bluuebunny/crossref_metadata_2025_split huggingface dataset:
An organelle-specific protein landscape identifies novel diseases and molecular mechanisms
Authors: Boldt Karsten , van Reeuwijk Jeroen , Lu Qianhao , Koutroumpas Konstantinos , Nguyen Thanh-Minh T. , Texier Yves , van Beersum Sylvia E. C. , Horn Nicola , Willer Jason R. , Mans Dorus A. , Dougherty Gerard , Lamers Ideke J. C. , Coene Karlien L. M. , Arts Heleen H. , Betts Matthew J. , Beyer Tina , Bolat Emine , Gloeckner Christian Johannes , Haidari Khatera , Hetterschijt Lisette , Iaconis Daniela , Jenkins Dagan , Klose Franziska , Knapp Barbara , Latour Brooke , Letteboer Stef J. F. , Marcelis Carlo L. , Mitic Dragana , Morleo Manuela , Oud Machteld M. , Riemersma Moniek , Rix Susan , Terhal Paulien A. , Toedt Grischa , van Dam Teunis J. P. , de Vrieze Erik , Wissinger Yasmin , Wu Ka Man , Apic Gordana , Beales Philip L. , Blacque Oliver E. , Gibson Toby J. , Huynen Martijn A. , Katsanis Nicholas , Kremer Hannie , Omran Heymut , van Wijk Erwin , Wolfrum Uwe , Kepes François , Davis Erica E. , Franco Brunella , Giles Rachel H. , Ueffing Marius , Russell Robert B. , Roepman Ronald ,   UK10K Rare Diseases Group, Al-Turki Saeed , Anderson Carl , Antony Dinu , Barroso Inês , Bentham Jamie , Bhattacharya Shoumo , Carss Keren , Chatterjee Krishna , Cirak Sebahattin , Cosgrove Catherine , Danecek Petr , Durbin Richard , Fitzpatrick David , Floyd Jamie , Reghan Foley A. , Franklin Chris , Futema Marta , Humphries Steve E. , Hurles Matt , Joyce Chris , McCarthy Shane , Mitchison Hannah M. , Muddyman Dawn , Muntoni Francesco , O'Rahilly Stephen , Onoufriadis Alexandros , Payne Felicity , Plagnol Vincent , Raymond Lucy , Savage David B. , Scambler Peter , Schmidts Miriam , Schoenmakers Nadia , Semple Robert , Serra Eva , Stalker Jim , van Kogelenberg Margriet , Vijayarangakannan Parthiban , Walter Klaudia , Whittall Ros , Williamson Kathy 
Published: May 2016

AbstractCellular organelles provide opportunities to relate biological mechanisms to disease. Here we use affinity proteomics, genetics and cell biology to interrogate cilia: poorly understood organelles, where defects cause genetic diseases. Two hundred and seventeen tagged human ciliary proteins create a final landscape of 1,319 proteins, 4,905 interactions and 52 complexes. Reverse tagging, repetition of purifications and statistical analyses, produce a high-resolution network that reveals organelle-specific interactions and complexes not apparent in larger studies, and links vesicle transport, the cytoskeleton, signalling and ubiquitination to ciliary signalling and proteostasis. We observe sub-complexes in exocyst and intraflagellar transport complexes, which we validate biochemically, and by probing structurally predicted, disruptive, genetic variants from ciliary disease patients. The landscape suggests other genetic diseases could be ciliary including 3M syndrome. We show that 3M genes are involved in ciliogenesis, and that patient fibroblasts lack cilia. Overall, this organelle-specific targeting strategy shows considerable promise for Systems Medicine.
Behavioural traits propagate across generations via segregated iterative-somatic and gametic epigenetic mechanisms
Authors: Mitchell Emma , Klein Shifra L. , Argyropoulos Kimon V. , Sharma Ali , Chan Robin B. , Toth Judit Gal , Barboza Luendreo , Bavley Charlotte , Bortolozzi Analia , Chen Qiuying , Liu Bingfang , Ingenito Joanne , Mark Willie , Dudakov Jarrod , Gross Steven , Di Paolo Gilbert , Artigas Francesc , van den Brink Marcel , Toth Miklos 
Published: May 2016

AbstractParental behavioural traits can be transmitted by non-genetic mechanisms to the offspring. Although trait transmission via sperm has been extensively researched, epidemiological studies indicate the exclusive/prominent maternal transmission of many non-genetic traits. Since maternal conditions impact the offspring during gametogenesis and through fetal/early-postnatal life, the resultant phenotype is likely the aggregate of consecutive germline and somatic effects; a concept that has not been previously studied. Here, we dissected a complex maternally transmitted phenotype, reminiscent of comorbid generalized anxiety/depression, to elementary behaviours/domains and their transmission mechanisms in mice. We show that four anxiety/stress-reactive traits are transmitted via independent iterative-somatic and gametic epigenetic mechanisms across multiple generations. Somatic/gametic transmission alters DNA methylation at enhancers within synaptic genes whose functions can be linked to the behavioural traits. Traits have generation-dependent penetrance and sex specificity resulting in pleiotropy. A transmission-pathway-based concept can refine current inheritance models of psychiatric diseases and facilitate the development of better animal models and new therapeutic approaches.
Argonaute-associated short introns are a novel class of gene regulators
Authors: Hansen Thomas B. , Venø Morten T. , Jensen Trine I. , Schaefer Anne , Damgaard Christian K. , Kjems Jørgen 
Published: May 2016

AbstractMicroRNAs (miRNAs) are short (∼22 nucleotides) regulators of gene expression acting by direct base pairing to 3′-UTR target sites in messenger RNAs. Mature miRNAs are produced by two sequential endonucleolytic cleavages facilitated by Drosha in the nucleus and Dicer in the cytoplasm. A subclass of miRNAs, termed mirtrons, derives from short introns and enters the miRNA biogenesis pathway as Dicer substrates. Here we uncover a third biogenesis strategy that, similar to mirtron biogenesis, initiates from short introns but bypasses Dicer cleavage. These short introns (80–100 nucleotides), coined agotrons, are associated with and stabilized by Argonaute (Ago) proteins in the cytoplasm. Some agotrons are completely conserved in mammalian species, suggesting that they are functionally important. Furthermore, we demonstrate that the agotrons are capable of repressing mRNAs with seed-matching target sequences in the 3′-UTR. These data provide evidence for a novel RNA regulator of gene expression, which bypasses the canonical miRNA biogenesis machinery.
Evidence that phytochrome functions as a protein kinase in plant light signalling
Authors: Shin Ah-Young , Han Yun-Jeong , Baek Ayoung , Ahn Taeho , Kim Soo Young , Nguyen Thai Son , Son Minky , Lee Keun Woo , Shen Yu , Song Pill-Soon , Kim Jeong-Il 
Published: May 2016

AbstractIt has been suggested that plant phytochromes are autophosphorylating serine/threonine kinases. However, the biochemical properties and functional roles of putative phytochrome kinase activity in plant light signalling are largely unknown. Here, we describe the biochemical and functional characterization of Avena sativa phytochrome A (AsphyA) as a potential protein kinase. We provide evidence that phytochrome-interacting factors (PIFs) are phosphorylated by phytochromes in vitro. Domain mapping of AsphyA shows that the photosensory core region consisting of PAS-GAF-PHY domains in the N-terminal is required for the observed kinase activity. Moreover, we demonstrate that transgenic plants expressing mutant versions of AsphyA, which display reduced activity in in vitro kinase assays, show hyposensitive responses to far-red light. Further analysis reveals that far-red light-induced phosphorylation and degradation of PIF3 are significantly reduced in these transgenic plants. Collectively, these results suggest a positive relationship between phytochrome kinase activity and photoresponses in plants.
Patient-specific factors influence somatic variation patterns in von Hippel–Lindau disease renal tumours
Authors: Fei Suzanne S. , Mitchell Asia D. , Heskett Michael B. , Vocke Cathy D. , Ricketts Christopher J. , Peto Myron , Wang Nicholas J. , Sönmez Kemal , Linehan W. Marston , Spellman Paul T. 
Published: May 2016

AbstractCancer development is presumed to be an evolutionary process that is influenced by genetic background and environment. In laboratory animals, genetics and environment are variables that can largely be held constant. In humans, it is possible to compare independent tumours that have developed in the same patient, effectively constraining genetic and environmental variation and leaving only stochastic processes. Patients affected with von Hippel–Lindau disease are at risk of developing multiple independent clear cell renal carcinomas. Here we perform whole-genome sequencing on 40 tumours from six von Hippel-Lindau patients. We confirm that the tumours are clonally independent, having distinct somatic single-nucleotide variants. Although tumours from the same patient show many differences, within-patient patterns are discernible. Single-nucleotide substitution type rates are significantly different between patients and show biases in trinucleotide mutation context. We also observe biases in chromosome copy number aberrations. These results show that genetic background and/or environment can influence the types of mutations that occur.
Modelled drift patterns of fish larvae link coastal morphology to seabird colony distribution
Authors: Sandvik Hanno , Barrett Robert T. , Erikstad Kjell Einar , Myksvoll Mari S. , Vikebø Frode , Yoccoz Nigel G. , Anker-Nilssen Tycho , Lorentsen Svein-Håkon , Reiertsen Tone K. , Skarðhamar Jofrid , Skern-Mauritzen Mette , Systad Geir Helge 
Published: May 2016

AbstractColonial breeding is an evolutionary puzzle, as the benefits of breeding in high densities are still not fully explained. Although the dynamics of existing colonies are increasingly understood, few studies have addressed the initial formation of colonies, and empirical tests are rare. Using a high-resolution larval drift model, we here document that the distribution of seabird colonies along the Norwegian coast can be explained by variations in the availability and predictability of fish larvae. The modelled variability in concentration of fish larvae is, in turn, predicted by the topography of the continental shelf and coastline. The advection of fish larvae along the coast translates small-scale topographic characteristics into a macroecological pattern,viz.the spatial distribution of top-predator breeding sites. Our findings provide empirical corroboration of the hypothesis that seabird colonies are founded in locations that minimize travel distances between breeding and foraging locations, thereby enabling optimal foraging by central-place foragers.
From a retrovirus infection of mice to a long noncoding RNA that induces proto-oncogene transcription and oncogenesis via an epigenetic transcription switch
Authors: Garen Alan 
Published: May 2016

AbstractHere I review the properties of the mouse retroelement VL30-1, which apparently derived from retrotranspostions of a founder VL30 retrovirus that infected the mouse germline after the mouse–human speciation. The VL30-1 gene is transcribed as a long noncoding RNA (lncRNA) with an essential host function in an epigenetic transcription switch (ETS) that regulates transcription of multiple genes, including proto-oncogenes that control cell proliferation and oncogenesis. The ETS involves the tumor suppressor protein PSF that has a DNA-binding domain (DBD) and two RNA-binding domains (RBDs). The DBD binds to promoters that have a DBD-binding sequence and switches off transcription, and the RBDs bind lncRNAs that have a RBD-binding sequence, releasing PSF and switching on transcription. VL30-1 lncRNA has two RBD-binding sequences, apparently acquired by mutations during retrotranspositions of the founder retrovirus, which drive proto-oncogene transcription and oncogenesis via the ETS. VL30-1 lncRNA is a seminal example of the key role of endogenous retroviruses (ERVs) and their retroelements in the evolution of transcription regulatory systems.
NADPH oxidase is implicated in the pathogenesis of oxidative phosphorylation dysfunction in mice fed a high-fat diet
Authors: García-Ruiz Inmaculada , Solís-Muñoz Pablo , Fernández-Moreira Daniel , Grau Montserrat , Muñoz-Yagüe Teresa , Solís-Herruzo José A. 
Published: May 2016

AbstractThe aim of this study was to evaluate the role of NADPH oxidase (NADPHox) in the pathogenesis of oxidative phosphorylation (OXPHOS) dysfunction as found in mice fed a high-fat diet (HFD). C57BL/6J mice were distributed in four groups: WT/SCD: six wild-type (WT) mice fed a standard chow diet (SCD); WT/HFD, six WT mice fed a HFD; NOX2−/−/SCD, six NADPHox-deficient mice on a SCD; (4) NOX2−/−/HFD, six NADPHox-deficient mice on a HFD. After 32 weeks, we studied the liver for: histology; OXPHOS complex activity; fully assembled OXPHOS complexes and their subunits; gene expression of OXPHOS subunits; oxidative and nitrosative stress; and oxidative DNA damage. In the liver of WT/HFD mice, we found a significant decreased in the activity of all OXPHOS complexes, in fully assembled complexes, in the amount of OXPHOS subunits and in gene expression of mitochondrial DNA-encoded subunits. 8-hydroxy-2′-deoxyguanosine was only increased in mitochondrial DNA. The liver of NOX−/−/HFD mice showed mild steatosis but no non-alcoholic steatohepatitis (NASH) lesions were found. OXPHOS activity, OXPHOS subunits and assembly of subunits into OXPHOS complexes were normal in these mice. We conclude that this study shows that NADPH deficiency protects mice from developing OXPHOS dysfunction and NASH caused by a HFD.
Intracellular chromobody delivery by mesoporous silica nanoparticles for antigen targeting and visualization in real time
Authors: Chiu Hsin-Yi , Deng Wen , Engelke Hanna , Helma Jonas , Leonhardt Heinrich , Bein Thomas 
Published: May 2016

AbstractChromobodies have recently drawn great attention as bioimaging nanotools. They offer high antigen binding specificity and affinity comparable to conventional antibodies, but much smaller size and higher stability. Chromobodies can be used in live cell imaging for specific spatio-temporal visualization of cellular processes. To date, functional application of chromobodies requires lengthy genetic manipulation of the target cell. Here, we develop multifunctional large-pore mesoporous silica nanoparticles (MSNs) as nanocarriers to directly transport chromobodies into living cells for antigen-visualization in real time. The multifunctional large-pore MSNs feature high loading capacity for chromobodies and are efficiently taken up by cells. By functionalizing the internal MSN surface with nitrilotriacetic acid-metal ion complexes, we can control the release of His6-tagged chromobodies from MSNs in acidified endosomes and observe successful chromobody-antigen binding in the cytosol. Hence, by combining the two nanotools, chromobodies and MSNs, we establish a new powerful approach for chromobody applications in living cells.
Modeling and fitting protein-protein complexes to predict change of binding energy
Authors: Dourado Daniel F.A.R. , Flores Samuel Coulbourn 
Published: May 2016

AbstractIt is possible to accurately and economically predict change in protein-protein interaction energy upon mutation (ΔΔG), when a high-resolution structure of the complex is available. This is of growing usefulness for design of high-affinity or otherwise modified binding proteins for therapeutic, diagnostic, industrial, and basic science applications. Recently the field has begun to pursue ΔΔG prediction for homology modeled complexes, but so far this has worked mostly for cases of high sequence identity. If the interacting proteins have been crystallized in free (uncomplexed) form, in a majority of cases it is possible to find a structurally similar complex which can be used as the basis for template-based modeling. We describe how to use MMB to create such models, and then use them to predict ΔΔG, using a dataset consisting of free target structures, co-crystallized template complexes with sequence identify with respect to the targets as low as 44%, and experimental ΔΔG measurements. We obtain similar results by fitting to a low-resolution Cryo-EM density map. Results suggest that other structural constraints may lead to a similar outcome, making the method even more broadly applicable.
The recombined cccDNA produced using minicircle technology mimicked HBV genome in structure and function closely
Authors: Guo Xiaoyan , Chen Ping , Hou Xiaohu , Xu Wenjuan , Wang Dan , Wang Tian-yan , Zhang Liping , Zheng Gang , Gao Zhi-liang , He Cheng-Yi , Zhou Boping , Chen Zhi-Ying 
Published: May 2016

AbstractHBV covalently closed circular DNA (cccDNA) is drug-resistant and responsible for viral persistence. To facilitate the development of anti-cccDNA drugs, we developed a minicircle DNA vector (MC)-based technology to produce large quantity of recombined cccDNA (rcccDNA) resembling closely to its wild-type counterpart both in structure and function. The rcccDNA differed to the wild-type cccDNA (wtcccDNA) only in that it carried an extra 36-bp DNA recombinant product attR upstream of the preC/C gene. Using a procedure similar to standard plasmid production, milligrams of rcccDNA can be generated in common laboratories conveniently. The rcccDNA demonstrated many essential biological features of wtcccDNA, including: (1) undergoing nucleation upon nucleus entry; (2) serving as template for production of all HBV RNAs and proteins; (3) deriving virions capable of infecting tree shrew, and subsequently producing viral mRNAs, proteins, rcccDNA and infectious virions. As an example to develop anti-cccDNA drugs, we used the Crispr/Cas9 system to provide clear-cut evidence that rcccDNA was cleaved by this DNA editing tool in vitro. In summary, we have developed a convenient technology to produce large quantity of rcccDNA as a surrogate of wtcccDNA for investigating HBV biology and developing treatment to eradicate this most wide-spreading virus.
CD3brightCD56+ T cells associate with pegylated interferon-alpha treatment nonresponse in chronic hepatitis B patients
Authors: Guo Chuang , Shen Xiaokun , Fu Binqing , Liu Yanyan , Chen Yongyan , Ni Fang , Ye Ying , Sun Rui , Li Jiabin , Tian Zhigang , Wei Haiming 
Published: May 2016

AbstractChronic hepatitis B (CHB) infection is a serious and prevalent health concern worldwide and the development of effective drugs and strategies to combat this disease is urgently needed. Currently, pegylated interferon-alpha (peg-IFNα) and nucleoside/nucleotide analogues (NA) are the most commonly prescribed treatments. However, sustained response rates in patients remain low and the reasons are not well understood. Here, we observed that CHB patients preferentially harbored CD3brightCD56+ T cells, a newly identified CD56+ T cell population. Patients with this unique T cell population exhibited relatively poor responses to peg-IFNα treatment. CD3brightCD56+ T cells expressed remarkably high levels of the inhibitory molecule NKG2A as well as low levels of CD8. Even if patients were systematically treated with peg-IFNα, CD3brightCD56+ T cells remained in an inhibitory state throughout treatment and exhibited suppressed antiviral function. Furthermore, peg-IFNα treatment rapidly increased inhibitory TIM-3 expression on CD3brightCD56+ T cells, which negatively correlated with IFNγ production and might have led to their dysfunction. This study identified a novel CD3brightCD56+ T cell population preferentially shown in CHB patients and indicated that the presence of CD3brightCD56+ T cells in CHB patients may be useful as a new indicator associated with poor therapeutic responses to peg-IFNα treatment.
Network Meta-Analysis of the Effectiveness of Neoadjuvant Endocrine Therapy for Postmenopausal, HR–Positive Breast Cancer
Authors: Wang Wei , Liu Chenghao , Zhou Wenbin , Xia Tiansong , Xie Hui , Wang Shui 
Published: May 2016

AbstractIn clinical practice, it is necessary to define an optimal choice from many different therapeutic regimens. This study aimed to assess the efficacy and safety of neoadjuvant endocrine therapy (NET) for breast cancer patients. Randomized clinical trials were included. Nine studies comprising 2133 patients were included in the final analysis. Network meta-analysis showed that everolimus plus letrozole was more easily accepted by patients than exemestane (≥20wks) (odds ratio (OR): 856697.02, 95% confidence intervals (95%CI): 1.88 to 87242934...); exemestane (≥20wks) had worse acceptability than letrozole (OR: 0.00, 95%CI: 0.00 to 0.98). Letrozole produced a better clinical objective response (COR) than tamoxifen (OR: 1.99, 95%CI: 1.04 to 3.80). The incidence of fatigue between the anastrozole plus gefitinib group and the everolimus plus letrozole group was significantly different (OR: 0.08, 95%CI: 0.01 to 0.83). The exemestane (<20wks) plus celecoxib group had fewer hot flushes than others. Ranking showed the everolimus plus letrozole was most likely rank first in comparisons of COR and acceptability, and had a 64% possibility to rank first after stochastic multi-criteria acceptability analysis. In conclusion, our study showed that letrozole plus everolimus is the most effective treatment for postmenopausal, hormone receptor-positive breast cancer in the neoadjuvant setting.
Coldest Temperature Extreme Monotonically Increased and Hottest Extreme Oscillated over Northern Hemisphere Land during Last 114 Years
Authors: Zhou Chunlüe , Wang Kaicun 
Published: May 2016

AbstractMost studies on global warming rely on global mean surface temperature, whose change is jointly determined by anthropogenic greenhouse gases (GHGs) and natural variability. This introduces a heated debate on whether there is a recent warming hiatus and what caused the hiatus. Here, we presented a novel method and applied it to a 5° × 5° grid of Northern Hemisphere land for the period 1900 to 2013. Our results show that the coldest 5% of minimum temperature anomalies (the coldest deviation) have increased monotonically by 0.22 °C/decade, which reflects well the elevated anthropogenic GHG effect. The warmest 5% of maximum temperature anomalies (the warmest deviation), however, display a significant oscillation following the Atlantic Multidecadal Oscillation (AMO), with a warming rate of 0.07 °C/decade from 1900 to 2013. The warmest (0.34 °C/decade) and coldest deviations (0.25 °C/decade) increased at much higher rates over the most recent decade than last century mean values, indicating the hiatus should not be interpreted as a general slowing of climate change. The significant oscillation of the warmest deviation provides an extension of previous study reporting no pause in the hottest temperature extremes since 1979, and first uncovers its increase from 1900 to 1939 and decrease from 1940 to 1969.
Identification of P-Rex1 as an anti-inflammatory and anti-fibrogenic target for pulmonary fibrosis
Authors: Liang Qing , Cheng Ni , Zhang Gufang , Liang Yurong , Qian Feng , Wu Dianqing , Ye Richard D. 
Published: May 2016

AbstractPulmonary fibrosis (PF) leads to progressive and often irreversible loss of lung functions, posing a health threat with no effective cure. We examined P-Rex1, a PI3K- and G protein βγ-regulated guanine nucleotide exchange factor (GEF) of the Rac small GTPase, for its potential involvement in PF. In a bleomycin-induced PF model, mice deficient in p-rex1 had well-preserved alveolar structure and survived significantly better than their wild type (WT) littermates. The p-rex1−/− mice expressed significantly less proinflammatory cytokines and chemokines and had reduced leukocyte infiltration in the lung tissue than their WT littermates. P-Rex1 was detected in lung fibroblasts of WT mice and its genetic deletion attenuated TGFβ-1-stimulated lung fibroblast migration, Rac1 activation and p38 MAPK phosphorylation. The p-rex1−/− mice showed significantly reduced pathological changes including the expression of α-smooth muscle actin, fibronectin and TGFβ-1 compared with their WT controls. Expression of a GEF-deficient P-Rex1 mutant effectively blocked Smads-dependent transcriptional activation, suggesting that P-Rex1 is a downstream mediator of TGFβ-1 signaling. These findings identify P-Rex1 as a novel player of PF, suggesting that targeting P-Rex1 may simultaneously block the inflammatory and fibrogenic processes of PF.