bluuebunny/crossref_metadata_2025_split huggingface dataset:
Preprinting Microbiology
Authors: Schloss Patrick D. 
Published: May 2017

ABSTRACT
The field of microbiology has experienced significant growth due to transformative advances in technology and the influx of scientists driven by a curiosity to understand how microbes sustain myriad biochemical processes that maintain Earth. With this explosion in scientific output, a significant bottleneck has been the ability to rapidly disseminate new knowledge to peers and the public. Preprints have emerged as a tool that a growing number of microbiologists are using to overcome this bottleneck. Posting preprints can help to transparently recruit a more diverse pool of reviewers prior to submitting to a journal for formal peer review. Although the use of preprints is still limited in the biological sciences, early indications are that preprints are a robust tool that can complement and enhance peer-reviewed publications. As publishing moves to embrace advances in Internet technology, there are many opportunities for preprints and peer-reviewed journals to coexist in the same ecosystem.
Mutations That Alter the Bacterial Cell Envelope Increase Lipid Production
Authors: Lemmer Kimberly C. , Zhang Weiping , Langer Samantha J. , Dohnalkova Alice C. , Hu Dehong , Lemke Rachelle A. , Piotrowski Jeff S. , Orr Galya , Noguera Daniel R. , Donohue Timothy J. 
Published: May 2017

ABSTRACT

Lipids from microbes offer a promising source of renewable alternatives to petroleum-derived compounds. In particular, oleaginous microbes are of interest because they accumulate a large fraction of their biomass as lipids. In this study, we analyzed genetic changes that alter lipid accumulation in
Rhodobacter sphaeroides
. By screening an
R. sphaeroides
Tn
5
mutant library for insertions that increased fatty acid content, we identified 10 high-lipid (HL) mutants for further characterization. These HL mutants exhibited increased sensitivity to drugs that target the bacterial cell envelope and changes in shape, and some had the ability to secrete lipids, with two HL mutants accumulating ~60% of their total lipids extracellularly. When one of the highest-lipid-secreting strains was grown in a fed-batch bioreactor, its lipid content was comparable to that of oleaginous microbes, with the majority of the lipids secreted into the medium. Based on the properties of these HL mutants, we conclude that alterations of the cell envelope are a previously unreported approach to increase microbial lipid production. We also propose that this approach may be combined with knowledge about biosynthetic pathways, in this or other microbes, to increase production of lipids and other chemicals.

IMPORTANCE
This paper reports on experiments to understand how to increase microbial lipid production. Microbial lipids are often cited as one renewable replacement for petroleum-based fuels and chemicals, but strategies to increase the yield of these compounds are needed to achieve this goal. While lipid biosynthesis is often well understood, increasing yields of these compounds to industrially relevant levels is a challenge, especially since genetic, synthetic biology, or engineering approaches are not feasible in many microbes. We show that altering the bacterial cell envelope can be used to increase microbial lipid production. We also find that the utility of some of these alterations can be enhanced by growing cells in bioreactor configurations that can be used industrially. We propose that our findings can inform current and future efforts to increase production of microbial lipids, other fuels, or chemicals that are currently derived from petroleum.
CNOT4-Mediated Ubiquitination of Influenza A Virus Nucleoprotein Promotes Viral RNA Replication
Authors: Lin Yu-Chen , Jeng King-Song , Lai Michael M. C. 
Published: May 2017

ABSTRACT

Influenza A virus (IAV) RNA segments are individually packaged with viral nucleoprotein (NP) and RNA polymerases to form a viral ribonucleoprotein (vRNP) complex. We previously reported that NP is a monoubiquitinated protein which can be deubiquitinated by a cellular ubiquitin protease, USP11. In this study, we identified an E3 ubiquitin ligase, CNOT4 (Ccr4-Not transcription complex subunit 4), which can ubiquitinate NP. We found that the levels of viral RNA, protein, viral particles, and RNA polymerase activity in CNOT4 knockdown cells were lower than those in the control cells upon IAV infection. Conversely, overexpression of CNOT4 rescued viral RNP activity. In addition, CNOT4 interacted with the NP in the cell. An
in vitro
ubiquitination assay also showed that NP could be ubiquitinated by
in vitro
-translated CNOT4, but ubiquitination did not affect the protein stability of NP. Significantly, CNOT4 increased NP ubiquitination, whereas USP11 decreased it. Mass spectrometry analysis of ubiquitinated NP revealed multiple ubiquitination sites on the various lysine residues of NP. Three of these, K184, K227, and K273, are located on the RNA-binding groove of NP. Mutations of these sites to arginine reduced viral RNA replication. These results indicate that CNOT4 is a ubiquitin ligase of NP, and ubiquitination of NP plays a positive role in viral RNA replication.

IMPORTANCE
Influenza virus, particularly influenza A virus, causes severe and frequent outbreaks among human and avian species. Finding potential target sites for antiviral agents is of utmost importance from the public health point of view. We previously found that viral nucleoprotein (NP) is ubiquitinated, and ubiquitination enhances viral RNA replication. In this study, we found a cellular ubiquitin ligase, CNOT4, capable of ubiquitinating NP. The ubiquitination sites are scattered on the surface of the NP molecule, which is critical for RNA replication. CNOT4 and a ubiquitin protease, USP11, together regulate the extent of NP ubiquitination and thereby the efficiency of RNA replication. This study thus identifies a potential antiviral target site and reveals a novel posttranslational mechanism for regulating viral replication. This represents a novel finding in the literature of influenza virus research.
Predictors of incident proteinuria among patients with SLE
Authors: Duarte-García Alí , Barr Erik , Magder Laurence S , Petri Michelle 
Published: May 2017

ObjectiveTo identify fixed and time-varying predictors of incident proteinuria.MethodsThis analysis was based on patients who did not have a history of diabetes and who did not have a prior episode of renal involvement. We defined an incident case of proteinuria as two or more measures of urine protein to creatinine ratio (or 24-hour protein measure) greater than 0.5 in two visits separated by more than 30 days and less than 180 days. We estimated rates of incident proteinuria in subgroups of patients with lupus defined by time-invariant and time-varying predictors.ResultsAmong 895 patients included in the analysis, 840 (94%) were female, and 518 (58%) were Caucasian, 304 (34%) African-American, with mean age of 42 years at the start of follow-up. We observed 57 incident cases of proteinuria over a span of 4669 person-years of cohort follow-up. The overall rate of incident proteinuria was 12.2 per 1000 person-years. The rate was significantly lower among those of older age, and higher among those who were not Caucasian. In those with a very low C3 measure in a previous cohort visit, the rate was increased by a factor of 16.1 and in those with a very low C4 by 16.3. The rate among those prescribed hydroxychloroquine or ACE inhibitors/ARB was similar to those not on them.ConclusionsOlder patients with SLE are at low risk for developing proteinuria. There was not strong evidence that hydroxychloroquine or angiotensin-converting-enzyme (ACE) inhibitor reduced the risk of proteinuria. The highest rates of incident proteinuria were among those with recent low complement.
Influence of TiO2 content on microstructures and optoelectronic properties of titanium-doped ZnO nanofilms
Authors: Chen Zhenying , Chen Xiaowei , Li Fei , Xu Shoulei , Huang Wenhua , Deng Wen 
Published: May 2017

Thin films of TiO2-doped ZnO (TZO) with TiO2 contents from 0.5 to 3.0 wt.% were deposited on glass substrates by RF magnetron sputtering. The microstructures and optoelectronic properties of the TZO films were characterized by XRD, Hall effect analyzer, UV–VIS spectrophotometry and physical property measurement (PPMS-9). Results indicate that the microstructure and optoelectronic properties of TZO films are strongly affected by the TiO2 content. The best optoelectronic properties were obtained with the film having 2.0 wt.% TiO2. This film had superior crystal properties, high average optical transmittance (89.0%), and the lowest resistivity (9.58 × 10[Formula: see text] [Formula: see text] ⋅ cm). Furthermore, the resistivity of this film changed with temperature between 10 and 350 K, they experienced an initial decrease followed by an increase as the temperature increased.
Growth, structural, optical, piezoelectric and etching analysis of L-lysine p-nitrophenolate monohydrate single crystals
Authors: Alexandar A. , Lakshmanan A. , Sakthy Priya S. , Surendran P. , Rameshkumar P. 
Published: May 2017

Nonlinear optical single crystals of L-lysine p-nitrophenolate monohydrate (LLPNP) were grown in aqueous solution by the slow evaporation solution technique (SEST). The grown crystals were subjected to powder X-ray diffraction analysis, (PXRD) and it was found that the title compound was crystallized in the orthorhombic crystal system with noncentrosymmetric space group of [Formula: see text]212121. The vibrational frequencies of various functional groups present in the crystal were analyzed using the FTIR spectrum with a wavenumber range between 450 cm[Formula: see text] and 4000 cm[Formula: see text]. The microhardness analysis of the sample revealed that the crystal belongs to the soft material category. Piezoelectric analysis was performed to measure the value of the piezoelectric (d[Formula: see text]) coefficient. Blue light emission of the material was confirmed using the photoluminescence spectrum. Thermal stability of the grown crystal was analyzed using a melting point apparatus and it was found that the LLPNP is stable upto 175[Formula: see text]C. Etching analysis was performed at various durations, in order to identify the surface properties of the LLPNP crystal.
Large-scale parallel genome assembler over cloud computing environment
Authors: Das Arghya Kusum , Koppa Praveen Kumar , Goswami Sayan , Platania Richard , Park Seung-Jong 
Published: May 2017

The size of high throughput DNA sequencing data has already reached the terabyte scale. To manage this huge volume of data, many downstream sequencing applications started using locality-based computing over different cloud infrastructures to take advantage of elastic (pay as you go) resources at a lower cost. However, the locality-based programming model (e.g. MapReduce) is relatively new. Consequently, developing scalable data-intensive bioinformatics applications using this model and understanding the hardware environment that these applications require for good performance, both require further research. In this paper, we present a de Bruijn graph oriented Parallel Giraph-based Genome Assembler (GiGA), as well as the hardware platform required for its optimal performance. GiGA uses the power of Hadoop (MapReduce) and Giraph (large-scale graph analysis) to achieve high scalability over hundreds of compute nodes by collocating the computation and data. GiGA achieves significantly higher scalability with competitive assembly quality compared to contemporary parallel assemblers (e.g. ABySS and Contrail) over traditional HPC cluster. Moreover, we show that the performance of GiGA is significantly improved by using an SSD-based private cloud infrastructure over traditional HPC cluster. We observe that the performance of GiGA on 256 cores of this SSD-based cloud infrastructure closely matches that of 512 cores of traditional HPC cluster.
Liver Metastasis Is Facilitated by the Adherence of Circulating Tumor Cells to Vascular Fibronectin Deposits
Authors: Barbazán Jorge , Alonso-Alconada Lorena , Elkhatib Nadia , Geraldo Sara , Gurchenkov Vasily , Glentis Alexandros , van Niel Guillaume , Palmulli Roberta , Fernández Beatriz , Viaño Patricia , Garcia-Caballero Tomas , López-López Rafael , Abal Miguel , Vignjevic Danijela Matic 
Published: May 2017

Abstract
The interaction between circulating tumor cells (CTC) and endothelial cells during extravasation is a critical process during metastatic colonization, but its mechanisms remain poorly characterized. Here we report that the luminal side of liver blood vessels contains fibronectin deposits that are enriched in mice bearing primary tumors and are also present in vessels from human livers affected with metastases. Cancer cells attached to endothelial fibronectin deposits via talin1, a major component of focal adhesions. Talin1 depletion impaired cancer cell adhesion to the endothelium and transendothelial migration, resulting in reduced liver metastasis formation in vivo. Talin1 expression levels in patient CTC's correlated with prognosis and therapy response. Together, our findings uncover a new mechanism for liver metastasis formation involving an active contribution of hepatic vascular fibronectin and talin1 in cancer cells. Cancer Res; 77(13); 3431–41. ©2017 AACR.
Immune Checkpoint Blockade, Immunogenic Chemotherapy or IFN-α Blockade Boost the Local and Abscopal Effects of Oncolytic Virotherapy
Authors: Fend Laetitia , Yamazaki Takahiro , Remy Christelle , Fahrner Catherine , Gantzer Murielle , Nourtier Virginie , Préville Xavier , Quéméneur Eric , Kepp Oliver , Adam Julien , Marabelle Aurélien , Pitt Jonathan M. , Kroemer Guido , Zitvogel Laurence 
Published: May 2017

Abstract
Athough the clinical efficacy of oncolytic viruses has been demonstrated for local treatment, the ability to induce immune-mediated regression of distant metastases is still poorly documented. We report here that the engineered oncolytic vaccinia virus VVWR-TK−RR−-Fcu1 can induce immunogenic cell death and generate a systemic immune response. Effects on tumor growth and survival was largely driven by CD8+ T cells, and immune cell infiltrate in the tumor could be reprogrammed toward a higher ratio of effector T cells to regulatory CD4+ T cells. The key role of type 1 IFN pathway in oncolytic virotherapy was also highlighted, as we observed a strong abscopal response in Ifnar−/− tumors. In this model, single administration of virus directly into the tumors on one flank led to regression in the contralateral flank. Moreover, these effects were further enhanced when oncolytic treatment was combined with immunogenic chemotherapy or with immune checkpoint blockade. Taken together, our results suggest how to safely improve the efficacy of local oncolytic virotherapy in patients whose tumors are characterized by dysregulated IFNα signaling. Cancer Res; 77(15); 4146–57. ©2017 AACR.
SIRT3-Mediated Dimerization of IDH2 Directs Cancer Cell Metabolism and Tumor Growth
Authors: Zou Xianghui , Zhu Yueming , Park Seong-Hoon , Liu Guoxiang , O'Brien Joseph , Jiang Haiyan , Gius David 
Published: May 2017

Abstract
The isocitrate dehydrogenase IDH2 produces α-ketoglutarate by oxidizing isocitrate, linking glucose metabolism to oxidative phosphorylation. In this study, we report that loss of SIRT3 increases acetylation of IDH2 at lysine 413 (IDH2-K413-Ac), thereby decreasing its enzymatic activity by reducing IDH2 dimer formation. Expressing a genetic acetylation mimetic IDH2 mutant (IDH2K413Q) in cancer cells decreased IDH2 dimerization and enzymatic activity and increased cellular reactive oxygen species and glycolysis, suggesting a shift in mitochondrial metabolism. Concurrently, overexpression of IDH2K413Q promoted cell transformation and tumorigenesis in nude mice, resulting in a tumor-permissive phenotype. IHC staining showed that IDH2 acetylation was elevated in high-risk luminal B patients relative to low-risk luminal A patients. Overall, these results suggest a potential relationship between SIRT3 enzymatic activity, IDH2-K413 acetylation-determined dimerization, and a cancer-permissive phenotype. Cancer Res; 77(15); 3990–9. ©2017 AACR.
3D Mathematical Modeling of Glioblastoma Suggests That Transdifferentiated Vascular Endothelial Cells Mediate Resistance to Current Standard-of-Care Therapy
Authors: Yan Huaming , Romero-López Mónica , Benitez Lesly I. , Di Kaijun , Frieboes Hermann B. , Hughes Christopher C.W. , Bota Daniela A. , Lowengrub John S. 
Published: May 2017

Abstract
Glioblastoma (GBM), the most aggressive brain tumor in human patients, is decidedly heterogeneous and highly vascularized. Glioma stem/initiating cells (GSC) are found to play a crucial role by increasing cancer aggressiveness and promoting resistance to therapy. Recently, cross-talk between GSC and vascular endothelial cells has been shown to significantly promote GSC self-renewal and tumor progression. Furthermore, GSC also transdifferentiate into bona fide vascular endothelial cells (GEC), which inherit mutations present in GSC and are resistant to traditional antiangiogenic therapies. Here we use three-dimensional mathematical modeling to investigate GBM progression and response to therapy. The model predicted that GSCs drive invasive fingering and that GEC spontaneously form a network within the hypoxic core, consistent with published experimental findings. Standard-of-care treatments using DNA-targeted therapy (radiation/chemo) together with antiangiogenic therapies reduced GBM tumor size but increased invasiveness. Anti-GEC treatments blocked the GEC support of GSCs and reduced tumor size but led to increased invasiveness. Anti-GSC therapies that promote differentiation or disturb the stem cell niche effectively reduced tumor invasiveness and size, but were ultimately limited in reducing tumor size because GECs maintain GSCs. Our study suggests that a combinatorial regimen targeting the vasculature, GSCs, and GECs, using drugs already approved by the FDA, can reduce both tumor size and invasiveness and could lead to tumor eradication. Cancer Res; 77(15); 4171–84. ©2017 AACR.
Distinct Roles of HES1 in Normal Stem Cells and Tumor Stem-like Cells of the Intestine
Authors: Goto Norihiro , Ueo Taro , Fukuda Akihisa , Kawada Kenji , Sakai Yoshiharu , Miyoshi Hiroyuki , Taketo Makoto Mark , Chiba Tsutomu , Seno Hiroshi 
Published: May 2017

Abstract
Cancer stem cells (CSC) have attracted attention as therapeutic targets; however, CSC-targeting therapy may disrupt normal tissue homeostasis because many CSC molecules are also expressed by normal stem cells (NSC). Here, we demonstrate that NSC-specific and CSC-specific roles of the stem cell transcription factor Hes1 in the intestine enable the feasibility of a specific cancer therapy. Hes1 expression was upregulated in NSCs and intestinal tumors. Lineage-tracing experiments in adult mouse intestine revealed that Hes1 deletion in Lgr5+ or Bmi1+ NSCs resulted in loss of self-renewal but did not perturb homeostasis. Furthermore, in Lgr5+ NSC, deletion of Hes1 and β-catenin stabilization limited tumor formation and prolonged host survival. Notably, in Lgr5+ or Dclk1+ tumor stem cells derived from established intestinal tumors, Hes1 deletion triggered immediate apoptosis, reducing tumor burden. Our results show how Hes1 plays different roles in NSCs and CSCs, in which Hes1 disruption leads to tumor regression without perturbing normal stem cell homeostasis, preclinically validating Hes1 as a cancer therapeutic target. Cancer Res; 77(13); 3442–54. ©2017 AACR.
Gene Expression Profiling in BRAF-Mutated Melanoma Reveals Patient Subgroups with Poor Outcomes to Vemurafenib That May Be Overcome by Cobimetinib Plus Vemurafenib
Authors: Wongchenko Matthew J. , McArthur Grant A. , Dréno Brigitte , Larkin James , Ascierto Paolo A. , Sosman Jeffrey , Andries Luc , Kockx Mark , Hurst Stephen D. , Caro Ivor , Rooney Isabelle , Hegde Priti S. , Molinero Luciana , Yue Huibin , Chang Ilsung , Amler Lukas , Yan Yibing , Ribas Antoni 
Published: May 2017

Abstract
Purpose: The association of tumor gene expression profiles with progression-free survival (PFS) outcomes in patients with BRAFV600-mutated melanoma treated with vemurafenib or cobimetinib combined with vemurafenib was evaluated.
Experimental Design: Gene expression of archival tumor samples from patients in four trials (BRIM-2, BRIM-3, BRIM-7, and coBRIM) was evaluated. Genes significantly associated with PFS (P &lt; 0.05) were identified by univariate Cox proportional hazards modeling, then subjected to unsupervised hierarchical clustering, principal component analysis, and recursive partitioning to develop optimized gene signatures.
Results: Forty-six genes were identified as significantly associated with PFS in both BRIM-2 (n = 63) and the vemurafenib arm of BRIM-3 (n = 160). Two distinct signatures were identified: cell cycle and immune. Among vemurafenib-treated patients, the cell-cycle signature was associated with shortened PFS compared with the immune signature in the BRIM-2/BRIM-3 training set [hazard ratio (HR) 1.8; 95% confidence interval (CI), 1.3–2.6, P = 0.0001] and in the coBRIM validation set (n = 101; HR, 1.6; 95% CI, 1.0–2.5; P = 0.08). The adverse impact of the cell-cycle signature on PFS was not observed in patients treated with cobimetinib combined with vemurafenib (n = 99; HR, 1.1; 95% CI, 0.7–1.8; P = 0.66).
Conclusions: In vemurafenib-treated patients, the cell-cycle gene signature was associated with shorter PFS. However, in cobimetinib combined with vemurafenib-treated patients, both cell cycle and immune signature subgroups had comparable PFS. Cobimetinib combined with vemurafenib may abrogate the adverse impact of the cell-cycle signature. Clin Cancer Res; 23(17); 5238–45. ©2017 AACR.
MELK and EZH2 Cooperate to Regulate Medulloblastoma Cancer Stem-like Cell Proliferation and Differentiation
Authors: Liu Hailong , Sun Qianwen , Sun Youliang , Zhang Junping , Yuan Hongyu , Pang Shuhuan , Qi Xueling , Wang Haoran , Zhang Mingshan , Zhang Hongwei , Yu Chunjiang , Gu Chunyu 
Published: May 2017

Abstract
Medulloblastoma is the most common malignant brain tumor in children. Although accumulated research has suggested that cancer stem-like cells play a key role in medulloblastoma tumorigenesis, the specific molecular mechanism regarding proliferation remains elusive. Here, we reported more abundant expression of maternal embryonic leucine-zipper kinase (MELK) and enhancer of zeste homolog 2 (EZH2) in medulloblastoma stem-like cells than in neural stem cells and the interaction between the two proteins could mediate the self-renewal of sonic hedgehog subtype medulloblastoma. In human medulloblastoma, extensive nodularity and large-cell/anaplastic subgroups differed according to the staining levels of MELK and EZH2 from the other two subgroups. The proportion of MELK- or EZH2-positive staining status could be considered as a potential indicator for survival. Mechanistically, MELK bound to and phosphorylated EZH2, and its methylation was induced by EZH2 in medulloblastoma, which could regulate the proliferation of cancer stem-like cells. In xenografts, loss of MELK or EZH2 attenuated medulloblastoma stem-like cell-derived tumor growth and promoted differentiation. These findings indicate that MELK-induced phosphorylation and EZH2-mediated methylation in MELK/EZH2 pathway are essential for medulloblastoma stem-like cell-derived tumor proliferation, thereby identifying a potential therapeutic strategy for these patients.
Implications: This study demonstrates that the interaction occurring between MELK and EZH2 promotes self-proliferation and stemness, thus representing an attractive therapeutic target and potential candidate for diagnosis of medulloblastoma. Mol Cancer Res; 15(9); 1275–86. ©2017 AACR.