bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Rustenburg Layered Suite formed as a stack of mush with transient magma chambers
Authors: Yao Zhuosen , Mungall James E. , Jenkins M. Christopher 
Published: January 2021

AbstractThe Rustenburg Layered Suite of the Bushveld Complex of South Africa is a vast layered accumulation of mafic and ultramafic rocks. It has long been regarded as a textbook result of fractional crystallization from a melt-dominated magma chamber. Here, we show that most units of the Rustenburg Layered Suite can be derived with thermodynamic models of crustal assimilation by komatiitic magma to form magmatic mushes without requiring the existence of a magma chamber. Ultramafic and mafic cumulate layers below the Upper and Upper Main Zone represent multiple crystal slurries produced by assimilation-batch crystallization in the upper and middle crust, whereas the chilled marginal rocks represent complementary supernatant liquids. Only the uppermost third formed via lower-crustal assimilation–fractional crystallization and evolved by fractional crystallization within a melt-rich pocket. Layered intrusions need not form in open magma chambers. Mineral deposits hitherto attributed to magma chamber processes might form in smaller intrusions of any geometric form, from mushy systems entirely lacking melt-dominated magma chambers.
Southern Ocean in-situ temperature trends over 25 years emerge from interannual variability
Authors: Auger Matthis , Morrow Rosemary , Kestenare Elodie , Sallée Jean-Baptiste , Cowley Rebecca 
Published: January 2021

AbstractDespite playing a major role in global ocean heat storage, the Southern Ocean remains the most sparsely measured region of the global ocean. Here, a unique 25-year temperature time-series of the upper 800 m, repeated several times a year across the Southern Ocean, allows us to document the long-term change within water-masses and how it compares to the interannual variability. Three regions stand out as having strong trends that dominate over interannual variability: warming of the subantarctic waters (0.29 ± 0.09 °C per decade); cooling of the near-surface subpolar waters (−0.07 ± 0.04 °C per decade); and warming of the subsurface subpolar deep waters (0.04 ± 0.01 °C per decade). Although this subsurface warming of subpolar deep waters is small, it is the most robust long-term trend of our section, being in a region with weak interannual variability. This robust warming is associated with a large shoaling of the maximum temperature core in the subpolar deep water (39 ± 09 m per decade), which has been significantly underestimated by a factor of 3 to 10 in past studies. We find temperature changes of comparable magnitude to those reported in Amundsen–Bellingshausen Seas, which calls for a reconsideration of current ocean changes with important consequences for our understanding of future Antarctic ice-sheet mass loss.
SVIP is a molecular determinant of lysosomal dynamic stability, neurodegeneration and lifespan
Authors: Johnson Alyssa E. , Orr Brian O. , Fetter Richard D. , Moughamian Armen J. , Primeaux Logan A. , Geier Ethan G. , Yokoyama Jennifer S. , Miller Bruce L. , Davis Graeme W. 
Published: January 2021

AbstractMissense mutations in Valosin-Containing Protein (VCP) are linked to diverse degenerative diseases including IBMPFD, amyotrophic lateral sclerosis (ALS), muscular dystrophy and Parkinson’s disease. Here, we characterize a VCP-binding co-factor (SVIP) that specifically recruits VCP to lysosomes. SVIP is essential for lysosomal dynamic stability and autophagosomal–lysosomal fusion. SVIP mutations cause muscle wasting and neuromuscular degeneration while muscle-specific SVIP over-expression increases lysosomal abundance and is sufficient to extend lifespan in a context, stress-dependent manner. We also establish multiple links between SVIP and VCP-dependent disease in our Drosophila model system. A biochemical screen identifies a disease-causing VCP mutation that prevents SVIP binding. Conversely, over-expression of an SVIP mutation that prevents VCP binding is deleterious. Finally, we identify a human SVIP mutation and confirm the pathogenicity of this mutation in our Drosophila model. We propose a model for VCP disease based on the differential, co-factor-dependent recruitment of VCP to intracellular organelles.
Myomerger promotes fusion pore by elastic coupling between proximal membrane leaflets and hemifusion diaphragm
Authors: Golani Gonen , Leikina Evgenia , Melikov Kamran , Whitlock Jarred M. , Gamage Dilani G. , Luoma-Overstreet Gracia , Millay Douglas P. , Kozlov Michael M. , Chernomordik Leonid V. 
Published: January 2021

AbstractMyomerger is a muscle-specific membrane protein involved in formation of multinucleated muscle cells by mediating the transition from the early hemifusion stage to complete fusion. Here, we considered the physical mechanism of the Myomerger action based on the hypothesis that Myomerger shifts the spontaneous curvature of the outer membrane leaflets to more positive values. We predicted, theoretically, that Myomerger generates the outer leaflet elastic stresses, which propagate into the hemifusion diaphragm and accelerate the fusion pore formation. We showed that Myomerger ectodomain indeed generates positive spontaneous curvature of lipid monolayers. We substantiated the mechanism by experiments on myoblast fusion and influenza hemagglutinin-mediated cell fusion. In both processes, the effects of Myomerger ectodomain were strikingly similar to those of lysophosphatidylcholine known to generate a positive spontaneous curvature of lipid monolayers. The control of post-hemifusion stages by shifting the spontaneous curvature of proximal membrane monolayers may be utilized in diverse fusion processes.
Osteoclast fusion and bone loss are restricted by interferon inducible guanylate binding proteins
Authors: Place David E. , Malireddi R. K. Subbarao , Kim Jieun , Vogel Peter , Yamamoto Masahiro , Kanneganti Thirumala-Devi 
Published: January 2021

AbstractChronic inflammation during many diseases is associated with bone loss. While interferons (IFNs) are often inhibitory to osteoclast formation, the complex role that IFN and interferon-stimulated genes (ISGs) play in osteoimmunology during inflammatory diseases is still poorly understood. We show that mice deficient in IFN signaling components including IFN alpha and beta receptor 1 (IFNAR1), interferon regulatory factor 1 (IRF1), IRF9, and STAT1 each have reduced bone density and increased osteoclastogenesis compared to wild type mice. The IFN-inducible guanylate-binding proteins (GBPs) on mouse chromosome 3 (GBP1, GBP2, GBP3, GBP5, GBP7) are required to negatively regulate age-associated bone loss and osteoclastogenesis. Mechanistically, GBP2 and GBP5 both negatively regulate in vitro osteoclast differentiation, and loss of GBP5, but not GBP2, results in greater age-associated bone loss in mice. Moreover, mice deficient in GBP5 or chromosome 3 GBPs have greater LPS-mediated inflammatory bone loss compared to wild type mice. Overall, we find that GBP5 contributes to restricting age-associated and inflammation-induced bone loss by negatively regulating osteoclastogenesis.
Universal toxin-based selection for precise genome engineering in human cells
Authors: Li Songyuan , Akrap Nina , Cerboni Silvia , Porritt Michelle J. , Wimberger Sandra , Lundin Anders , Möller Carl , Firth Mike , Gordon Euan , Lazovic Bojana , Sieńska Aleksandra , Pane Luna Simona , Coelho Matthew A. , Ciotta Giovanni , Pellegrini Giovanni , Sini Marcella , Xu Xiufeng , Mitra Suman , Bohlooly-Y Mohammad , Taylor Benjamin J. M. , Sienski Grzegorz , Maresca Marcello 
Published: January 2021

AbstractProkaryotic restriction enzymes, recombinases and Cas proteins are powerful DNA engineering and genome editing tools. However, in many primary cell types, the efficiency of genome editing remains low, impeding the development of gene- and cell-based therapeutic applications. A safe strategy for robust and efficient enrichment of precisely genetically engineered cells is urgently required. Here, we screen for mutations in the receptor for Diphtheria Toxin (DT) which protect human cells from DT. Selection for cells with an edited DT receptor variant enriches for simultaneously introduced, precisely targeted gene modifications at a second independent locus, such as nucleotide substitutions and DNA insertions. Our method enables the rapid generation of a homogenous cell population with bi-allelic integration of a DNA cassette at the selection locus, without clonal isolation. Toxin-based selection works in both cancer-transformed and non-transformed cells, including human induced pluripotent stem cells and human primary T-lymphocytes, as well as it is applicable also in vivo, in mice with humanized liver. This work represents a flexible, precise, and efficient selection strategy to engineer cells using CRISPR-Cas and base editing systems.
Oncogenic herpesvirus KSHV triggers hallmarks of alternative lengthening of telomeres
Authors: Lippert Timothy P. , Marzec Paulina , Idilli Aurora I. , Sarek Grzegorz , Vancevska Aleksandra , Bower Mark , Farrell Paul J. , Ojala Päivi M. , Feldhahn Niklas , Boulton Simon J. 
Published: January 2021

AbstractTo achieve replicative immortality, cancer cells must activate telomere maintenance mechanisms to prevent telomere shortening. ~85% of cancers circumvent telomeric attrition by re-expressing telomerase, while the remaining ~15% of cancers induce alternative lengthening of telomeres (ALT), which relies on break-induced replication (BIR) and telomere recombination. Although ALT tumours were first reported over 20 years ago, the mechanism of ALT induction remains unclear and no study to date has described a cell-based model that permits the induction of ALT. Here, we demonstrate that infection with Kaposi’s sarcoma herpesvirus (KSHV) induces sustained acquisition of ALT-like features in previously non-ALT cell lines. KSHV-infected cells acquire hallmarks of ALT activity that are also observed in KSHV-associated tumour biopsies. Down-regulating BIR impairs KSHV latency, suggesting that KSHV co-opts ALT for viral functionality. This study uncovers KSHV infection as a means to study telomere maintenance by ALT and reveals features of ALT in KSHV-associated tumours.
Large organized chromatin lysine domains help distinguish primitive from differentiated cell populations
Authors: Madani Tonekaboni Seyed Ali , Haibe-Kains Benjamin , Lupien Mathieu 
Published: January 2021

AbstractThe human genome is partitioned into a collection of genomic features, inclusive of genes, transposable elements, lamina interacting regions, early replicating control elements and cis-regulatory elements, such as promoters, enhancers, and anchors of chromatin interactions. Uneven distribution of these features within chromosomes gives rise to clusters, such as topologically associating domains (TADs), lamina-associated domains, clusters of cis-regulatory elements or large organized chromatin lysine (K) domains (LOCKs). Here we show that LOCKs from diverse histone modifications discriminate primitive from differentiated cell types. Active LOCKs (H3K4me1, H3K4me3 and H3K27ac) cover a higher fraction of the genome in primitive compared to differentiated cell types while repressive LOCKs (H3K9me3, H3K27me3 and H3K36me3) do not. Active LOCKs in differentiated cells lie proximal to highly expressed genes while active LOCKs in primitive cells tend to be bivalent. Genes proximal to bivalent LOCKs are minimally expressed in primitive cells. Furthermore, bivalent LOCKs populate TAD boundaries and are preferentially bound by regulators of chromatin interactions, including CTCF, RAD21 and ZNF143. Together, our results argue that LOCKs discriminate primitive from differentiated cell populations.
Controlling nanochannel orientation and dimensions in graphene-based nanofluidic membranes
Authors: Liu Muchun , Weston Paula J. , Hurt Robert H. 
Published: January 2021

AbstractThere is great interest in exploiting van der Waals gaps in layered materials as nanofluidic channels. Graphene oxide (GO) nanosheets are known to spontaneously assemble into stacked planar membranes with transport properties that are highly selective to molecular structure. Use of conventional GO membranes in liquid-phase applications is often limited by low flux values, due to intersheet nanochannel alignment perpendicular to the desired Z-directional transport, which leads to circuitous fluid pathways that are orders of magnitude longer than the membrane thickness. Here we demonstrate an approach that uses compressive instability in Zr-doped GO thin films to create wrinkle patterns that rotate nanosheets to high angles. Capturing this structure in polymer matrices and thin sectioning produce fully dense membranes with arrays of near-vertically aligned nanochannels. These robust nanofluidic devices offer pronounced reduction in fluid path-length, while retaining the high selectivity for water over non-polar molecules characteristic of GO interlayer nanochannels.
Alt-RPL36 downregulates the PI3K-AKT-mTOR signaling pathway by interacting with TMEM24
Authors: Cao Xiongwen , Khitun Alexandra , Luo Yang , Na Zhenkun , Phoodokmai Thitima , Sappakhaw Khomkrit , Olatunji Elizabeth , Uttamapinant Chayasith , Slavoff Sarah A. 
Published: January 2021

AbstractThousands of human small and alternative open reading frames (smORFs and alt-ORFs, respectively) have recently been annotated. Many alt-ORFs are co-encoded with canonical proteins in multicistronic configurations, but few of their functions are known. Here, we report the detection of alt-RPL36, a protein co-encoded with human RPL36. Alt-RPL36 partially localizes to the endoplasmic reticulum, where it interacts with TMEM24, which transports the phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) precursor phosphatidylinositol from the endoplasmic reticulum to the plasma membrane. Knock-out of alt-RPL36 increases plasma membrane PI(4,5)P2 levels, upregulates PI3K-AKT-mTOR signaling, and increases cell size. Alt-RPL36 contains four phosphoserine residues, point mutations of which abolish interaction with TMEM24 and, consequently, alt-RPL36 effects on PI3K signaling and cell size. These results implicate alt-RPL36 as an upstream regulator of PI3K-AKT-mTOR signaling. More broadly, the RPL36 transcript encodes two sequence-independent polypeptides that co-regulate translation via different molecular mechanisms, expanding our knowledge of multicistronic human gene functions.
MVP predicts the pathogenicity of missense variants by deep learning
Authors: Qi Hongjian , Zhang Haicang , Zhao Yige , Chen Chen , Long John J. , Chung Wendy K. , Guan Yongtao , Shen Yufeng 
Published: January 2021

AbstractAccurate pathogenicity prediction of missense variants is critically important in genetic studies and clinical diagnosis. Previously published prediction methods have facilitated the interpretation of missense variants but have limited performance. Here, we describe MVP (Missense Variant Pathogenicity prediction), a new prediction method that uses deep residual network to leverage large training data sets and many correlated predictors. We train the model separately in genes that are intolerant of loss of function variants and the ones that are tolerant in order to take account of potentially different genetic effect size and mode of action. We compile cancer mutation hotspots and de novo variants from developmental disorders for benchmarking. Overall, MVP achieves better performance in prioritizing pathogenic missense variants than previous methods, especially in genes tolerant of loss of function variants. Finally, using MVP, we estimate that de novo coding variants contribute to 7.8% of isolated congenital heart disease, nearly doubling previous estimates.
A hybrid additive manufacturing platform to create bulk and surface composition gradients on scaffolds for tissue regeneration
Authors: Sinha Ravi , Cámara-Torres Maria , Scopece Paolo , Verga Falzacappa Emanuele , Patelli Alessandro , Moroni Lorenzo , Mota Carlos 
Published: January 2021

AbstractScaffolds with gradients of physico-chemical properties and controlled 3D architectures are crucial for engineering complex tissues. These can be produced using multi-material additive manufacturing (AM) techniques. However, they typically only achieve discrete gradients using separate printheads to vary compositions. Achieving continuous composition gradients, to better mimic tissues, requires material dosing and mixing controls. No such AM solution exists for most biomaterials. Existing AM techniques also cannot selectively modify scaffold surfaces to locally stimulate cell adhesion. A hybrid AM solution to cover these needs is reported here. A dosing- and mixing-enabled, dual-material printhead and an atmospheric pressure plasma jet to selectively activate/coat scaffold filaments during manufacturing were combined on one platform. Continuous composition gradients in both 2D hydrogels and 3D thermoplastic scaffolds were fabricated. An improvement in mechanical properties of continuous gradients compared to discrete gradients in the 3D scaffolds, and the ability to selectively enhance cell adhesion were demonstrated.
Fibroblast growth factor receptor facilitates recurrence of minimal residual disease following trastuzumab emtansine therapy
Authors: Akhand Saeed S. , Chen Hao , Purdy Stephen Connor , Liu Zian , Anderson Joshua C. , Willey Christopher D. , Wendt Michael K. 
Published: January 2021

AbstractTrastuzumab-emtansine (T-DM1) is an antibody-drug conjugate (ADC) that efficiently delivers a highly potent microtubule inhibitor to HER2 overexpressing cells. Herein, we utilize HER2 transformed human mammary epithelial cells (HME2) to demonstrate in vitro and in vivo response and recurrence upon T-DM1 treatment. Continuous in vitro dosing of HME2 cells with T-DM1 failed to produce a spontaneously resistant cell line. However, induction of epithelial–mesenchymal transition (EMT) via pretreatment with TGF-β1 was capable of promoting emergence of T-DM1-resistant (TDM1R) cells. Flow cytometric analyses indicated that induction of EMT decreased trastuzumab binding, prior to overt loss of HER2 expression in TDM1R cells. Kinome analyses of TDM1R cells indicated increased phosphorylation of ErbB1, ErbB4, and FGFR1. TDM1R cells failed to respond to the ErbB kinase inhibitors lapatinib and afatinib, but they acquired sensitivity to FIIN4, a covalent FGFR kinase inhibitor. In vivo, minimal residual disease (MRD) remained detectable via bioluminescent imaging following T-DM1-induced tumor regression. Upon cessation of the ADC, relapse occurred and secondary tumors were resistant to additional rounds of T-DM1. These recurrent tumors could be inhibited by FIIN4. Moreover, ectopic overexpression of FGFR1 was sufficient to enhance tumor growth, diminish trastuzumab binding, and promote recurrence following T-DM1-induced MRD. Finally, patient-derived xenografts from a HER2+ breast cancer patient who had progressed on trastuzumab failed to respond to T-DM1, but tumor growth was significantly inhibited by FIIN4. Overall, our studies strongly support therapeutic combination of TDM1 with FGFR-targeted agents in HER2+ breast cancer.
An asymmetric variation of hot and cold SST extremes in the China Seas during the recent warming hiatus period
Authors: Li Yan , Wang Qingyuan , Li Qingquan , Liu Yiwei , Wang Yan 
Published: January 2021

AbstractExtreme sea surface temperatures (SSTs) attract much attention in recent years. However, the detailed spatial and temporal pattern of the extreme SSTs in China Seas has not been well understood. Using the daily SST data set of OISST v2 from January 1, 1982 to December 31, 2013, and based on four extreme SST indices, the frequency and intensity of SST extremes in the China Seas were examined. The analysis showed that the annual mean SST exhibited cooling trend, on pace with a trend of − 0.34 °C/decade during 1998–2013, confirming the previous studies that China Seas also experienced the recent global warming hiatus. But during this recent global warming hiatus, there was a notable asymmetric pattern of greater cooling trends in cold SSTs as compared to the hot SSTs in this region. During 1998–2013, the cold days (CDs) frequency increased significantly by 13 days per decade and cold SST extremes which were below the 10th percentile of each year (SST10p) notably decreased by 0.4 °C per decade. Hot days (HD) and hot SST extremes which were above the 90th percentile of each year (SST90p) slowed down, but without any distinct tendency. Meanwhile, the rates of SST10p and CDs were highly heterogeneous in space. Cold extremes in the near-shore areas are much more sensitive to the global warming hiatus than these in the eastern of the Kuroshio Current. Importantly, hot extremes do not reveal any distinct cooling tendency during 1998–2013, there were more frequent hot days and more intense hot SSTs in this region comparing with 1982–1997. These hot extremes could push some marine organisms, fisheries and ecosystems beyond the limits of their resilience, with cascading impacts on economies and societies.
Sea-level stands from the Western Mediterranean over the past 6.5 million years
Authors: Dumitru Oana A. , Austermann Jacqueline , Polyak Victor J. , Fornós Joan J. , Asmerom Yemane , Ginés Joaquín , Ginés Angel , Onac Bogdan P. 
Published: January 2021

AbstractSea-level reconstructions are important for understanding past ice sheet variability and its response to past and future warming. Here we present Neogene and Quaternary sea-level snapshots using phreatic overgrowths on speleothems (POS) from caves on Mallorca, Spain. POS are excellent sea level index points because of their clear relationship to sea level and precise U–Pb chronology. We find that local sea-level before and at the onset of the Messinian Salinity Crisis was at 33.3 ± 0.25 m (6.54 ± 0.37 Ma) and 31.8 ± 0.25 m (5.86 ± 0.60 Ma) above present levels, respectively. We further present global mean sea level (GMSL) estimates, i.e. local sea level corrected for glacial isostatic adjustment and long-term uplift, for three other POS. The results show that GMSL during the Pliocene–Pleistocene Transition was 6.4 m (− 2.0–8.8 m) at 2.63 ± 0.11 Ma and during the beginning and the end of the Mid-Pleistocene Transition was − 1.1 m (− 5.6–2.4 m) and 5 m (1.5–8.1 m), respectively. These estimates provide important constraints for the past evolution of sea level and show that local sea level prior to the MSC was similar to the highest stand during the Pliocene, with markedly lower position afterwards.