bluuebunny/crossref_metadata_2025_split huggingface dataset:
A mutation in VPS15 (PIK3R4) causes a ciliopathy and affects IFT20 release from the cis-Golgi
Authors: Stoetzel Corinne , Bär Séverine , De Craene Johan-Owen , Scheidecker Sophie , Etard Christelle , Chicher Johana , Reck Jennifer R. , Perrault Isabelle , Geoffroy Véronique , Chennen Kirsley , Strähle Uwe , Hammann Philippe , Friant Sylvie , Dollfus Hélène 
Published: November 2016

AbstractCiliopathies are a group of diseases that affect kidney and retina among other organs. Here, we identify a missense mutation in PIK3R4 (phosphoinositide 3-kinase regulatory subunit 4, named VPS15) in a family with a ciliopathy phenotype. Besides being required for trafficking and autophagy, we show that VPS15 regulates primary cilium length in human fibroblasts, as well as ciliary processes in zebrafish. Furthermore, we demonstrate its interaction with the golgin GM130 and its localization to the Golgi. The VPS15-R998Q patient mutation impairs Golgi trafficking functions in humanized yeast cells. Moreover, in VPS15-R998Q patient fibroblasts, the intraflagellar transport protein IFT20 is not localized to vesicles trafficking to the cilium but is restricted to the Golgi. Our findings suggest that at the Golgi, VPS15 and GM130 form a protein complex devoid of VPS34 to ensure the IFT20-dependent sorting and transport of membrane proteins from the cis-Golgi to the primary cilium.
ISGylation controls exosome secretion by promoting lysosomal degradation of MVB proteins
Authors: Villarroya-Beltri Carolina , Baixauli Francesc , Mittelbrunn María , Fernández-Delgado Irene , Torralba Daniel , Moreno-Gonzalo Olga , Baldanta Sara , Enrich Carlos , Guerra Susana , Sánchez-Madrid Francisco 
Published: November 2016

AbstractExosomes are vesicles secreted to the extracellular environment through fusion with the plasma membrane of specific endosomes called multivesicular bodies (MVB) and mediate cell-to-cell communication in many biological processes. Posttranslational modifications are involved in the sorting of specific proteins into exosomes. Here we identify ISGylation as a ubiquitin-like modification that controls exosome release. ISGylation induction decreases MVB numbers and impairs exosome secretion. Using ISG15-knockout mice and mice expressing the enzymatically inactive form of the de-ISGylase USP18, we demonstrate in vitro and in vivo that ISG15 conjugation regulates exosome secretion. ISG15 conjugation triggers MVB co-localization with lysosomes and promotes the aggregation and degradation of MVB proteins. Accordingly, inhibition of lysosomal function or autophagy restores exosome secretion. Specifically, ISGylation of the MVB protein TSG101 induces its aggregation and degradation, being sufficient to impair exosome secretion. These results identify ISGylation as a novel ubiquitin-like modifier in the control of exosome production.
Repression of RNA polymerase by the archaeo-viral regulator ORF145/RIP
Authors: Sheppard Carol , Blombach Fabian , Belsom Adam , Schulz Sarah , Daviter Tina , Smollett Katherine , Mahieu Emilie , Erdmann Susanne , Tinnefeld Philip , Garrett Roger , Grohmann Dina , Rappsilber Juri , Werner Finn 
Published: November 2016

AbstractLittle is known about how archaeal viruses perturb the transcription machinery of their hosts. Here we provide the first example of an archaeo-viral transcription factor that directly targets the host RNA polymerase (RNAP) and efficiently represses its activity. ORF145 from the temperate Acidianus two-tailed virus (ATV) forms a high-affinity complex with RNAP by binding inside the DNA-binding channel where it locks the flexible RNAP clamp in one position. This counteracts the formation of transcription pre-initiation complexes in vitro and represses abortive and productive transcription initiation, as well as elongation. Both host and viral promoters are subjected to ORF145 repression. Thus, ORF145 has the properties of a global transcription repressor and its overexpression is toxic for Sulfolobus. On the basis of its properties, we have re-named ORF145 RNAP Inhibitory Protein (RIP).
Neutralization mechanism of a highly potent antibody against Zika virus
Authors: Zhang Shuijun , Kostyuchenko Victor A. , Ng Thiam-Seng , Lim Xin-Ni , Ooi Justin S. G. , Lambert Sebastian , Tan Ter Yong , Widman Douglas G. , Shi Jian , Baric Ralph S. , Lok Shee-Mei 
Published: November 2016

AbstractThe rapid spread of Zika virus (ZIKV), which causes microcephaly and Guillain-Barré syndrome, signals an urgency to identify therapeutics. Recent efforts to rescreen dengue virus human antibodies for ZIKV cross-neutralization activity showed antibody C10 as one of the most potent. To investigate the ability of the antibody to block fusion, we determined the cryoEM structures of the C10-ZIKV complex at pH levels mimicking the extracellular (pH8.0), early (pH6.5) and late endosomal (pH5.0) environments. The 4.0 Å resolution pH8.0 complex structure shows that the antibody binds to E proteins residues at the intra-dimer interface, and the virus quaternary structure-dependent inter-dimer and inter-raft interfaces. At pH6.5, antibody C10 locks all virus surface E proteins, and at pH5.0, it locks the E protein raft structure, suggesting that it prevents the structural rearrangement of the E proteins during the fusion event—a vital step for infection. This suggests antibody C10 could be a good therapeutic candidate.
Telomeres are elongated in older individuals in a hibernating rodent, the edible dormouse (Glis glis)
Authors: Hoelzl Franz , Smith Steve , Cornils Jessica S. , Aydinonat Denise , Bieber Claudia , Ruf Thomas 
Published: November 2016

AbstractTelomere shortening is thought to be an important biomarker for life history traits such as lifespan and aging, and can be indicative of genome integrity, survival probability and the risk of cancer development. In humans and other animals, telomeres almost always shorten with age, with more rapid telomere attrition in short-lived species. Here, we show that in the edible dormouse (Glis glis) telomere length significantly increases from an age of 6 to an age of 9 years. While this finding could be due to higher survival of individuals with longer telomeres, we also found, using longitudinal measurements, a positive effect of age on the rate of telomere elongation within older individuals. To our knowledge, no previous study has reported such an effect of age on telomere lengthening. We attribute this exceptional pattern to the peculiar life-history of this species, which skips reproduction in years with low food availability. Further, we show that this “sit tight” strategy in the timing of reproduction is associated with an increasing likelihood for an individual to reproduce as it ages. As reproduction could facilitate telomere attrition, this life-history strategy may have led to the evolution of increased somatic maintenance and telomere elongation with increasing age.
V(D)J recombination process and the Pre-B to immature B-cells transition are altered in Fanca−/− mice
Authors: Nguyen Thuy Vy , Pawlikowska Patrycja , Firlej Virginie , Rosselli Filippo , Aoufouchi Saïd 
Published: November 2016

AbstractB-lymphocytes in the bone marrow (BM) must generate a functional B-cell receptor and overcome the negative selection induced by reactivity with autoantigens. Two rounds of DNA recombination are required for the production of functional immunoglobulin heavy (Ig-HCs) and light (LCs) chains necessary for the continuation of B-lymphocyte development in the BM. Both rounds depend on the joint action of recombination activating gene-1 (RAG-1) and RAG-2 endonucleases with the DNA non-homologous end-joining pathway. Loss of the FANC gene leads to the chromosome breakage and cancer predisposition syndrome Fanconi anemia. Because the FANC proteins are involved in certain aspects of the recombination process, we sought to determine the impact of the FANC pathway on the Ig diversification process using Fanca−/− mice. In this work we demonstrated that Fanca−/− animals have a mild B-cell differentiation defect characterized by a specific alteration of the IgM− to IgM+ transition of the B220low B-cell population. Pre-B cells from Fanca−/− mice show evidence of impaired kLC rearrangement at the level of the Vk-Jk junction. Furthermore, Fanca−/− mice showed a skewed Vκ gene usage during formation of the LCs Vk-Jk junctions. Therefore, the Fanca protein appears as a yet unidentified factor involved in the primary diversification of Ig.
Bumble bee parasite strains vary in resistance to phytochemicals
Authors: Palmer-Young Evan C. , Sadd Ben M. , Stevenson Philip C. , Irwin Rebecca E. , Adler Lynn S. 
Published: November 2016

AbstractNectar and pollen contain diverse phytochemicals that can reduce disease in pollinators. However, prior studies showed variable effects of nectar chemicals on infection, which could reflect variable phytochemical resistance among parasite strains. Inter-strain variation in resistance could influence evolutionary interactions between plants, pollinators, and pollinator disease, but testing direct effects of phytochemicals on parasites requires elimination of variation between bees. Using cell cultures of the bumble bee parasiteCrithidia bombi, we determined (1) growth-inhibiting effects of nine floral phytochemicals and (2) variation in phytochemical resistance among four parasite strains.C. bombigrowth was unaffected by naturally occurring concentrations of the known antitrypanosomal phenolics gallic acid, caffeic acid, and chlorogenic acid. However,C. bombigrowth was inhibited by anabasine, eugenol, and thymol. Strains varied >3-fold in phytochemical resistance, suggesting that selection for phytochemical resistance could drive parasite evolution. Inhibitory concentrations of thymol (4.53–22.2 ppm) were similar to concentrations inThymus vulgarisnectar (mean 5.2 ppm). Exposure ofC. bombito naturally occurring levels of phytochemicals—either within bees or during parasite transmission via flowers—could influence infection in nature. Flowers that produce antiparasitic phytochemicals, including thymol, could potentially reduce infection inBombuspopulations, thereby counteracting a possible contributor to pollinator decline.
Systemic and mucosal immune responses following oral adenoviral delivery of influenza vaccine to the human intestine by radio controlled capsule
Authors: Kim Leesun , Martinez C. Josefina , Hodgson Katie A. , Trager George R. , Brandl Jennifer R. , Sandefer Erik P. , Doll Walter J. , Liebowitz Dave , Tucker Sean N. 
Published: November 2016

AbstractThere are several benefits of oral immunization including the ability to elicit mucosal immune responses that may protect against pathogens that invade through a mucosal surface. Our understanding of human immune biology is hampered by the difficulty in isolating mucosal cells from humans, and the fact that animal models may or may not completely mirror human intestinal immunobiology. In this human pharmacodynamic study, a novel adenovirus vector-based platform expressing influenza hemagglutinin was explored. We used radio-controlled capsules to deliver the vaccine to either the jejunum or the ileum. The resulting immune responses induced by immunization at each of the intestinal sites were investigated. Both intestinal sites were capable of inducing mucosal and systemic immune responses to influenza hemagglutinin, but ileum delivery induced higher numbers of antibody secreting cells of IgG and IgA isotypes, increased mucosal homing B cells, and higher number of vaccine responders. Overall, these data provided substantial insights into human mucosal inductive sites, and aided in the design and selection of indications that could be used with this oral vaccine platform.
Antibody-antigen kinetics constrain intracellular humoral immunity
Authors: Bottermann Maria , Lode Heidrun Elisabeth , Watkinson Ruth E. , Foss Stian , Sandlie Inger , Andersen Jan Terje , James Leo C. 
Published: November 2016

AbstractDuring infection with non-enveloped viruses, antibodies stimulate immunity from inside cells by activating the cytosolic Fc receptor TRIM21. This intracellular humoral response relies on opsonized viral particles reaching the cytosol intact but the antigenic and kinetic constraints involved are unknown. We have solved the structure of a potent TRIM21-dependent neutralizing antibody in complex with human adenovirus 5 hexon and show how these properties influence immune activity. Structure-guided mutagenesis was used to generate antibodies with 20,000-fold variation in affinity, on-rates that differ by ~50-fold and off-rates by >175-fold. Characterization of these variants during infection revealed that TRIM21-dependent neutralization and NFκB activation was largely unaffected by on-rate kinetics. In contrast, TRIM21 antiviral activity was exquisitely dependent upon off-rate, with sub-μM affinity antibodies nevertheless unable to stimulate signaling because of fast dissociation kinetics. These results define the antibody properties required to elicit an efficient intracellular immune response during viral infection.
Fabrication of Ion-Shaped Anisotropic Nanoparticles and their Orientational Imaging by Second-Harmonic Generation Microscopy
Authors: Slablab Abdallah , Isotalo Tero J. , Mäkitalo Jouni , Turquet Léo , Coulon Pierre-Eugène , Niemi Tapio , Ulysse Christian , Kociak Mathieu , Mailly Dominique , Rizza Giancarlo , Kauranen Martti 
Published: November 2016

AbstractIon beam shaping is a novel and powerful tool to engineer nanocomposites with effective three-dimensional (3D) architectures. In particular, this technique offers the possibility to precisely control the size, shape and 3D orientation of metallic nanoparticles at the nanometer scale while keeping the particle volume constant. Here, we use swift heavy ions of xenon for irradiation in order to successfully fabricate nanocomposites consisting of anisotropic gold nanoparticle that are oriented in 3D and embedded in silica matrix. Furthermore, we investigate individual nanorods using a nonlinear optical microscope based on second-harmonic generation (SHG). A tightly focused linearly or radially-polarized laser beam is used to excite nanorods with different orientations. We demonstrate high sensitivity of the SHG response for these polarizations to the orientation of the nanorods. The SHG measurements are in excellent agreement with the results of numerical modeling based on the boundary element method.
Effects of MeJA on Arabidopsis metabolome under endogenous JA deficiency
Authors: Cao Jingjing , Li Mengya , Chen Jian , Liu Pei , Li Zhen 
Published: November 2016

AbstractJasmonates (JAs) play important roles in plant growth, development and defense. Comprehensive metabolomics profiling of plants under JA treatment provides insights into the interaction and regulation network of plant hormones. Here we applied high resolution mass spectrometry based metabolomics approach on Arabidopsis wild type and JA synthesis deficiency mutant opr3. The effects of exogenous MeJA treatment on the metabolites of opr3 were investigated. More than 10000 ion signals were detected and more than 2000 signals showed significant variation in different genotypes and treatment groups. Multivariate statistic analyses (PCA and PLS-DA) were performed and a differential compound library containing 174 metabolites with high resolution precursor ion-product ions pairs was obtained. Classification and pathway analysis of 109 identified compounds in this library showed that glucosinolates and tryptophan metabolism, amino acids and small peptides metabolism, lipid metabolism, especially fatty acyls metabolism, were impacted by endogenous JA deficiency and exogenous MeJA treatment. These results were further verified by quantitative reverse transcription PCR (RT-qPCR) analysis of 21 related genes involved in the metabolism of glucosinolates, tryptophan and α-linolenic acid pathways. The results would greatly enhance our understanding of the biological functions of JA.
On-demand Hydrogen Production from Organosilanes at Ambient Temperature Using Heterogeneous Gold Catalysts
Authors: Mitsudome Takato , Urayama Teppei , Kiyohiro Taizo , Maeno Zen , Mizugaki Tomoo , Jitsukawa Koichiro , Kaneda Kiyotomi 
Published: November 2016

AbstractAn environmentally friendly (“green”), H2-generation system was developed that involved hydrolytic oxidation of inexpensive organosilanes as hydrogen storage materials with newly developed heterogeneous gold nanoparticle catalysts. The gold catalyst functioned well at ambient temperature under aerobic conditions, providing efficient production of pure H2. The newly developed size-selective gold nanoparticle catalysts could be separated easily from the reaction mixture containing organosilanes, allowing an on/off-switchable H2-production by the introduction and removal of the catalyst. This is the first report of an on/off-switchable H2-production system employing hydrolytic oxidation of inexpensive organosilanes without requiring additional energy.
mQC: A Heuristic Quality-Control Metric for High-Throughput Drug Combination Screening
Authors: Chen Lu , Wilson Kelli , Goldlust Ian , Mott Bryan T. , Eastman Richard , Davis Mindy I. , Zhang Xiaohu , McKnight Crystal , Klumpp-Thomas Carleen , Shinn Paul , Simmons John , Gormally Mike , Michael Sam , Thomas Craig J. , Ferrer Marc , Guha Rajarshi 
Published: November 2016

AbstractQuality control (QC) metrics are critical in high throughput screening (HTS) platforms to ensure reliability and confidence in assay data and downstream analyses. Most reported HTS QC metrics are designed for plate level or single well level analysis. With the advent of high throughput combination screening there is a need for QC metrics that quantify the quality of combination response matrices. We introduce a predictive, interpretable, matrix-level QC metric, mQC, based on a mix of data-derived and heuristic features. mQC accurately reproduces the expert assessment of combination response quality and correctly identifies unreliable response matrices that can lead to erroneous or misleading characterization of synergy. When combined with the plate-level QC metric, Z’, mQC provides a more appropriate determination of the quality of a drug combination screen. Retrospective analysis on a number of completed combination screens further shows that mQC is able to identify problematic screens whereas plate-level QC was not able to. In conclusion, our data indicates that mQC is a reliable QC filter that can be used to identify problematic drug combinations matrices and prevent further analysis on erroneously active combinations as well as for troubleshooting failed screens. The R source code of mQC is available athttp://matrix.ncats.nih.gov/mQC.
An In Silico study of TiO2 nanoparticles interaction with twenty standard amino acids in aqueous solution
Authors: Liu Shengtang , Meng Xuan-Yu , Perez-Aguilar Jose Manuel , Zhou Ruhong 
Published: November 2016

AbstractTitanium dioxide (TiO2) is probably one of the most widely used nanomaterials, and its extensive exposure may result in potentially adverse biological effects. Yet, the underlying mechanisms of interaction involving TiO2NPs and macromolecules,e.g., proteins, are still not well understood. Here, we perform all-atom molecular dynamics simulations to investigate the interactions between TiO2NPs and the twenty standard amino acids in aqueous solution exploiting a newly developed TiO2force field. We found that charged amino acids play a dominant role during the process of binding to the TiO2surface, with both basic and acidic residues overwhelmingly preferred over the non-charged counterparts. By calculating the Potential Mean Force, we showed that Arg is prone to direct binding onto the NP surface, while Lys needs to overcome a ~2 kT free energy barrier. On the other hand, acidic residues tend to form “water bridges” between their sidechains and TiO2surface, thus displaying an indirect binding. Moreover, the overall preferred positions and configurations of different residues are highly dependent on properties of the first and second solvation water. These molecular insights learned from this work might help with a better understanding of the interactions between biomolecules and nanomaterials.
Interaction between β-hexachlorocyclohexane and ADIPOQ genotypes contributes to the risk of type 2 diabetes mellitus in East Chinese adults
Authors: Li Shushu , Wang Xichen , Yang Lu , Yao Shen , Zhang Ruyang , Xiao Xue , Zhang Zhan , Wang Li , Xu Qiujin , Wang Shou-Lin 
Published: November 2016

AbstractGrowing evidence links environmental exposure to hexachlorocyclohexanes (HCHs) to the risk of type 2 diabetes mellitus (T2DM), and ADIPOQ that encodes adiponectin is considered as an important gene for T2DM. However, the role of ADIPOQ-HCH interaction on T2DM risk remains unclear. Thus, a paired case-control study was conducted in an East Chinese community. A total of 1446 subjects, including 723 cases and 723 controls matched on age, gender and residence, were enrolled, and 4 types of HCH isomers were measured in serum samples using GC-MS/MS. Additionally, 4 candidate ADIPOQ SNPs (rs182052, rs266729, rs6810075, and rs16861194) were genotyped by TaqMan assay, and plasma adiponectin was measured using ELISA. No associations between 4 SNPs and T2DM risk were found, but T2DM risk significantly increased with serum levels of β-HCH (P < 0.001). Furthermore, the synergistic interaction between β-HCH and rs182052 significantly increased T2DM risk (OR I-additive model = 2.20, OR I-recessive model = 2.13). Additionally, individuals carrying only rs182052 (A allele) with high levels of β-HCH had significant reduction in adiponectin levels (P = 0.016). These results indicate that the interaction between rs182052 and β-HCH might increase the risk of T2DM by jointly decreasing the adiponectin level and potentially trigger T2DM development.
Genome-wide transcriptome analysis revealed organelle specific responses to temperature variations in algae
Authors: Shin HyeonSeok , Hong Seong-Joo , Yoo Chan , Han Mi-Ae , Lee Hookeun , Choi Hyung-Kyoon , Cho Suhyung , Lee Choul-Gyun , Cho Byung-Kwan 
Published: November 2016

AbstractTemperature is a critical environmental factor that affects microalgal growth. However, microalgal coping mechanisms for temperature variations are unclear. Here, we determined changes in transcriptome, total carbohydrate, total fatty acid methyl ester, and fatty acid composition of Tetraselmis sp. KCTC12432BP, a strain with a broad temperature tolerance range, to elucidate the tolerance mechanisms in response to large temperature variations. Owing to unavailability of genome sequence information, de novo transcriptome assembly coupled with BLAST analysis was performed using strand specific RNA-seq data. This resulted in 26,245 protein-coding transcripts, of which 83.7% could be annotated to putative functions. We identified more than 681 genes differentially expressed, suggesting an organelle-specific response to temperature variation. Among these, the genes related to the photosynthetic electron transfer chain, which are localized in the plastid thylakoid membrane, were upregulated at low temperature. However, the transcripts related to the electron transport chain and biosynthesis of phosphatidylethanolamine localized in mitochondria were upregulated at high temperature. These results show that the low energy uptake by repressed photosynthesis under low and high temperature conditions is compensated by different mechanisms, including photosystem I and mitochondrial oxidative phosphorylation, respectively. This study illustrates that microalgae tolerate different temperature conditions through organelle specific mechanisms.