bluuebunny/crossref_metadata_2025_split huggingface dataset:
Rapid climate change results in long-lasting spatial homogenization of phylogenetic diversity
Authors: Saladin Bianca , Pellissier Loïc , Graham Catherine H. , Nobis Michael P. , Salamin Nicolas , Zimmermann Niklaus E. 
Published: September 2020

AbstractScientific understanding of biodiversity dynamics, resulting from past climate oscillations and projections of future changes in biodiversity, has advanced over the past decade. Little is known about how these responses, past or future, are spatially connected. Analyzing the spatial variability in biodiversity provides insight into how climate change affects the accumulation of diversity across space. Here, we evaluate the spatial variation of phylogenetic diversity of European seed plants among neighboring sites and assess the effects of past rapid climate changes during the Quaternary on these patterns. Our work shows a marked homogenization in phylogenetic diversity across Central and Northern Europe linked to high climate change velocity and large distances to refugia. Our results suggest that the future projected loss in evolutionary heritage may be even more dramatic, as homogenization in response to rapid climate change has occurred among sites across large landscapes, leaving a legacy that has lasted for millennia.
Intercalated disc protein Xinβ is required for Hippo-YAP signaling in the heart
Authors: Guo Haipeng , Lu Yao Wei , Lin Zhiqiang , Huang Zhan-Peng , Liu Jianming , Wang Yi , Seok Hee Young , Hu Xiaoyun , Ma Qing , Li Kathryn , Kyselovic Jan , Wang Qingchuan , Lin Jenny L.-C. , Lin Jim J.-C. , Cowan Douglas B. , Naya Francisco , Chen Yuguo , Pu William T. , Wang Da-Zhi 
Published: September 2020

AbstractIntercalated discs (ICD), specific cell-to-cell contacts that connect adjacent cardiomyocytes, ensure mechanical and electrochemical coupling during contraction of the heart. Mutations in genes encoding ICD components are linked to cardiovascular diseases. Here, we show that loss of Xinβ, a newly-identified component of ICDs, results in cardiomyocyte proliferation defects and cardiomyopathy. We uncovered a role for Xinβ in signaling via the Hippo-YAP pathway by recruiting NF2 to the ICD to modulate cardiac function. In Xinβ mutant hearts levels of phosphorylated NF2 are substantially reduced, suggesting an impairment of Hippo-YAP signaling. Cardiac-specific overexpression of YAP rescues cardiac defects in Xinβ knock-out mice—indicating a functional and genetic interaction between Xinβ and YAP. Our study reveals a molecular mechanism by which cardiac-expressed intercalated disc protein Xinβ modulates Hippo-YAP signaling to control heart development and cardiac function in a tissue specific manner. Consequently, this pathway may represent a therapeutic target for the treatment of cardiovascular diseases.
Translational pharmacology of an inhaled small molecule αvβ6 integrin inhibitor for idiopathic pulmonary fibrosis
Authors: John Alison E. , Graves Rebecca H. , Pun K. Tao , Vitulli Giovanni , Forty Ellen J. , Mercer Paul F. , Morrell Josie L. , Barrett John W. , Rogers Rebecca F. , Hafeji Maryam , Bibby Lloyd I. , Gower Elaine , Morrison Valerie S. , Man Yim , Roper James A. , Luckett Jeni C. , Borthwick Lee A. , Barksby Ben S. , Burgoyne Rachel A. , Barnes Rory , Le Joelle , Flint David J. , Pyne Susan , Habgood Anthony , Organ Louise A. , Joseph Chitra , Edwards-Pritchard Rochelle C. , Maher Toby M. , Fisher Andrew J. , Gudmann Natasja Stæhr , Leeming Diana J. , Chambers Rachel C. , Lukey Pauline T. , Marshall Richard P. , Macdonald Simon J. F. , Jenkins R. Gisli , Slack Robert J. 
Published: September 2020

AbstractThe αvβ6 integrin plays a key role in the activation of transforming growth factor-β (TGFβ), a pro-fibrotic mediator that is pivotal to the development of idiopathic pulmonary fibrosis (IPF). We identified a selective small molecule αvβ6 RGD-mimetic, GSK3008348, and profiled it in a range of disease relevant pre-clinical systems. To understand the relationship between target engagement and inhibition of fibrosis, we measured pharmacodynamic and disease-related end points. Here, we report, GSK3008348 binds to αvβ6 with high affinity in human IPF lung and reduces downstream pro-fibrotic TGFβ signaling to normal levels. In human lung epithelial cells, GSK3008348 induces rapid internalization and lysosomal degradation of the αvβ6 integrin. In the murine bleomycin-induced lung fibrosis model, GSK3008348 engages αvβ6, induces prolonged inhibition of TGFβ signaling and reduces lung collagen deposition and serum C3M, a marker of IPF disease progression. These studies highlight the potential of inhaled GSK3008348 as an anti-fibrotic therapy.
Arrangement and symmetry of the fungal E3BP-containing core of the pyruvate dehydrogenase complex
Authors: Forsberg B. O. , Aibara S. , Howard R. J. , Mortezaei N. , Lindahl E. 
Published: September 2020

AbstractThe pyruvate dehydrogenase complex (PDC) is a multienzyme complex central to aerobic respiration, connecting glycolysis to mitochondrial oxidation of pyruvate. Similar to the E3-binding protein (E3BP) of mammalian PDC, PX selectively recruits E3 to the fungal PDC, but its divergent sequence suggests a distinct structural mechanism. Here, we report reconstructions of PDC from the filamentous fungus Neurospora crassa by cryo-electron microscopy, where we find protein X (PX) interior to the PDC core as opposed to substituting E2 core subunits as in mammals. Steric occlusion limits PX binding, resulting in predominantly tetrahedral symmetry, explaining previous observations in Saccharomyces cerevisiae. The PX-binding site is conserved in (and specific to) fungi, and complements possible C-terminal binding motifs in PX that are absent in mammalian E3BP. Consideration of multiple symmetries thus reveals a differential structural basis for E3BP-like function in fungal PDC.
Bacteria are important dimethylsulfoniopropionate producers in marine aphotic and high-pressure environments
Authors: Zheng Yanfen , Wang Jinyan , Zhou Shun , Zhang Yunhui , Liu Ji , Xue Chun-Xu , Williams Beth T. , Zhao Xiuxiu , Zhao Li , Zhu Xiao-Yu , Sun Chuang , Zhang Hong-Hai , Xiao Tian , Yang Gui-Peng , Todd Jonathan D. , Zhang Xiao-Hua 
Published: September 2020

AbstractDimethylsulfoniopropionate (DMSP) is an important marine osmolyte. Aphotic environments are only recently being considered as potential contributors to global DMSP production. Here, our Mariana Trench study reveals a typical seawater DMSP/dimethylsulfide (DMS) profile, with highest concentrations in the euphotic zone and decreased but consistent levels below. The genetic potential for bacterial DMSP synthesis via the dsyB gene and its transcription is greater in the deep ocean, and is highest in the sediment.s DMSP catabolic potential is present throughout the trench waters, but is less prominent below 8000 m, perhaps indicating a preference to store DMSP in the deep for stress protection. Deep ocean bacterial isolates show enhanced DMSP production under increased hydrostatic pressure. Furthermore, bacterial dsyB mutants are less tolerant of deep ocean pressures than wild-type strains. Thus, we propose a physiological function for DMSP in hydrostatic pressure protection, and that bacteria are key DMSP producers in deep seawater and sediment.
Materializing efficient methanol oxidation via electron delocalization in nickel hydroxide nanoribbon
Authors: Wang Xiaopeng , Xi Shibo , Lee Wee Siang Vincent , Huang Pengru , Cui Peng , Zhao Lei , Hao Weichang , Zhao Xinsheng , Wang Zhenbo , Wu Haijun , Wang Hao , Diao Caozheng , Borgna Armando , Du Yonghua , Yu Zhi Gen , Pennycook Stephen , Xue Junmin 
Published: September 2020

AbstractAchieving a functional and durable non-platinum group metal-based methanol oxidation catalyst is critical for a cost-effective direct methanol fuel cell. While Ni(OH)2 has been widely studied as methanol oxidation catalyst, the initial process of oxidizing Ni(OH)2 to NiOOH requires a high potential of 1.35 V vs. RHE. Such potential would be impractical since the theoretical potential of the cathodic oxygen reduction reaction is at 1.23 V. Here we show that a four-coordinated nickel atom is able to form charge-transfer orbitals through delocalization of electrons near the Fermi energy level. As such, our previously reported periodically arranged four-six-coordinated nickel hydroxide nanoribbon structure (NR-Ni(OH)2) is able to show remarkable methanol oxidation activity with an onset potential of 0.55 V vs. RHE and suggests the operability in direct methanol fuel cell configuration. Thus, this strategy offers a gateway towards the development of high performance and durable non-platinum direct methanol fuel cell.
Cage-confined photocatalysis for wide-scope unusually selective [2 + 2] cycloaddition through visible-light triplet sensitization
Authors: Wang Jing-Si , Wu Kai , Yin Changzhen , Li Kang , Huang Yahao , Ruan Jia , Feng Ximin , Hu Peng , Su Cheng-Yong 
Published: September 2020

AbstractLight-induced [2 + 2] cycloaddition is the most straightforward way to generate cyclobutanes, which are core structures of many natural products, drugs and bioactive compounds. Despite continuous advances in selective [2 + 2] cycloaddition research, general method for intermolecular photocatalysis of acyclic olefins with specific regio- and diastereoselectivity, for example, syn-head-to-head (syn-HH) cyclobutane derivatives, is still lack of development but highly desired. Herein, we report a cage-confined photocatalytic protocol to enable unusual intermolecular [2 + 2] cycloaddition for α,β-unsaturated carbonyl compounds. The syn-HH diastereomers are readily generated with diastereoselectivity up to 99%. The cage-catalyst is highly efficient and robust, covering a diverse substrate range with excellent substituent tolerance. The mimic-enzyme catalysis is proposed through a host-guest mediated procedure expedited by aqueous phase transition of reactant and product, where the supramolecular cage effect plays an important role to facilitate substrates inclusion and pre-orientation, offering a promising avenue for general and eco-friendly cycloaddition photocatalysis with special diastereoselectivity.
Addition of alkynes and osmium carbynes towards functionalized dπ–pπ conjugated systems
Authors: Chen Shiyan , Liu Longzhu , Gao Xiang , Hua Yuhui , Peng Lixia , Zhang Ying , Yang Liulin , Tan Yuanzhi , He Feng , Xia Haiping 
Published: September 2020

AbstractThe metal-carbon triple bonds and carbon-carbon triple bonds are both highly unsaturated bonds. As a result, their reactions tend to afford cycloaddition intermediates or products. Herein, we report a reaction of M≡C and C≡C bonds that affords acyclic addition products. These newly discovered reactions are highly efficient, regio- and stereospecific, with good functional group tolerance, and are robust under air at room temperature. The isotope labeling NMR experiments and theoretical calculations reveal the reaction mechanism. Employing these reactions, functionalizeddπ-pπconjugated systems can be easily constructed and modified. The resultingdπ-pπconjugated systems were found to be good electron transport layer materials in organic solar cells, with power conversion efficiency up to 16.28% based on the PM6: Y6 non-fullerene system. This work provides a facile, efficient methodology for the preparation ofdπ-pπconjugated systems for use in functional materials.
Systemic muscle wasting and coordinated tumour response drive tumourigenesis
Authors: Newton Holly , Wang Yi-Fang , Camplese Laura , Mokochinski Joao B. , Kramer Holger B. , Brown André E. X. , Fets Louise , Hirabayashi Susumu 
Published: September 2020

AbstractCancer cells demand excess nutrients to support their proliferation, but how tumours exploit extracellular amino acids during systemic metabolic perturbations remain incompletely understood. Here, we use aDrosophilamodel of high-sugar diet (HSD)-enhanced tumourigenesis to uncover a systemic host-tumour metabolic circuit that supports tumour growth. We demonstrate coordinate induction of systemic muscle wasting with tumour-autonomous Yorkie-mediated SLC36-family amino acid transporter expression as a proline-scavenging programme to drive tumourigenesis. We identify Indole-3-propionic acid as an optimal amino acid derivative to rationally target the proline-dependency of tumour growth. Insights from this whole-animalDrosophilamodel provide a powerful approach towards the identification and therapeutic exploitation of the amino acid vulnerabilities of tumourigenesis in the context of a perturbed systemic metabolic network.
IRF1-mediated downregulation of PGC1α contributes to cardiorenal syndrome type 4
Authors: Huang Yinghui , Wang Shaobo , Zhou Jie , Liu Yong , Du Changhong , Yang Ke , Bi Xianjin , Liu Mingying , Han Wenhao , Wang Kailong , Xiong Jiachuan , Wang Song , Wang Yue , Nie Ling , Liu Chi , Zhang Daohai , Gu Jun , Zeng Chunyu , Zhao Jinghong 
Published: September 2020

AbstractCardiorenal syndrome type 4 (CRS4) is a common complication of chronic kidney disease (CKD), but the pathogenic mechanisms remain elusive. Here we report that morphological and functional changes in myocardial mitochondria are observed in CKD mice, especially decreases in oxidative phosphorylation and fatty acid metabolism. High phosphate (HP), a hallmark of CKD, contributes to myocardial energy metabolism dysfunction by downregulating peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1α). Furthermore, the transcriptional factor interferon regulatory factor 1 (IRF1) is revealed as the key molecule upregulated by HP through histone H3K9 acetylation, and responsible for the HP-mediated transcriptional inhibition of PGC1α by directly binding to its promoter region. Conversely, restoration of PGC1α expression or genetic knockdown of IRF1 significantly attenuates HP-induced alterations in vitro and in vivo. These findings demonstrate that IRF1-PGC1α axis-mediated myocardial energy metabolism remodeling plays a crucial role in the pathogenesis of CRS4.
Mechanism for the reactivation of the peroxidase activity of human cyclooxygenases: investigation using phenol as a reducing cosubstrate
Authors: Yang Chengxi , Li Peng , Ding Xiaoli , Sui Hao Chen , Rao Shun , Hsu Chia-Hsiang , Leung Wing-Por , Cheng Gui-Juan , Wang Pan , Zhu Bao Ting 
Published: September 2020

AbstractIt has been known for many years that the peroxidase activity of cyclooxygenase 1 and 2 (COX-1 and COX-2) can be reactivated in vitro by the presence of phenol, which serves as a reducing compound, but the underlying mechanism is still poorly understood. In the present study, we use phenol as a model compound to investigate the mechanism by which the peroxidase activity of human COXs is reactivated after each catalytic cycle. Molecular docking and quantum mechanics calculations are carried out to probe the interaction of phenol with the peroxidase site of COXs and the reactivation mechanism. It is found that the oxygen atom associated with the Fe ion in the heme group (i.e., the complex of Fe ion and porphyrin) of COXs can be removed by addition of two protons. Following its removal, phenol can readily bind inside the peroxidase active sites of the COX enzymes, and directly interact with Fe in heme to facilitate electron transfer from phenol to heme. This investigation provides theoretical evidence for several intermediates formed in the COX peroxidase reactivation cycle, thereby unveiling mechanistic details that would aid in future rational design of drugs that target the peroxidase site.
Characterisation of the novel spontaneously immortalized and invasively growing human skin keratinocyte line HaSKpw
Authors: Pavez Lorie Elizabeth , Stricker Nicola , Plitta-Michalak Beata , Chen I.-Peng , Volkmer Beate , Greinert Rüdiger , Jauch Anna , Boukamp Petra , Rapp Alexander 
Published: September 2020

AbstractWe here present the spontaneously immortalised cell line, HaSKpw, as a novel model for the multistep process of skin carcinogenesis. HaSKpw cells were established from the epidermis of normal human adult skin that, without crisis, are now growing unrestricted and feeder-independent. At passage 22, clonal populations were established and clone7 (HaSKpwC7) was further compared to the also spontaneously immortalized HaCaT cells. As important differences, the HaSKpw cells express wild-type p53, remain pseudodiploid, and show a unique chromosomal profile with numerous complex aberrations involving chromosome 20. In addition, HaSKpw cells overexpress a pattern of genes and miRNAs such as KRT34, LOX, S100A9, miR21, and miR155; all pointing to a tumorigenic status. In concordance, HaSKpw cells exhibit reduced desmosomal contacts that provide them with increased motility and a highly migratory/invasive phenotype as demonstrated in scratch- and Boyden chamber assays. In 3D organotypic cultures, both HaCaT and HaSKpw cells form disorganized epithelia but only the HaSKpw cells show tumorcell-like invasive growth. Together, HaSKpwC7 and HaCaT cells represent two spontaneous (non-genetically engineered) “premalignant” keratinocyte lines from adult human skin that display different stages of the multistep process of skin carcinogenesis and thus represent unique models for analysing skin cancer development and progression.
Modified parylene-N films as chemical microenvironments for differentiation and spheroid formation of osteoblast cells
Authors: Kim Tae-Hun , Lee Jong-Sook , Jo Hanhee , Park Yusun , Yun Mijin , Song Zhiquan , Pyun Jae-Chul , Lee Misu 
Published: September 2020

AbstractIn this work, the influence of parylene N film on the spheroid formation of osteoblast-like cells (MG-63) was determined and compared with that of high-hydrophilicity microenvironments, such as hydrophilic culture matrix and ultraviolet-treated parylene N film. To elucidate the change in cell properties due to the microenvironment of parylene N film, global gene expression profiles of MG-63 cells on parylene N film were analyzed. We confirmed the upregulated expression of osteoblast differentiation- and proliferation-related genes, such as Runx2, ALPL, and BGLAP and MKi67 and PCNA, respectively, using the real-time polymerase chain reaction. In addition, the differentiation and proliferation of osteoblast cells cultured on parylene N film were validated using immunostaining. Finally, the formation of spheroids and regulation of differentiation in human mesenchymal stem cells (MSCs) on parylene N film was demonstrated. The results of this study confirm that the microenvironment with the controlled hydrophobic property of parylene N film could effectively trigger the bone differentiation and maintains the proliferation of MSCs, similar to MG-63 cells without any scaffold structures or physical treatments.
Biogeographic problem-solving reveals the Late Pleistocene translocation of a short-faced bear to the California Channel Islands
Authors: Mychajliw Alexis M. , Rick Torben C. , Dagtas Nihan D. , Erlandson Jon M. , Culleton Brendan J. , Kennett Douglas J. , Buckley Michael , Hofman Courtney A. 
Published: September 2020

AbstractAn accurate understanding of biodiversity of the past is critical for contextualizing biodiversity patterns and trends in the present. Emerging techniques are refining our ability to decipher otherwise cryptic human-mediated species translocations across the Quaternary, yet these techniques are often used in isolation, rather than part of an interdisciplinary hypothesis-testing toolkit, limiting their scope and application. Here we illustrate the use of such an integrative approach and report the occurrence of North America’s largest terrestrial mammalian carnivore, the short-faced bear,Arctodus simus,from Daisy Cave (CA-SMI-261), an important early human occupation site on the California Channel Islands. We identified the specimen by corroborating morphological, protein, and mitogenomic lines of evidence, and evaluated the potential natural and anthropogenic mechanisms of its transport and deposition. While representing just a single specimen, our combination of techniques opened a window into the behavior of an enigmatic species, suggesting thatA. simuswas a wide-ranging scavenger utilizing terrestrial and marine carcasses. This discovery highlights the utility of bridging archaeological and paleontological datasets to disentangle complex biogeographic scenarios and reveal unexpected biodiversity for island systems worldwide.
Small-residue packing motifs modulate the structure and function of a minimal de novo membrane protein
Authors: Curnow Paul , Hardy Benjamin J. , Dufour Virginie , Arthur Christopher J. , Stenner Richard , Hodgson Lorna R. , Verkade Paul , Williams Christopher , Shoemark Deborah K. , Sessions Richard B. , Crump Matthew P. , Jones Michael R. , Anderson J. L. Ross 
Published: September 2020

AbstractAlpha-helical integral membrane proteins contain conserved sequence motifs that are known to be important in helix packing. These motifs are a promising starting point for the construction of artificial proteins, but their potential has not yet been fully explored. Here, we study the impact of introducing a common natural helix packing motif to the transmembrane domain of a genetically-encoded and structurally dynamic de novo membrane protein. The resulting construct is an artificial four-helix bundle with lipophilic regions that are defined only by the amino acids L, G, S, A and W. This minimal proto-protein could be recombinantly expressed by diverse prokaryotic and eukaryotic hosts and was found to co-sediment with cellular membranes. The protein could be extracted and purified in surfactant micelles and was monodisperse and stable in vitro, with sufficient structural definition to support the rapid binding of a heme cofactor. The reduction in conformational diversity imposed by this design also enhances the nascent peroxidase activity of the protein-heme complex. Unexpectedly, strains ofEscherichia coliexpressing this artificial protein specifically accumulated zinc protoporphyrin IX, a rare cofactor that is not used by natural metalloenzymes. Our results demonstrate that simple sequence motifs can rigidify elementary membrane proteins, and that orthogonal artificial membrane proteins can influence the cofactor repertoire of a living cell. These findings have implications for rational protein design and synthetic biology.