bluuebunny/crossref_metadata_2025_split huggingface dataset:
Accounting for Vertical Subgrid‐Scale Heterogeneity in Low‐Level Cloud Fraction Parameterizations
Authors: Jouhaud J. , Dufresne J.‐L. , Madeleine J.‐B. , Hourdin F. , Couvreux F. , Villefranque N. , Jam A. 
Published: October 2018

AbstractMany general circulation models (GCMs) assume some heterogeneity of water amounts in their grid boxes and use probability density functions to parameterize cloud fractions CF and amounts of condensed water qc. Most GCM cloud schemes calculate the CF as the volume of the grid box that contains clouds (CFvol), whereas radiative fluxes primarily depend on the CF by surface (CFsurf), that is, the surface of the grid box covered by clouds when looking from above. This discrepancy matters as previous findings suggest that CFsurf is typically greater than CFvol by about 30%. In this paper we modify the single column model version of the LMDz GCM cloud scheme by introducing the vertical subgrid‐scale heterogeneity of water content. This allows to distinctly compute the two fractions, CFvol and CFsurf, as well as the amount of condensed water qc. This study is one of the first to take into account such vertical subgrid‐scale heterogeneity in a GCM cloud scheme. Three large eddy simulation cases of cumuliform boundary layer clouds are used to test and calibrate two different parameterizations. These new developments increase cloud cover by about 10% for the oceanic cases RICO and Barbados Oceanographic Meteorological Experiment and by up to 50% for the continental case ARM. The change in condensed water reduces the liquid water path by 10–20% and therefore the cloud opacity by 5–50%. These results show the potential of the new scheme to reduce the too few, too bright bias by increasing low‐level CF and decreasing cloud reflectance.
A subtype of cancer-associated fibroblasts with lower expression of alpha-smooth muscle actin suppresses stemness through BMP4 in oral carcinoma
Authors: Patel Ankit Kumar , Vipparthi Kavya , Thatikonda Venu , Arun Indu , Bhattacharjee Samsiddhi , Sharan Rajeev , Arun Pattatheyil , Singh Sandeep 
Published: October 2018

AbstractCancer-associated fibroblasts (CAFs) demonstrate the characteristics of myofibroblast differentiation by often expressing the ultrastructure of alpha-smooth muscle actin (αSMA). However, heterogeneity among cancer-associated fibroblasts (CAFs), with respect to αSMA expression, has been demonstrated in several clinical studies of oral cancer. Like normal stem cells, stem-like cancer cells (SLCCs) are also regulated extrinsically by its microenvironment; therefore, we postulated that the heterogeneous oral-CAFs would differently regulate oral-SLCCs. Using transcriptomics, we clearly demonstrated that the gene expression differences between oral tumor-derived CAFs were indeed the molecular basis of heterogeneity. This also grouped these CAFs in two distinct clusters, which were named as C1 and C2. Interestingly, the oral-CAFs belonging to C1 or C2 clusters showed low or high αSMA-score, respectively. Our data with tumor tissues and in vitro co-culture experiments interestingly demonstrated a negative correlation between αSMA-score and cell proliferation, whereas, the frequency of oral-SLCCs was significantly positively correlated with αSMA-score. The oral-CAF-subtype with lower score for αSMA (C1-type CAFs) was more supportive for cell proliferation but suppressive for the self-renewal growth of oral-SLCCs. Further, we found the determining role of BMP4 in C1-type CAFs-mediated suppression of self-renewal of oral-SLCCs. Overall, we have discovered an unexplored interaction between CAFs with lower-αSMA expression and SLCCs in oral tumors and provided the first evidence about the involvement of CAF-expressed BMP4 in regulation of self-renewal of oral-SLCCs.
Suppression of SUN2 by DNA methylation is associated with HSCs activation and hepatic fibrosis
Authors: Chen Xin , Li Wan-Xia , Chen Yu , Li Xiao-Feng , Li Hai-Di , Huang Hui-Min , Bu Fang-Tian , Pan Xue-Yin , Yang Yang , Huang Cheng , Meng Xiao-Ming , Li Jun 
Published: October 2018

AbstractHepatic myofibroblasts, activated hepatic stellate cells (HSCs), are the main cell type of extracellular matrix (ECM) deposition during hepatic fibrosis. Aberrant DNA methylation-regulated HSCs activation in liver fibrogenesis has been reported, but the functional roles and mechanisms of DNA methylation in hepatic fibrosis remain to be elucidated. In the present study, reduced representation bisulfite sequencing (RRBS) analysis of primary HSCs revealed hypermethylation patterns in hepatic fibrosis. Interestingly, we found SAD1/UNC84 domain protein-2 (SUN2) gene hypermethylation at CpG sites during liver fibrogenesis in mice with CCl4-induced hepatic fibrosis, which was accompanied by low expression of SUN2. In vivo overexpression of SUN2 following adeno-associated virus-9 (AAV9) administration inhibited CCl4-induced liver injury and reduced fibrogenesis marker expression. Consistently, in vitro experiments showed that enforced expression of SUN2 suppressed HSCs activation and exerted anti-fibrogenesis effects in TGF-β1-activated HSC-T6 cells. In addition, the signaling mechanisms related to SUN2 expression were investigated in vivo and in vitro. Methyltransferase-3b (DNMT3b) is the principal regulator of SUN2 expression. Mechanistically, inhibition of protein kinase B (AKT) phosphorylation may be a crucial pathway for SUN2-mediated HSCs activation. In conclusion, these findings provide substantial new insights into SUN2 in hepatic fibrosis.
Akt2 mediates glucocorticoid resistance in lymphoid malignancies through FoxO3a/Bim axis and serves as a direct target for resistance reversal
Authors: Xie Mixue , Yang Apeng , Ma Jiexian , Wu Min , Xu Hongyue , Wu Kefei , Jin Youxin , Xie Yanhui 
Published: October 2018

AbstractGlucocorticoids (GCs) are widely used drugs in the treatment of lymphoid malignancies; resistance of GCs in lymphocytes confers poor prognosis and the mechanisms are poorly understood. Here, we found T-acute lymphoblastic leukemia (T-ALL) cells acquire resistance to dexamethasone (DEX)-mediated killing through abnormal activation of Akt, resulting in inhibition of the FoxO3a/Bim pathway. The resistant state was reported to be associated with increased glycolysis, NOTCH1 activating mutations and activated PI3K/ serum GS regulated kinases (SGK) pathway. Use of aforementioned pathway inhibitors blocked FoxO3a-phosphorylation and partially improved DEX-mediated killing of GC-resistant T-ALL cells, further revealing the essential role of the FoxO3a/Bim pathway in the development of GC resistance. Inhibition of Akt is most effective at restoring sensitivity to DEX of GC-resistant lymphocytes in vitro and in vivo, but shows significant hepatotoxicity in vivo. A significantly elevated expression of Akt2 not Akt1 in intrinsically, secondarily GC-resistant lymphocytes and relapsed/refractory ALL patients implicates a more specific target for GC resistance. Mechanistically, Akt2 has a stronger binding capacity with FoxO3a compared to Akt1, and acts as a direct and major negative regulator of FoxO3a activity driving GC resistance. Pharmacologic inhibition of Akt2 more effectively restores sensitivity to GCs than inhibition of Akt1 in vitro, shows higher synergistic effect acting with DEX, and reverses GC resistance in GC-resistant T- or B- lymphoid tumors in vivo with reduced liver toxicity. In summary, these results suggest that Akt2 might serve as a more direct and specific kinase mediating GC resistance through FoxO3a/Bim signaling pathway, and Akt2 inhibition may be explored as a promising target for treating GC-resistant hematopoietic malignancies.
Novel engineered, membrane-localized variants of vascular endothelial growth factor (VEGF) protect retinal ganglion cells: a proof-of-concept study
Authors: Shen Junhui , Xiao Ru , Bair Jeffrey , Wang Fang , Vandenberghe Luk H. , Dartt Darlene , Baranov Petr , Ng Yin Shan Eric 
Published: October 2018

AbstractEndogenous vascular endothelial growth factor (VEGF-A) can protect retinal ganglion cells (RGC) from stress-induced cell death in ocular hypertensive glaucoma. To exploit the neuroprotective function of VEGF-A for therapeutic application in ocular disorders such as glaucoma while minimizing unwanted vascular side effects, we engineered two novel VEGF variants, eVEGF-38 and eVEGF-53. These variants of the diffusible VEGF-A isoform VEGF121 are expressed as dimeric concatamers and remain tethered to the cell membrane, thus restricting the effects of the engineered VEGF to the cells expressing the protein. For comparison, we tested a Myc-tagged version of VEGF189, an isoform that binds tightly to the extracellular matrix and heparan sulfate proteoglycans at the cell surface, supporting only autocrine and localized juxtacrine signaling. In human retinal endothelial cells (hREC), expression of eVEGF-38, eVEGF-53, or VEGF189 increased VEGFR2 phosphorylation without increasing expression of pro-inflammatory markers, relative to VEGF165 protein and vector controls. AAV2-mediated transduction of eVEGF-38, eVEGF-53, or VEGF189 into primary mouse RGC promoted synaptogenesis and increased the average total length of neurites and axons per RGC by ~ 12-fold, an increase that was mediated by VEGFR2 and PI3K/AKT signaling. Expression of eVEGF-38 in primary RGC enhanced expression of genes associated with neuritogenesis, axon outgrowth, axon guidance, and cell survival. Transduction of primary RGC with any of the membrane-associated VEGF constructs increased survival both under normal culture conditions and in the presence of the cytotoxic chemicals H2O2 (via VEGFR2/PI3K/AKT signaling) and N-methyl-d-aspartate (via reduced Ca2+ influx). Moreover, RGC number was increased in mouse embryonic stem cell-derived retinal organoid cultures transduced with the eVEGF-53 construct. The novel, engineered VEGF variants eVEGF-38 and eVEGF-53 show promise as potential therapeutics for retinal RGC neuroprotection when delivered using a gene therapy approach.
Transient receptor potential channel 6 knockdown prevents apoptosis of renal tubular epithelial cells upon oxidative stress via autophagy activation
Authors: Hou Xin , Xiao Haitao , Zhang Yanhong , Zeng Xixi , Huang Mengjun , Chen Xiaoyun , Birnbaumer Lutz , Liao Yanhong 
Published: October 2018

AbstractReactive oxygen species (ROS) are generated under various pathological conditions such as renal ischemia/reperfusion (I/R) injury and provoke damage to multiple cellular organelles and processes. Overproduction of ROS causes oxidative stress and contributes to damages of renal proximal tubular cells (PTC), which are the main cause of the pathogenesis of renal I/R injury. Autophagy is a dynamic process that removes long-lived proteins and damaged organelles via lysosome-mediated degradation, which has an antioxidant effect that relieves oxidative stress. The canonical transient receptor potential channel 6 (TRPC6), a nonselective cation channel that allows passage of Ca2+, plays an important role in renal disease. Yet, the relationship between TRPC6 and autophagy, as well as their functions in renal oxidative stress injury, remains unclear. In this study, we found that oxidative stress triggered TRPC6-dependent Ca2+ influx in PTC to inhibit autophagy, thereby rendering cells more susceptible to death. We also demonstrated that TRPC6 knockout (TRPC6-/-) or inhibition by SAR7334, a TRPC6-selective inhibitor, increased autophagic flux and mitigated oxidative stress-induced apoptosis of PTC. The protective effects of TRPC6 ablation were prevented by autophagy inhibitors Chloroquine and Bafilomycin A1. Moreover, this study also shows that TRPC6 blockage promotes autophagic flux via inhibiting the PI3K/Akt/mTOR and ERK1/2 signaling pathways. This is the first evidence showing that TRPC6-mediated Ca2+ influx plays a novel role in suppressing cytoprotective autophagy triggered by oxidative stress in PTC, and it may become a novel therapeutic target for the treatment of renal oxidative stress injury in the future.
Long noncoding RNA MEG3 regulates LATS2 by promoting the ubiquitination of EZH2 and inhibits proliferation and invasion in gallbladder cancer
Authors: Jin Longyang , Cai Qiang , Wang Shouhua , Wang Shuqing , Mondal Tanmoy , Wang Jiandong , Quan Zhiwei 
Published: October 2018

AbstractGallbladder cancer (GBC) is the most common type of biliary tract cancer worldwide. Long noncoding RNAs (lncRNAs) play essential roles in physiological and pathological development. LncRNA MEG3, a tumor suppressor, has been reported to play important roles in some cancers, but the role of MEG3 in GBC remains largely unknown. The purpose of the present study was to explore the role of MEG3 in proliferation and invasion and the potential molecular mechanism in GBC. We found that MEG3 was downregulated in GBC tissues and cells, and low expression of MEG3 was correlated with poor prognostic outcomes in patients. Overexpression of MEG3 inhibited GBC cell proliferation and invasion, induced cell apoptosis and decreased tumorigenicity in nude mice. Moreover, we found that MEG3 was associated with EZH2 and attenuated EZH2 by promoting its ubiquitination. Furthermore, MEG3 executed its functions via EZH2 to regulate the downstream target gene LATS2. Taken together, these findings suggest that MEG3 is an effective target for GBC therapy and may facilitate the development of lncRNA-directed diagnostics and therapeutics against GBC.
A sulfotransferase dosage-dependently regulates mouthpart polyphenism in the nematode Pristionchus pacificus
Authors: Bui Linh T. , Ivers Nicholas A. , Ragsdale Erik J. 
Published: October 2018

AbstractPolyphenism, the extreme form of developmental plasticity, is the ability of a genotype to produce discrete morphologies matched to alternative environments. Because polyphenism is likely to be under switch-like molecular control, a comparative genetic approach could reveal the molecular targets of plasticity evolution. Here we report that the lineage-specific sulfotransferase SEUD-1, which responds to environmental cues, dosage-dependently regulates polyphenism of mouthparts in the nematode Pristionchus pacificus. SEUD-1 is expressed in cells producing dimorphic morphologies, thereby integrating an intercellular signalling mechanism at its ultimate target. Additionally, multiple alterations of seud-1 support it as a potential target for plasticity evolution. First, a recent duplication of seud-1 in a sister species reveals a direct correlation between genomic dosage and polyphenism threshold. Second, inbreeding to produce divergent polyphenism thresholds resulted in changes in transcriptional dosage of seud-1. Our study thus offers a genetic explanation for how plastic responses evolve.
Maintaining and breaking symmetry in homomeric coiled-coil assemblies
Authors: Rhys Guto G. , Wood Christopher W. , Lang Eric J. M. , Mulholland Adrian J. , Brady R. Leo , Thomson Andrew R. , Woolfson Derek N. 
Published: October 2018

AbstractIn coiled-coil (CC) protein structures α-helices wrap around one another to form rope-like assemblies. Most natural and designed CCs have two–four helices and cyclic (Cn) or dihedral (Dn) symmetry. Increasingly, CCs with five or more helices are being reported. A subset of these higher-order CCs is of interest as they have accessible central channels that can be functionalised; they are α-helical barrels. These extended cavities are surprising given the drive to maximise buried hydrophobic surfaces during protein folding and assembly in water. Here, we show that α-helical barrels can be maintained by the strategic placement of β-branched aliphatic residues lining the lumen. Otherwise, the structures collapse or adjust to give more-complex multi-helix assemblies without Cnor Dnsymmetry. Nonetheless, the structural hallmark of CCs—namely, knobs-into-holes packing of side chains between helices—is maintained leading to classes of CCs hitherto unobserved in nature or accessed by design.
Sequencing HIV-neutralizing antibody exons and introns reveals detailed aspects of lineage maturation
Authors: Johnson Erik L. , Doria-Rose Nicole A. , Gorman Jason , Bhiman Jinal N. , Schramm Chaim A. , Vu Ashley Q. , Law William H. , Zhang Baoshan , Bekker Valerie , Abdool Karim Salim S. , Ippolito Gregory C. , Morris Lynn , Moore Penny L. , Kwong Peter D. , Mascola John R. , Georgiou George 
Published: October 2018

AbstractThe developmental pathways of broadly neutralizing antibodies (bNAbs) against HIV are of great importance for the design of immunogens that can elicit protective responses. Here we show the maturation features of the HIV-neutralizing anti-V1V2 VRC26 lineage by simultaneously sequencing the exon together with the downstream intron of VRC26 members. Using the mutational landscapes of both segments and the selection-free nature of the intron region, we identify multiple events of amino acid mutational convergence in the complementarity-determining region 3 (CDR3) of VRC26 members, and determine potential intermediates with diverse CDR3s to a late stage bNAb from 2 years prior to its isolation. Moreover, we functionally characterize the earliest neutralizing intermediates with critical CDR3 mutations, with some emerging only 14 weeks after initial lineage detection and containing only ~6% V gene mutations. Our results thus underscore the utility of analyzing exons and introns simultaneously for studying antibody maturation and repertoire selection.
Typing tumors using pathways selected by somatic evolution
Authors: Wang Sheng , Ma Jianzhu , Zhang Wei , Shen John Paul , Huang Justin , Peng Jian , Ideker Trey 
Published: October 2018

AbstractMany recent efforts to analyze cancer genomes involve aggregation of mutations within reference maps of molecular pathways and protein networks. Here, we find these pathway studies are impeded by molecular interactions that are functionally irrelevant to cancer or the patient’s tumor type, as these interactions diminish the contrast of driver pathways relative to individual frequently mutated genes. This problem can be addressed by creating stringent tumor-specific networks of biophysical protein interactions, identified by signatures of epistatic selection during tumor evolution. Using such an evolutionarily selected pathway (ESP) map, we analyze the major cancer genome atlases to derive a hierarchical classification of tumor subtypes linked to characteristic mutated pathways. These pathways are clinically prognostic and predictive, including the TP53-AXIN-ARHGEF17 combination in liver and CYLC2-STK11-STK11IP in lung cancer, which we validate in independent cohorts. This ESP framework substantially improves the definition of cancer pathways and subtypes from tumor genome data.
Haplosaurus computes protein haplotypes for use in precision drug design
Authors: Spooner William , McLaren William , Slidel Timothy , Finch Donna K. , Butler Robin , Campbell Jamie , Eghobamien Laura , Rider David , Kiefer Christine Mione , Robinson Matthew J. , Hardman Colin , Cunningham Fiona , Vaughan Tristan , Flicek Paul , Huntington Catherine Chaillan 
Published: October 2018

AbstractSelecting the most appropriate protein sequences is critical for precision drug design. Here we describe Haplosaurus, a bioinformatic tool for computation of protein haplotypes. Haplosaurus computes protein haplotypes from pre-existing chromosomally-phased genomic variation data. Integration into the Ensembl resource provides rapid and detailed protein haplotypes retrieval. Using Haplosaurus, we build a database of unique protein haplotypes from the 1000 Genomes dataset reflecting real-world protein sequence variability and their prevalence. For one in seven genes, their most common protein haplotype differs from the reference sequence and a similar number differs on their most common haplotype between human populations. Three case studies show how knowledge of the range of commonly encountered protein forms predicted in populations leads to insights into therapeutic efficacy. Haplosaurus and its associated database is expected to find broad applications in many disciplines using protein sequences and particularly impactful for therapeutics design.
Transformation of amorphous calcium phosphate to bone-like apatite
Authors: Lotsari Antiope , Rajasekharan Anand K. , Halvarsson Mats , Andersson Martin 
Published: October 2018

AbstractMineralisation of calcium phosphates in bone has been proposed to proceed via an initial amorphous precursor phase which transforms into nanocrystalline, carbonated hydroxyapatite. While calcium phosphates have been under intense investigation, the exact steps during the crystallisation of spherical amorphous particles to platelet-like bone apatite are unclear. Herein, we demonstrate a detailed transformation mechanism of amorphous calcium phosphate spherical particles to apatite platelet-like crystals, within the confined nanodomains of a bone-inspired nanocomposite. The transformation is initiated under the presence of humidity, where nanocrystalline areas are formed and crystallisation advances via migration of nanometre sized clusters by forming steps at the growth front. We propose that such transformation is a possible crystallisation mechanism and is characteristic of calcium phosphates from a thermodynamic perspective and might be unrelated to the environment. Our observations provide insight into a crucial but unclear stage in bone mineralisation, the origins of the nanostructured, platelet-like bone apatite crystals.
Highly selective transition-metal-free transamidation of amides and amidation of esters at room temperature
Authors: Li Guangchen , Szostak Michal 
Published: October 2018

AbstractAmide chemistry has an essential role in the synthesis of high value molecules, such as pharmaceuticals, natural products, and fine chemicals. Over the past years, several examples of transamidation reactions have been reported. In general, transition-metal-based catalysts or harsh conditions are employed for these transformations due to unfavorable kinetics and thermodynamics of the process. Herein, we report a significant advance in this area and present the general method for transition-metal-free transamidation of amides and amidation of esters by highly selective acyl cleavage with non-nucleophilic amines at room temperature. In contrast to metal-catalyzed protocols, the method is operationally-simple, environmentally-friendly, and operates under exceedingly mild conditions. The practical value is highlighted by the synthesis of valuable amides in high yields. Considering the key role of amides in various branches of chemical science, we envision that this broadly applicable method will be of great interest in organic synthesis, drug discovery, and biochemistry.
Mediterranean UNESCO World Heritage at risk from coastal flooding and erosion due to sea-level rise
Authors: Reimann Lena , Vafeidis Athanasios T. , Brown Sally , Hinkel Jochen , Tol Richard S. J. 
Published: October 2018

AbstractUNESCO World Heritage sites (WHS) located in coastal areas are increasingly at risk from coastal hazards due to sea-level rise. In this study, we assess Mediterranean cultural WHS at risk from coastal flooding and erosion under four sea-level rise scenarios until 2100. Based on the analysis of spatially explicit WHS data, we develop an index-based approach that allows for ranking WHS at risk from both coastal hazards. Here we show that of 49 cultural WHS located in low-lying coastal areas of the Mediterranean, 37 are at risk from a 100-year flood and 42 from coastal erosion, already today. Until 2100, flood risk may increase by 50% and erosion risk by 13% across the region, with considerably higher increases at individual WHS. Our results provide a first-order assessment of where adaptation is most urgently needed and can support policymakers in steering local-scale research to devise suitable adaptation strategies for each WHS.