bluuebunny/crossref_metadata_2025_split huggingface dataset:
MD2 activation by direct AGE interaction drives inflammatory diabetic cardiomyopathy
Authors: Wang Yi , Luo Wu , Han Jibo , Khan Zia A. , Fang Qilu , Jin Yiyi , Chen Xuemei , Zhang Yali , Wang Meihong , Qian Jianchang , Huang Weijian , Lum Hazel , Wu Gaojun , Liang Guang 
Published: May 2020

AbstractHyperglycemia activates toll-like receptor 4 (TLR4) to induce inflammation in diabetic cardiomyopathy (DCM). However, the mechanisms of TLR4 activation remain unclear. Here we examine the role of myeloid differentiation 2 (MD2), a co-receptor of TLR4, in high glucose (HG)- and diabetes-induced inflammatory cardiomyopathy. We show increased MD2 in heart tissues of diabetic mice and serum of human diabetic subjects. MD2 deficiency in mice inhibits TLR4 pathway activation, which correlates with reduced myocardial remodeling and improved cardiac function. Mechanistically, we show that HG induces extracellular advanced glycation end products (AGEs), which bind directly to MD2, leading to formation of AGEs-MD2-TLR4 complex and initiation of pro-inflammatory pathways. We further detect elevated AGE-MD2 complexes in heart tissues and serum of diabetic mice and human subjects with DCM. In summary, we uncover a new mechanism of HG-induced inflammatory responses and myocardial injury, in which AGE products directly bind MD2 to drive inflammatory DCM.
Proimmunogenic impact of MEK inhibition synergizes with agonist anti-CD40 immunostimulatory antibodies in tumor therapy
Authors: Baumann Daniel , Hägele Tanja , Mochayedi Julian , Drebant Jennifer , Vent Caroline , Blobner Sven , Noll Julia Han , Nickel Irena , Schumacher Corinna , Boos Sophie Luise , Daniel Aline Sophie , Wendler Susann , Volkmar Michael , Strobel Oliver , Offringa Rienk 
Published: May 2020

AbstractCancer types with lower mutational load and a non-permissive tumor microenvironment are intrinsically resistant to immune checkpoint blockade. While the combination of cytostatic drugs and immunostimulatory antibodies constitutes an attractive concept for overcoming this refractoriness, suppression of immune cell function by cytostatic drugs may limit therapeutic efficacy. Here we show that targeted inhibition of mitogen-activated protein kinase (MAPK) kinase (MEK) does not impair dendritic cell-mediated T cell priming and activation. Accordingly, combining MEK inhibitors (MEKi) with agonist antibodies (Abs) targeting the immunostimulatory CD40 receptor results in potent synergistic antitumor efficacy. Detailed analysis of the mechanism of action of MEKi shows that this drug exerts multiple pro-immunogenic effects, including the suppression of M2-type macrophages, myeloid derived suppressor cells and T-regulatory cells. The combination of MEK inhibition with agonist anti-CD40 Ab is therefore a promising therapeutic concept, especially for the treatment of mutant Kras-driven tumors such as pancreatic ductal adenocarcinoma.
Effective combinatorial immunotherapy for penile squamous cell carcinoma
Authors: Huang Tianhe , Cheng Xi , Chahoud Jad , Sarhan Ahmed , Tamboli Pheroze , Rao Priya , Guo Ming , Manyam Ganiraju , Zhang Li , Xiang Yu , Han Leng , Shang Xiaoying , Deng Pingna , Luo Yanting , Lu Xuemin , Feng Shan , Ferrer Magaly Martinez , Alan Wang Y. , DePinho Ronald A. , Pettaway Curtis A. , Lu Xin 
Published: May 2020

AbstractPenile squamous cell carcinoma (PSCC) accounts for over 95% of penile malignancies and causes significant mortality and morbidity in developing countries. Molecular mechanisms and therapies of PSCC are understudied, owing to scarcity of laboratory models. Herein, we describe a genetically engineered mouse model of PSCC, by co-deletion of Smad4 and Apc in the androgen-responsive epithelium of the penis. Mouse PSCC fosters an immunosuppressive microenvironment with myeloid-derived suppressor cells (MDSCs) as a dominant population. Preclinical trials in the model demonstrate synergistic efficacy of immune checkpoint blockade with the MDSC-diminishing drugs cabozantinib or celecoxib. A critical clinical problem of PSCC is chemoresistance to cisplatin, which is induced by Pten deficiency on the backdrop of Smad4/Apc co-deletion. Drug screen studies informed by targeted proteomics identify a few potential therapeutic strategies for PSCC. Our studies have established what we believe to be essential resources for studying PSCC biology and developing therapeutic strategies.
DIP/Dpr interactions and the evolutionary design of specificity in protein families
Authors: Sergeeva Alina P. , Katsamba Phinikoula S. , Cosmanescu Filip , Brewer Joshua J. , Ahlsen Goran , Mannepalli Seetha , Shapiro Lawrence , Honig Barry 
Published: May 2020

AbstractDifferential binding affinities among closely related protein family members underlie many biological phenomena, including cell-cell recognition. Drosophila DIP and Dpr proteins mediate neuronal targeting in the fly through highly specific protein-protein interactions. We show here that DIPs/Dprs segregate into seven specificity subgroups defined by binding preferences between their DIP and Dpr members. We then describe a sequence-, structure- and energy-based computational approach, combined with experimental binding affinity measurements, to reveal how specificity is coded on the canonical DIP/Dpr interface. We show that binding specificity of DIP/Dpr subgroups is controlled by “negative constraints”, which interfere with binding. To achieve specificity, each subgroup utilizes a different combination of negative constraints, which are broadly distributed and cover the majority of the protein-protein interface. We discuss the structural origins of negative constraints, and potential general implications for the evolutionary origins of binding specificity in multi-protein families.
Estrogen receptor-α expressing neurons in the ventrolateral VMH regulate glucose balance
Authors: He Yanlin , Xu Pingwen , Wang Chunmei , Xia Yan , Yu Meng , Yang Yongjie , Yu Kaifan , Cai Xing , Qu Na , Saito Kenji , Wang Julia , Hyseni Ilirjana , Robertson Matthew , Piyarathna Badrajee , Gao Min , Khan Sohaib A. , Liu Feng , Chen Rui , Coarfa Cristian , Zhao Zhongming , Tong Qingchun , Sun Zheng , Xu Yong 
Published: May 2020

AbstractBrain glucose-sensing neurons detect glucose fluctuations and prevent severe hypoglycemia, but mechanisms mediating functions of these glucose-sensing neurons are unclear. Here we report that estrogen receptor-α (ERα)-expressing neurons in the ventrolateral subdivision of the ventromedial hypothalamic nucleus (vlVMH) can sense glucose fluctuations, being glucose-inhibited neurons (GI-ERαvlVMH) or glucose-excited neurons (GE-ERαvlVMH). Hypoglycemia activates GI-ERαvlVMH neurons via the anoctamin 4 channel, and inhibits GE-ERαvlVMH neurons through opening the ATP-sensitive potassium channel. Further, we show that GI-ERαvlVMH neurons preferentially project to the medioposterior arcuate nucleus of the hypothalamus (mpARH) and GE-ERαvlVMH neurons preferentially project to the dorsal Raphe nuclei (DRN). Activation of ERαvlVMH to mpARH circuit and inhibition of ERαvlVMH to DRN circuit both increase blood glucose. Thus, our results indicate that ERαvlVMH neurons detect glucose fluctuations and prevent severe hypoglycemia in mice.
Structural changes in noble metal nanoparticles during CO oxidation and their impact on catalyst activity
Authors: Chee See Wee , Arce-Ramos Juan Manuel , Li Wenqing , Genest Alexander , Mirsaidov Utkur 
Published: May 2020

AbstractThe dynamical structure of a catalyst determines the availability of active sites on its surface. However, how nanoparticle (NP) catalysts re-structure under reaction conditions and how these changes associate with catalytic activity remains poorly understood. Using operando transmission electron microscopy, we show that Pd NPs exhibit reversible structural and activity changes during heating and cooling in mixed gas environments containing O2 and CO. Below 400 °C, the NPs form flat low index facets and are inactive towards CO oxidation. Above 400 °C, the NPs become rounder, and conversion of CO to CO2 increases significantly. This behavior reverses when the temperature is later reduced. Pt and Rh NPs under similar conditions do not exhibit such reversible transformations. We propose that adsorbed CO molecules suppress the activity of Pd NPs at lower temperatures by stabilizing low index facets and reducing the number of active sites. This hypothesis is supported by thermodynamic calculations.
Endothelin-1 signaling maintains glial progenitor proliferation in the postnatal subventricular zone
Authors: Adams Katrina L. , Riparini Giulia , Banerjee Payal , Breur Marjolein , Bugiani Marianna , Gallo Vittorio 
Published: May 2020

AbstractSignaling molecules that regulate neurodevelopmental processes in the early postnatal subventricular zone (SVZ) are critical for proper brain development yet remain poorly characterized. Here, we report that Endothelin-1 (ET-1), a molecular component of the postnatal SVZ, promotes radial glial cell maintenance and proliferation in an autocrine manner via Notch signaling. Loss of ET-1 signaling increases neurogenesis and reduces oligodendrocyte progenitor cell proliferation (OPC) in the developing SVZ, thereby altering cellular output of the stem cell niche. We also show that ET-1 is required for increased neural stem cell and OPC proliferation in the adult mouse SVZ following demyelination. Lastly, high levels of ET-1 in the SVZ of patients with Cathepsin A-related arteriopathy with strokes and leukoencephalopathy correlate with an increased number of SVZ OPCs, suggesting ET-1’s role as a regulator of glial progenitor proliferation may be conserved in humans. ET-1 signaling therefore presents a potential new therapeutic target for promoting SVZ-mediated cellular repair.
Electronic-photonic arithmetic logic unit for high-speed computing
Authors: Ying Zhoufeng , Feng Chenghao , Zhao Zheng , Dhar Shounak , Dalir Hamed , Gu Jiaqi , Cheng Yue , Soref Richard , Pan David Z. , Chen Ray T. 
Published: May 2020

AbstractThe past two decades have witnessed the stagnation of the clock speed of microprocessors followed by the recent faltering of Moore’s law as nanofabrication technology approaches its unavoidable physical limit. Vigorous efforts from various research areas have been made to develop power-efficient and ultrafast computing machines in this post-Moore’s law era. With its unique capacity to integrate complex electro-optic circuits on a single chip, integrated photonics has revolutionized the interconnects and has shown its striking potential in optical computing. Here, we propose an electronic-photonic computing architecture for a wavelength division multiplexing-based electronic-photonic arithmetic logic unit, which disentangles the exponential relationship between power and clock rate, leading to an enhancement in computation speed and power efficiency as compared to the state-of-the-art transistors-based circuits. We experimentally demonstrate its practicality by implementing a 4-bit arithmetic logic unit consisting of 8 high-speed microdisk modulators and operating at 20 GHz. This approach paves the way to future power-saving and high-speed electronic-photonic computing circuits.
A common allosteric mechanism regulates homeostatic inactivation of auxin and gibberellin
Authors: Takehara Sayaka , Sakuraba Shun , Mikami Bunzo , Yoshida Hideki , Yoshimura Hisako , Itoh Aya , Endo Masaki , Watanabe Nobuhisa , Nagae Takayuki , Matsuoka Makoto , Ueguchi-Tanaka Miyako 
Published: May 2020

AbstractAllosteric regulation is protein activation by effector binding at a site other than the active site. Here, we show via X-ray structural analysis of gibberellin 2-oxidase 3 (GA2ox3), and auxin dioxygenase (DAO), that such a mechanism maintains hormonal homeostasis in plants. Both enzymes form multimers by interacting via GA4 and indole-3-acetic acid (IAA) at their binding interface. Via further functional analyses we reveal that multimerization of these enzymes gradually proceeds with increasing GA4 and IAA concentrations; multimerized enzymes have higher specific activities than monomer forms, a system that should favour the maintenance of homeostasis for these phytohormones. Molecular dynamic analysis suggests a possible mechanism underlying increased GA2ox3 activity by multimerization—GA4 in the interface of oligomerized GA2ox3s may be able to enter the active site with a low energy barrier. In summary, homeostatic systems for maintaining GA and IAA levels, based on a common allosteric mechanism, appear to have developed independently.
Stress-induced expression is enriched for evolutionarily young genes in diverse budding yeasts
Authors: Doughty Tyler W. , Domenzain Iván , Millan-Oropeza Aaron , Montini Noemi , de Groot Philip A. , Pereira Rui , Nielsen Jens , Henry Céline , Daran Jean-Marc G. , Siewers Verena , Morrissey John P. 
Published: May 2020

AbstractThe Saccharomycotina subphylum (budding yeasts) spans 400 million years of evolution and includes species that thrive in diverse environments. To study niche-adaptation, we identify changes in gene expression in three divergent yeasts grown in the presence of various stressors. Duplicated and non-conserved genes are significantly more likely to respond to stress than genes that are conserved as single-copy orthologs. Next, we develop a sorting method that considers evolutionary origin and duplication timing to assign an evolutionary age to each gene. Subsequent analysis reveals that genes that emerged in recent evolutionary time are enriched amongst stress-responsive genes for each species. This gene expression pattern suggests that budding yeasts share a stress adaptation mechanism, whereby selective pressure leads to functionalization of young genes to improve growth in adverse conditions. Further characterization of young genes from species that thrive in harsh environments can inform the design of more robust strains for biotechnology.
Systemic short chain fatty acids limit antitumor effect of CTLA-4 blockade in hosts with cancer
Authors: Coutzac Clélia , Jouniaux Jean-Mehdi , Paci Angelo , Schmidt Julien , Mallardo Domenico , Seck Atmane , Asvatourian Vahe , Cassard Lydie , Saulnier Patrick , Lacroix Ludovic , Woerther Paul-Louis , Vozy Aurore , Naigeon Marie , Nebot-Bral Laetitia , Desbois Mélanie , Simeone Ester , Mateus Christine , Boselli Lisa , Grivel Jonathan , Soularue Emilie , Lepage Patricia , Carbonnel Franck , Ascierto Paolo Antonio , Robert Caroline , Chaput Nathalie 
Published: May 2020

AbstractGut microbiota composition influences the clinical benefit of immune checkpoints in patients with advanced cancer but mechanisms underlying this relationship remain unclear. Molecular mechanism whereby gut microbiota influences immune responses is mainly assigned to gut microbial metabolites. Short-chain fatty acids (SCFA) are produced in large amounts in the colon through bacterial fermentation of dietary fiber. We evaluate in mice and in patients treated with anti-CTLA-4 blocking mAbs whether SCFA levels is related to clinical outcome. High blood butyrate and propionate levels are associated with resistance to CTLA-4 blockade and higher proportion of Treg cells. In mice, butyrate restrains anti-CTLA-4-induced up-regulation of CD80/CD86 on dendritic cells and ICOS on T cells, accumulation of tumor-specific T cells and memory T cells. In patients, high blood butyrate levels moderate ipilimumab-induced accumulation of memory and ICOS + CD4 + T cells and IL-2 impregnation. Altogether, these results suggest that SCFA limits anti-CTLA-4 activity.
The Set1 N-terminal domain and Swd2 interact with RNA polymerase II CTD to recruit COMPASS
Authors: Bae Hyun Jin , Dubarry Marion , Jeon Jongcheol , Soares Luis M. , Dargemont Catherine , Kim Jaehoon , Geli Vincent , Buratowski Stephen 
Published: May 2020

AbstractMethylation of histone H3 lysine 4 (H3K4) by Set1/COMPASS occurs co-transcriptionally, and is important for gene regulation. Set1/COMPASS associates with the RNA polymerase II C-terminal domain (CTD) to establish proper levels and distribution of H3K4 methylations. However, details of CTD association remain unclear. Here we report that the Set1 N-terminal region and the COMPASS subunit Swd2, which interact with each other, are both needed for efficient CTD binding in Saccharomyces cerevisiae. Moreover, a single point mutation in Swd2 that affects its interaction with Set1 also impairs COMPASS recruitment to chromatin and H3K4 methylation. A CTD interaction domain (CID) from the protein Nrd1 can partially substitute for the Set1 N-terminal region to restore CTD interactions and histone methylation. However, even when Set1/COMPASS is recruited via the Nrd1 CID, histone H2B ubiquitylation is still required for efficient H3K4 methylation, indicating that H2Bub acts after the initial recruitment of COMPASS to chromatin.
Microbial predictors of healing and short-term effect of debridement on the microbiome of chronic wounds
Authors: Verbanic Samuel , Shen Yuning , Lee Juhee , Deacon John M. , Chen Irene A. 
Published: May 2020

AbstractChronic wounds represent a large and growing disease burden. Infection and biofilm formation are two of the leading impediments of wound healing, suggesting an important role for the microbiome of these wounds. Debridement is a common and effective treatment for chronic wounds. We analyzed the bacterial content of the wound surface from 20 outpatients with chronic wounds before and immediately after debridement, as well as healthy skin. Given the large variation observed among different wounds, we introduce a Bayesian statistical method that models patient-to-patient variability and identify several genera that were significantly enriched in wounds vs. healthy skin. We found no difference between the microbiome of the original wound surface and that exposed by a single episode of sharp debridement, suggesting that this debridement did not directly alter the wound microbiome. However, we found that aerobes and especially facultative anaerobes were significantly associated with wounds that did not heal within 6 months. The facultative anaerobic genus Enterobacter was significantly associated with lack of healing. The results suggest that an abundance of facultative anaerobes is a negative prognostic factor in the chronic wound microbiome, possibly due to the increased robustness of such communities to different metabolic environments.
Single-atom energy-conversion device with a quantum load
Authors: Van Horne Noah , Yum Dahyun , Dutta Tarun , Hänggi Peter , Gong Jiangbin , Poletti Dario , Mukherjee Manas 
Published: May 2020

AbstractWe report on a single-atom energy-conversion quantum device operating as an engine, or a refrigerator, coupled to a quantum load. The ‘working fluid’ consists of the two optical levels of an ion, while the load is one of its vibrational modes, cooled down to the quantum regime. We explore two important differences with classical engines: (1) the presence of a strong generic coupling interaction between engine and load, which can induce correlations between them and (2) the use of nonthermal baths. We examine the ergotropy of the load, which indicates the maximum amount of energy of the load extractable using solely unitary operations. We show that ergotropy rises with the number of engine cycles despite an increase in the information entropy of the load. The increase of ergotropy of the load points to the possibility of using the phonon distribution of a single atom as a form of quantum battery.
Dynamics of heavy chain junctional length biases in antibody repertoires
Authors: Sankar Kannan , Hoi Kam Hon , Hötzel Isidro 
Published: May 2020

AbstractAntibody variable domain sequence diversity is generated by recombination of germline segments. The third complementarity-determining region of the heavy chain (CDR H3) is the region of highest sequence diversity and is formed by the joining of heavy chain VH, DH and JH germline segments combined with random nucleotide trimming and additions between these segments. We show that CDR H3 and junctional segment length distributions are biased in human antibody repertoires as a function of VH, VL and JH germline segment utilization. Most length biases are apparent in the naive and antigen experienced B cell compartments but not in nonproductive recombination products, indicating B cell selection as a major driver of these biases. Our findings reveal biases in the antibody CDR H3 diversity landscape shaped by VH, VL, and JH germline segment use during naive and antigen-experienced repertoire selection.
Single-cell expression and Mendelian randomization analyses identify blood genes associated with lifespan and chronic diseases
Authors: Chignon Arnaud , Bon-Baret Valentin , Boulanger Marie-Chloé , Li Zhonglin , Argaud Deborah , Bossé Yohan , Thériault Sébastien , Arsenault Benoit J. , Mathieu Patrick 
Published: May 2020

AbstractThe human lifespan is a heritable trait, which is intricately linked to the development of disorders. Here, we show that genetic associations for the parental lifespan are enriched in open chromatin of blood cells. By using blood expression quantitative trait loci (eQTL) derived from 31,684 samples, we identified for the lifespan 125cis-and 559trans-regulated expressed genes (eGenes) enriched in adaptive and innate responses. Analysis of blood single-cell expression data showed that eGenes were enriched in dendritic cells (DCs) and the modelling of cell ligand-receptor interactions predicted crosstalk between DCs and a cluster of monocytes with a signature of cytotoxicity. In two-sample Mendelian randomization (MR), we identified 16 bloodcis-eGenes causally associated with the lifespan. In MR, the majority ofcis-eGene-disorder association pairs had concordant effects with the lifespan. The present work underlined that the lifespan is linked with the immune response and identifies eGenes associated with the lifespan and disorders.
A human protein hydroxylase that accepts D-residues
Authors: Choi Hwanho , Hardy Adam P. , Leissing Thomas M. , Chowdhury Rasheduzzaman , Nakashima Yu , Ge Wei , Markoulides Marios , Scotti John S. , Gerken Philip A. , Thorbjornsrud Helen , Kang Dahye , Hong Sungwoo , Lee Joongoo , McDonough Michael A. , Park Hwangseo , Schofield Christopher J. 
Published: May 2020

AbstractFactor inhibiting hypoxia-inducible factor (FIH) is a 2-oxoglutarate-dependent protein hydroxylase that catalyses C3 hydroxylations of protein residues. We report FIH can accept (D)- and (L)-residues for hydroxylation. The substrate selectivity of FIH differs for (D) and (L) epimers, e.g., (D)- but not (L)-allylglycine, and conversely (L)- but not (D)-aspartate, undergo monohydroxylation, in the tested sequence context. The (L)-Leu-containing substrate undergoes FIH-catalysed monohydroxylation, whereas (D)-Leu unexpectedly undergoes dihydroxylation. Crystallographic, mass spectrometric, and DFT studies provide insights into the selectivity of FIH towards (L)- and (D)-residues. The results of this work expand the potential range of known substrates hydroxylated by isolated FIH and imply that it will be possible to generate FIH variants with altered selectivities.