bluuebunny/crossref_metadata_2025_split huggingface dataset:
Protection from β-cell apoptosis by inhibition of TGF-β/Smad3 signaling
Authors: Lee Ji-Hyeon , Mellado-Gil Jose Manuel , Bahn Young Jae , Pathy Sushrut M. , Zhang Ying E. , Rane Sushil G. 
Published: March 2020

AbstractPrevailing insulin resistance and the resultant hyperglycemia elicits a compensatory response from pancreatic islet beta cells (β-cells) that involves increases in β-cell function and β-cell mass. However, the sustained metabolic stress eventually leads to β-cell failure characterized by severe β-cell dysfunction and progressive loss of β-cell mass. Whereas, β-cell dysfunction is relatively well understood at the mechanistic level, the avenues leading to loss of β-cell mass are less clear with reduced proliferation, dedifferentiation, and apoptosis all potential mechanisms. Butler and colleagues documented increased β-cell apoptosis in pancreas from lean and obese human Type 2 diabetes (T2D) subjects, with no changes in rates of β-cell replication or neogenesis, strongly suggesting a role for apoptosis in β-cell failure. Here, we describe a permissive role for TGF-β/Smad3 in β-cell apoptosis. Human islets undergoing β-cell apoptosis release increased levels of TGF-β1 ligand and phosphorylation levels of TGF-β’s chief transcription factor, Smad3, are increased in human T2D islets suggestive of an autocrine role for TGF-β/Smad3 signaling in β-cell apoptosis. Smad3 phosphorylation is similarly increased in diabetic mouse islets undergoing β-cell apoptosis. In mice, β-cell-specific activation of Smad3 promotes apoptosis and loss of β-cell mass in association with β-cell dysfunction, glucose intolerance, and diabetes. In contrast, inactive Smad3 protects from apoptosis and preserves β-cell mass while improving β-cell function and glucose tolerance. At the molecular level, Smad3 associates with Foxo1 to propagate TGF-β-dependent β-cell apoptosis. Indeed, genetic or pharmacologic inhibition of TGF-β/Smad3 signals or knocking down Foxo1 protects from β-cell apoptosis. These findings reveal the importance of TGF-β/Smad3 in promoting β-cell apoptosis and demonstrate the therapeutic potential of TGF-β/Smad3 antagonism to restore β-cell mass lost in diabetes.
MMP9 mediates acute hyperglycemia-induced human cardiac stem cell death by upregulating apoptosis and pyroptosis in vitro
Authors: Yadav Santosh K. , Kambis Tyler N. , Kar Sumit , Park Song Y. , Mishra Paras K. 
Published: March 2020

AbstractProviding a conducive microenvironment is critical to increase survival of transplanted stem cells in regenerative therapy. Hyperglycemia promotes stem cell death impairing cardiac regeneration in the diabetic heart. Understanding the molecular mechanisms of high glucose-induced stem cell death is important for improving cardiac regeneration in diabetic patients. Matrix metalloproteinase-9 (MMP9), a collagenase, is upregulated in the diabetic heart, and ablation of MMP9 decreases infarct size in the non-diabetic myocardial infarction heart. In the present study, we aim to investigate whether MMP9 is a mediator of hyperglycemia-induced cell death in human cardiac stem cells (hCSCs) in vitro. We created MMP9−/− hCSCs to test the hypothesis that MMP9 mediates hyperglycemia-induced oxidative stress and cell death via apoptosis and pyroptosis in hCSCs, which is attenuated by the lack of MMP9. We found that hyperglycemia induced oxidative stress and increased cell death by promoting pyroptosis and apoptosis in hCSCs, which was prevented in MMP9−/− hCSCs. These findings revealed a novel intracellular role of MMP9 in mediating stem cell death and provide a platform to assess whether MMP9 inhibition could improve hCSCs survival in stem cell therapy at least in acute hyperglycemic microenvironment.
Strain-induced stripe phase in charge-ordered single layer NbSe2
Authors: Cossu Fabrizio , Palotás Krisztián , Sarkar Sagar , Di Marco Igor , Akbari Alireza 
Published: March 2020

AbstractCharge density waves are ubiquitous phenomena in metallic transition metal dichalcogenides. In NbSe2, a triangular 3 × 3 structural modulation is coupled to a charge modulation. Recent experiments reported evidence for a triangular-stripe transition at the surface, due to strain or accidental doping and associated to a 4 × 4 modulation. We employ ab initio calculations to investigate the strain-induced structural instabilities in a pristine single layer and analyse the energy hierarchy of the structural and charge modulations. Our results support the observation of phase separation between triangular and stripe phases in 1H-NbSe2, relating the stripe phase to compressive isotropic strain, favouring the 4 × 4 modulation. The observed wavelength of the charge modulation is also reproduced with a good accuracy.
Carbon dots-fed Shewanella oneidensis MR-1 for bioelectricity enhancement
Authors: Yang Chenhui , Aslan Hüsnü , Zhang Peng , Zhu Shoujun , Xiao Yong , Chen Lixiang , Khan Nasar , Boesen Thomas , Wang Yuanlin , Liu Yang , Wang Lei , Sun Ye , Feng Yujie , Besenbacher Flemming , Zhao Feng , Yu Miao 
Published: March 2020

AbstractBioelectricity generation, by Shewanella oneidensis (S. oneidensis) MR-1, has become particularly alluring, thanks to its extraordinary prospects for energy production, pollution treatment, and biosynthesis. Attempts to improve its technological output by modification of S. oneidensis MR-1 remains complicated, expensive and inefficient. Herein, we report on the augmentation of S. oneidensis MR-1 with carbon dots (CDs). The CDs-fed cells show accelerated extracellular electron transfer and metabolic rate, with increased intracellular charge, higher adenosine triphosphate level, quicker substrate consumption and more abundant extracellular secretion. Meanwhile, the CDs promote cellular adhesion, electronegativity, and biofilm formation. In bioelectrical systems the CDs-fed cells increase the maximum current value, 7.34 fold, and power output, 6.46 fold. The enhancement efficacy is found to be strongly dependent on the surface charge of the CDs. This work demonstrates a simple, cost-effective and efficient route to improve bioelectricity generation of S. oneidensis MR-1, holding promise in all relevant technologies.
Extracellular nanovesicles for packaging of CRISPR-Cas9 protein and sgRNA to induce therapeutic exon skipping
Authors: Gee Peter , Lung Mandy S. Y. , Okuzaki Yuya , Sasakawa Noriko , Iguchi Takahiro , Makita Yukimasa , Hozumi Hiroyuki , Miura Yasutomo , Yang Lucy F. , Iwasaki Mio , Wang Xiou H. , Waller Matthew A. , Shirai Nanako , Abe Yasuko O. , Fujita Yoko , Watanabe Kei , Kagita Akihiro , Iwabuchi Kumiko A. , Yasuda Masahiko , Xu Huaigeng , Noda Takeshi , Komano Jun , Sakurai Hidetoshi , Inukai Naoto , Hotta Akitsu 
Published: March 2020

AbstractProlonged expression of the CRISPR-Cas9 nuclease and gRNA from viral vectors may cause off-target mutagenesis and immunogenicity. Thus, a transient delivery system is needed for therapeutic genome editing applications. Here, we develop an extracellular nanovesicle-based ribonucleoprotein delivery system named NanoMEDIC by utilizing two distinct homing mechanisms. Chemical induced dimerization recruits Cas9 protein into extracellular nanovesicles, and then a viral RNA packaging signal and two self-cleaving riboswitches tether and release sgRNA into nanovesicles. We demonstrate efficient genome editing in various hard-to-transfect cell types, including human induced pluripotent stem (iPS) cells, neurons, and myoblasts. NanoMEDIC also achieves over 90% exon skipping efficiencies in skeletal muscle cells derived from Duchenne muscular dystrophy (DMD) patient iPS cells. Finally, single intramuscular injection of NanoMEDIC induces permanent genomic exon skipping in a luciferase reporter mouse and in mdx mice, indicating its utility for in vivo genome editing therapy of DMD and beyond.
Paradoxical activation of the protein kinase-transcription factor ERK5 by ERK5 kinase inhibitors
Authors: Lochhead Pamela A. , Tucker Julie A. , Tatum Natalie J. , Wang Jinhua , Oxley David , Kidger Andrew M. , Johnson Victoria P. , Cassidy Megan A. , Gray Nathanael S. , Noble Martin E. M. , Cook Simon J. 
Published: March 2020

AbstractThe dual protein kinase-transcription factor, ERK5, is an emerging drug target in cancer and inflammation, and small-molecule ERK5 kinase inhibitors have been developed. However, selective ERK5 kinase inhibitors fail to recapitulate ERK5 genetic ablation phenotypes, suggesting kinase-independent functions for ERK5. Here we show that ERK5 kinase inhibitors cause paradoxical activation of ERK5 transcriptional activity mediated through its unique C-terminal transcriptional activation domain (TAD). Using the ERK5 kinase inhibitor, Compound 26 (ERK5-IN-1), as a paradigm, we have developed kinase-active, drug-resistant mutants of ERK5. With these mutants, we show that induction of ERK5 transcriptional activity requires direct binding of the inhibitor to the kinase domain. This in turn promotes conformational changes in the kinase domain that result in nuclear translocation of ERK5 and stimulation of gene transcription. This shows that both the ERK5 kinase and TAD must be considered when assessing the role of ERK5 and the effectiveness of anti-ERK5 therapeutics.
Plasmonic nanostar photocathodes for optically-controlled directional currents
Authors: Pettine Jacob , Choo Priscilla , Medeghini Fabio , Odom Teri W. , Nesbitt David J. 
Published: March 2020

AbstractPlasmonic nanocathodes offer unique opportunities for optically driving, switching, and steering femtosecond photocurrents in nanoelectronic devices and pulsed electron sources. However, angular photocurrent distributions in nanoplasmonic systems remain poorly understood and are therefore difficult to anticipate and control. Here, we provide a direct momentum-space characterization of multiphoton photoemission from plasmonic gold nanostars and demonstrate all-optical control over these currents. Versatile angular control is achieved by selectively exciting different tips on single nanostars via laser frequency or linear polarization, thereby rotating the tip-aligned directional photoemission as observed with angle-resolved 2D velocity mapping and 3D reconstruction. Classical plasmonic field simulations combined with quantum photoemission theory elucidate the role of surface-mediated nonlinear excitation for plasmonic field enhancements highly concentrated at the sharp tips (Rtip = 3.4 nm). We thus establish a simple mechanism for femtosecond spatiotemporal current control in designer nanosystems.
Microglia clear neuron-released α-synuclein via selective autophagy and prevent neurodegeneration
Authors: Choi Insup , Zhang Yuanxi , Seegobin Steven P. , Pruvost Mathilde , Wang Qian , Purtell Kerry , Zhang Bin , Yue Zhenyu 
Published: March 2020

AbstractMicroglia maintain brain homeostasis by removing neuron-derived components such as myelin and cell debris. The evidence linking microglia to neurodegenerative diseases is growing; however, the precise mechanisms remain poorly understood. Herein, we report a neuroprotective role for microglia in the clearance of neuron-released α-synuclein. Neuronal α-synuclein activates microglia, which in turn engulf α-synuclein into autophagosomes for degradation via selective autophagy (termed synucleinphagy). Synucleinphagy requires the presence of microglial Toll-like receptor 4 (TLR4), which induces transcriptional upregulation ofp62/SQSTM1through the NF-κB signaling pathway. Induction of p62, an autophagy receptor, is necessary for the formation of α-synuclein/ubiquitin-positive puncta that are degraded by autophagy. Finally, disruption of microglial autophagy in mice expressing human α-synuclein promotes the accumulation of misfolded α-synuclein and causes midbrain dopaminergic neuron degeneration. Our study thus identifies a neuroprotective function of microglia in the clearance of α-synuclein via TLR4-NF-κB-p62 mediated synucleinphagy.
Amyloid-β42/40 ratio drives tau pathology in 3D human neural cell culture models of Alzheimer’s disease
Authors: Kwak Sang Su , Washicosky Kevin J. , Brand Emma , von Maydell Djuna , Aronson Jenna , Kim Susan , Capen Diane E. , Cetinbas Murat , Sadreyev Ruslan , Ning Shen , Bylykbashi Enjana , Xia Weiming , Wagner Steven L. , Choi Se Hoon , Tanzi Rudolph E. , Kim Doo Yeon 
Published: March 2020

AbstractThe relationship between amyloid-β (Aβ) species and tau pathology in Alzheimer’s disease (AD) is not fully understood. Here, we provide direct evidence that Aβ42/40 ratio, not total Aβ level, plays a critical role in inducing neurofibrillary tangles (NTFs) in human neurons. Using 3D-differentiated clonal human neural progenitor cells (hNPCs) expressing varying levels of amyloid β precursor protein (APP) and presenilin 1 (PS1) with AD mutations, we show that pathogenic tau accumulation and aggregation are tightly correlated with Aβ42/40 ratio. Roles of Aβ42/40 ratio on tau pathology are also confirmed with APP transmembrane domain (TMD) mutant hNPCs, which display differential Aβ42/40 ratios without mutant PS1. Moreover, naïve hNPCs co-cultured with APP TMD I45F (high Aβ42/40) cells, not with I47F cells (low Aβ42/40), develop robust tau pathology in a 3D non-cell autonomous cell culture system. These results emphasize the importance of reducing the Aβ42/40 ratio in AD therapy.
Dichloromethylation of enones by carbon nitride photocatalysis
Authors: Mazzanti Stefano , Kurpil Bogdan , Pieber Bartholomäus , Antonietti Markus , Savateev Aleksandr 
Published: March 2020

AbstractSmall organic radicals are ubiquitous intermediates in photocatalysis and are used in organic synthesis to install functional groups and to tune electronic properties and pharmacokinetic parameters of the final molecule. Development of new methods to generate small organic radicals with added functionality can further extend the utility of photocatalysis for synthetic needs. Herein, we present a method to generate dichloromethyl radicals from chloroform using a heterogeneous potassium poly(heptazine imide) (K-PHI) photocatalyst under visible light irradiation for C1-extension of the enone backbone. The method is applied on 15 enones, with γ,γ-dichloroketones yields of 18–89%. Due to negative zeta-potential (−40 mV) and small particle size (100 nm) K-PHI suspension is used in quasi-homogeneous flow-photoreactor increasing the productivity by 19 times compared to the batch approach. The resulting γ,γ-dichloroketones, are used as bifunctional building blocks to access value-added organic compounds such as substituted furans and pyrroles.
Dynamics of bacterial population growth in biofilms resemble spatial and structural aspects of urbanization
Authors: Paula Amauri J. , Hwang Geelsu , Koo Hyun 
Published: March 2020

AbstractBiofilms develop from bacteria bound on surfaces that grow into structured communities (microcolonies). Although surface topography is known to affect bacterial colonization, how multiple individual settlers develop into microcolonies simultaneously remains underexplored. Here, we use multiscale population-growth and 3D-morphometric analyses to assess the spatiotemporal development of hundreds of bacterial colonizers towards submillimeter-scale microcolony communities. Using an oral bacterium (Streptococcus mutans), we find that microbial cells settle on the surface randomly under sucrose-rich conditions, regardless of surface topography. However, only a subset of colonizers display clustering behavior and growth following a power law. These active colonizers expand three-dimensionally by amalgamating neighboring bacteria into densely populated microcolonies. Clustering and microcolony assembly are dependent on exopolysaccharides, while population growth dynamics and spatial structure are affected by cooperative or antagonistic microbes. Our work suggests that biofilm assembly resembles certain spatial-structural features of urbanization, where population growth and expansion can be influenced by type of settlers, neighboring cells, and further community merging and scaffolding occurring at various scales.
Single molecule analysis reveals monomeric XPA bends DNA and undergoes episodic linear diffusion during damage search
Authors: Beckwitt Emily C. , Jang Sunbok , Carnaval Detweiler Isadora , Kuper Jochen , Sauer Florian , Simon Nina , Bretzler Johanna , Watkins Simon C. , Carell Thomas , Kisker Caroline , Van Houten Bennett 
Published: March 2020

AbstractNucleotide excision repair (NER) removes a wide range of DNA lesions, including UV-induced photoproducts and bulky base adducts. XPA is an essential protein in eukaryotic NER, although reports about its stoichiometry and role in damage recognition are controversial. Here, by PeakForce Tapping atomic force microscopy, we show that human XPA binds and bends DNA by ∼60° as a monomer. Furthermore, we observe XPA specificity for the helix-distorting base adduct N-(2’-deoxyguanosin-8-yl)-2-acetylaminofluorene over non-damaged dsDNA. Moreover, single molecule fluorescence microscopy reveals that DNA-bound XPA exhibits multiple modes of linear diffusion between paused phases. The presence of DNA damage increases the frequency of pausing. Truncated XPA, lacking the intrinsically disordered N- and C-termini, loses specificity for DNA lesions and shows less pausing on damaged DNA. Our data are consistent with a working model in which monomeric XPA bends DNA, displays episodic phases of linear diffusion along DNA, and pauses in response to DNA damage.
Saving less in China facilitates global CO2 mitigation
Authors: Lin Chen , Qi Jianchuan , Liang Sai , Feng Cuiyang , Wiedmann Thomas O. , Liao Yihan , Yang Xuechun , Li Yumeng , Mi Zhifu , Yang Zhifeng 
Published: March 2020

AbstractTransforming China’s economic growth pattern from investment-driven to consumption-driven can significantly change global CO2 emissions. This study is the first to analyse the impacts of changes in China’s saving rates on global CO2 emissions both theoretically and empirically. Here, we show that the increase in the saving rates of Chinese regions has led to increments of global industrial CO2 emissions by 189 million tonnes (Mt) during 2007–2012. A 15-percentage-point decrease in the saving rate of China can lower global CO2 emissions by 186 Mt, or 0.7% of global industrial CO2 emissions. Greener consumption in China can lead to a further 14% reduction in global industrial CO2 emissions. In particular, decreasing the saving rate of Shandong has the most massive potential for global CO2 reductions, while that of Inner Mongolia has adverse effects. Removing economic frictions to allow the production system to fit China’s increased consumption can facilitate global CO2 mitigation.
How paired PSII–LHCII supercomplexes mediate the stacking of plant thylakoid membranes unveiled by structural mass-spectrometry
Authors: Albanese Pascal , Tamara Sem , Saracco Guido , Scheltema Richard A. , Pagliano Cristina 
Published: March 2020

AbstractGrana are a characteristic feature of higher plants’ thylakoid membranes, consisting of stacks of appressed membranes enriched in Photosystem II (PSII) and associated light-harvesting complex II (LHCII) proteins, together forming the PSII-LHCII supercomplex. Grana stacks undergo light-dependent structural changes, mainly by reorganizing the supramolecular structure of PSII-LHCII supercomplexes. LHCII is vital for grana formation, in which also PSII-LHCII supercomplexes are involved. By combining top-down and crosslinking mass spectrometry we uncover the spatial organization of paired PSII-LHCII supercomplexes within thylakoid membranes. The resulting model highlights a basic molecular mechanism whereby plants maintain grana stacking at changing light conditions. This mechanism relies on interactions between stroma-exposed N-terminal loops of LHCII trimers and Lhcb4 subunits facing each other in adjacent membranes. The combination of light-dependent LHCII N-terminal trimming and extensive N-terminal α-acetylation likely affects interactions between pairs of PSII-LHCII supercomplexes across the stromal gap, ultimately mediating membrane folding in grana stacks.
Improved secretion of glycoproteins using an N-glycan-restricted passport sequence tag recognized by cargo receptor
Authors: Yagi Hirokazu , Yagi-Utsumi Maho , Honda Rena , Ohta Yusaku , Saito Taiki , Nishio Miho , Ninagawa Satoshi , Suzuki Kousuke , Anzai Takahiro , Kamiya Yukiko , Aoki Kazuhiro , Nakanishi Mahito , Satoh Tadashi , Kato Koichi 
Published: March 2020

AbstractMCFD2 and ERGIC-53, which are the products of causative genes of combined factor V and factor VIII deficiency, form a cargo receptor complex responsible for intracellular transport of these coagulation factors in the early secretory pathway. In this study, using an NMR technique, we successfully identified an MCFD2-binding segment from factor VIII composed of a 10 amino acid sequence that enhances its secretion. This prompted us to examine possible effects of attaching this sequence to recombinant glycoproteins on their secretion. We found that the secretion level of recombinant erythropoietin was significantly increased simply by tagging it with the passport sequence. Our findings not only provide molecular basis for the intracellular trafficking of coagulation factors and their genetic deficiency but also offer a potentially useful tool for increasing the production yields of recombinant glycoproteins of biopharmaceutical interest.
Cation insertion to break the activity/stability relationship for highly active oxygen evolution reaction catalyst
Authors: Yang Chunzhen , Rousse Gwenaëlle , Louise Svane Katrine , Pearce Paul E. , Abakumov Artem M. , Deschamps Michael , Cibin Giannantonio , Chadwick Alan V. , Dalla Corte Daniel Alves , Anton Hansen Heine , Vegge Tejs , Tarascon Jean-Marie , Grimaud Alexis 
Published: March 2020

AbstractThe production of hydrogen at a large scale by the environmentally-friendly electrolysis process is currently hampered by the slow kinetics of the oxygen evolution reaction (OER). We report a solid electrocatalyst α-Li2IrO3 which upon oxidation/delithiation chemically reacts with water to form a hydrated birnessite phase, the OER activity of which is five times greater than its non-reacted counterpart. This reaction enlists a bulk redox process during which hydrated potassium ions from the alkaline electrolyte are inserted into the structure while water is oxidized and oxygen evolved. This singular charge balance process for which the electrocatalyst is solid but the reaction is homogeneous in nature allows stabilizing the surface of the catalyst while ensuring stable OER performances, thus breaking the activity/stability tradeoff normally encountered for OER catalysts.