bluuebunny/crossref_metadata_2025_split huggingface dataset:
Extracellular vesicles from human urine-derived stem cells prevent osteoporosis by transferring CTHRC1 and OPG
Authors: Chen Chun-Yuan , Rao Shan-Shan , Tan Yi-Juan , Luo Ming-Jie , Hu Xiong-Ke , Yin Hao , Huang Jie , Hu Yin , Luo Zhong-Wei , Liu Zheng-Zhao , Wang Zhen-Xing , Cao Jia , Liu Yi-Wei , Li Hong-Ming , Chen Yang , Du Wei , Liu Jiang-Hua , Zhang Yan , Chen Tuan-Hui , Liu Hao-Ming , Wu Ben , Yue Tao , Wang Yi-Yi , Xia Kun , Lei Peng-Fei , Tang Si-Yuan , Xie Hui 
Published: June 2019

AbstractOsteoporosis is a debilitating bone disease affecting millions of people. Here, we used human urine-derived stem cells (USCs), which were noninvasively harvested from unlimited and easily available urine, as a “factory” to obtain extracellular vesicles (USC-EVs) and demonstrated that the systemic injection of USC-EVs effectively alleviates bone loss and maintains bone strength in osteoporotic mice by enhancing osteoblastic bone formation and suppressing osteoclastic bone resorption. More importantly, the anti-osteoporotic properties of USC-EVs are not notably disrupted by the age, gender, or health condition (with or without osteoporosis) of the USC donor. Mechanistic studies determined that collagen triple-helix repeat containing 1 (CTHRC1) and osteoprotegerin (OPG) proteins are enriched in USC-EVs and required for USC-EV-induced pro-osteogenic and anti-osteoclastic effects. Our results suggest that autologous USC-EVs represent a promising novel therapeutic agent for osteoporosis by promoting osteogenesis and inhibiting osteoclastogenesis by transferring CTHRC1 and OPG.
The interaction between SPARC and GRP78 interferes with ER stress signaling and potentiates apoptosis via PERK/eIF2α and IRE1α/XBP-1 in colorectal cancer
Authors: Chern Yi-Jye , Wong John C. T. , Cheng Grace S. W. , Yu Angel , Yin Yaling , Schaeffer David F. , Kennecke Hagen F. , Morin Gregg , Tai Isabella T. 
Published: June 2019

AbstractTherapy-refractory disease is one of the main contributors of treatment failure in cancer. In colorectal cancer (CRC), SPARC can function as a sensitizer to conventional chemotherapy by enhancing apoptosis by interfering with the activity of Bcl-2. Here, we examine a novel mechanism by which SPARC further potentiates apoptosis via its modulation of the unfolded protein response (UPR). Using mass spectrometry to identify SPARC-associated proteins, GRP78 was identified as a protein partner for SPARC in CRC. In vitro studies conducted to assess the signaling events resulting from this interaction, included induction of ER stress with tunicamycin, 5-fluorouracil (5-FU), and irinotecan (CPT-11). We found that the interaction between GRP78 and SPARC increased during exposure to 5-FU, CPT-11, and tunicamycin, resulting in an attenuation of GRP78’s inhibition of apoptosis. In addition, we also show that SPARC can sensitize CRC cells to PERK/eIF2α and IRE1α/XBP-1 UPR signaling by interfering with ER stress following binding to GRP78, which leads to ER stress-associated cell death in CRC cells. In line with these findings, a lower expression of GRP78 relative to SPARC in CRC is associated with a lower IC50for 5-FU in either sensitive or therapy-refractory CRC cells. Interestingly, this observation correlates with tissue microarray analysis of 143 human CRC, where low GRP78 to SPARC expression level was prognostic of higher survival rate (P = 0.01) in individuals with CRC. This study demonstrates that modulation of UPR signaling by SPARC promotes ER stress-associated death and potentiates apoptosis. This may be an effective strategy that can be combined with current treatment options to improve therapeutic efficacy in CRC.
Homo- and heterodehydrocoupling of phosphines mediated by alkali metal catalysts
Authors: Wu Lipeng , Annibale Vincent T. , Jiao Haijun , Brookfield Adam , Collison David , Manners Ian 
Published: June 2019

AbstractCatalytic chemistry that involves the activation and transformation of main group substrates is relatively undeveloped and current examples are generally mediated by expensive transition metal species. Herein, we describe the use of inexpensive and readily availabletBuOK as a catalyst for P–P and P–E (E = O, S, or N) bond formation. Catalytic quantities oftBuOK in the presence of imine, azobenzene hydrogen acceptors, or a stoichiometric amount oftBuOK with hydrazobenzene, allow efficient homodehydrocoupling of phosphines under mild conditions (e.g. 25 °C and < 5 min). Further studies demonstrate that the hydrogen acceptors play an intimate mechanistic role. We also show that ourtBuOK catalysed methodology is general for the heterodehydrocoupling of phosphines with alcohols, thiols and amines to generate a range of potentially useful products containing P–O, P–S, or P–N bonds.
Inhibition of CRISPR-Cas9 ribonucleoprotein complex assembly by anti-CRISPR AcrIIC2
Authors: Thavalingam Annoj , Cheng Zhi , Garcia Bianca , Huang Xue , Shah Megha , Sun Wei , Wang Min , Harrington Lucas , Hwang Sungwon , Hidalgo-Reyes Yurima , Sontheimer Erik J. , Doudna Jennifer , Davidson Alan R. , Moraes Trevor F. , Wang Yanli , Maxwell Karen L. 
Published: June 2019

AbstractCRISPR-Cas adaptive immune systems function to protect bacteria from invasion by foreign genetic elements. The CRISPR-Cas9 system has been widely adopted as a powerful genome-editing tool, and phage-encoded inhibitors, known as anti-CRISPRs, offer a means of regulating its activity. Here, we report the crystal structures of anti-CRISPR protein AcrIIC2Nme alone and in complex with Nme1Cas9. We demonstrate that AcrIIC2Nme inhibits Cas9 through interactions with the positively charged bridge helix, thereby preventing sgRNA loading. In vivo phage plaque assays and in vitro DNA cleavage assays show that AcrIIC2Nme mediates its activity through a large electronegative surface. This work shows that anti-CRISPR activity can be mediated through the inhibition of Cas9 complex assembly.
Targeting a therapeutic LIF transgene to muscle via the immune system ameliorates muscular dystrophy
Authors: Welc Steven S. , Flores Ivan , Wehling-Henricks Michelle , Ramos Julian , Wang Ying , Bertoni Carmen , Tidball James G. 
Published: June 2019

AbstractMany potentially therapeutic molecules have been identified for treating Duchenne muscular dystrophy. However, targeting those molecules only to sites of active pathology is an obstacle to their clinical use. Because dystrophic muscles become extensively inflamed, we tested whether expressing a therapeutic transgene in leukocyte progenitors that invade muscle would provide selective, timely delivery to diseased muscle. We designed a transgene in which leukemia inhibitory factor (LIF) is under control of a leukocyte-specific promoter and transplanted transgenic cells into dystrophic mice. Transplantation diminishes pathology, reduces Th2 cytokines in muscle and biases macrophages away from a CD163+/CD206+ phenotype that promotes fibrosis. Transgenic cells also abrogate TGFβ signaling, reduce fibro/adipogenic progenitor cells and reduce fibrogenesis of muscle cells. These findings indicate that leukocytes expressing a LIF transgene reduce fibrosis by suppressing type 2 immunity and highlight a novel application by which immune cells can be genetically modified as potential therapeutics to treat muscle disease.
Insights into real-time chemical processes in a calcium sensor protein-directed dynamic library
Authors: Canal-Martín Andrea , Sastre Javier , Sánchez-Barrena María José , Canales Angeles , Baldominos Sara , Pascual Naiara , Martínez-González Loreto , Molero Dolores , Fernández-Valle Mª Encarnación , Sáez Elena , Blanco-Gabella Patricia , Gómez-Rubio Elena , Martín-Santamaría Sonsoles , Sáiz Almudena , Mansilla Alicia , Cañada F. Javier , Jiménez-Barbero Jesús , Martínez Ana , Pérez-Fernández Ruth 
Published: June 2019

AbstractDynamic combinatorial chemistry (DCC) has proven its potential in drug discovery speeding the identification of modulators of biological targets. However, the exchange chemistries typically take place under specific reaction conditions, with limited tools capable of operating under physiological parameters. Here we report a catalyzed protein-directed DCC working at low temperatures that allows the calcium sensor NCS-1 to find the best ligands in situ. Ultrafast NMR identifies the reaction intermediates of the acylhydrazone exchange, tracing the molecular assemblies and getting a real-time insight into the essence of DCC processes at physiological pH. Additionally, NMR, X-ray crystallography and computational methods are employed to elucidate structural and mechanistic aspects of the molecular recognition event. The DCC approach leads us to the identification of a compound stabilizing the NCS-1/Ric8a complex and whose therapeutic potential is proven in a Drosophila model of disease with synaptic alterations.
Common and distinct transcriptional signatures of mammalian embryonic lethality
Authors: Collins John E. , White Richard J. , Staudt Nicole , Sealy Ian M. , Packham Ian , Wali Neha , Tudor Catherine , Mazzeo Cecilia , Green Angela , Siragher Emma , Ryder Edward , White Jacqueline K. , Papatheodoru Irene , Tang Amy , Füllgrabe Anja , Billis Konstantinos , Geyer Stefan H. , Weninger Wolfgang J. , Galli Antonella , Hemberger Myriam , Stemple Derek L. , Robertson Elizabeth , Smith James C. , Mohun Timothy , Adams David J. , Busch-Nentwich Elisabeth M. 
Published: June 2019

AbstractThe Deciphering the Mechanisms of Developmental Disorders programme has analysed the morphological and molecular phenotypes of embryonic and perinatal lethal mouse mutant lines in order to investigate the causes of embryonic lethality. Here we show that individual whole-embryo RNA-seq of 73 mouse mutant lines (>1000 transcriptomes) identifies transcriptional events underlying embryonic lethality and associates previously uncharacterised genes with specific pathways and tissues. For example, our data suggest that Hmgxb3 is involved in DNA-damage repair and cell-cycle regulation. Further, we separate embryonic delay signatures from mutant line-specific transcriptional changes by developing a baseline mRNA expression catalogue of wild-type mice during early embryogenesis (4–36 somites). Analysis of transcription outside coding sequence identifies deregulation of repetitive elements in Morc2a mutants and a gene involved in gene-specific splicing. Collectively, this work provides a large scale resource to further our understanding of early embryonic developmental disorders.
Strain-gradient mediated local conduction in strained bismuth ferrite films
Authors: Yang Ming-Min , Iqbal Affan N. , Peters Jonathan J. P. , Sanchez Ana M. , Alexe Marin 
Published: June 2019

AbstractIt has been recently shown that the strain gradient is able to separate the light-excited electron-hole pairs in semiconductors, but how it affects the photoelectric properties of the photo-active materials remains an open question. Here, we demonstrate the critical role of the strain gradient in mediating local photoelectric properties in the strained BiFeO3 thin films by systematically characterizing the local conduction with nanometre lateral resolution in both dark and illuminated conditions. Due to the giant strain gradient manifested at the morphotropic phase boundaries, the associated flexo-photovoltaic effect induces on one side an enhanced photoconduction in the R-phase, and on the other side a negative photoconductivity in the morphotropic $$T\prime$$
T
′
-phase. This work offers insight and implication of the strain gradient on the electronic properties in both optoelectronic and photovoltaic devices.
Unconventional CN vacancies suppress iron-leaching in Prussian blue analogue pre-catalyst for boosted oxygen evolution catalysis
Authors: Yu Zi-You , Duan Yu , Liu Jian-Dang , Chen Yu , Liu Xiao-Kang , Liu Wei , Ma Tao , Li Yi , Zheng Xu-Sheng , Yao Tao , Gao Min-Rui , Zhu Jun-Fa , Ye Bang-Jiao , Yu Shu-Hong 
Published: June 2019

AbstractThe incorporation of defects, such as vacancies, into functional materials could substantially tailor their intrinsic properties. Progress in vacancy chemistry has enabled advances in many technological applications, but creating new type of vacancies in existing material system remains a big challenge. We show here that ionized nitrogen plasma can break bonds of iron-carbon-nitrogen-nickel units in nickel-iron Prussian blue analogues, forming unconventional carbon-nitrogen vacancies. We study oxygen evolution reaction on the carbon-nitrogen vacancy-mediated Prussian blue analogues, which exhibit a low overpotential of 283 millivolts at 10 milliamperes per square centimeter in alkali, far exceeding that of original Prussian blue analogues and previously reported oxygen evolution catalysts with vacancies. We ascribe this enhancement to the in-situ generated nickel-iron oxy(hydroxide) active layer during oxygen evolution reaction, where the Fe leaching was significantly suppressed by the unconventional carbon-nitrogen vacancies. This work opens up opportunities for producing vacancy defects in nanomaterials for broad applications.
Loss of fixed nitrogen causes net oxygen gain in a warmer future ocean
Authors: Oschlies Andreas , Koeve Wolfgang , Landolfi Angela , Kähler Paul 
Published: June 2019

AbstractOceanic anoxic events have been associated with warm climates in Earth history, and there are concerns that current ocean deoxygenation may eventually lead to anoxia. Here we show results of a multi-millennial global-warming simulation that reveal, after a transitory deoxygenation, a marine oxygen inventory 6% higher than preindustrial despite an average 3 °C ocean warming. An interior-ocean oxygen source unaccounted for in previous studies explains two thirds of the oxygen excess reached after a few thousand years. It results from enhanced denitrification replacing part of today’s ocean’s aerobic respiration in expanding oxygen-deficient regions: The resulting loss of fixed nitrogen is equivalent to an oceanic oxygen gain and depends on an incomplete compensation of denitrification by nitrogen fixation. Elevated total oxygen in a warmer ocean with larger oxygen-deficient regions poses a new challenge for explaining global oceanic anoxic events and calls for an improved understanding of environmental controls on nitrogen fixation.
Distribution and dynamics of Greenland subglacial lakes
Authors: Bowling J. S. , Livingstone S. J. , Sole A. J. , Chu W. 
Published: June 2019

AbstractFew subglacial lakes have been identified beneath the Greenland Ice Sheet (GrIS) despite extensive documentation in Antarctica, where periodic release of water can impact ice flow. Here we present an ice-sheet-wide survey of Greenland subglacial lakes, identifying 54 candidates from airborne radio-echo sounding, and 2 lakes from ice-surface elevation changes. These range from 0.2–5.9 km in length, and are mostly distributed away from ice divides, beneath relatively slow-moving ice. Based on our results and previous observations, we suggest three zones of formation: stable lakes in northern and eastern regions above the Equilibrium Line Altitude (ELA) but away from the interior; hydrologically-active lakes near the ELA recharged by surface meltwater and; small, seasonally-active lakes below the ELA, which form over winter and drain during the melt season. These observations provide important constraints on the GrIS's basal thermal regime and help refine our understanding of the subglacial hydrological system.
DOT1L inhibition reveals a distinct subset of enhancers dependent on H3K79 methylation
Authors: Godfrey Laura , Crump Nicholas T. , Thorne Ross , Lau I-Jun , Repapi Emmanouela , Dimou Dimitra , Smith Alastair L. , Harman Joe R. , Telenius Jelena M. , Oudelaar A. Marieke , Downes Damien J. , Vyas Paresh , Hughes Jim R. , Milne Thomas A. 
Published: June 2019

AbstractEnhancer elements are a key regulatory feature of many important genes. Several general features including the presence of specific histone modifications are used to demarcate potentially active enhancers. Here we reveal that putative enhancers marked with H3 lysine 79 (H3K79) di or trimethylation (me2/3) (which we name H3K79me2/3 enhancer elements or KEEs) can be found in multiple cell types. Mixed lineage leukemia gene (MLL) rearrangements (MLL-r) such as MLL-AF4 are a major cause of incurable acute lymphoblastic leukemias (ALL). Using the DOT1L inhibitor EPZ-5676 in MLL-AF4 leukemia cells, we show that H3K79me2/3 is required for maintaining chromatin accessibility, histone acetylation and transcription factor binding specifically at KEEs but not non-KEE enhancers. We go on to show that H3K79me2/3 is essential for maintaining enhancer-promoter interactions at a subset of KEEs. Together, these data implicate H3K79me2/3 as having a functional role at a subset of active enhancers in MLL-AF4 leukemia cells.
Direct electrochemical oxidation of alcohols with hydrogen evolution in continuous-flow reactor
Authors: Wang Dan , Wang Pan , Wang Shengchun , Chen Yi-Hung , Zhang Heng , Lei Aiwen 
Published: June 2019

AbstractAlcohol oxidation reactions are widely used for the preparation of aldehydes and ketones. The electrolysis of alcohols to carbonyl compounds have been underutilized owing to low efficiency. Herein, we report an electrochemical oxidation of various alcohols in a continuous-flow reactor without external oxidants, base or mediators. The robust electrochemical oxidation is performed for a variety of alcohols with good functional group tolerance, high efficiency and atom economy, whereas mechanistic studies support the benzylic radical intermediate formation and hydrogen evolution. The electrochemical oxidation proves viable on diols with excellent levels of selectivity for the benzylic position.
Chloramphenicol inhibits eukaryotic Ser/Thr phosphatase and infection-specific cell differentiation in the rice blast fungus
Authors: Nozaka Akihito , Nishiwaki Ayaka , Nagashima Yuka , Endo Shogo , Kuroki Misa , Nakajima Masahiro , Narukawa Megumi , Kamisuki Shinji , Arazoe Takayuki , Taguchi Hayao , Sugawara Fumio , Kamakura Takashi 
Published: June 2019

AbstractChloramphenicol (Cm) is a broad-spectrum classic antibiotic active against prokaryotic organisms. However, Cm has severe side effects in eukaryotes of which the cause remains unknown. The plant pathogenic fungusMagnaporthe oryzae, which causes rice blast, forms an appressorium to infect the host cell via single-cell differentiation. Chloramphenicol specifically inhibits appressorium formation, which indicates that Cm has a novel molecular target (or targets) in the rice blast fungus. Application of the T7 phage display method inferred that MoDullard, a Ser/Thr-protein phosphatase, may be a target of Cm. In animals Dullard functions in cell differentiation and protein synthesis, but in fungi its role is poorly understood.In vivoandin vitroanalyses showed that MoDullard is required for appressorium formation, and that Cm can bind to and inhibit MoDullard function. Given that human phosphatase CTDSP1 complemented the MoDullard function during appressorium formation byM. oryzae, CTDSP1 may be a novel molecular target of Cm in eukaryotes.
Melanin presence inhibits melanoma cell spread in mice in a unique mechanical fashion
Authors: Sarna Michal , Krzykawska-Serda Martyna , Jakubowska Monika , Zadlo Andrzej , Urbanska Krystyna 
Published: June 2019

AbstractMelanoma is a highly aggressive cancer that exhibits metastasis to various critical organs. Unlike any other cancer cells, melanoma cells can synthesize melanin in large amounts, becoming heavily pigmented. Until now the role of melanin in melanoma, particularly the effect of melanin presence on the abilities of melanoma cells to spread and metastasize remains unknown. Recently, we have shown that melanin dramatically modified elastic properties of melanoma cells and inhibited the cells invasive abilities in vitro. Here, we inoculated human melanoma cells with different melanin content into nude mice and tested the hypothesis that cell elasticity is an important property of cancer cells for their efficient spread in vivo. The obtained results clearly showed that cells containing melanin were less capable to spread in mice than cells without the pigment. Our findings indicate that the presence of melanin inhibits melanoma metastasis, emphasizing possible clinical implications of such an inhibitory effect.
Contextual influences in the peripheral retina of patients with macular degeneration
Authors: Contemori Giulio , Battaglini Luca , Casco Clara 
Published: June 2019

AbstractMacular degeneration (MD) is the leading cause of low vision in the elderly population worldwide. In case of complete bilateral loss of central vision, MD patients start to show a preferred retinal region for fixation (PRL). Previous literature has reported functional changes that are connected with the emergence of the PRL. In this paper, we question whether the PRL undergoes a use-dependent cortical reorganization that alters the range of spatial lateral interactions between low-level filters. We asked whether there is a modulation of the excitatory/inhibitory lateral interactions or whether contextual influences are well accounted for by the same law that describes the integration response in normal viewers. In a group of 13 MD patients and 7 age-matched controls, we probed contextual influences by measuring the contrast threshold for a vertical target Gabor, flanked by two collinear high-contrast Gabors. Contextual influences of the collinear flankers were indicated by the changes in contrast threshold obtained at different target-to-flanker distances (λs) relative to the baseline orthogonal condition. Results showed that MDs had higher thresholds in the baseline condition and functional impairment in the identification tasks. Moreover, at the shortest λ, we found facilitatory rather than inhibitory contextual influence. No difference was found between the PRL and a symmetrical retinal position (non-PRL). By pulling together data from MD and controls we showed that in the periphery this inversion occurs when the target threshold approach the flankers’ contrast (about 1:3 ratio) and that for patients it does occur in both the PRL and a symmetrical retinal position (non-PRL). We conclude that contrary to previous interpretations, this modulation doesn’t seem to reflect use-dependent cortical reorganization but rather, it might result from a reduction of contrast gain for the target that promotes target-flankers grouping.