bluuebunny/crossref_metadata_2025_split huggingface dataset:
Microscale residual stresses in additively manufactured stainless steel
Authors: Chen Wen , Voisin Thomas , Zhang Yin , Forien Jean-Baptiste , Spadaccini Christopher M. , McDowell David L. , Zhu Ting , Wang Y. Morris 
Published: September 2019

AbstractAdditively manufactured (AM) metallic materials commonly possess substantial microscale internal stresses that manifest as intergranular and intragranular residual stresses. However, the impact of these residual stresses on the mechanical behaviour of AM materials remains unexplored. Here we combine in situ synchrotron X-ray diffraction experiments and computational modelling to quantify the lattice strains in different families of grains with specific orientations and associated intergranular residual stresses in an AM 316L stainless steel under uniaxial tension. We measure pronounced tension–compression asymmetries in yield strength and work hardening for as-printed stainless steel, and show they are associated with back stresses originating from heterogeneous dislocation distributions and resultant intragranular residual stresses. We further report that heat treatment relieves microscale residual stresses, thereby reducing the tension–compression asymmetries and altering work-hardening behaviour. This work establishes the mechanistic connections between the microscale residual stresses and mechanical behaviour of AM stainless steel.
Ageing affects DNA methylation drift and transcriptional cell-to-cell variability in mouse muscle stem cells
Authors: Hernando-Herraez Irene , Evano Brendan , Stubbs Thomas , Commere Pierre-Henri , Jan Bonder Marc , Clark Stephen , Andrews Simon , Tajbakhsh Shahragim , Reik Wolf 
Published: September 2019

AbstractAge-related tissue alterations have been associated with a decline in stem cell number and function. Although increased cell-to-cell variability in transcription or epigenetic marks has been proposed to be a major hallmark of ageing, little is known about the molecular diversity of stem cells during ageing. Here we present a single cell multi-omics study of mouse muscle stem cells, combining single-cell transcriptome and DNA methylome profiling. Aged cells show a global increase of uncoordinated transcriptional heterogeneity biased towards genes regulating cell-niche interactions. We find context-dependent alterations of DNA methylation in aged stem cells. Importantly, promoters with increased methylation heterogeneity are associated with increased transcriptional heterogeneity of the genes they drive. These results indicate that epigenetic drift, by accumulation of stochastic DNA methylation changes in promoters, is associated with the degradation of coherent transcriptional networks during stem cell ageing. Furthermore, our observations also shed light on the mechanisms underlying the DNA methylation clock.
Human PI3Kγ deficiency and its microbiota-dependent mouse model reveal immunodeficiency and tissue immunopathology
Authors: Takeda Andrew J. , Maher Timothy J. , Zhang Yu , Lanahan Stephen M. , Bucklin Molly L. , Compton Susan R. , Tyler Paul M. , Comrie William A. , Matsuda Makoto , Olivier Kenneth N. , Pittaluga Stefania , McElwee Joshua J. , Long Priel Debra A. , Kuhns Douglas B. , Williams Roger L. , Mustillo Peter J. , Wymann Matthias P. , Koneti Rao V. , Lucas Carrie L. 
Published: September 2019

AbstractPhosphatidylinositol 3-kinase-gamma (PI3Kγ) is highly expressed in leukocytes and is an attractive drug target for immune modulation. Different experimental systems have led to conflicting conclusions regarding inflammatory and anti-inflammatory functions of PI3Kγ. Here, we report a human patient with bi-allelic, loss-of-function mutations inPIK3CGresulting in absence of the p110γ catalytic subunit of PI3Kγ. She has a history of childhood-onset antibody defects, cytopenias, and T lymphocytic pneumonitis and colitis, with reduced peripheral blood memory B, memory CD8+ T, and regulatory T cells and increased CXCR3+ tissue-homing CD4 T cells. PI3Kγ-deficient macrophages and monocytes produce elevated inflammatory IL-12 and IL-23 in a GSK3α/β-dependent manner upon TLR stimulation.Pik3cg-deficient mice recapitulate major features of human disease after exposure to natural microbiota through co-housing with pet-store mice. Together, our results emphasize the physiological importance of PI3Kγ in restraining inflammation and promoting appropriate adaptive immune responses in both humans and mice.
MHC matching fails to prevent long-term rejection of iPSC-derived neurons in non-human primates
Authors: Aron Badin Romina , Bugi Aurore , Williams Susannah , Vadori Marta , Michael Marie , Jan Caroline , Nassi Alberto , Lecourtois Sophie , Blancher Antoine , Cozzi Emanuele , Hantraye Philippe , Perrier Anselme L. 
Published: September 2019

AbstractCell therapy products (CTP) derived from pluripotent stem cells (iPSCs) may constitute a renewable, specifically differentiated source of cells to potentially cure patients with neurodegenerative disorders. However, the immunogenicity of CTP remains a major issue for therapeutic approaches based on transplantation of non-autologous stem cell-derived neural grafts. Despite its considerable side-effects, long-term immunosuppression, appears indispensable to mitigate neuro-inflammation and prevent rejection of allogeneic CTP. Matching iPSC donors’ and patients’ HLA haplotypes has been proposed as a way to access CTP with enhanced immunological compatibility, ultimately reducing the need for immunosuppression. In the present work, we challenge this paradigm by grafting autologous, MHC-matched and mis-matched neuronal grafts in a primate model of Huntington’s disease. Unlike previous reports in unlesioned hosts, we show that in the absence of immunosuppression MHC matching alone is insufficient to grant long-term survival of neuronal grafts in the lesioned brain.
Purified F-ATP synthase forms a Ca2+-dependent high-conductance channel matching the mitochondrial permeability transition pore
Authors: Urbani Andrea , Giorgio Valentina , Carrer Andrea , Franchin Cinzia , Arrigoni Giorgio , Jiko Chimari , Abe Kazuhiro , Maeda Shintaro , Shinzawa-Itoh Kyoko , Bogers Janna F. M. , McMillan Duncan G. G. , Gerle Christoph , Szabò Ildikò , Bernardi Paolo 
Published: September 2019

AbstractThe molecular identity of the mitochondrial megachannel (MMC)/permeability transition pore (PTP), a key effector of cell death, remains controversial. By combining highly purified, fully active bovine F-ATP synthase with preformed liposomes we show that Ca2+ dissipates the H+ gradient generated by ATP hydrolysis. After incorporation of the same preparation into planar lipid bilayers Ca2+ elicits currents matching those of the MMC/PTP. Currents were fully reversible, were stabilized by benzodiazepine 423, a ligand of the OSCP subunit of F-ATP synthase that activates the MMC/PTP, and were inhibited by Mg2+ and adenine nucleotides, which also inhibit the PTP. Channel activity was insensitive to inhibitors of the adenine nucleotide translocase (ANT) and of the voltage-dependent anion channel (VDAC). Native gel-purified oligomers and dimers, but not monomers, gave rise to channel activity. These findings resolve the long-standing mystery of the MMC/PTP and demonstrate that Ca2+ can transform the energy-conserving F-ATP synthase into an energy-dissipating device.
Damage sensing by a Nox-Ask1-MKK3-p38 signaling pathway mediates regeneration in the adult Drosophila midgut
Authors: Patel Parthive H. , Pénalva Clothilde , Kardorff Michael , Roca Marianne , Pavlović Bojana , Thiel Anja , Teleman Aurelio A. , Edgar Bruce A. 
Published: September 2019

AbstractEpithelia are exposed to diverse types of stress and damage from pathogens and the environment, and respond by regenerating. Yet, the proximal mechanisms that sense epithelial damage remain poorly understood. Here we report that p38 signaling is activated in adult Drosophila midgut enterocytes in response to diverse stresses including pathogenic bacterial infection and chemical and mechanical insult. Two upstream kinases, Ask1 and Licorne (MKK3), are required for p38 activation following infection, oxidative stress, detergent exposure and wounding. Ask1-p38 signaling in enterocytes is required upon infection to promote full intestinal stem cell (ISC) activation and regeneration, partly through Upd3/Jak-Stat signaling. Furthermore, reactive oxygen species (ROS) produced by the NADPH oxidase Nox in enterocytes, are required for p38 activation in enterocytes following infection or wounding, and for ISC activation upon infection or detergent exposure. We propose that Nox-ROS-Ask1-MKK3-p38 signaling in enterocytes integrates multiple different stresses to induce regeneration.
The role of highly oxygenated organic molecules in the Boreal aerosol-cloud-climate system
Authors: Roldin Pontus , Ehn Mikael , Kurtén Theo , Olenius Tinja , Rissanen Matti P. , Sarnela Nina , Elm Jonas , Rantala Pekka , Hao Liqing , Hyttinen Noora , Heikkinen Liine , Worsnop Douglas R. , Pichelstorfer Lukas , Xavier Carlton , Clusius Petri , Öström Emilie , Petäjä Tuukka , Kulmala Markku , Vehkamäki Hanna , Virtanen Annele , Riipinen Ilona , Boy Michael 
Published: September 2019

AbstractOver Boreal regions, monoterpenes emitted from the forest are the main precursors for secondary organic aerosol (SOA) formation and the primary driver of the growth of new aerosol particles to climatically important cloud condensation nuclei (CCN). Autoxidation of monoterpenes leads to rapid formation of Highly Oxygenated organic Molecules (HOM). We have developed the first model with near-explicit representation of atmospheric new particle formation (NPF) and HOM formation. The model can reproduce the observed NPF, HOM gas-phase composition and SOA formation over the Boreal forest. During the spring, HOM SOA formation increases the CCN concentration by ~10 % and causes a direct aerosol radiative forcing of −0.10 W/m2. In contrast, NPF reduces the number of CCN at updraft velocities < 0.2 m/s, and causes a direct aerosol radiative forcing of +0.15 W/m2. Hence, while HOM SOA contributes to climate cooling, NPF can result in climate warming over the Boreal forest.
Massive computational acceleration by using neural networks to emulate mechanism-based biological models
Authors: Wang Shangying , Fan Kai , Luo Nan , Cao Yangxiaolu , Wu Feilun , Zhang Carolyn , Heller Katherine A. , You Lingchong 
Published: September 2019

AbstractFor many biological applications, exploration of the massive parametric space of a mechanism-based model can impose a prohibitive computational demand. To overcome this limitation, we present a framework to improve computational efficiency by orders of magnitude. The key concept is to train a neural network using a limited number of simulations generated by a mechanistic model. This number is small enough such that the simulations can be completed in a short time frame but large enough to enable reliable training. The trained neural network can then be used to explore a much larger parametric space. We demonstrate this notion by training neural networks to predict pattern formation and stochastic gene expression. We further demonstrate that using an ensemble of neural networks enables the self-contained evaluation of the quality of each prediction. Our work can be a platform for fast parametric space screening of biological models with user defined objectives.
R-spondin 3 promotes stem cell recovery and epithelial regeneration in the colon
Authors: Harnack Christine , Berger Hilmar , Antanaviciute Agne , Vidal Ramon , Sauer Sascha , Simmons Alison , Meyer Thomas F. , Sigal Michael 
Published: September 2019

AbstractThe colonic epithelial turnover is driven by crypt-base stem cells that express the R-spondin receptor Lgr5. Signals that regulate epithelial regeneration upon stem cell injury are largely unknown. Here, we explore the dynamics of Wnt signaling in the colon. We identify two populations of cells with active Wnt signaling: highly proliferative Lgr5+/Axin2+ cells, as well as secretory Lgr5−/Axin2+ cells. Upon Lgr5+ cell depletion, these cells are recruited to contribute to crypt regeneration. Chemical injury induced by DSS leads to a loss of both Lgr5+ cells and Axin2+ cells and epithelial regeneration is driven by Axin2− cells, including differentiated Krt20+ surface enterocytes. Regeneration requires stromal Rspo3, which is present at increased levels upon injury and reprograms Lgr5− but Lgr4+ differentiated cells. In contrast, depletion of stromal Rspo3 impairs crypt regeneration, even upon mild injury. We demonstrate that Rspo3 is essential for epithelial repair via induction of Wnt signaling in differentiated cells.
Low CO2 levels of the entire Pleistocene epoch
Authors: Da Jiawei , Zhang Yi Ge , Li Gen , Meng Xianqiang , Ji Junfeng 
Published: September 2019

AbstractQuantifying ancient atmosphericpCO2provides valuable insights into the interplay between greenhouse gases and global climate. Beyond the 800-ky history uncovered by ice cores, discrepancies in both the trend and magnitude ofpCO2changes remain among different proxy-derived results. The traditional paleosolpCO2paleobarometer suffers from largely unconstrained soil-respired CO2concentration (S(z)). Using finely disseminated carbonates precipitated in paleosols from the Chinese Loess Plateau, here we identified that theirS(z) can be quantitatively constrained by soil magnetic susceptibility. Based on this approach, we reconstructedpCO2during 2.6–0.9 Ma, which documents overall lowpCO2levels (<300 ppm) comparable with ice core records, indicating that the Earth system has operated under late PleistocenepCO2levels for an extended period. ThepCO2levels do not show statistically significant differences across the mid-Pleistocene Transition (ca. 1.2–0.8 Ma), suggesting that CO2is probably not the driver of this important climate change event.
Structural color three-dimensional printing by shrinking photonic crystals
Authors: Liu Yejing , Wang Hao , Ho Jinfa , Ng Ryan C. , Ng Ray J. H. , Hall-Chen Valerian H. , Koay Eleen H. H. , Dong Zhaogang , Liu Hailong , Qiu Cheng-Wei , Greer Julia R. , Yang Joel K. W. 
Published: September 2019

AbstractThe coloration of some butterflies, Pachyrhynchus weevils, and many chameleons are notable examples of natural organisms employing photonic crystals to produce colorful patterns. Despite advances in nanotechnology, we still lack the ability to print arbitrary colors and shapes in all three dimensions at this microscopic length scale. Here, we introduce a heat-shrinking method to produce 3D-printed photonic crystals with a 5x reduction in lattice constants, achieving sub-100-nm features with a full range of colors. With these lattice structures as 3D color volumetric elements, we printed 3D microscopic scale objects, including the first multi-color microscopic model of the Eiffel Tower measuring only 39 µm tall with a color pixel size of 1.45 µm. The technology to print 3D structures in color at the microscopic scale promises the direct patterning and integration of spectrally selective devices, such as photonic crystal-based color filters, onto free-form optical elements and curved surfaces.
Tankyrase disrupts metabolic homeostasis and promotes tumorigenesis by inhibiting LKB1-AMPK signalling
Authors: Li Nan , Wang Yifan , Neri Shinya , Zhen Yuanli , Fong Lon Wolf R. , Qiao Yawei , Li Xu , Chen Zhen , Stephan Clifford , Deng Weiye , Ye Rui , Jiang Wen , Zhang Shuxing , Yu Yonghao , Hung Mien-Chie , Chen Junjie , Lin Steven H. 
Published: September 2019

AbstractThe LKB1/AMPK pathway plays a major role in cellular homeostasis and tumor suppression. Down-regulation of LKB1/AMPK occurs in several human cancers and has been implicated in metabolic diseases. However, the precise upstream regulation of LKB1-AMPK pathway is largely unknown. Here, we report that AMPK activation by LKB1 is regulated by tankyrases. Tankyrases interact with and ribosylate LKB1, promoting its K63-linked ubiquitination by an E3 ligase RNF146, which blocks LKB1/STRAD/MO25 complex formation and LKB1 activation. LKB1 activation by tankyrase inhibitors induces AMPK activation and suppresses tumorigenesis. Similarly, the tankyrase inhibitor G007-LK effectively regulates liver metabolism and glycemic control in diabetic mice in a LKB1-dependent manner. In patients with lung cancer, tankyrase levels negatively correlate with p-AMPK levels and poor survival. Taken together, these findings suggest that tankyrase and RNF146 are major up-stream regulators of LKB1-AMPK pathway and provide another focus for cancer and metabolic disease therapies.
Modulation of M2 macrophage polarization by the crosstalk between Stat6 and Trim24
Authors: Yu Tao , Gan Shucheng , Zhu Qingchen , Dai Dongfang , Li Ni , Wang Hui , Chen Xiaosong , Hou Dan , Wang Yan , Pan Qiang , Xu Jing , Zhang Xingli , Liu Junli , Pei Siyu , Peng Chao , Wu Ping , Romano Simona , Mao Chaoming , Huang Mingzhu , Zhu Xiaodong , Shen Kunwei , Qin Jun , Xiao Yichuan 
Published: September 2019

AbstractStat6 is known to drive macrophage M2 polarization. However, how macrophage polarization is fine-tuned by Stat6 is poorly understood. Here, we find that Lys383 of Stat6 is acetylated by the acetyltransferase CREB-binding protein (CBP) during macrophage activation to suppress macrophage M2 polarization. Mechanistically, Trim24, a CBP-associated E3 ligase, promotes Stat6 acetylation by catalyzing CBP ubiquitination at Lys119 to facilitate the recruitment of CBP to Stat6. Loss of Trim24 inhibits Stat6 acetylation and thus promotes M2 polarization in both mouse and human macrophages, potentially compromising antitumor immune responses. By contrast, Stat6 mediates the suppression of TRIM24 expression in M2 macrophages to contribute to the induction of an immunosuppressive tumor niche. Taken together, our findings establish Stat6 acetylation as an essential negative regulatory mechanism that curtails macrophage M2 polarization.
Spatiotemporal material functionalization via competitive supramolecular complexation of avidin and biotin analogs
Authors: Kamperman Tom , Koerselman Michelle , Kelder Cindy , Hendriks Jan , Crispim João F. , de Peuter Xandra , Dijkstra Pieter J. , Karperien Marcel , Leijten Jeroen 
Published: September 2019

AbstractSpatiotemporal control over engineered tissues is highly desirable for various biomedical applications as it emulates the dynamic behavior of natural tissues. Current spatiotemporal biomaterial functionalization approaches are based on cytotoxic, technically challenging, or non-scalable chemistries, which has hampered their widespread usage. Here we report a strategy to spatiotemporally functionalize (bio)materials based on competitive supramolecular complexation of avidin and biotin analogs. Specifically, an injectable hydrogel is orthogonally post-functionalized with desthiobiotinylated moieties using multivalent neutravidin. In situ exchange of desthiobiotin by biotin enables spatiotemporal material functionalization as demonstrated by the formation of long-range, conformal, and contra-directional biochemical gradients within complex-shaped 3D hydrogels. Temporal control over engineered tissue biochemistry is further demonstrated by timed presentation and sequestration of growth factors using desthiobiotinylated antibodies. The method’s universality is confirmed by modifying hydrogels with biotinylated fluorophores, peptides, nanoparticles, enzymes, and antibodies. Overall, this work provides a facile, cytocompatible, and universal strategy to spatiotemporally functionalize materials.
Bioorthogonal protein-DNA conjugation methods for force spectroscopy
Authors: Synakewicz Marie , Bauer Daniela , Rief Matthias , Itzhaki Laura S. 
Published: September 2019

AbstractAccurate and stable site-specific attachment of DNA molecules to proteins is a requirement for many single-molecule force spectroscopy techniques. The most commonly used method still relies on maleimide chemistry involving cysteine residues in the protein of interest. Studies have consequently often focused on model proteins that either have no cysteines or with a small number of cysteines that can be deleted so that cysteines can then be introduced at specific sites. However, many proteins, especially in eukaryotes, contain too many cysteine residues to be amenable to this strategy, and therefore there is tremendous need for new and broadly applicable approaches to site-specific conjugation. Here we present bioorthogonal approaches for making DNA-protein conjugates required in force spectroscopy experiments. Unnatural amino acids are introduced site-specifically and conjugated to DNA oligos bearing the respective modifications to undergo either strain-promoted azidealkyne cycloaddition (SPAAC) or inverse-electron-demand Diels-Alder (IE-DA) reactions. We furthermore show that SPAAC is compatible with a previously published peptide-based attachment approach. By expanding the available toolkit to tag-free methods based on bioorthogonal reactions, we hope to enable researchers to interrogate the mechanics of a much broader range of proteins than is currently possible.
Lipidated Polyaza Crown Ethers as Membrane Anchors for DNA-Controlled Content Mixing between Liposomes
Authors: Löffler Philipp M. G. , Hansen Anders Højgaard , Ries Oliver , Jakobsen Ulla , Rabe Alexander , Sørensen Kristian T. , Glud Kasper , Vogel Stefan 
Published: September 2019

AbstractThe ability to manipulate and fuse nano-compartmentalized volumes addresses a demand for spatiotemporal control in the field of synthetic biology, for example in the bottom-up construction of (bio)chemical nanoreactors and for the interrogation of enzymatic reactions in confined space. Herein, we mix entrapped sub-attoliter volumes of liposomes (~135 nm diameter) via lipid bilayer fusion, facilitated by the hybridization of membrane-anchored lipidated oligonucleotides. We report on an improved synthesis of the membrane-anchor phosphoramidites that allows for a flexible choice of lipophilic moiety. Lipid-nucleic acid conjugates (LiNAs) with and without triethylene glycol spacers between anchor and the 17 nt binding sequence were synthesized and their fusogenic potential evaluated. A fluorescence-based content mixing assay was employed for kinetic monitoring of fusion of the bulk liposome populations at different temperatures. Data obtained at 50 °C indicated a quantitative conversion of the limiting liposome population into fused liposomes and an unprecedently high initial fusion rate was observed. For most conditions and designs only low leakage during fusion was observed. These results consolidate LiNA-mediated membrane fusion as a robust platform for programming compartmentalized chemical and enzymatic reactions.
Cross-linked chitosan aerogel modified with Pd(II)/phthalocyanine: Synthesis, characterization, and catalytic application
Authors: Al-Azmi Amal , Keshipour Sajjad 
Published: September 2019

AbstractPalladium(II) phthalocyanine (PdPc) tetrasulfonate was chemically bonded to an amine moiety of chitosan aerogel. The reaction was promoted by the transformation of sulfonic acid groups of PdPc to sulfonyl chloride, which is highly active for amination. The porous composite showed good catalytic activity in the oxidation reaction of some alkylarenes, aliphatic and benzylic alcohols, and cyclohexanol. High conversions and excellent selectivities were obtained for the solvent-free reactions under aerobic conditions at 80 °C during 24 h. While many oxidation reactions have been reported catalysed with palladium phthalocyanine, this is the first reported oxidation of alkylarenes via this catalyst. The organometallic compound is applicable as a heterogeneous catalyst having high chemical stability with recyclability up to six times.