bluuebunny/crossref_metadata_2025_split huggingface dataset:
Batch-Scale Hydrofluorination of Li27BeF4 to Support Molten Salt Reactor Development
Authors: Kelleher Brian C. , Dolan Kieran P. , Brooks Paul , Anderson Mark H. , Sridharan Kumar 
Published: June 2015

Li 2 BeF 4 , or flibe, is the primary candidate coolant for the fluoride-salt-cooled high-temperature nuclear reactor (FHR). Kilogram quantities of pure flibe are required for repeatable corrosion tests of modern reactor materials. This paper details fluoride salt purification by the hydrofluorination–hydrogen process, which was used to regenerate 57.4 kg of flibe originating from the secondary loop of the molten salt reactor experiment (MSRE) at Oak Ridge National Laboratory (ORNL). Additionally, it expounds upon necessary handling precautions required to produce high-quality flibe and includes technological advancements which ease the purification and analysis process. Flibe batches produced at the University of Wisconsin are the largest since the MSRE program, enabling new corrosion, radiation, and thermal hydraulic testing around the United States.
Mutation atembBCodon 306, a Potential Marker for the Identification of Multidrug Resistance Associated with Ethambutol in Mycobacterium tuberculosis
Authors: Cuevas-Córdoba Betzaida , Juárez-Eusebio Dulce María , Almaraz-Velasco Raquel , Muñiz-Salazar Raquel , Laniado-Laborin Rafael , Zenteno-Cuevas Roberto 
Published: June 2015

ABSTRACTEthambutol inhibits arabinogalactan and lipoarabinomannan biosynthesis in mycobacteria. The occurrence of mutations inembBcodon 306 in ethambutol-susceptible isolates and their absence in resistant isolates has raised questions regarding the utility of this codon as a potential marker for resistance against ethambutol. The characterization of mutations onembB306 will contribute to a better understanding of the mechanisms of resistance to this drug; therefore, the purpose of this study was to investigate the association betweenembB306 mutations and first-line drug resistance profiles in tuberculosis isolates. We sequenced the region surrounding theembB306 codon in 175 tuberculosis clinical isolates, divided according to drug sensitivity, in three groups: 110 were resistant to at least one first-line drug, of which 61 were resistant to ethambutol (EMBr), 49 were sensitive to ethambutol (EMBs) but were resistant to another drug, and 65 were pansensitive isolates (Ps). The associations betweenembB306 mutations and phenotypic resistance to all first-line drugs were determined, and their validity and safety as a diagnostic marker were assessed. One of the Psisolates (1/65), one of the EMBsisolates (1/49), and 20 of the EMBrisolates (20/61) presented with anembB306 mutation. Four different single-nucleotide polymorphisms (SNPs) atembB306 were associated with simultaneous resistance to ethambutol, isoniazid, and rifampin (odds ratio [OR], 17.7; confidence interval [CI], 5.6 to 56.1) and showed a positive predictive value of 82%, with a specificity of 97% for diagnosing multidrug resistance associated with ethambutol, indicating its potential as a molecular marker for several drugs.
Telavancin Demonstrates Activity against Methicillin-Resistant Staphylococcus aureus Isolates with Reduced Susceptibility to Vancomycin, Daptomycin, and Linezolid in Broth Microdilution MIC and One-Compartment Pharmacokinetic/Pharmacodynamic Models
Authors: Smith Jordan R. , Barber Katie E. , Hallesy Jessica , Raut Animesh , Rybak Michael J. 
Published: June 2015

ABSTRACT

Methicillin-resistant
Staphylococcus aureus
(MRSA) isolates have arisen with reduced susceptibility to several anti-MRSA agents. Telavancin (TLV), a novel anti-MRSA agent, retains low MICs against these organisms. Our objective was to determine the MICs for TLV, daptomycin (DAP), vancomycin (VAN), and linezolid (LZD) against daptomycin-nonsusceptible (DNS)
S. aureus
, vancomycin-intermediate
S. aureus
(VISA), heteroresistant VISA (hVISA), and linezolid-resistant (LZD
r
)
S. aureus
. We also evaluated these agents against each phenotype in pharmacokinetic/pharmacodynamic (PK/PD) models. Seventy DNS, 100 VISA, 180 hVISA, and 25 LZD
r
MRSA isolates were randomly selected from our library and tested to determine their MICs against TLV, DAP, VAN, and LZD via broth microdilution and a Trek panel. Four isolates were randomly selected for 168-h
in vitro
models to evaluate treatment with TLV at 10 mg/kg of body weight/day, DAP at 10 mg/kg/day, VAN at 1 g every 12 h (q12h), and LZD at 600 mg q12h. The MIC
50/90
for TLV, DAP, VAN, and LZD against 70 DNS
S. aureus
isolates were 0.06/0.125 μg/ml, 2/4 μg/ml, 1/2 μg/ml, and 2/2 μg/ml, respectively. Against 100 VISA isolates, the MIC
50/90
were 0.06/0.125 μg/ml, 1/1 μg/ml, 4/8 μg/ml, and 1/2 μg/ml, respectively. Against 170 hVISA isolates, the MIC
50/90
were 0.06/0.125 μg/ml, 0.5/1 μg/ml, 1/2 μg/ml, and 1/2 μg/ml, respectively. Against 25 LZD
r
isolates, the MIC
50/90
were 0.03/0.06 μg/ml, 1/1 μg/ml, 2/2 μg/ml, and 8/8 μg/ml, respectively. The TLV MIC was >0.125 μg/ml for 10/365 (2.7%) isolates. In PK/PD models, TLV was universally bactericidal at 168 h and statistically superior to all antibiotics against DNS
S. aureus
strain R2334. These data further establish the potency of TLV against resistant MRSA. The model data demonstrate
in vitro
bactericidal activity of TLV against hVISA, VISA, DNS
S. aureus
, and LZD
r
S. aureus
strains. Further clinical research is warranted.
IscR Regulates Synthesis of Colonization Factor Antigen I Fimbriae in Response to Iron Starvation in Enterotoxigenic Escherichia coli
Authors: Haines Sara , Arnaud-Barbe Nadège , Poncet David , Reverchon Sylvie , Wawrzyniak Julien , Nasser William , Renauld-Mongénie Geneviève 
Published: June 2015

ABSTRACT

Iron availability functions as an environmental cue for enteropathogenic bacteria, signaling arrival within the human host. As enterotoxigenic
Escherichia coli
(ETEC) is a major cause of human diarrhea, the effect of iron on ETEC virulence factors was evaluated here. ETEC pathogenicity is directly linked to production of fimbrial colonization factors and secretion of heat-labile enterotoxin (LT) and/or heat-stable enterotoxin (ST). Efficient colonization of the small intestine further requires at least the flagellin binding adhesin EtpA. Under iron starvation, production of the CFA/I fimbriae was increased in the ETEC H10407 prototype strain. In contrast, LT secretion was inhibited. Furthermore, under iron starvation, gene expression of the
cfa
(CFA/I) and
etp
(EtpBAC) operons was induced, whereas transcription of toxin genes was either unchanged or repressed. Transcriptional reporter fusion experiments focusing on the
cfa
operon further showed that iron starvation stimulated
cfaA
promoter activity in ETEC, indicating that the impact of iron on CFA/I production was mediated by transcriptional regulation. Evaluation of
cfaA
promoter activity in heterologous
E. coli
single mutant knockout strains identified IscR as the regulator responsible for inducing
cfa
fimbrial gene expression in response to iron starvation, and this was confirmed in an ETEC Δ
iscR
strain. The global iron response regulator, Fur, was not implicated. IscR binding sites were identified
in silico
within the
cfaA
promoter and fixation confirmed by DNase I footprinting, indicating that IscR directly binds the promoter region to induce CFA/I.

IMPORTANCE
Pathogenic enterobacteria modulate expression of virulence genes in response to iron availability. Although the Fur transcription factor represents the global regulator of iron homeostasis in
Escherichia coli
, we show that several ETEC virulence factors are modulated by iron, with expression of the major fimbriae under the control of the iron-sulfur cluster regulator, IscR. Furthermore, we demonstrate that the apo form of IscR, lacking an Fe-S cluster, is able to directly fix the corresponding promoter region. These results provide further evidence implicating IscR in bacterial virulence and suggest that IscR may represent a more general regulator mediating the iron response in enteropathogens.
Cyclic Di-GMP Regulates Type IV Pilus-Dependent Motility in Myxococcus xanthus
Authors: Skotnicka Dorota , Petters Tobias , Heering Jan , Hoppert Michael , Kaever Volkhard , Søgaard-Andersen Lotte 
Published: June 2015

ABSTRACT

The nucleotide-based second messenger bis-(3′-5′)-cyclic dimeric GMP (c-di-GMP) is involved in regulating a plethora of processes in bacteria that are typically associated with lifestyle changes.
Myxococcus xanthus
undergoes major lifestyle changes in response to nutrient availability, with the formation of spreading colonies in the presence of nutrients and spore-filled fruiting bodies in the absence of nutrients. Here, we investigated the function of c-di-GMP in
M. xanthus
and show that this bacterium synthesizes c-di-GMP during growth. Manipulation of the c-di-GMP level by expression of either an active, heterologous diguanylate cyclase or an active, heterologous phosphodiesterase correlated with defects in type IV pilus (T4P)-dependent motility, whereas gliding motility was unaffected. An increased level of c-di-GMP correlated with reduced transcription of the
pilA
gene (which encodes the major pilin of T4P), reduced the assembly of T4P, and altered cell agglutination, whereas a decreased c-di-GMP level correlated with altered cell agglutination. The systematic inactivation of the 24 genes in
M. xanthus
encoding proteins containing GGDEF, EAL, or HD-GYP domains, which are associated with c-di-GMP synthesis, degradation, or binding, identified three genes encoding proteins important for T4P-dependent motility, whereas all mutants had normal gliding motility. Purified DmxA had diguanylate cyclase activity, whereas the hybrid histidine protein kinases TmoK and SgmT, each of which contains a GGDEF domain, did not have diguanylate cyclase activity. These results demonstrate that c-di-GMP is important for T4P-dependent motility in
M. xanthus
.

IMPORTANCE
We provide the first direct evidence that
M. xanthus
synthesizes c-di-GMP and demonstrate that c-di-GMP is important for T4P-dependent motility, whereas we did not obtain evidence that c-di-GMP regulates gliding motility. The data presented uncovered a novel mechanism for regulation of T4P-dependent motility, in which increased levels of c-di-GMP inhibit transcription of the
pilA
gene (which encodes the major pilin of T4P), ultimately resulting in the reduced assembly of T4P. Moreover, we identified an enzymatically active diguanylate cyclase that is important for T4P-dependent motility.
Deletion of
nfnAB
in Thermoanaerobacterium saccharolyticum and Its Effect on Metabolism
Authors: Lo Jonathan , Zheng Tianyong , Olson Daniel G. , Ruppertsberger Natalie , Tripathi Shital A. , Guss Adam M. , Lynd Lee R. 
Published: June 2015

ABSTRACT

NfnAB catalyzes the reversible transfer of electrons from reduced ferredoxin and NADH to 2 NADP
+
. The NfnAB complex has been hypothesized to be the main enzyme for ferredoxin oxidization in strains of
Thermoanaerobacterium saccharolyticum
engineered for increased ethanol production. NfnAB complex activity was detectable in crude cell extracts of
T. saccharolyticum
. Activity was also detected using activity staining of native PAGE gels. The
nfnAB
gene was deleted in different strains of
T. saccharolyticum
to determine its effect on end product formation. In wild-type
T. saccharolyticum
, deletion of
nfnAB
resulted in a 46% increase in H
2
formation but otherwise little change in other fermentation products. In two engineered strains with 80% theoretical ethanol yield, loss of
nfnAB
caused two different responses: in one strain, ethanol yield decreased to about 30% of the theoretical value, while another strain had no change in ethanol yield. Biochemical analysis of cell extracts showed that the Δ
nfnAB
strain with decreased ethanol yield had NADPH-linked alcohol dehydrogenase (ADH) activity, while the Δ
nfnAB
strain with unchanged ethanol yield had NADH-linked ADH activity. Deletion of
nfnAB
caused loss of NADPH-linked ferredoxin oxidoreductase activity in all cell extracts. Significant NADH-linked ferredoxin oxidoreductase activity was seen in all cell extracts, including those that had lost
nfnAB
. This suggests that there is an unidentified NADH:ferredoxin oxidoreductase (distinct from
nfnAB
) playing a role in ethanol formation. The NfnAB complex plays a key role in generating NADPH in a strain that had become reliant on NADPH-ADH activity.

IMPORTANCE
Thermophilic anaerobes that can convert biomass-derived sugars into ethanol have been investigated as candidates for biofuel formation. Many anaerobes have been genetically engineered to increase biofuel formation; however, key aspects of metabolism remain unknown and poorly understood. One example is the mechanism for ferredoxin oxidation and transfer of electrons to NAD(P)
+
. The electron-bifurcating enzyme complex NfnAB is known to catalyze the reversible transfer of electrons from reduced ferredoxin and NADH to 2 NADP
+
and is thought to play key roles linking NAD(P)(H) metabolism with ferredoxin metabolism. We report the first deletion of
nfnAB
and demonstrate a role for NfnAB in metabolism and ethanol formation in
Thermoanaerobacterium saccharolyticum
and show that this may be an important feature among other thermophilic ethanologenic anaerobes.
CD10-positive mantle cell lymphoma: biologically distinct entity or an aberrant immunophenotype? Insight, through gene expression profile in a unique case series
Authors: Akhter Ariz , Mahe Etienne , Street Lesley , Pournazari Payam , Perizzolo Marco , Shabani-Rad Meer-Taher , Stewart Douglas A , Mansoor Adnan 
Published: June 2015

BackgroundMantle cell lymphoma (MCL) is an aggressive disease with genetic heterogeneity and discrete clinical subtypes. MCL is rarelyCD10positive. These cases raise the question whether a subset of MCL may be germinal centre (GC) derived, and have distinct clinicopathological characteristics.Aims and methodsA series of nineCD10-positive MCL cases is described herein. The clinicopathological and immunophenotypic features, immunoglobulin somatic hypermutation (SHM) status and gene expression profile (GEP) data are detailed. These features were compared with two independent sets (n=20, each) ofCD10-negative MCL cases (controls), which were randomly selected from our institutional registry.ResultsGEP showed distinct expression of a GC signature inCD10-positive MCL cases with minimal impact on downstream signalling pathways. There were no significant differences in the clinicopathological features or clinical outcome between ourCD10-positive andCD10-negative MCL cases. The frequency of SHM was comparable with established data.ConclusionsThis study provides convincing evidence thatCD10expression is related to a distinct GC signature in MCL cases, but without clinical or biological implications.
Pancreatic cancer: current understanding of molecular and genetic aetiologies
Authors: Gall Tamara M H , Wasan Harpreet , Jiao Long R 
Published: June 2015

ABSTRACT
Pancreatic ductal adenocarcinoma (PDAC) is one of the few cancers where prognosis has not improved over the past few decades. However, there have been several advances in our understanding of the disease leading to earlier detection and targeted therapeutic treatment. It is now understood that specific somatic and germline mutations lead to the development of the disease, and the risk factors associated with this are clearer. Further, several precursor lesions have been identified which, with early detection and surveillance, allows treatment before the development of carcinoma. PDAC can now be diagnosed with a high sensitivity and specificity following advances in radiology, and treatment can be commenced at an earlier stage of the disease. With continued research we are hopeful that the next decade will see an improved survival rate for all patients with pancreatic cancer.
CRMP5 Controls Glioblastoma Cell Proliferation and Survival through Notch-Dependent Signaling
Authors: Moutal Aubin , Honnorat Jérôme , Massoma Patrick , Désormeaux Pauline , Bertrand Caroline , Malleval Céline , Watrin Chantal , Chounlamountri Naura , Mayeur Marie-Eve , Besançon Roger , Naudet Nicolas , Magadoux Léa , Khanna Rajesh , Ducray François , Meyronet David , Thomasset Nicole 
Published: June 2015

Abstract
Collapsin response mediator protein 5 (CRMP5) belongs to a family of five cytosolic proteins that play a major role in nervous system development. This protein was first described in cancer-induced autoimmune processes, causing neurodegenerative disorders (paraneoplastic neurologic syndromes). CRMP5 expression has been reported to serve as a biomarker for high-grade lung neuroendocrine carcinomas; however, its functional roles have not been examined in any setting of cancer pathophysiology. In this study, we report two different CRMP5 expression patterns observed in human glioblastoma (GBM) biopsies that establish connections between CRMP5 expression, Notch receptor signaling, and GBM cell proliferation. We demonstrated that elevated CRMP5 promotes Notch receptor expression and Akt activation in human tumor cell lines, GBM stem cells, and primary tumor biopsies. We have shown that the high CRMP5 and Notch expression in GBM xenograft is related to stem cells. This suggests that high CRMP5 expression pattern in GBM biopsies encompasses a subset of stem cells. Mechanistically, CRMP5 functioned by hijacking Notch receptors from Itch-dependent lysosomal degradation. Our findings suggest that CRMP5 serves as a major mediator of Notch signaling and Akt activation by controlling the degradation of the Notch receptor, with implications for defining a biomarker signature in GBM that correlates with and may predict patient survival. Cancer Res; 75(17); 3519–28. ©2015 AACR.
Identification of Prognostic Groups in High-Grade Serous Ovarian Cancer Treated with Platinum–Taxane Chemotherapy
Authors: Chen Ping , Huhtinen Kaisa , Kaipio Katja , Mikkonen Piia , Aittomäki Viljami , Lindell Rony , Hynninen Johanna , Auranen Annika , Grénman Seija , Lehtonen Rainer , Carpén Olli , Hautaniemi Sampsa 
Published: June 2015

AbstractDisseminated high-grade serous ovarian cancer (HGS-OvCa) is an aggressive disease treated with platinum and taxane combination therapy. While initial response can be favorable, the disease typically relapses and becomes resistant to treatment. As genomic alterations in HGS-OvCa are heterogeneous, identification of clinically meaningful molecular markers for outcome prediction is challenging. We developed a novel computational approach (PSFinder) that fuses transcriptomics and clinical data to identify HGS-OvCa prognostic subgroups for targeted treatment. Application of PSFinder to transcriptomics data from 180 HGS-OvCa patients treated with platinum–taxane therapy revealed 61 transcript isoforms that characterize two poor and one good survival-associated groups (P = 0.007). These groups were validated in eight independent data sets, including a prospectively collected ovarian cancer cohort. Two poor prognostic groups have distinct expression profiles and are characteristic by increased hypermethylation and stroma-related genes. Integration of the PSFinder signature and BRCA1/2 mutation status allowed even better stratification of HGS-OvCa patients' prognosis. The herein introduced novel and generally applicable computational approach can identify outcome-related subgroups and facilitate the development of precision medicine to overcome drug resistance. A limited set of biomarkers divides HGS-OvCa into three prognostic groups and predicts patients in need of targeted therapies. Cancer Res; 75(15); 2987–98. ©2015 AACR.
Diverse Targets of β-Catenin during the Epithelial–Mesenchymal Transition Define Cancer Stem Cells and Predict Disease Relapse
Authors: Chang Yi-Wen , Su Ying-Jhen , Hsiao Michael , Wei Kuo-Chen , Lin Wei-Hsin , Liang Chi-Jung , Chen Shin-Cheh , Lee Jia-Lin 
Published: June 2015

Abstract
Wnt signaling contributes to the reprogramming and maintenance of cancer stem cell (CSC) states that are activated by epithelial–mesenchymal transition (EMT). However, the mechanistic relationship between EMT and the Wnt pathway in CSC is not entirely clear. Chromatin immunoprecipitation with high-throughput sequencing (ChIP-seq) indicated that EMT induces a switch from the β-catenin/E-cadherin/Sox15 complex to the β-catenin/Twist1/TCF4 complex, the latter of which then binds to CSC-related gene promoters. Tandem coimmunoprecipitation and re-ChIP experiments with epithelial-type cells further revealed that Sox15 associates with the β-catenin/E-cadherin complex, which then binds to the proximal promoter region of CASP3. Through this mechanism, Twist1 cleavage is triggered to regulate a β-catenin–elicited promotion of the CSC phenotype. During EMT, we documented that Twist1 binding to β-catenin enhanced the transcriptional activity of the β-catenin/TCF4 complex, including by binding to the proximal promoter region of ABCG2, a CSC marker. In terms of clinical application, our definition of a five-gene CSC signature (nuclear β-cateninHigh/nuclear Twist1High/E-cadherinLow/Sox15Low/CD133High) may provide a useful prognostic marker for human lung cancer. Cancer Res; 75(16); 3398–410. ©2015 AACR.
Endothelial Thermotolerance Impairs Nanoparticle Transport in Tumors
Authors: Bagley Alexander F. , Scherz-Shouval Ruth , Galie Peter A. , Zhang Angela Q. , Wyckoff Jeffrey , Whitesell Luke , Chen Christopher S. , Lindquist Susan , Bhatia Sangeeta N. 
Published: June 2015

Abstract
The delivery of diagnostic and therapeutic agents to solid tumors is limited by physical transport barriers within tumors, and such restrictions directly contribute to decreased therapeutic efficacy and the emergence of drug resistance. Nanomaterials designed to perturb the local tumor environment with precise spatiotemporal control have demonstrated potential to enhance drug delivery in preclinical models. Here, we investigated the ability of one class of heat-generating nanomaterials called plasmonic nanoantennae to enhance tumor transport in a xenograft model of ovarian cancer. We observed a temperature-dependent increase in the transport of diagnostic nanoparticles into tumors. However, a transient, reversible reduction in this enhanced transport was seen upon reexposure to heating, consistent with the development of vascular thermotolerance. Harnessing these observations, we designed an improved treatment protocol combining plasmonic nanoantennae with diffusion-limited chemotherapies. Using a microfluidic endothelial model and genetic tools to inhibit the heat-shock response, we found that the ability of thermal preconditioning to limit heat-induced cytoskeletal disruption is an important component of vascular thermotolerance. This work, therefore, highlights the clinical relevance of cellular adaptations to nanomaterials and identifies molecular pathways whose modulation could improve the exposure of tumors to therapeutic agents. Cancer Res; 75(16); 3255–67. ©2015 AACR.