bluuebunny/crossref_metadata_2025_split huggingface dataset:
Production of Ophthalmic Acid Using Engineered Escherichia coli
Authors: Ito Tomokazu , Tokoro Maiko , Hori Ran , Hemmi Hisashi , Yoshimura Tohru 
Published: January 2018

ABSTRACT

Ophthalmic acid (OA;
l
-γ-glutamyl-
l
-2-aminobutyryl-glycine) is an analog of glutathione (GSH;
l
-γ-glutamyl-
l
-cysteinyl-glycine) in which the cysteine moiety is replaced by
l
-2-aminobutyrate. OA is a useful peptide for the pharmaceutical and/or food industries. Herein, we report a method for the production of OA using engineered
Escherichia coli
cells.
yggS
-deficient
E. coli
, which lacks the highly conserved pyridoxal 5′-phosphate-binding protein YggS and naturally accumulates OA, was selected as the starting strain. To increase the production of OA, we overexpressed the OA biosynthetic enzymes glutamate-cysteine ligase (GshA) and glutathione synthase (GshB), desensitized the product inhibition of GshA, and eliminated the OA catabolic enzyme γ-glutamyltranspeptidase. The production of OA was further enhanced by the deletion of
miaA
and
ridA
with the aim of increasing the availability of ATP and attenuating the unwanted degradation of amino acids, respectively. The final strain developed in this study successfully produced 277 μmol/liter of OA in 24 h without the formation of by-products in a minimal synthetic medium containing 1 mM each glutamate, 2-aminobutyrate, and glycine.

IMPORTANCE
Ophthalmic acid (OA) is a peptide that has the potential for use in the pharmaceutical and/or food industries. An efficient method for the production of OA would allow us to expand our knowledge about its physiological functions and enable the industrial/pharmaceutical application of this compound. We demonstrated the production of OA using
Escherichia coli
cells in which OA biosynthetic enzymes and degradation enymes were engineered. We also showed that unique approaches, including the use of a Δ
yggS
mutant as a starting strain, the establishment of an S495F mutation in GshA, and the deletion of
ridA
or
miaA
, facilitated the efficient production of OA in
E. coli
.
Efficacy of T2 Magnetic Resonance Assay in Monitoring Candidemia after Initiation of Antifungal Therapy: the Serial Therapeutic and Antifungal Monitoring Protocol (STAMP) Trial
Authors: Mylonakis Eleftherios , Zacharioudakis Ioannis M. , Clancy Cornelius J. , Nguyen M. Hong , Pappas Peter G. 
Published: January 2018

ABSTRACT

The performance of blood culture for monitoring candidemia clearance is hampered by its low sensitivity, especially during antifungal therapy. The T2 magnetic resonance (T2MR) assay combines magnetic resonance with nanotechnology to identify whole
Candida
species cells. A multicenter clinical trial studied the performance of T2MR in monitoring candidemia clearance compared to blood culture. Adults with a blood culture positive for yeast were enrolled and had blood cultures and T2MR testing performed on prespecified days. Thirty-one patients completed the trial. Thirteen of the 31 patients (41.9%) had at least one positive surveillance T2MR and/or blood culture result. All positive blood cultures (7/7 [100%]) had an accompanying positive T2MR result with concordance in the identified
Candida
sp., while only 7/23 (30.4%) T2MR results had an accompanying positive blood culture. There was one case of discordance in species identification between T2MR and the preenrollment blood culture with evidence to support deep-seated infection by the
Candida
spp. detected by the T2MR assay. Based on the log rank test, there was a statistically significant improvement in posttreatment surveillance using the T2MR assay compared to blood culture (
P
= 0.004). Limitations of the study include the small sample size and lack of outcome data. In conclusion, the T2MR assay significantly outperformed blood cultures for monitoring the clearance of candidemia in patients receiving antifungal therapy and may be useful in determining adequate source control, timing for deescalation, and optimal duration of treatment. However, further studies are needed to determine the viability of
Candida
species cells detected by the T2MR assay and correlate the results with patient outcomes. (This study is registered at ClinicalTrials.gov under registration number NCT02163889.)
Human Papillomavirus 16 E7 Stabilizes APOBEC3A Protein by Inhibiting Cullin 2-Dependent Protein Degradation
Authors: Westrich Joseph A. , Warren Cody J. , Klausner Michael J. , Guo Kejun , Liu Chang-Wei , Santiago Mario L. , Pyeon Dohun 
Published: January 2018

ABSTRACT

APOBEC3 (A3) mutation signatures have been observed in a variety of human cancer genomes, including those of cervical and head and neck cancers caused by human papillomavirus (HPV) infection. However, the driving forces that promote off-target A3 activity remain mostly unclear. Here, we report a mechanism for the dramatic increase of A3A protein levels in HPV-positive keratinocytes. We show that expression of the viral protein E7 from high-risk HPVs, but not E7 from low-risk HPVs, significantly prolongs the cellular half-life of A3A protein in human keratinocytes and HPV-positive cancer cell lines. We have mapped several residues within the cullin 2 (CUL2) binding motif of HPV16 E7 as being important for mediating A3A protein stabilization. Furthermore, we provide direct evidence that both A3A and HPV16 E7 interact with CUL2, suggesting that the E7-CUL2 complex formed during HPV infection may regulate A3A protein levels in the cell. Using an
in vitro
cytidine deaminase assay, we show that E7-stabilized A3A remains catalytically active. Taken together, our findings suggest that the HPV oncoprotein E7 dysregulates endogenous A3A protein levels and thus provides novel mechanistic insight into cellular triggers of A3 mutations in HPV-positive cancers.

IMPORTANCE
Human papillomavirus (HPV) is causally associated with over 5% of all human malignancies. Several recent studies have shown that a subset of cancers, including HPV-positive head and neck and cervical cancers, have distinct mutational signatures potentially caused by members of the APOBEC3 cytidine deaminase family. However, the mechanism that induces APOBEC3 activity in cancer cells is poorly understood. Here, we report that the HPV oncoprotein E7 stabilizes the APOBEC3A (A3A) protein in human keratinocytes by inhibiting ubiquitin-dependent protein degradation in a cullin-dependent manner. Interestingly, the HPV E7-stabilized A3A protein maintains its deaminase activity. These findings provide a new insight into cancer mutagenesis enhanced by virus-induced A3A protein stabilization.
Combined fit to the cross-sections of e+e−→ π+π−ψ(3686) and e+e−→ Λc+Λc−
Authors: Zhang Jielei , Yuan Limin 
Published: January 2018

The cross-sections of [Formula: see text] and [Formula: see text] have been measured by Belle experiment. A resonance [Formula: see text] is observed in [Formula: see text] decay mode, while another resonance [Formula: see text] is observed in [Formula: see text] decay mode. The two resonances [Formula: see text] and [Formula: see text]’s parameters are consistent with each other, so a combined fit is performed to the two cross-sections assuming [Formula: see text] and [Formula: see text] are same resonance. [Formula: see text]’s parameters are determined to be [Formula: see text], [Formula: see text], where the first uncertainties are statistical and the second systematic. The ratio [Formula: see text] is also obtained and it indicates that [Formula: see text]’s main decay modes may be [Formula: see text]. We determine the lower limit of its leptonic decay width of around 40 eV, which can be compared with the theoretical expectations of different models.
CCR5 Governs DNA Damage Repair and Breast Cancer Stem Cell Expansion
Authors: Jiao Xuanmao , Velasco-Velázquez Marco A. , Wang Min , Li Zhiping , Rui Hallgeir , Peck Amy R. , Korkola James E. , Chen Xuelian , Xu Shaohua , DuHadaway James B. , Guerrero-Rodriguez Sandra , Addya Sankar , Sicoli Daniela , Mu Zhaomei , Zhang Gang , Stucky Andres , Zhang Xi , Cristofanilli Massimo , Fatatis Alessandro , Gray Joe W. , Zhong Jiang F. , Prendergast George C. , Pestell Richard G. 
Published: January 2018

Abstract
The functional significance of the chemokine receptor CCR5 in human breast cancer epithelial cells is poorly understood. Here, we report that CCR5 expression in human breast cancer correlates with poor outcome. CCR5+ breast cancer epithelial cells formed mammospheres and initiated tumors with &gt;60-fold greater efficiency in mice. Reintroduction of CCR5 expression into CCR5-negative breast cancer cells promoted tumor metastases and induced DNA repair gene expression and activity. CCR5 antagonists Maraviroc and Vicriviroc dramatically enhanced cell killing mediated by DNA-damaging chemotherapeutic agents. Single-cell analysis revealed CCR5 governs PI3K/Akt, ribosomal biogenesis, and cell survival signaling. As CCR5 augments DNA repair and is reexpressed selectively on cancerous, but not normal breast epithelial cells, CCR5 inhibitors may enhance the tumor-specific activities of DNA damage response–based treatments, allowing a dose reduction of standard chemotherapy and radiation.
Significance: This study offers a preclinical rationale to reposition CCR5 inhibitors to improve the treatment of breast cancer, based on their ability to enhance the tumor-specific activities of DNA-damaging chemotherapies administered in that disease. Cancer Res; 78(7); 1657–71. ©2018 AACR.
2-Hydroxyglutarate-Mediated Autophagy of the Endoplasmic Reticulum Leads to an Unusual Downregulation of Phospholipid Biosynthesis in Mutant IDH1 Gliomas
Authors: Viswanath Pavithra , Radoul Marina , Izquierdo-Garcia Jose Luis , Ong Wei Qiang , Luchman Hema Artee , Cairncross J. Gregory , Huang Bo , Pieper Russell O. , Phillips Joanna J. , Ronen Sabrina M. 
Published: January 2018

Abstract
Tumor metabolism is reprogrammed to meet the demands of proliferating cancer cells. In particular, cancer cells upregulate synthesis of the membrane phospholipids phosphatidylcholine (PtdCho) and phosphatidylethanolamine (PtdE) in order to allow for rapid membrane turnover. Nonetheless, we show here that, in mutant isocitrate dehydrogenase 1 (IDHmut) gliomas, which produce the oncometabolite 2-hydroxyglutarate (2-HG), PtdCho and PtdE biosynthesis is downregulated and results in lower levels of both phospholipids when compared with wild-type IDH1 cells. 2-HG inhibited collagen-4-prolyl hydroxylase activity, leading to accumulation of misfolded procollagen-IV in the endoplasmic reticulum (ER) of both genetically engineered and patient-derived IDHmut glioma models. The resulting ER stress triggered increased expression of FAM134b, which mediated autophagic degradation of the ER (ER-phagy) and a reduction in the ER area. Because the ER is the site of phospholipid synthesis, ER-phagy led to reduced PtdCho and PtdE biosynthesis. Inhibition of ER-phagy via pharmacological or molecular approaches restored phospholipid biosynthesis in IDHmut glioma cells, triggered apoptotic cell death, inhibited tumor growth, and prolonged the survival of orthotopic IDHmut glioma-bearing mice, pointing to a potential therapeutic opportunity. Glioma patient biopsies also exhibited increased ER-phagy and downregulation of PtdCho and PtdE levels in IDHmut samples compared with wild-type, clinically validating our observations. Collectively, this study provides detailed and clinically relevant insights into the functional link between oncometabolite-driven ER-phagy and phospholipid biosynthesis in IDHmut gliomas.
Significance: Downregulation of phospholipid biosynthesis via ER-phagy is essential for proliferation and clonogenicity of mutant IDH1 gliomas, a finding with immediate therapeutic implications. Cancer Res; 78(9); 2290–304. ©2018 AACR.
Safety, Activity, and Biomarkers of SHR-1210, an Anti-PD-1 Antibody, for Patients with Advanced Esophageal Carcinoma
Authors: Huang Jing , Xu Binghe , Mo Hongnan , Zhang Weilong , Chen Xuelian , Wu Dawei , Qu Dong , Wang Xingyuan , Lan Bo , Yang Beibei , Wang Pei , Zhang Hongtu , Yang Qing , Jiao Yuchen 
Published: January 2018

Abstract
Purpose: The current management of advanced esophageal squamous cell carcinoma (ESCC) remains unsatisfactory. We investigated the safety, efficacy, and biomarkers of SHR-1210, an anti-PD-1 antibody, in patients with recurrent or metastatic ESCC.
Experimental Design: This study was part of a phase I trial in China. Patients with advanced ESCC who were refractory or intolerant to previous chemotherapy were enrolled. Eligible patients received intravenous SHR-1210 at a dose of 60 mg, with escalation to 200 and 400 mg (4-week interval after first dose followed by a 2-week schedule) until disease progression or intolerable toxicity. The associations between candidate biomarkers (PD-L1 and somatic mutation load) and the efficacy of SHR-1210 were also explored.
Results: Between May 11, 2016, and December 9, 2016, a total of 30 patients from one site in China were enrolled. Ten patients (33.3%) had an independently assessed objective response. Median progression-free survival was 3.6 months (95% CI, 0–7.2). Three (10.0%) treatment-related grade 3 adverse events were reported: two (6.7%) pneumonitis and one (3.3%) increased cardiac troponin I. No grade 4 or grade 5 treatment-related adverse events were reported. The exome sequencing and analysis showed that the mutational burden and the potential mutation-associated neoantigen count were associated with better responses. An objective response was more common in patients with PD-L1–positive tumors as defined by ≥5% staining (7 of 15 patients) than in those with PD-L1–negative tumors (1 of 9 patients).
Conclusions: In this population of ESCC patients, SHR-1210 had a manageable safety profile and promising antitumor activity. Clin Cancer Res; 24(6); 1296–304. ©2018 AACR.
Beyond Concurrent Chemoradiation: The Emerging Role of PD-1/PD-L1 Inhibitors in Stage III Lung Cancer
Authors: McCall Neal S. , Dicker Adam P. , Lu Bo 
Published: January 2018

Abstract
Concurrent chemoradiation (cCRT) with platinum-based chemotherapy is standard-of-care therapy for patients with stage III unresectable non–small cell lung cancer (NSCLC). Although cCRT is potentially curative, 5-year overall survival has hovered around 20%, despite extensive efforts to improve outcomes with increasing doses of conformal radiation and intensification of systemic therapy with either induction or consolidation chemotherapy. PD-1/PD-L1 immune checkpoint inhibitors have demonstrated unprecedented efficacy in patients with stage IV NSCLC. In addition, preclinical and early clinical evidence suggests that chemotherapy and radiation may work synergistically with anti-PD-1/PD-L1 therapy to promote antitumor immunity, which has led to the initiation of clinical trials testing these drugs in patients with stage III NSCLC. A preliminary report of a randomized phase III trial, the PACIFIC trial, demonstrated an impressive increase in median progression-free survival with consolidative durvalumab, a PD-L1 inhibitor, compared with observation after cCRT. Here, we discuss the clinical and translational implications of integrating PD-1/PD-L1 inhibitors in the management of patients with unresectable stage III NSCLC. Clin Cancer Res; 24(6); 1271–6. ©2018 AACR.
Pembrolizumab Plus Pegylated Interferon alfa-2b or Ipilimumab for Advanced Melanoma or Renal Cell Carcinoma: Dose-Finding Results from the Phase Ib KEYNOTE-029 Study
Authors: Atkins Michael B. , Hodi F. Stephen , Thompson John A. , McDermott David F. , Hwu Wen-Jen , Lawrence Donald P. , Dawson Nancy A. , Wong Deborah J. , Bhatia Shailender , James Marihella , Jain Lokesh , Robey Seth , Shu Xinxin , Homet Moreno Blanca , Perini Rodolfo F. , Choueiri Toni K. , Ribas Antoni 
Published: January 2018

Abstract
Purpose: Pembrolizumab monotherapy, ipilimumab monotherapy, and pegylated interferon alfa-2b (PEG-IFN) monotherapy are active against melanoma and renal cell carcinoma (RCC). We explored the safety and preliminary antitumor activity of pembrolizumab combined with either ipilimumab or PEG-IFN in patients with advanced melanoma or RCC.
Experimental Design: The phase Ib KEYNOTE-029 study (ClinicalTrials.gov, NCT02089685) included independent pembrolizumab plus reduced-dose ipilimumab and pembrolizumab plus PEG-IFN cohorts. Pembrolizumab 2 mg/kg every 3 weeks (Q3W) plus 4 doses of ipilimumab 1 mg/kg Q3W was tolerable if ≤6 of 18 patients experienced a dose-limiting toxicity (DLT). The target DLT rate for pembrolizumab 2 mg/kg Q3W plus PEG-IFN was 30%, with a maximum of 14 patients per dose level. Response was assessed per RECIST v1.1 by central review.
Results: The ipilimumab cohort enrolled 22 patients, including 19 evaluable for DLTs. Six patients experienced ≥1 DLT. Grade 3 to 4 treatment-related adverse events occurred in 13 (59%) patients. Responses occurred in 5 of 12 (42%) patients with melanoma and 3 of 10 (30%) patients with RCC. In the PEG-IFN cohort, DLTs occurred in 2 of 14 (14%) patients treated at dose level 1 (PEG-IFN 1 μg/kg/week) and 2 of 3 (67%) patients treated at dose level 2 (PEG-IFN 2 μg/kg/week). Grade 3 to 4 treatment-related adverse events occurred in 10 of 17 (59%) patients. Responses occurred in 1 of 5 (20%) patients with melanoma and 2 of 12 (17%) patients with RCC.
Conclusions: Pembrolizumab 2 mg/kg Q3W plus ipilimumab 1 mg/kg Q3W was tolerable and provided promising antitumor activity in patients with advanced melanoma or RCC. The maximum tolerated dose of pembrolizumab plus PEG-IFN had limited antitumor activity in this population. Clin Cancer Res; 24(8); 1805–15. ©2018 AACR.
The Sky in Edvard Munch’s The Scream
Authors: Prata Fred , Robock Alan , Hamblyn Richard 
Published: January 2018

AbstractThe Scream is a well-known painting by Edvard Munch (1863–1944). The Norwegian word used by Munch is “skrik,” which can be translated as “shriek” or “scream.” The Scream may be of interest to meteorologists because of the quite striking representation of the sky. It has been suggested that the dramatic red-colored sky was inspired by a volcanic sunset seen by Munch after the Krakatau eruption in 1883 and by a sighting of stratospheric nacreous clouds, and also that it is part of the artist’s expression of a scream from nature. The evidence for the volcanic sunset theory and Munch’s psyche are briefly reviewed. We provide support that Munch’s inspiration may have been from a sighting of nacreous clouds, observable from southern Norway during the winter months. We show that the colors and patterns of the sky in Munch’s painting match the sunset colors better if nacreous clouds are present. Their sudden appearance around and after sunset creates an impressive and dramatic effect. By comparing the color content of photographs and paintings of regular sunsets, volcanic sunsets, and nacreous clouds after sunset with the color content of the sky in The Scream, the match is better with nacreous clouds present. If this conjecture is correct, then Munch’s sky in The Scream represents one of the earliest visual documentations of a nacreous cloud display.
Precipitation Susceptibility and Aerosol Buffering of Warm- and Mixed-Phase Orographic Clouds in Idealized Simulations
Authors: Glassmeier Franziska , Lohmann Ulrike 
Published: January 2018

Abstract
The sensitivity of warm- and mixed-phase orographic precipitation to the aerosol background with simultaneous changes in the abundance of cloud condensation nuclei and ice nucleating particles is explored in an idealized, two-dimensional modeling study. The concept of precipitation susceptibility dlnP/dlnN, where P is the precipitation mixing ratio and N the cloud droplet number, is adapted for orographic clouds. Precipitation susceptibility is found to be low because perturbations to different precipitation formation pathways compensate each other. For mixed-phase conditions, this in particular means a redistribution between warm and cold pathways. The compensating behavior is described as a consequence of a balance equation for the cloud water along parcel trajectories that constrains the total precipitation formation to match the drying from condensation and vapor deposition on ice-phase hydrometeors caused by the mountain flow. For an aerosol-independent condensation rate (saturation adjustment), this balance requirement limits aerosol impacts on orographic precipitation (i) to the evaporation of hydrometeors and (ii) to the glaciation state of the cloud, which controls the contribution of vapor deposition to drying. The redistribution of precipitation formation pathways is coupled to a redistribution of the total hydrometeor mass between hydrometeor categories. Aerosol effects on the glaciation state of the cloud enhance this redistribution effect such that liquid and ice adjustments do not compensate. For the externally constrained, fully adjusted steady-state situation studied, precipitation susceptibility quantifies the redistribution effect rather than changes in precipitation production as in previous studies.
Atmospheric Patterns over the Antarctic Peninsula
Authors: Gonzalez Sergi , Vasallo Francisco , Recio-Blitz Cayetana , Guijarro José A. , Riesco Jesús 
Published: January 2018

Abstract
Using clustering analysis for the sea level pressure field of the ERA-Interim reanalysis between 1979 and 2016, five synoptic pressure patterns have been obtained for the Drake area and Antarctic Peninsula (AP) region (45°–75°S, 20°–120°W), and the resulting daily series has been made available to the scientific community. The five patterns have been named according to their most important features as follows: low over the Weddell Sea (LWS), low over the Amundsen and Bellingshausen Seas (LAB), low over the Drake Passage (LDP), zonal flow over the Drake Passage (ZDP), and ridge over the Antarctic Peninsula (RAP). Each atmospheric pattern is described after analyzing its development and evolution. A frequency analysis shows that the five atmospheric patterns present a similar annual frequency but a large seasonal variability. The transitions from one pattern to another tend to follow a cycle in which synoptic atmospheric waves are displaced eastward by a quarter wavelength. Four of the five atmospheric patterns (all except RAP) are very influenced by the southern annular mode (SAM); however, only LAB and LWS are influenced to some degree by ENSO. The occurrence of the LAB pattern presents a positive trend showing agreement with other studies that indicate an enhancement of the Amundsen–Bellingshausen Seas low. Finally, atmospheric circulation patterns have been related to the airmass advection and precipitation in Livingston Island, showing the potential application for studying the changes in the surface mass balance on the AP cryosphere.
Optimizing the Definition of a Sudden Stratospheric Warming
Authors: Butler Amy H. , Gerber Edwin P. 
Published: January 2018

AbstractVarious criteria exist for determining the occurrence of a major sudden stratospheric warming (SSW), but the most common is based on the reversal of the climatological westerly zonal-mean zonal winds at 60° latitude and 10 hPa in the winter stratosphere. This definition was established at a time when observations of the stratosphere were sparse. Given greater access to data in the satellite era, a systematic analysis of the optimal parameters of latitude, altitude, and threshold for the wind reversal is now possible. Here, the frequency of SSWs, the strength of the wave forcing associated with the events, changes in stratospheric temperature and zonal winds, and surface impacts are examined as a function of the stratospheric wind reversal parameters. The results provide a methodical assessment of how to best define a standard metric for major SSWs. While the continuum nature of stratospheric variability makes it difficult to identify a decisively optimal threshold, there is a relatively narrow envelope of thresholds that work well—and the original focus at 60° latitude and 10 hPa lies within this window.