y). Objective The objective of this study was to investigate serum A4 levels in early adolescent and young adult prenatally androgenized (PNA) female rats, a model for PCOS. Methods Pregnant rats were injected with 5 mg T daily during gestational days 16–19 (PNA rats, experimental group) or an equal volume of vehicle (control group). Female offspring of both groups had tail vein blood drawn for serum analysis at 8 and 16 weeks of age. ELISAs were used to quantify serum A4 and T levels. Results Serum A4 and T were elevated in 16-week-old PNA rats compared to controls. There was no significant difference in either hormone at 8 weeks of age. Conclusions The PNA rats demonstrated elevated serum A4 and T in young adulthood, as has been observed in women with PCOS, further validating this as a model for PCOS and underscoring the importance of serum A4 elevation as a parameter inherent to PCOS and a rodent model for the disorder. Significant A4 elevation develops between early adolescence and early adulthood in this PNA rat model.
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  • 49
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    Publication Date: 2018-05-04
    Description: by Katherine Bradbury, Katherine Morton, Rebecca Band, Anne van Woezik, Rebecca Grist, Richard J. McManus, Paul Little, Lucy Yardley Background For behaviour-change interventions to be successful they must be acceptable to users and overcome barriers to behaviour change. The Person-Based Approach can help to optimise interventions to maximise acceptability and engagement. This article presents a novel, efficient and systematic method that can be used as part of the Person-Based Approach to rapidly analyse data from development studies to inform intervention modifications. We describe how we used this approach to optimise a digital intervention for patients with hypertension (HOME BP), which aims to implement medication and lifestyle changes to optimise blood pressure control. Methods In study 1, hypertensive patients (N = 12) each participated in three think-aloud interviews, providing feedback on a prototype of HOME BP. In study 2 patients (N = 11) used HOME BP for three weeks and were then interviewed about their experiences. Studies 1 and 2 were used to identify detailed changes to the intervention content and potential barriers to engagement with HOME BP. In study 3 (N = 7) we interviewed hypertensive patients who were not interested in using an intervention like HOME BP to identify potential barriers to uptake, which informed modifications to our recruitment materials. Analysis in all three studies involved detailed tabulation of patient data and comparison to our modification criteria. Results Studies 1 and 2 indicated that the HOME BP procedures were generally viewed as acceptable and feasible, but also highlighted concerns about monitoring blood pressure correctly at home and making medication changes remotely. Patients in study 3 had additional concerns about the safety and security of the intervention. Modifications improved the acceptability of the intervention and recruitment materials. Conclusions This paper provides a detailed illustration of how to use the Person-Based Approach to refine a digital intervention for hypertension. The novel, efficient approach to analysis and criteria for deciding when to implement intervention modifications described here may be useful to others developing interventions.
    Electronic ISSN: 1932-6203
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    Publication Date: 2018-05-04
    Description: by Andrea Corsello, Luigi Di Filippo, Sara Massironi, Federica Sileo, Anna Dolcetta Capuzzo, Marco Gemma, Claudia Carlucci, Claudio Cusini, Barbara Colombo, Alice Dallatomasina, Giulia Maria Franchi, Angelo Corti, Marco Federico Manzoni Background Chromogranin A (CgA) is a plasma biomarker widely used in the follow-up of patients with neuroendocrine neoplasms (NENs). However, its accuracy as a tumor biomarker is relatively low because plasma CgA can increase also in patients with other diseases or in subjects treated with proton-pump inhibitors (PPIs), a class of widely-used drugs. Methods In the attempt to identify a more reliable biomarker for NENs, we investigated, by ELISA, the circulating levels of full-length CgA (CgA 1-439 ) and of various CgA-derived fragments in 17 patients with ileal or pancreatic NENs, 10 healthy controls, and 21 healthy volunteers before and after treatment with PPIs. Results Patients with ileal or pancreatic NENs showed increased plasma levels of total-CgA and CgA 1-76 fragment (vasostatin-1, VS-1) compared to controls [median (25 th -75 th -percentiles); total-CgA: 1.85 nM (1.01–4.28) vs 0.75 nM (0.52–0.89), p = 0.004; VS-1: 2.76 nM (1.09–7.10) vs 0.29 nM (0.26–0.32), p
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    Publication Date: 2018-05-04
    Description: by Andrea Pereira, Jan-Willem van Prooijen Because punishments are expected to give offenders what they deserve proportionally to the severity of their offenses, the punishment of an entire group because of the misdeed of a few of its members is generally considered as unfair. Group entitativity might increase support for such collective punishment, because members of highly entitative groups are perceived as more similar and interchangeable. We designed three experiments comparing support for third-party collective punishment of low versus high entitative groups. As comparison base-rate, we included conditions in which participants punish an individual wrongdoer (Experiments 1 & 2). Results show that although support for individual punishment is higher than support for collective punishment, this difference was reduced (Experiment 1) or absent (Experiment 2) when the group was highly entitative. Experiment 3 replicated the increasing effect of group entitativity on support for collective punishment. We conclude that group entitativity increases the likelihood of an entire group being treated as a single unit, facilitating collective punishment when a few group members commit an offense.
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    Publication Date: 2018-05-04
    Description: by Nicole Filion, Andrew Fenelon, Michel Boudreaux Purpose To examine the reported mental health outcomes of adolescent foreign-born non-citizens and adolescent foreign-born U.S. citizens compared to adolescent U.S.-born citizens. Methods Using the Strengths and Difficulties Questionnaire in the National Health Interview Survey, we compared mental health status of U.S.-born adolescent citizens to foreign-born citizens and non-citizens in the years 2010–2015, and examined how differences in emotional difficulty changed based on time spent in the U.S. Results Results suggest that non-citizen adolescents experience better mental health outcomes than U.S.-born citizens. However, the mental health status of foreign-born citizens is indistinguishable from that of the U.S.-born, after accounting for basic socio-demographic characteristics. The prevalence of emotional difficulty experienced by immigrant adolescents increased with a family’s duration in the U.S. Conclusion Our findings are consistent with a broader health advantage for the foreign-born, but we present new evidence that the mental health advantage of foreign-born adolescents exists only for non-citizens.
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  • 53
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    Publication Date: 2018-05-04
    Description: by Hongyi Zhou, Mu Gao, Jeffrey Skolnick To exploit the plethora of information provided by Next Generation Sequencing, the identification of the genetic mutations responsible for disease in general or cancer in particular, among the thousands of neutral germline or somatic variations is a crucial task. Genome-wide association studies for the detection of disease-associated genes or cancer drivers can only identify common variations or driver genes in a cohort of patients. Thus, they cannot discover unique disease-associated mutations or cancer driver genes on a personal basis. Moreover, even when there are such common variations, their significance is unknown. Here, we extend the machine learning based approach ENTPRISE developed for predicting the disease association of missense mutations to frameshift and nonsense mutations. The new approach, ENTPRISE-X, is shown to outperform the state-of-the-art methods VEST-indel and DDIG-in for predicting the disease association of germline frameshift mutations in terms of balanced measure Matthew’s correlation coefficient, MCC, with a MCC of 0.586 for ENTPRISE-X, versus 0.412 by VEST-indel and 0.321 by DDIG-in, respectively. Large scale testing on the ExAC dataset shows ENTPRISE-X has a much lower fraction of 16% of variations classified as disease causing, as compared to VEST-indel’s 26% and DDIG-in’s 65% of predictions as being disease-associated. A web server for ENTPRISE-X is freely available for academic users at http://cssb2.biology.gatech.edu/entprise-x.
    Electronic ISSN: 1932-6203
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  • 54
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    Publication Date: 2018-05-04
    Description: by Naomi Mochizuki, Tsuyoshi Fujita, Masao Kobayashi, Yukinao Yamazaki, Shuichi Terao, Tsuyoshi Sanuki, Akihiko Okada, Masayasu Adachi, Manabu Murakami, Yoshifumi Arisaka, Koji Uno, Atsuhiro Masuda, Masaru Yoshida, Eiji Umegaki, Hiromu Kutsumi, Takeshi Azuma Background We aimed to clarify the factors associated with the presentation of erosive esophagitis (EE) symptoms in subjects undergoing health checkups. Methods We utilized baseline data from 7,552 subjects who underwent upper endoscopy for health screening in a prospective, multicenter cohort study. The subjects were asked to complete a questionnaire detailing their upper abdominal symptoms and lifestyle. Based on the heartburn and/or acid regurgitation frequency, the EE subjects were stratified into the following three groups: (1) at least one day a week (symptomatic EE [sEE]), (2) less than one day a week (mild symptomatic EE [msEE]), and (3) never (asymptomatic EE [aEE]). Postprandial distress syndrome (PDS) and epigastric pain syndrome (EPS) were defined according to the Rome III criteria. Results Of the 1,262 (16.7%) subjects (male 83.8%, mean age 52.6 years) with EE, the proportions of sEE, msEE and aEE were 15.0%, 37.2% and 47.9%, respectively. The sEE group showed significant associations with overlapping EPS (OR: 58.4, 95% CI: 25.2–160.0), overlapping PDS (OR: 9.96, 95% CI: 3.91–26.8), severe hiatal hernia (OR: 2.43, 95% CI: 1.43–4.05), experiencing high levels of stress (OR: 2.20, 95% CI: 1.43–3.40), atrophic gastritis (OR: 1.57, 95% CI: 1.03–2.36) and Los Angeles (LA) grade B or worse (OR: 1.72, 95% CI: 1.12–2.60) in the multivariate analysis. Conclusions Approximately one-sixth of EE subjects were symptomatic. A multifactorial etiology, including factors unrelated to gastric acid secretion, was associated with the symptom presentation of EE subjects.
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    Publication Date: 2018-05-04
    Description: by Junji Chida, Hideyuki Hara, Masashi Yano, Keiji Uchiyama, Nandita Rani Das, Etsuhisa Takahashi, Hironori Miyata, Yukiko Tomioka, Toshihiro Ito, Hiroshi Kido, Suehiro Sakaguchi The cellular prion protein, designated PrP C , is a membrane glycoprotein expressed abundantly in brains and to a lesser extent in other tissues. Conformational conversion of PrP C into the amyloidogenic isoform is a key pathogenic event in prion diseases. However, the physiological functions of PrP C remain largely unknown, particularly in non-neuronal tissues. Here, we show that PrP C is expressed in lung epithelial cells, including alveolar type 1 and 2 cells and bronchiolar Clara cells. Compared with wild-type (WT) mice, PrP C -null mice ( Prnp 0/0 ) were highly susceptible to influenza A viruses (IAVs), with higher mortality. Infected Prnp 0/0 lungs were severely injured, with higher inflammation and higher apoptosis of epithelial cells, and contained higher reactive oxygen species (ROS) than control WT lungs. Treatment with a ROS scavenger or an inhibitor of xanthine oxidase (XO), a major ROS-generating enzyme in IAV-infected lungs, rescued Prnp 0/0 mice from the lethal infection with IAV. Moreover, Prnp 0/0 mice transgenic for PrP with a deletion of the Cu-binding octapeptide repeat (OR) region, Tg(PrPΔOR)/ Prnp 0/0 mice, were also highly susceptible to IAV infection. These results indicate that PrP C has a protective role against lethal infection with IAVs through the Cu-binding OR region by reducing ROS in infected lungs. Cu content and the activity of anti-oxidant enzyme Cu/Zn-dependent superoxide dismutase, SOD1, were lower in Prnp 0/0 and Tg(PrPΔOR)/ Prnp 0/0 lungs than in WT lungs. It is thus conceivable that PrP C functions to maintain Cu content and regulate SOD1 through the OR region in lungs, thereby reducing ROS in IAV-infected lungs and eventually protecting them from lethal infection with IAVs. Our current results highlight the role of PrP C in protection against IAV infection, and suggest that PrP C might be a novel target molecule for anti-influenza therapeutics.
    Print ISSN: 1553-7366
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  • 56
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    Publication Date: 2018-05-04
    Description: by Henrik H. De Fine Licht
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  • 57
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    Publication Date: 2018-05-04
    Description: by Natalia S. Barbosa, Leila R. Mendonça, Marcos V. S. Dias, Marjorie C. Pontelli, Elaine Z. M. da Silva, Miria F. Criado, Mara E. da Silva-Januário, Michael Schindler, Maria C. Jamur, Constance Oliver, Eurico Arruda, Luis L. P. daSilva Peribunyaviridae is a large family of RNA viruses with several members that cause mild to severe diseases in humans and livestock. Despite their importance in public heath very little is known about the host cell factors hijacked by these viruses to support assembly and cell egress. Here we show that assembly of Oropouche virus, a member of the genus Orthobunyavirus that causes a frequent arboviral infection in South America countries, involves budding of virus particles toward the lumen of Golgi cisternae. As viral replication progresses, these Golgi subcompartments become enlarged and physically separated from Golgi stacks, forming Oropouche viral factory (Vfs) units. At the ultrastructural level, these virally modified Golgi cisternae acquire an MVB appearance, and while they lack typical early and late endosome markers, they become enriched in endosomal complex required for transport (ESCRT) proteins that are involved in MVB biogenesis. Further microscopy and viral replication analysis showed that functional ESCRT machinery is required for efficient Vf morphogenesis and production of infectious OROV particles. Taken together, our results indicate that OROV attracts ESCRT machinery components to Golgi cisternae to mediate membrane remodeling events required viral assembly and budding at these compartments. This represents an unprecedented mechanism of how viruses hijack host cell components for coordinated morphogenesis.
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  • 58
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    Publication Date: 2018-05-04
    Description: by Quirine A. ten Bosch, Hannah E. Clapham, Louis Lambrechts, Veasna Duong, Philippe Buchy, Benjamin M. Althouse, Alun L. Lloyd, Lance A. Waller, Amy C. Morrison, Uriel Kitron, Gonzalo M. Vazquez-Prokopec, Thomas W. Scott, T. Alex Perkins Despite estimates that, each year, as many as 300 million dengue virus (DENV) infections result in either no perceptible symptoms (asymptomatic) or symptoms that are sufficiently mild to go undetected by surveillance systems (inapparent), it has been assumed that these infections contribute little to onward transmission. However, recent blood-feeding experiments with Aedes aegypti mosquitoes showed that people with asymptomatic and pre-symptomatic DENV infections are capable of infecting mosquitoes. To place those findings into context, we used models of within-host viral dynamics and human demographic projections to (1) quantify the net infectiousness of individuals across the spectrum of DENV infection severity and (2) estimate the fraction of transmission attributable to people with different severities of disease. Our results indicate that net infectiousness of people with asymptomatic infections is 80% (median) that of people with apparent or inapparent symptomatic infections (95% credible interval (CI): 0–146%). Due to their numerical prominence in the infectious reservoir, clinically inapparent infections in total could account for 84% (CI: 82–86%) of DENV transmission. Of infections that ultimately result in any level of symptoms, we estimate that 24% (95% CI: 0–79%) of onward transmission results from mosquitoes biting individuals during the pre-symptomatic phase of their infection. Only 1% (95% CI: 0.8–1.1%) of DENV transmission is attributable to people with clinically detected infections after they have developed symptoms. These findings emphasize the need to (1) reorient current practices for outbreak response to adoption of pre-emptive strategies that account for contributions of undetected infections and (2) apply methodologies that account for undetected infections in surveillance programs, when assessing intervention impact, and when modeling mosquito-borne virus transmission.
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    Publication Date: 2018-05-04
    Description: by J. Kennon Smith, Mavis Agbandje-McKenna The Adeno-associated virus (AAV) gene delivery system is ushering in a new and exciting era in the United States; following the first approved gene therapy (Glybera) in Europe, the FDA has approved a second therapy, Luxturna [1]. However, challenges to this system remain. In viral gene therapy, the surface of the capsid is an important determinant of tissue tropism, impacts gene transfer efficiency, and is targeted by the human immune system. Preexisting immunity is a significant challenge to this approach, and the ability to visualize areas of antibody binding (“footprints”) can inform efforts to improve the efficacy of viral vectors. Atomic resolution, smaller proteins, and asymmetric structures are the goals to attain in cryo-electron microscopy and image reconstruction (cryo-EM) as of late. The versatility of the technique and the ability to vitrify a wide range of heterogeneous molecules in solution allow structural biologists to characterize a variety of protein–DNA and protein–protein interactions at lower resolution. Cryo-EM has served as an important means to study key surface areas of the AAV gene delivery vehicle—specifically, those involved with binding neutralizing antibodies (NAbs) [2–4]. This method offers a unique opportunity for visualizing antibody binding “hotspots” on the surface of these and other viral vectors. When combined with mutagenesis, one can eliminate these hotspots to create viral vectors with the ability to avoid preexisting host immune recognition during gene delivery and genetic defect correction in disease treatment. Here, we discuss the use of structure-guided site-directed mutagenesis and directed evolution to create “stealth” AAV vectors with modified surface amino acid sequences that allow NAb avoidance while maintaining natural capsid functions or gaining desired novel tropisms.
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  • 60
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    Publication Date: 2018-05-04
    Description: by Ines Martin-Martin, Andrezza Campos Chagas, Anderson B. Guimaraes-Costa, Laura Amo, Fabiano Oliveira, Ian N. Moore, Thiago S. DeSouza-Vieira, Elda E. Sanchez, Montamas Suntravat, Jesus G. Valenzuela, Jose M. C. Ribeiro, Eric Calvo Salivary components from disease vectors help arthropods to acquire blood and have been shown to enhance pathogen transmission in different model systems. Here we show that two salivary enzymes from Lutzomyia longipalpis have a synergist effect that facilitates a more efficient blood meal intake and diffusion of other sialome components. We have previously shown that Lundep, a highly active endonuclease, enhances parasite infection and prevent blood clotting by inhibiting the intrinsic pathway of coagulation. To investigate the physiological role of a salivary hyaluronidase in blood feeding we cloned and expressed a recombinant hyaluronidase from Lu . longipalpis . Recombinant hyaluronidase (LuloHya) was expressed in mammalian cells and biochemically characterized in vitro . Our study showed that expression of neutrophil CXC chemokines and colony stimulating factors were upregulated in HMVEC cells after incubation with LuloHya and Lundep. These results were confirmed by the acute hemorrhage, edema and inflammation in a dermal necrosis (dermonecrotic) assay involving a massive infiltration of leukocytes, especially neutrophils, in mice co-injected with hemorrhagic factor and these two salivary proteins. Moreover, flow cytometry results showed that LuloHya and Lundep promote neutrophil recruitment to the bite site that may serve as a vehicle for establishment of Leishmania infection. A vaccination experiment demonstrated that LuloHya and Lundep confer protective immunity against cutaneous leishmaniasis using the Lu . longipalpis—Leishmania major combination as a model. Animals (C57BL/6) immunized with LuloHya or Lundep showed minimal skin damage while lesions in control animals remained ulcerated. This protective immunity was abrogated when B-cell-deficient mice were used indicating that antibodies against both proteins play a significant role for disease protection. Rabbit-raised anti-LuloHya antibodies completely abrogated hyaluronidase activity in vitro . Moreover, in vivo experiments demonstrated that blocking LuloHya with specific antibodies interferes with sand fly blood feeding. This work highlights the relevance of vector salivary components in blood feeding and parasite transmission and further suggests the inclusion of these salivary proteins as components for an anti- Leishmania vaccine.
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    Publication Date: 2018-04-05
    Description: by Stanley E. Lazic, Charlie J. Clarke-Williams, Marcus R. Munafò Biologists determine experimental effects by perturbing biological entities or units. When done appropriately, independent replication of the entity–intervention pair contributes to the sample size ( N ) and forms the basis of statistical inference. If the wrong entity–intervention pair is chosen, an experiment cannot address the question of interest. We surveyed a random sample of published animal experiments from 2011 to 2016 where interventions were applied to parents and effects examined in the offspring, as regulatory authorities provide clear guidelines on replication with such designs. We found that only 22% of studies (95% CI = 17%–29%) replicated the correct entity–intervention pair and thus made valid statistical inferences. Nearly half of the studies (46%, 95% CI = 38%–53%) had pseudoreplication while 32% (95% CI = 26%–39%) provided insufficient information to make a judgement. Pseudoreplication artificially inflates the sample size, and thus the evidence for a scientific claim, resulting in false positives. We argue that distinguishing between biological units, experimental units, and observational units clarifies where replication should occur, describe the criteria for genuine replication, and provide concrete examples of in vitro, ex vivo, and in vivo experimental designs.
    Print ISSN: 1544-9173
    Electronic ISSN: 1545-7885
    Topics: Biology
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  • 62
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    Publication Date: 2018-05-05
    Description: by Khan Rubayet Rahaman, Quazi K. Hassan, Ehsan H. Chowdhury
    Electronic ISSN: 1932-6203
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  • 63
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    Publication Date: 2018-05-05
    Description: by Annabelle de St. Maurice, Jessica Harmon, Luke Nyakarahuka, Stephen Balinandi, Alex Tumusiime, Jackson Kyondo, Sophia Mulei, Annemarion Namutebi, Barbara Knust, Trevor Shoemaker, Stuart T. Nichol, Anita K. McElroy, Christina F. Spiropoulou Rift Valley fever virus is an arbovirus that affects both livestock and humans throughout Africa and in the Middle East. Despite its endemicity throughout Africa, it is a rare event to identify an infected individual during the acute phase of the disease and an even rarer event to collect serial blood samples from the affected patient. Severely affected patients can present with hemorrhagic manifestations of disease. In this study we identified three Ugandan men with RVFV disease that was accompanied by hemorrhagic manifestations. Serial blood samples from these men were analyzed for a series of biomarkers specific for various aspects of human pathophysiology including inflammation, endothelial function and coagulopathy. There were significant differences between biomarker levels in controls and cases both early during the illness and after clearance of viremia. Positive correlation of viral load with markers of inflammation (IP-10, CRP, Eotaxin, MCP-2 and Granzyme B), markers of fibrinolysis (tPA and D-dimer), and markers of endothelial function (sICAM-1) were all noted. However, and perhaps most interesting given the fact that these individuals exhibited hemorrhagic manifestations of disease, was the finding of a negative correlation between viral load and P-selectin, ADAMTS13, and fibrinogen all of which are associated with coagulation pathways occurring on the endothelial surface.
    Print ISSN: 1935-2727
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  • 64
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    Publication Date: 2018-05-05
    Description: by Mónica Clavel San Emeterio, Rubén Fernández-Ortiz, Jesús Arteaga-Ortiz, Pablo Dorta-González The objective of this paper is to fill a gap in the literature on internationalization, in relation to the absence of objective and measurable performance indicators for the process of how firms sequentially enter external markets. To that end, this research develops a quantitative tool for use as a performance indicator of gradualness for firms entering external markets at a sectoral level. The performance indicator is based on firms’ export volumes, number of years operating in the export market, geographic areas targeted for export and when exports began to each area. The indicator is tested empirically in the wine sector. The main contribution of this study is the creation of a reliable international priority index, which can serve more widely as a valuable tool because of its potential use in other industry sectors and geographic areas, and which would allow the analysis of how geographically differentiated internationalization strategies develop.
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    Publication Date: 2018-05-05
    Description: by Anne M. G. Neevel, Tessa Hemrika, Eric Claassen, Linda H. M. van de Burgwal Background Despite the existence of safe and effective vaccines, rabies disease still causes an estimated 59,000 human deaths a year in the endemic areas in Asia and Africa. These numbers reflect severe drawbacks regarding the implementation of PrEP and PEP in endemic settings, such as lack of political will and low priority given to rabies. Since these contextual factors have proven to be persistent, there is an urgency to improve current strategies or develop novel approaches in order to control rabies disease in the future. Methods/Findings This study aimed to identify and systematically prioritize the research needs, through interviews and questionnaires with key-opinion-leaders (KOLs). A total of 46 research needs were identified and prioritized. The top research needs are considered very high priority based on both importance for rabies control and need for improvement. KOLs agree that animal rabies control remains most important for rabies control, while research on human host, agent (rabies virus) and the environment should be prioritized in terms of need for improvement. A wide variety in perceptions is observed between and within the disciplines of virology, public health and veterinary health and between KOLs with more versus those with less experience in the field. Conclusion/Significance The results of this study give well-defined, prioritized issues that stress the drawbacks that are experienced by KOLs in daily practice. The most important research domains are: 1) cheap and scalable production system for RIG 2) efficacy of dog mass vaccination programs and 3) cheap human vaccines. Addressing these research needs should exist next to and may reinforce current awareness and mass vaccination campaigns. The differences in perspectives between actors revealed in this study are informative for effective execution of the One Health research agenda.
    Print ISSN: 1935-2727
    Electronic ISSN: 1935-2735
    Topics: Medicine
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  • 66
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    Publication Date: 2018-05-05
    Description: by Laith Hussain-Alkhateeb, Axel Kroeger, Piero Olliaro, Joacim Rocklöv, Maquins Odhiambo Sewe, Gustavo Tejeda, David Benitez, Balvinder Gill, S. Lokman Hakim, Roberta Gomes Carvalho, Leigh Bowman, Max Petzold Background Dengue outbreaks are increasing in frequency over space and time, affecting people’s health and burdening resource-constrained health systems. The ability to detect early emerging outbreaks is key to mounting an effective response. The early warning and response system (EWARS) is a toolkit that provides countries with early-warning systems for efficient and cost-effective local responses. EWARS uses outbreak and alarm indicators to derive prediction models that can be used prospectively to predict a forthcoming dengue outbreak at district level. Methods We report on the development of the EWARS tool, based on users’ recommendations into a convenient, user-friendly and reliable software aided by a user’s workbook and its field testing in 30 health districts in Brazil, Malaysia and Mexico. Findings 34 Health officers from the 30 study districts who had used the original EWARS for 7 to 10 months responded to a questionnaire with mainly open-ended questions. Qualitative content analysis showed that participants were generally satisfied with the tool but preferred open-access vs. commercial software. EWARS users also stated that the geographical unit should be the district, while access to meteorological information should be improved. These recommendations were incorporated into the second-generation EWARS-R, using the free R software, combined with recent surveillance data and resulted in higher sensitivities and positive predictive values of alarm signals compared to the first-generation EWARS. Currently the use of satellite data for meteorological information is being tested and a dashboard is being developed to increase user-friendliness of the tool. The inclusion of other Aedes borne viral diseases is under discussion. Conclusion EWARS is a pragmatic and useful tool for detecting imminent dengue outbreaks to trigger early response activities.
    Electronic ISSN: 1932-6203
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  • 67
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    Publication Date: 2018-05-05
    Description: by Frieder Graef, Stefan Sieber Research and development increasingly apply participatory approaches that involve both stakeholders and scientists. This article presents an evaluation of German and Tanzanian researchers’ perceptions during their activities as part of a large interdisciplinary research project in Tanzania. The project focused on prioritizing and implementing food-securing upgrading strategies across the components of rural food value chains. The participants involved during the course of the project were asked to provide feedback on 10 different research steps and to evaluate eight core features related to the functioning and potential shortcomings of the project. The study discriminated among evaluation differences linked to culture, gender, and institutional status. Perceptions differed between Tanzanian and German participants depending on the type and complexity of the participatory research steps undertaken and the intensity of stakeholder participation. There were differences in perception linked to gender and hierarchical status; however, those differences were not as concise and significant as those linked to nationality. These findings indicate that participatory action research of this nature requires more targeted strategies and planning tailored to the type of activity. Such planning would result in more efficient and satisfactory communication, close collaboration, and mutual feedback to avoid conflicts and other problems. We further conclude that it would be advisable to carefully incorporate training on these aspects into future project designs.
    Electronic ISSN: 1932-6203
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    Publication Date: 2018-05-05
    Description: by T. Gupalova, G. Leontieva, T. Kramskaya, K. Grabovskaya, E. Bormotova, D. Korjevski, A. Suvorov Streptococcus agalactiae , or group B streptococcus (GBS), is an important pathogen as it is the leading cause of neonatal deaths due to sepsis, meningitis or bacterial pneumonia. Although the development of an effective and safe GBS vaccine is on the agenda of many research labs, there is no GBS vaccine on the market yet. In the present study we attempted to engineer a live vaccine strain based on Bac, a surface protein of GBS, incorporated into a surface fimbrial protein of probiotic Enterococcus. The resulting strain induced specific systemic and local immune responses in mice and provided protection against GBS when administered via the intranasal, oral or intravaginal immunization routes.
    Electronic ISSN: 1932-6203
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  • 69
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    Publication Date: 2018-05-05
    Description: by Hongyan Yang, Shenghua Tian, Constance Flamand-Roze, Ling Gao, Wei Zhang, Yan Li, Jiajia Wang, Zhou Sun, Ying Su, Libin Zhao, Zhihou Liang There is a severe lack of aphasia screening tools for bedside use in Chinese. A number of aphasia assessment tools have recently been developed abroad, but some of these scales were not suitable for patients with acute stroke. The Language Screening Test (which includes two parallel versions [a/b]) in French has been proven to be an effective and time-saving aphasia screening scale for early-stage stroke patients. Therefore, we worked out a Chinese version of the LAST taking into consideration Chinese language and culture. Two preliminary parallel versions (a/b) were tested on 154 patients with stroke at acute phase and 107 patients with stroke at non-acute phase, with the Western Aphasia Battery serving as a gold standard. The equivalence between the two parallel versions and the reliability/validity of each version were assessed. The median time to complete one preliminary Chinese version (each had some item redundancy) was 98 seconds. Two final parallel versions were established after adjustment/elimination of the redundant items and were found to be equivalent (intra-class correlation coefficient: 0.991). Internal consistency is(Cronbach α for each version [a/b] was 0.956 and 0.965, respectively) good. Internal validity was fine: (a) no floor or ceiling effect/item redundancy; (b) construct validity revealed a 1-dimension structure, just like the French version. The higher educated subjects scored higher than their lower educated counterparts ( p
    Electronic ISSN: 1932-6203
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  • 70
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    Publication Date: 2018-05-05
    Description: by Teboho N. Tsotetsi, Nicola E. Collins, Marinda C. Oosthuizen, Kgomotso P. Sibeko-Matjila The reliability of any quantitative real-time polymerase chain reaction (qPCR) experiment can be seriously compromised by variations between samples as well as between PCR runs. This usually result from errors in sample quantification, especially with samples that are obtained from different individuals and tissues and have been collected at various time intervals. Errors also arise from differences in qPCR efficiency between assays performed simultaneously to target multiple genes on the same plate. Consequently, the derived quantitative data for the target genes become distorted. To avoid this grievous error, an endogenous control, with relatively constant transcription levels in the target individual or tissue, is included in the qPCR assay to normalize target gene expression levels in the analysis. Several housekeeping genes (HKGs) have been used as endogenous controls in quantification studies of mRNA transcripts; however, there is no record in the literature of the evaluation of these genes for the tick-borne protozoan parasite, Theileria parva . Importantly, the expression of these genes should be invariable between different T . parva stocks, ideally under different experimental conditions, to gain extensive application in gene expression studies of this parasite. Thus, the expression of several widely used HKGs was evaluated in this study, including the genes encoding β-actin, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), 28S rRNA, cytochrome b and fructose-2.6-biphosphate aldolase (F6P) proteins. The qPCR analysis revealed that the expression of genes encoding cytochrome b, F6P and GAPDH varied considerably between the two T . parva stocks investigated, the cattle-derived T . parva Muguga and the buffalo-derived T . parva 7014. 28S rRNA and β-actin gene expression was the most stable; thus, these genes were considered suitable candidates to be used as endogenous control genes for mRNA quantification studies in T . parva .
    Electronic ISSN: 1932-6203
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    Publication Date: 2018-05-05
    Description: by Yu-Tong Miao, Yao Deng, Hao-Kang Jia, Yu-Di Liu, Mao-Lin Hou The white-backed planthopper, Sogatella furcifera , is a phloem sap feeder that secretes watery and gelling saliva during feeding. In this study, we identified the major proteins in watery saliva of S . furcifera by shotgun LC-MS/MS analysis combined with transcriptomic analysis. A total of 161 proteins were identified, which were divided into 8 function categories, including enzymes, transporter, calcium ion binding protein, salivary sheath protein, cytoskeleton protein, DNA-, RNA-, and protein-binding or regulating proteins, other non-enzyme proteins and unknown proteins. Gene expression pattern of 11 secretory proteins were analyzed by real time quantitative-PCR. We detected the mucin-like protein, which had a unique expression level in salivary gland, most likely to be a candidate effector involved in regulation of plant defense. This study identified the watery saliva component of S . furcifera and it provided a list of proteins which may play a role in interaction between S . furcifera and rice.
    Electronic ISSN: 1932-6203
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    Publication Date: 2018-05-05
    Description: by Yujiao Tang, Trishna Debnath, Eun-Ju Choi, Young Wook Kim, Jung Pyo Ryu, Sejin Jang, Sang Uk Chung, Young-Jin Choi, Eun-Kyung Kim Tenebrio molitor ( T . molitor ) larvae provide food at low environmental cost and contribute positively to livelihoods. In this research, we compared the amino acids compositions and antioxidant activities of various extracts of T . molitor to enhance their quality as food. For the comparison, distilled water extracts, enzymatic hydrolysates, and condensed enzymatic hydrolysates of T . molitor larvae were prepared. Their amino acids (AAs) profiles and antioxidant activities, including ferric-reducing antioxidant power, oxygen radical absorption capacity, and DPPH, hydroxyl radical, and hydrogen peroxide radical scavenging properties assay were analyzed. DW extracts had the lowest AAs contents and antioxidant activity compared with enzymatic extracts. Condensed hydrolysates with a combination of alcalase and flavourzyme (C-A+F) exhibited the highest levels of total free AAs (11.1759 g/100 g). C-A+F produced higher total hydrolyzed AAs (32.5292 g/100 g) compared with the other groups. The C-A+F possessed the strongest antioxidant activity. Notably, the antioxidant activities of the hydrolysates and the total hydrolyzed AAs amount were correlated. Taken together, our findings showed that C-A+F was a promising technique for obtaining extracts of T . molitor larvae with antioxidant activity as potential nutritious functional food.
    Electronic ISSN: 1932-6203
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  • 73
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    Publication Date: 2018-05-09
    Description: by Li Guo, Yingjie Mei, Jijing Guan, Xiangliang Tan, Yikai Xu, Wufan Chen, Qianjin Feng, Yanqiu Feng Quantitative susceptibility mapping (QSM) is a magnetic resonance imaging technique that quantifies the magnetic susceptibility distribution within biological tissues. QSM calculates the underlying magnetic susceptibility by deconvolving the tissue magnetic field map with a unit dipole kernel. However, this deconvolution problem is ill-posed. The morphology enabled dipole inversion (MEDI) introduces total variation (TV) to regularize the susceptibility reconstruction. However, MEDI results still contain artifacts near tissue boundaries because MEDI only imposes TV constraint on voxels inside smooth regions. We introduce a Morphology-Adaptive TV (MATV) for improving TV-regularized QSM. The MATV method first classifies imaging target into smooth and nonsmooth regions by thresholding magnitude gradients. In the dipole inversion for QSM, the TV regularization weights are a monotonically decreasing function of magnitude gradients. Thus, voxels inside smooth regions are assigned with larger weights than those in nonsmooth regions. Using phantom and in vivo datasets, we compared the performance of MATV with that of MEDI. MATV results had better visual quality than MEDI results, especially near tissue boundaries. Preliminary brain imaging results illustrated that MATV has potential to improve the reconstruction of regions near tissue boundaries.
    Electronic ISSN: 1932-6203
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  • 74
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    Publication Date: 2018-05-09
    Description: by Emily N. Prendergast, Marcos Abraão de Souza Fonseca, Felipe Segato Dezem, Jenny Lester, Beth Y. Karlan, Houtan Noushmehr, Xianzhi Lin, Kate Lawrenson Exosomes are endosome-derived membrane vesicles that contain proteins, lipids, and nucleic acids. The exosomal transcriptome mediates intercellular communication, and represents an understudied reservoir of novel biomarkers for human diseases. Next-generation sequencing enables complex quantitative characterization of exosomal RNAs from diverse sources. However, detailed protocols describing exosome purification for preparation of exosomal RNA-sequence (RNA-Seq) libraries are lacking. Here we compared methods for isolation of exosomes and extraction of exosomal RNA from human cell-free serum, as well as strategies for attaining equal representation of samples within pooled RNA-Seq libraries. We compared commercial precipitation with ultracentrifugation for exosome purification and confirmed the presence of exosomes via both transmission electron microscopy and immunoblotting. Exosomal RNA extraction was compared using four different RNA purification methods. We determined the minimal starting volume of serum required for exosome preparation and showed that high quality exosomal RNA can be isolated from sera stored for over a decade. Finally, RNA-Seq libraries were successfully prepared with exosomal RNAs extracted from human cell-free serum, cataloguing both coding and non-coding exosomal transcripts. This method provides researchers with strategic options to prepare RNA-Seq libraries and compare RNA-Seq data quantitatively from minimal volumes of fresh and archival human cell-free serum for disease biomarker discovery.
    Electronic ISSN: 1932-6203
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  • 75
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    Publication Date: 2018-05-11
    Description: by Dhouha Kthiri, Alexander Loladze, P. R. MacLachlan, Amidou N’Diaye, Sean Walkowiak, Kirby Nilsen, Susanne Dreisigacker, Karim Ammar, Curtis J. Pozniak Widening the genetic basis of leaf rust resistance is a primary objective of the global durum wheat breeding effort at the International Wheat and Maize Improvement Center (CIMMYT). Breeding programs in North America are following suit, especially after the emergence of new races of Puccinia triticina such as BBG/BP and BBBQD in Mexico and the United States, respectively. This study was conducted to characterize and map previously undescribed genes for leaf rust resistance in durum wheat and to develop reliable molecular markers for marker-assisted breeding. Four recombinant inbred line (RIL) mapping populations derived from the resistance sources Amria, Byblos, Geromtel_3 and Tunsyr_2, which were crossed to the susceptible line ATRED #2, were evaluated for their reaction to the Mexican race BBG/BP of P . triticina . Genetic analyses of host reactions indicated that leaf rust resistance in these genotypes was based on major seedling resistance genes. Allelism tests among resistant parents supported that Amria and Byblos carried allelic or closely linked genes. The resistance in Geromtel_3 and Tunsyr_2 also appeared to be allelic. Bulked segregant analysis using the Infinium iSelect 90K single nucleotide polymorphism (SNP) array identified two genomic regions for leaf rust resistance; one on chromosome 6BS for Geromtel_3 and Tunsyr_2 and the other on chromosome 7BL for Amria and Byblos. Polymorphic SNPs identified within these regions were converted to kompetitive allele-specific PCR (KASP) assays and used to genotype the RIL populations. KASP markers usw215 and usw218 were the closest to the resistance genes in Geromtel_3 and Tunsyr_2, while usw260 was closely linked to the resistance genes in Amria and Byblos. DNA sequences associated with these SNP markers were anchored to the wild emmer wheat (WEW) reference sequence, which identified several candidate resistance genes. The molecular markers reported herein will be useful to effectively pyramid these resistance genes with other previously marked genes into adapted, elite durum wheat genotypes.
    Electronic ISSN: 1932-6203
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  • 76
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    Publication Date: 2018-05-11
    Description: by Louise E. Hogan, Emily Hanhauser, Kristen S. Hobbs, Christine D. Palmer, Yvonne Robles, Stephanie Jost, Anne S. LaCasce, Jeremy Abramson, Ayad Hamdan, Francisco M. Marty, Daniel R. Kuritzkes, Timothy J. Henrich Background Human Herpes Virus 8 (HHV8) can cause Kaposi’s Sarcoma (KS) in immunosuppressed individuals. However, little is known about the association between chemotherapy or hematopoietic stem cell transplantation (HSCT), circulating HHV8 DNA levels, and clinical KS in HIV-1-infected individuals with various malignancies. Therefore, we examined the associations between various malignancies, systemic cancer chemotherapy, T cell phenotypes, and circulating HHV8 DNA in 29 HIV-1-infected participants with concomitant KS or other cancer diagnoses. Methods We quantified HHV8 plasma viral loads and cell-associated HHV8 DNA and determined the relationship between circulating HHV8 DNA and lymphocyte counts, and markers of early and late lymphocyte activation, proliferation and exhaustion. Results There were no significant differences in plasma HHV8 DNA levels between baseline and post-chemotherapy time points or with the presence or absence of clinical KS. However, in two participants circulating HHV8 DNA increased following treatment for KS or HSCT for lymphoma,. We observed an approximately 2-log 10 reduction in plasma HHV8 DNA in an individual with KS and multicentric Castleman disease following rituximab monotherapy. Although individuals with clinical KS had lower mean CD4 + T cell counts and percentages as expected, there were no significant associations with these factors and plasma HHV8 levels. We identified increased proportions of CD8 + and CD4 + T cells expressing CD69 (P = 0.01 & P = 0.04 respectively), and increased CD57 expression on CD4 + T cells (P = 0.003) in participants with detectable HHV8. Conclusion These results suggest there is a complex relationship between circulating HHV8 DNA and tissue-based disease in HIV-1 and HHV8 co-infected individuals with various malignancies.
    Electronic ISSN: 1932-6203
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    Publication Date: 2018-05-11
    Description: by Efthymia Giosa, Christos Mammides, Savvas Zotos The degradation of natural wetlands has significant effects on the ecosystem services they provide and the biodiversity they sustain. Under certain conditions, these negative effects can be mitigated by the presence of artificial wetlands. However, the conservation value of artificial wetlands needs to be explored further. In addition, it is unclear how certain anthropogenic variables, such as road networks and hunting reserves (i.e., areas where hunting of birds is prohibited) affect biodiversity in both artificial and natural wetlands. Here, we use data from thirteen artificial and six natural wetlands in Cyprus, to assess their similarities in bird species diversity and composition, and to quantify the relationship between species diversity and the density of road networks, hunting reserves, wetland size, and wetland depth. We found that while on average natural wetlands have more species and support higher abundances, certain artificial wetlands have the potential to support similarly diverse communities. Overall, regardless of the type, larger wetlands, with shallower waters tend to be more biodiverse. The same is true for wetlands surrounded by a higher percentage of hunting reserves and a lower density of road networks, albeit the effect of road networks was weaker. We conclude, from our results, that although the conservation value of natural wetlands is higher, artificial wetlands have the potential to play a complimentary role in the conservation of bird communities, assuming those wetlands have the right characteristics (e.g., in terms of size and depth) and assuming that the disturbances resulting from high-impact human-activities (e.g., hunting) are minimized.
    Electronic ISSN: 1932-6203
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    Publication Date: 2018-05-11
    Description: by Sojung Yi, Yihan Lin, Grace Kansayisa, Ainhoa Costas-Chavarri Access to surgical care in low- and middle-income countries (LMICs) remains deficient without an adequate workforce. There is limited understanding of the gender gap in surgical trainees in LMICs. In Rwanda, females fill only one of 20 positions available. Understanding surgeons’ experiences and perceptions of surgical careers may help facilitate support for females to contribute to the global surgical workforce. We performed qualitative analysis on perceptions of surgical careers through semi-structured interviews of all female surgeons (n = 6) and corresponding male surgeons (n = 6) who are training or have trained at University of Rwanda. Transcripts were analyzed with code structure formed through an integrated approach. Question categories formed the deductive framework, while theoretical saturation was reached through inductive grounded theory. Themes were organized within two key points of the career timeline. First, for developing interest in surgery, three main themes were identified: role models, patient case encounters, and exposure to surgery. Second, for selecting and sustaining surgical careers, four main themes emerged: social expectations about roles within the family, physical and mental challenges, professional and personal support, and finances. All female surgeons emphasized gender assumptions and surgical working culture as obstacles, with a corresponding strong sense of self-confidence and internal motivation that drew them to select and maintain careers in surgery. Family, time, and physical endurance were cited as persistent challenges for female participants. Our study reveals concepts for further exploration about gendered perceptions of surgical careers. Efforts to improve support for female surgical careers as a strategy for shaping surgical work culture and professional development in Rwanda should be considered. Such strategies may be beneficial for improving the global surgical workforce.
    Electronic ISSN: 1932-6203
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    Publication Date: 2018-05-11
    Description: by Francis Bakewell, Sarah Addleman, Garth Dickinson, Venkatesh Thiruganasambandamoorthy Introduction In June 2012, the federal government made cuts to the Interim Federal Health (IFH) Program that reduced or eliminated health insurance for refugee claimants in Canada. The purpose of this study was to examine the effect of the cuts on emergency department (ED) use among patients claiming IFH benefits. Methods We conducted a health records review at two tertiary care EDs in Ottawa. We reviewed all ED visits where an IFH claim was made at triage, for 18 months before and 18 months after the changes to the program on June 30, 2012 (2011–2013). Claims made before and after the cuts were compared in terms of basic demographics, chief presenting complaints, acuity, diagnosis, presence of primary care, and financial status of the claim. Bivariate or multivariate logistic regression analysis was performed to yield odds ratios (OR) with 95% confidence intervals. Results There were a total of 612 IFH claims made in the ED from 2011–2013. The demographic characteristics, acuity of presentation and discharge diagnoses were similar during both the before and after periods. Overall, 28.6% fewer claims were made under the IFH program after the cuts. Of the claims made, significantly more were rejected after the cuts than before (13.7% after vs. 3.9% before, adjusted OR 4.28, 95% CI: 2.18–8.40; p
    Electronic ISSN: 1932-6203
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    Publication Date: 2018-05-11
    Description: by Hyunji Kim, Eunbee Kim, Eunkook M. Suh, Mitchell J. Callan The current research developed and validated a Korean-translated version of the Personal Relative Deprivation Scale (PRDS). The PRDS measures individual differences in people’s tendencies to feel resentful about what they have compared to what other people like them have. Across 2 studies, Exploratory Factor Analyses revealed that the two reverse-worded items from the original PRDS did not load onto the primary factor for the Korean-translated PRDS. A reduced 3-item Korean PRDS, however, showed good convergent validity. Replicating previous findings using Western samples, greater tendencies to make social comparisons of abilities (but not opinions) were associated with higher PRDS (Studies 1 and 2), and participants scoring higher on the 3-item Korean PRDS were more materialistic (Studies 1 and 2), reported worse physical health (Study 1), had lower self-esteem (Study 2) and experienced higher stress (Study 2).
    Electronic ISSN: 1932-6203
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    Publication Date: 2018-05-11
    Description: by Valeriy Kuznyetsov, Svetlana Madjunkova, Ran Antes, Rina Abramov, Gelareh Motamedi, Zenon Ibarrientos, Clifford Librach Objective To assess whether embryonic DNA isolated from blastocyst culture conditioned medium (BCCM) combined with blastocoel fluid (BF) could be used for blastocyst stage non-invasive preimplantation genetic testing for chromosomal aneuploidy (non-invasive preimplantation genetic screening, NIPGS). Patients 47 embryos from 35 patients undergoing IVF. Interventions DNA analysis of combined BCCM plus BF in comparison with trophectoderm (TE) biopsy and/or whole blastocyst (WB)using next generation sequencing (NGS). Results Embryonic DNA was successfully amplified in 47/47 NIPGS samples (28 frozen-thawed and 19 fresh culture samples) ranging from 6.3 to 44.0 ng/μl. For frozen-thawed embryos, the concordance rate for whole chromosome copy number per sample was equivalent between NIPGS vs. TE biopsy, NIPGS vs. WB and TE vs. WB samples taken from the same embryo was 87.5%; 96.4% and 91.7% respectively (P〉0.05), and the rate of concordance per single chromosome was 99.3%, 99.7% and 99.7%, respectively (P〉0.05). In fresh cases (Day 4 to Day 5/6 culture), the concordance rate for whole chromosome copy number per sample between NIPGS vs. TE samples taken from the same embryo was 100%, and the rate of concordance per single chromosome was 98.2% (P〉0.05). Conclusions A combination of BCCM and BF contains sufficient embryonic DNA for whole genome amplification and accurate aneuploidy screening. Our findings suggest that aneuploidy screening using BCCM combined with BF could potentially serve as a novel NIPGS approach for use in human IVF.
    Electronic ISSN: 1932-6203
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    Publication Date: 2018-05-11
    Description: by Young Bong Choi, Yeeun Choi, Edward William Harhaj Human herpesvirus 8 (HHV-8) is causally related to human malignancies. HHV-8 latent viral FLICE-inhibitory protein (vFLIP) is a viral oncoprotein that is linked to pathogenesis, but how its expression is regulated is largely unknown. In an attempt to understand the role of the mitochondrial antiviral signaling (MAVS) adaptor in HHV-8 infection, we discovered that vFLIP expression was post-translationally up-regulated by the MAVS signaling complex on peroxisomes. Furthermore, we demonstrated that vFLIP could be targeted to the peroxisomes, where it was oncogenically active, in a PEX19-dependent manner. Targeted disruption of vFLIP and MAVS interaction resulted in a decrease in vFLIP expression and selectively promoted death of latently HHV-8-infected cells, providing therapeutic potential for treating HHV-8 diseases. Collectively, our experimental results suggest novel involvement of peroxisomes and MAVS in the stabilization of vFLIP and thereby in the establishment or maintenance of HHV-8 latency and associated pathogenesis.
    Print ISSN: 1553-7366
    Electronic ISSN: 1553-7374
    Topics: Medicine
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    Publication Date: 2018-05-11
    Description: by Hsin Chi, Ching-Hu Chung, Yuh-Jyh Lin, Chyi-Her Lin Objectives To assess the nationwide seasonal peaks, risk factors, and utilization of medical resources of respiratory syncytial virus-associated hospitalization (RSVH) in preterm infants in Taiwan. Study design A Taiwan nationwide birth cohort was extracted from the Birth Certificate Application Database during 2007–2009 and prospectively linked to the National Health Insurance database. We evaluated the seasonal peaks and risk factors (gestational age [GA], chronologic age [CA], and bronchopulmonary dysplasia [BPD]) associated with the RSVH of preterm infants. The length of hospital stays (LOS), care in intensive care unit (ICU), and use of mechanical ventilation (MV) were also analyzed. Results There is a total duration of 9 months of RSVH season in Taiwan, three seasonal peaks and two seasonal peaks of RSVH in preterm infants with BPD and without BPD, respectively. Preterm infants had significantly higher RSVH rate than term infants (2.6% vs 0.9%, p
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    Public Library of Science (PLoS)
    Publication Date: 2018-05-11
    Description: by Éva Szentirmai, Levente Kapás We previously identified brown adipose tissue (BAT) as a source of sleep-inducing signals. Pharmacological activation of BAT enhances sleep while sleep loss leads to increased BAT thermogenesis. Recovery sleep after sleep loss is diminished in mice that lack uncoupling protein 1 (UCP-1), and also in wild-type (WT) mice after sensory denervation of the BAT. Systemic inflammation greatly affects metabolism and the function of adipose tissue, and also induces characteristic sleep responses. We hypothesized that sleep responses to acute inflammation are mediated by BAT-derived signals. To test this, we determined the effects of systemic inflammation on sleep and body temperature in UCP-1 knockout (KO) and WT mice. Intraperitoneal injections of lipopolysaccharide, tumor necrosis factor-α, interleukin-1 beta and clodronate containing liposomes were used to induce systemic inflammation. In WT animals, non-rapid-eye movement sleep (NREMS) was elevated in all four inflammatory models. All NREMS responses were completely abolished in UCP-1 KO animals. Systemic inflammation elicited an initial hypothermia followed by fever in WT mice. The hypothermic phase, but not the fever, was abolished in UCP-1 KO mice. The only recognized function of UCP-1 is to promote thermogenesis in brown adipocytes. Present results indicate that the presence of UCP-1 is necessary for increased NREMS but does not contribute to the development of fever in systemic inflammation.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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    Public Library of Science (PLoS)
    Publication Date: 2018-05-11
    Description: by Shanna K. Williams, Zachary P. Weiner, Robert D. Gilmore Borrelia burgdorferi , the agent of Lyme borreliosis, can elude hosts’ innate and adaptive immunity as part of the course of infection. The ability of B . burgdorferi to invade or be internalized by host cells in vitro has been proposed as a mechanism for the pathogen to evade immune responses or antimicrobials. We have previously shown that B . burgdorferi can be internalized by human neuroglial cells. In this study we demonstrate that these cells take up B . burgdorferi via coiling phagocytosis mediated by the formin, Daam1, a process similarly described for human macrophages. Following coincubation with glial cells, B . burgdorferi was enwrapped by Daam1-enriched coiling pseudopods. Coiling of B . burgdorferi was significantly reduced when neuroglial cells were pretreated with anti-Daam1 antibody indicating the requirement for Daam1 for borrelial phagocytosis. Confocal microscopy showed Daam1 colocalizing to the B . burgdorferi surface suggesting interaction with borrelial membrane protein(s). Using the yeast 2-hybrid system for identifying protein-protein binding, we found that the B . burgdorferi surface lipoprotein, BBA66, bound the FH2 subunit domain of Daam1. Recombinant proteins were used to validate binding by ELISA, pull-down, and co-immunoprecipitation. Evidence for native Daam1 and BBA66 interaction was suggested by colocalization of the proteins in the course of borrelial capture by the Daam1-enriched pseudopodia. Additionally, we found a striking reduction in coiling for a BBA66-deficient mutant strain compared to BBA66-expressing strains. These results show that coiling phagocytosis is a mechanism for borrelial internalization by neuroglial cells mediated by Daam1.
    Electronic ISSN: 1932-6203