bluuebunny/crossref_metadata_2025_split huggingface dataset:
Trapping IgE in a closed conformation by mimicking CD23 binding prevents and disrupts FcεRI interaction
Authors: Jabs Frederic , Plum Melanie , Laursen Nick S. , Jensen Rasmus K. , Mølgaard Brian , Miehe Michaela , Mandolesi Marco , Rauber Michèle M. , Pfützner Wolfgang , Jakob Thilo , Möbs Christian , Andersen Gregers R. , Spillner Edzard 
Published: December 2017

AbstractAnti-IgE therapeutics interfere with the ability of IgE to bind to its receptors on effector cells. Here we report the crystal structure of an anti-IgE single-domain antibody in complex with an IgE Fc fragment, revealing how the antibody inhibits interactions between IgE and the two receptors FcεRI and CD23. The epitope overlaps only slightly with the FcεRI-binding site but significantly with the CD23-binding site. Solution scattering studies of the IgE Fc reveal that antibody binding induces a half-bent conformation in between the well-known bent and extended IgE Fc conformations. The antibody acts as functional homolog of CD23 and induces a closed conformation of IgE Fc incompatible with FcεRI binding. Notably the antibody displaces IgE from both CD23 and FcεRI, and abrogates allergen-mediated basophil activation and facilitated allergen binding. The inhibitory mechanism might facilitate strategies for the future development of anti-IgE therapeutics for treatment of allergic diseases.
VAMPnets for deep learning of molecular kinetics
Authors: Mardt Andreas , Pasquali Luca , Wu Hao , Noé Frank 
Published: December 2017

AbstractThere is an increasing demand for computing the relevant structures, equilibria, and long-timescale kinetics of biomolecular processes, such as protein-drug binding, from high-throughput molecular dynamics simulations. Current methods employ transformation of simulated coordinates into structural features, dimension reduction, clustering the dimension-reduced data, and estimation of a Markov state model or related model of the interconversion rates between molecular structures. This handcrafted approach demands a substantial amount of modeling expertise, as poor decisions at any step will lead to large modeling errors. Here we employ the variational approach for Markov processes (VAMP) to develop a deep learning framework for molecular kinetics using neural networks, dubbed VAMPnets. A VAMPnet encodes the entire mapping from molecular coordinates to Markov states, thus combining the whole data processing pipeline in a single end-to-end framework. Our method performs equally or better than state-of-the-art Markov modeling methods and provides easily interpretable few-state kinetic models.
Perturbation-response genes reveal signaling footprints in cancer gene expression
Authors: Schubert Michael , Klinger Bertram , Klünemann Martina , Sieber Anja , Uhlitz Florian , Sauer Sascha , Garnett Mathew J. , Blüthgen Nils , Saez-Rodriguez Julio 
Published: December 2017

AbstractAberrant cell signaling can cause cancer and other diseases and is a focal point of drug research. A common approach is to infer signaling activity of pathways from gene expression. However, mapping gene expression to pathway components disregards the effect of post-translational modifications, and downstream signatures represent very specific experimental conditions. Here we present PROGENy, a method that overcomes both limitations by leveraging a large compendium of publicly available perturbation experiments to yield a common core of Pathway RespOnsive GENes. Unlike pathway mapping methods, PROGENy can (i) recover the effect of known driver mutations, (ii) provide or improve strong markers for drug indications, and (iii) distinguish between oncogenic and tumor suppressor pathways for patient survival. Collectively, these results show that PROGENy accurately infers pathway activity from gene expression in a wide range of conditions.
Homocysteine directly interacts and activates the angiotensin II type I receptor to aggravate vascular injury
Authors: Li Tuoyi , Yu Bing , Liu Zhixin , Li Jingyuan , Ma Mingliang , Wang Yingbao , Zhu Mingjiang , Yin Huiyong , Wang Xiaofeng , Fu Yi , Yu Fang , Wang Xian , Fang Xiaohong , Sun Jinpeng , Kong Wei 
Published: December 2017

AbstractHyperhomocysteinemia (HHcy) is a risk factor for various cardiovascular diseases. However, the mechanism underlying HHcy-aggravated vascular injury remains unclear. Here we show that the aggravation of abdominal aortic aneurysm by HHcy is abolished in mice with genetic deletion of the angiotensin II type 1 (AT1) receptor and in mice treated with an AT1 blocker. We find that homocysteine directly activates AT1 receptor signalling. Homocysteine displaces angiotensin II and limits its binding to AT1 receptor. Bioluminescence resonance energy transfer analysis reveals distinct conformational changes of AT1 receptor upon binding to angiotensin II and homocysteine. Molecular dynamics and site-directed mutagenesis experiments suggest that homocysteine regulates the conformation of the AT1 receptor both orthosterically and allosterically by forming a salt bridge and a disulfide bond with its Arg167 and Cys289 residues, respectively. Together, these findings suggest that strategies aimed at blocking the AT1 receptor may mitigate HHcy-associated aneurysmal vascular injuries.
Network connectivity determines cortical thinning in early Parkinson’s disease progression
Authors: Yau Y. , Zeighami Y. , Baker T. E. , Larcher K. , Vainik U. , Dadar M. , Fonov V. S. , Hagmann P. , Griffa A. , Mišić B. , Collins D. L. , Dagher A. 
Published: December 2017

AbstractHere we test the hypothesis that the neurodegenerative process in Parkinson’s disease (PD) moves stereotypically along neural networks, possibly reflecting the spread of toxic alpha-synuclein molecules. PD patients (n = 105) and matched controls (n = 57) underwent T1-MRI at entry and 1 year later as part of the Parkinson’s Progression Markers Initiative. Over this period, PD patients demonstrate significantly greater cortical thinning than controls in parts of the left occipital and bilateral frontal lobes and right somatomotor-sensory cortex. Cortical thinning is correlated to connectivity (measured functionally or structurally) to a “disease reservoir” evaluated by MRI at baseline. The atrophy pattern in the ventral frontal lobes resembles one described in certain cases of Alzheimer’s disease. Our findings suggest that disease propagation to the cortex in PD follows neuronal connectivity and that disease spread to the cortex may herald the onset of cognitive impairment.
Cooperative interactions between seed-borne bacterial and air-borne fungal pathogens on rice
Authors: Jung Boknam , Park Jungwook , Kim Namgyu , Li Taiying , Kim Soyeon , Bartley Laura E. , Kim Jinnyun , Kim Inyoung , Kang Yoonhee , Yun Kihoon , Choi Younghae , Lee Hyun-Hee , Ji Sungyeon , Lee Kwang Sik , Kim Bo Yeon , Shon Jong Cheol , Kim Won Cheol , Liu Kwang-Hyeon , Yoon Dahye , Kim Suhkman , Seo Young-Su , Lee Jungkwan 
Published: December 2017

AbstractBacterial-fungal interactions are widely found in distinct environments and contribute to ecosystem processes. Previous studies of these interactions have mostly been performed in soil, and only limited studies of aerial plant tissues have been conducted. Here we show that a seed-borne plant pathogenic bacterium, Burkholderia glumae (Bg), and an air-borne plant pathogenic fungus, Fusarium graminearum (Fg), interact to promote bacterial survival, bacterial and fungal dispersal, and disease progression on rice plants, despite the production of antifungal toxoflavin by Bg. We perform assays of toxoflavin sensitivity, RNA-seq analyses, lipid staining and measures of triacylglyceride content to show that triacylglycerides containing linolenic acid mediate resistance to reactive oxygen species that are generated in response to toxoflavin in Fg. As a result, Bg is able to physically attach to Fg to achieve rapid and expansive dispersal to enhance disease severity.
Development of a genetically encodable FRET system using fluorescent RNA aptamers
Authors: Jepsen Mette D. E. , Sparvath Steffen M. , Nielsen Thorbjørn B. , Langvad Ane H. , Grossi Guido , Gothelf Kurt V. , Andersen Ebbe S. 
Published: December 2017

AbstractFluorescent RNA aptamers are useful as markers for tracking RNA molecules inside cells and for creating biosensor devices. Förster resonance energy transfer (FRET) based on fluorescent proteins has been used to detect conformational changes, however, such FRET devices have not yet been produced using fluorescent RNA aptamers. Here we develop an RNA aptamer-based FRET (apta-FRET) system using single-stranded RNA origami scaffolds. To obtain FRET, the fluorescent aptamers Spinach and Mango are placed in close proximity on the RNA scaffolds and a new fluorophore is synthesized to increase spectral overlap. RNA devices that respond to conformational changes are developed, and finally, apta-FRET constructs are expressed in E. coli where FRET is observed, demonstrating that the apta-FRET system is genetically encodable and that the RNA nanostructures fold correctly in bacteria. We anticipate that the RNA apta-FRET system could have applications as ratiometric sensors for real-time studies in cell and synthetic biology.
Structural characterisation reveals insights into substrate recognition by the glutamine transporter ASCT2/SLC1A5
Authors: Scopelliti Amanda J , Font Josep , Vandenberg Robert J , Boudker Olga , Ryan Renae M 
Published: December 2017

AbstractCancer cells undergo a shift in metabolism where they become reliant on nutrients such as the amino-acid glutamine. Glutamine enters the cell via the alanine/serine/cysteine transporter 2 (ASCT2) that is upregulated in several cancers to maintain an increased supply of this nutrient and are therefore an attractive target in cancer therapeutic development. ASCT2 belongs to the glutamate transporter (SLC1A) family but is the only transporter in this family able to transport glutamine. The structural basis for glutamine selectivity of ASCT2 is unknown. Here, we identify two amino-acid residues in the substrate-binding site that are responsible for conferring glutamine selectivity. We introduce corresponding mutations into a prokaryotic homologue of ASCT2 and solve four crystal structures, which reveal the structural basis for neutral amino acid and inhibitor binding in this family. This structural model of ASCT2 may provide a basis for future development of selective ASCT2 inhibitors to treat glutamine-dependent cancers.
Inhibition of Poly(A)-binding protein with a synthetic RNA mimic reduces pain sensitization in mice
Authors: Barragán-Iglesias Paulino , Lou Tzu-Fang , Bhat Vandita D. , Megat Salim , Burton Michael D. , Price Theodore J. , Campbell Zachary T. 
Published: December 2017

AbstractNociceptors rely on cap-dependent translation to rapidly induce protein synthesis in response to pro-inflammatory signals. Comparatively little is known regarding the role of the regulatory factors bound to the 3′ end of mRNA in nociceptor sensitization. Poly(A)-binding protein (PABP) stimulates translation initiation by bridging the Poly(A) tail to the eukaryotic initiation factor 4F complex associated with the mRNA cap. Here, we use unbiased assessment of PABP binding specificity to generate a chemically modified RNA-based competitive inhibitor of PABP. The resulting RNA mimic, which we designated as the Poly(A) SPOT-ON, is more stable than unmodified RNA and binds PABP with high affinity and selectivity in vitro. We show that injection of the Poly(A) SPOT-ON at the site of an injury can attenuate behavioral response to pain. Collectively, these results suggest that PABP is integral for nociceptive plasticity. The general strategy described here provides a broad new source of mechanism-based inhibitors for RNA-binding proteins and is applicable for in vivo studies.
A unifying theory for top-heavy ecosystem structure in the ocean
Authors: Woodson C. Brock , Schramski John R. , Joye Samantha B. 
Published: December 2017

AbstractSize generally dictates metabolic requirements, trophic level, and consequently, ecosystem structure, where inefficient energy transfer leads to bottom-heavy ecosystem structure and biomass decreases as individual size (or trophic level) increases. However, many animals deviate from simple size-based predictions by either adopting generalist predatory behavior, or feeding lower in the trophic web than predicted from their size. Here we show that generalist predatory behavior and lower trophic feeding at large body size increase overall biomass and shift ecosystems from a bottom-heavy pyramid to a top-heavy hourglass shape, with the most biomass accounted for by the largest animals. These effects could be especially dramatic in the ocean, where primary producers are the smallest components of the ecosystem. This approach makes it possible to explore and predict, in the past and in the future, the structure of ocean ecosystems without biomass extraction and other impacts.
TNF blockade induces a dysregulated type I interferon response without autoimmunity in paradoxical psoriasis
Authors: Conrad Curdin , Di Domizio Jeremy , Mylonas Alessio , Belkhodja Cyrine , Demaria Olivier , Navarini Alexander A. , Lapointe Anne-Karine , French Lars E. , Vernez Maxime , Gilliet Michel 
Published: December 2017

AbstractAlthough anti-tumor necrosis factor (TNF) agents are highly effective in the treatment of psoriasis, 2–5% of treated patients develop psoriasis-like skin lesions called paradoxical psoriasis. The pathogenesis of this side effect and its distinction from classical psoriasis remain unknown. Here we show that skin lesions from patients with paradoxical psoriasis are characterized by a selective overexpression of type I interferons, dermal accumulation of plasmacytoid dendritic cells (pDC), and reduced T-cell numbers, when compared to classical psoriasis. Anti-TNF treatment prolongs type I interferon production by pDCs through inhibition of their maturation. The resulting type I interferon overexpression is responsible for the skin phenotype of paradoxical psoriasis, which, unlike classical psoriasis, is independent of T cells. These findings indicate that paradoxical psoriasis represents an ongoing overactive innate inflammatory process, driven by pDC-derived type I interferon that does not lead to T-cell autoimmunity.
Discovery of human cell selective effector molecules using single cell multiplexed activity metabolomics
Authors: Earl David C. , Ferrell P. Brent , Leelatian Nalin , Froese Jordan T. , Reisman Benjamin J. , Irish Jonathan M. , Bachmann Brian O. 
Published: December 2017

AbstractDiscovering bioactive metabolites within a metabolome is challenging because there is generally little foreknowledge of metabolite molecular and cell-targeting activities. Here, single-cell response profiles and primary human tissue comprise a response platform used to discover novel microbial metabolites with cell-type-selective effector properties in untargeted metabolomic inventories. Metabolites display diverse effector mechanisms, including targeting protein synthesis, cell cycle status, DNA damage repair, necrosis, apoptosis, or phosphoprotein signaling. Arrayed metabolites are tested against acute myeloid leukemia patient bone marrow and molecules that specifically targeted blast cells or nonleukemic immune cell subsets within the same tissue biopsy are revealed. Cell-targeting polyketides are identified in extracts from biosynthetically prolific bacteria, including a previously unreported leukemia blast-targeting anthracycline and a polyene macrolactam that alternates between targeting blasts or nonmalignant cells by way of light-triggered photochemical isomerization. High-resolution cell profiling with mass cytometry confirms response mechanisms and is used to validate initial observations.
Macrophages orchestrate breast cancer early dissemination and metastasis
Authors: Linde Nina , Casanova-Acebes Maria , Sosa Maria Soledad , Mortha Arthur , Rahman Adeeb , Farias Eduardo , Harper Kathryn , Tardio Ethan , Reyes Torres Ivan , Jones Joan , Condeelis John , Merad Miriam , Aguirre-Ghiso Julio A. 
Published: December 2017

AbstractCancer cell dissemination during very early stages of breast cancer proceeds through poorly understood mechanisms. Here we show, in a mouse model of HER2+ breast cancer, that a previously described sub-population of early-evolved cancer cells requires macrophages for early dissemination. Depletion of macrophages specifically during pre-malignant stages reduces early dissemination and also results in reduced metastatic burden at end stages of cancer progression. Mechanistically, we show that, in pre-malignant lesions, CCL2 produced by cancer cells and myeloid cells attracts CD206+/Tie2+ macrophages and induces Wnt-1 upregulation that in turn downregulates E-cadherin junctions in the HER2+ early cancer cells. We also observe macrophage-containing tumor microenvironments of metastasis structures in the pre-malignant lesions that can operate as portals for intravasation. These data support a causal role for macrophages in early dissemination that affects long-term metastasis development much later in cancer progression. A pilot analysis on human specimens revealed intra-epithelial macrophages and loss of E-cadherin junctions in ductal carcinoma in situ, supporting a potential clinical relevance.
RAD54 N-terminal domain is a DNA sensor that couples ATP hydrolysis with branch migration of Holliday junctions
Authors: Goyal Nadish , Rossi Matthew J. , Mazina Olga M. , Chi Yong , Moritz Robert L. , Clurman Bruce E. , Mazin Alexander V. 
Published: December 2017

AbstractIn eukaryotes, RAD54 catalyzes branch migration (BM) of Holliday junctions, a basic process during DNA repair, replication, and recombination. RAD54 also stimulates RAD51 recombinase and has other activities. Here, we investigate the structural determinants for different RAD54 activities. We find that the RAD54 N-terminal domain (NTD) is responsible for initiation of BM through two coupled, but distinct steps; specific binding to Holliday junctions and RAD54 oligomerization. Furthermore, we find that the RAD54 oligomeric state can be controlled by NTD phosphorylation at S49, a CDK2 consensus site, which inhibits RAD54 oligomerization and, consequently, BM. Importantly, the effect of phosphorylation on RAD54 oligomerization is specific for BM, as it does not affect stimulation of RAD51 recombinase by RAD54. Thus, the transition of the oligomeric states provides an important control of the biological functions of RAD54 and, likely, other multifunctional proteins.
Extreme haplotype variation in the desiccation-tolerant clubmoss Selaginella lepidophylla
Authors: VanBuren Robert , Wai Ching Man , Ou Shujun , Pardo Jeremy , Bryant Doug , Jiang Ning , Mockler Todd C. , Edger Patrick , Michael Todd P. 
Published: December 2017

AbstractPlant genome size varies by four orders of magnitude, and most of this variation stems from dynamic changes in repetitive DNA content. Here we report the small 109 Mb genome of Selaginella lepidophylla, a clubmoss with extreme desiccation tolerance. Single-molecule sequencing enables accurate haplotype assembly of a single heterozygous S. lepidophylla plant, revealing extensive structural variation. We observe numerous haplotype-specific deletions consisting of largely repetitive and heavily methylated sequences, with enrichment in young Gypsy LTR retrotransposons. Such elements are active but rapidly deleted, suggesting “bloat and purge” to maintain a small genome size. Unlike all other land plant lineages, Selaginella has no evidence of a whole-genome duplication event in its evolutionary history, but instead shows unique tandem gene duplication patterns reflecting adaptation to extreme drying. Gene expression changes during desiccation in S. lepidophylla mirror patterns observed across angiosperm resurrection plants.
Tutorial: Assessment and Analysis of Polysyllables in Young Children
Authors: Masso Sarah , McLeod Sharynne , Baker Elise 
Published: December 2017

Purpose
Polysyllables, words of 3 or more syllables, represent almost 30% of words used in American English. The purpose of this tutorial is to support speech-language pathologists' (SLPs') assessment and analysis of polysyllables, extending the focus of published assessment tools that focus on sampling and analyzing children's segmental accuracy and/or the presence of phonological error patterns.

Method
This tutorial will guide SLPs through a review of 53 research papers that have explored the use of polysyllables in assessment, including the sampling and analysis procedures used in different research studies. The tutorial will also introduce two new tools to analyze and interpret polysyllable speech samples: the Word-Level Analysis of Polysyllables (WAP; Masso, 2016b) and the Framework of Polysyllable Maturity (Framework; Masso, 2016a).

Results
Connected speech and single-word sampling tasks were used across the 53 studies to elicit polysyllables, and a number of analysis methods were reported, including measures of segmental accuracy and measures of structural and suprasegmental accuracy. The WAP and the Framework extend SLPs' depth of analysis of polysyllables.

Conclusion
SLPs need a range of clinical tools to support the assessment and analysis of polysyllables. A case study comparing different speech analysis methods demonstrates the clinical value in utilizing the WAP and the Framework to interpret children's polysyllable productions in addition to traditional methods of speech sampling and analysis.
Liver Injury in Hemolysis, Elevated Liver Enzymes, and Low Platelets Syndrome Measured by Diffusion-Weighted Magnetic Resonance Imaging
Authors: Khan Ambereen , Bailey April , Yokoo Takeshi , Pedrosa Ivan , McIntire Donald , Cunningham F. , Nelson David 
Published: December 2017

Objective The objective of this study was to evaluate acute liver injury (ALI) detected by diffusion-weighted magnetic resonance imaging (MRI) and the associated laboratory findings in women with hemolysis, elevated liver enzymes, and low platelet (HELLP) syndrome.
Study Design This was a retrospective, observational study of women with HELLP syndrome defined by serum aspartate aminotransferase (AST) levels ≥100 U/L and thrombocytopenia with platelets ≤100,000/µL. All women underwent MRI postpartum including diffusion-weighted imaging to estimate the volume of ALI with reconstructed apparent diffusion coefficient (ADC) maps. The ADC map and the volume of ALI were compared with laboratory abnormalities by Spearman's correlation analysis.
Results From March 2013 through August 2015, 16 women with HELLP syndrome underwent MRI, and of these, 14 (88%) women had areas of increased signal intensity suggestive of ALI. Their median (range) maximum AST level was 262 (140–1,958) IU/L, and at the time of MRI, AST was 103 (36–1,426) IU/L. Both of these AST levels significantly correlated with ADC map as well as the volume of ALI (both p-values <0.001).
Conclusion Women with HELLP syndrome frequently exhibited areas of abnormal diffusion in the liver on diffusion-weighted MRI, suggestive of ALI. The extent of liver injury was significantly correlated with serum AST.