bluuebunny/crossref_metadata_2025_split huggingface dataset:
Changing Patterns of Uncontested Seats in Southern State Legislative Elections, 1984–2012*
Authors: Myers Adam S. 
Published: May 2017

ObjectiveDespite the rise of two‐party politics in the American South, most state legislative elections in the region continue to feature only one major‐party candidate. I offer a new account of changes in partisan contestation of state legislative races in the region that centers on the growing importance of constituency partisanship over time.MethodUsing an original data set of district‐level presidential vote share between 1984 and 2012, I examine the changing effect of district partisanship on uncontestedness. I then estimate multivariate models predicting uncontested seats in 1988, 2000, and 2012.ResultsBetween 1984 and 2012, the effect of incumbency on uncontestedness declines while the effect of partisanship rises.ConclusionThe processes accounting for uncontested seats in southern legislative races have changed. Although uncontestedness in earlier periods was primarily driven by the incumbency advantage, in the contemporary period it is largely a result of the racially driven partisan sort of the southern electorate.
HENRY NELSON WIEMAN ON RELIGION AND REINHOLD NIEBUHR
Authors: Rice Daniel F. 
Published: May 2017

AbstractHenry Nelson Wieman and Reinhold Niebuhr were theologically poles apart—Wieman a “new naturalist” and Niebuhr a “new super naturalist”—according to Wieman's nomenclature. Wieman devoted more time and attention to Niebuhr than Niebuhr did to him. The reason for this was the result of Wieman's sustained attack on the “new supernaturalism” with which he identified Niebuhr as one of the major American representatives. This article traces the background to Wieman's view of Niebuhr—Wieman's own views on science, on religion, and on Christianity—then proceeds to Wieman's analysis of Niebuhr's theology and his relation to the “new supernaturalism,” concluding with Niebuhr's reply to Wieman.
FURNISHING THE SKILL WHICH CAN SAVE THE CHILD: DIPHTHERIA, GERM THEORY, AND THEODICY
Authors: Johnson Kristin 
Published: May 2017

AbstractAmid the diverse ways men and women have viewed the relationship between science and religion, explicit arguments that “Science is God's Provision” remain unexamined by historians. Such arguments are examined here as they relate to the problem of theodicy, by looking at a particular case study that inspired comments on the relationship between medicine and faith, namely, the discovery of the diphtheria antitoxin. This story highlights, first, the flexibility of the tradition of natural theology, and second, the important role the problem of theodicy has played in the history of the relationship between science and religion.
Mammalian target of rapamycin complex 2 regulates muscle glucose uptake during exercise in mice
Authors: Kleinert Maximilian , Parker Benjamin L. , Fritzen Andreas M. , Knudsen Jonas R. , Jensen Thomas E. , Kjøbsted Rasmus , Sylow Lykke , Ruegg Markus , James David E. , Richter Erik A. 
Published: May 2017

Key points
Exercise is a potent physiological stimulus to clear blood glucose from the circulation into skeletal muscle.
The mammalian target of rapamycin complex 2 (mTORC2) is an important regulator of muscle glucose uptake in response to insulin stimulation.
Here we report for the first time that the activity of mTORC2 in mouse muscle increases during exercise.
We further show that glucose uptake during exercise is decreased in mouse muscle that lacks mTORC2 activity.
We also provide novel identifications of new mTORC2 substrates during exercise in mouse muscle.
AbstractExercise increases glucose uptake into insulin‐resistant muscle. Thus, elucidating the exercise signalling network in muscle may uncover new therapeutic targets. The mammalian target of rapamycin complex 2 (mTORC2), a regulator of insulin‐controlled glucose uptake, has been reported to interact with ras‐related C3 botulinum toxin substrate 1 (Rac1), which plays a role in exercise‐induced glucose uptake in muscle. Therefore, we tested the hypothesis that mTORC2 activity is necessary for muscle glucose uptake during treadmill exercise. We used mice that specifically lack mTORC2 signalling in muscle by deletion of the obligatory mTORC2 component Rictor (Ric mKO). Running capacity and running‐induced changes in blood glucose, plasma lactate and muscle glycogen levels were similar in wild‐type (Ric WT) and Ric mKO mice. At rest, muscle glucose uptake was normal, but during running muscle glucose uptake was reduced by 40% in Ric mKO mice compared to Ric WT mice. Running increased muscle phosphorylated 5′ AMP‐activated protein kinase (AMPK) similarly in Ric WT and Ric mKO mice, and glucose transporter type 4 (GLUT4) and hexokinase II (HKII) protein expressions were also normal in Ric mKO muscle. The mTORC2 substrate, phosphorylated protein kinase C α (PKCα), and the mTORC2 activity readout, phosphorylated N‐myc downstream regulated 1 (NDRG1) protein increased with running in Ric WT mice, but were not altered by running in Ric mKO muscle. Quantitative phosphoproteomics uncovered several additional potential exercise‐dependent mTORC2 substrates, including contractile proteins, kinases, transcriptional regulators, actin cytoskeleton regulators and ion‐transport proteins. Our study suggests that mTORC2 is a component of the exercise signalling network that regulates muscle glucose uptake and we provide a resource of new potential members of the mTORC2 signalling network.
How do we know that we are assessing the “right things”?
Authors: Rudland Joy , Lacey Cameron , Kenrick Kristin , Tweed Mike 
Published: May 2017

Introduction: As assessment is perceived as a powerful tool for learning, it is important to ensure that assessments reflect the learning considered most significant. Assessment blueprinting offers the opportunity to ensure perceptions of what should be assessed align with what is assessed. Methods: An expert panel was asked to determine the percentage of undergraduate assessment that should be devoted to broad domain areas previously agreed to define the outcomes of an undergraduate curriculum; this provided the blueprint. Staff who co-ordinated, implemented and assessed students on clinical runs indicated the percentage of their assessments allocated to the domain areas. Staff who constructed end-of-year summative assessments also analysed their assessments in terms of the domain areas. The “expert panel” blueprint values were then compared using Mann–Whitney U with the actual assessment conducted to determine variations between the ideal and actual assessment. Results: What was considered important to assess closely aligned with what was assessed in most domain areas. The exceptions were the underassessment of two domains, Māori Health and Research and Information Literacy.Conclusions: The chosen methodology identified areas that were under-represented in the actual student assessments. This prompted the school to consider whether this under-representation is problematic; if so, whether to redistribute or increase assessment, and whether the required increases should occur in-course or at the end of the year.
Phenotypic and Molecular Evaluation of Echinocandin Susceptibility of Candida glabrata, Candida bracarensis, and Candida nivariensis Strains Isolated during 30 Years in Argentina
Authors: Morales-López Soraya , Dudiuk Catiana , Vivot Walter , Szusz Wanda , Córdoba Susana B. , Garcia-Effron Guillermo 
Published: May 2017

ABSTRACT

The echinocandin susceptibilities of 122
Candida glabrata
complex strains (including 5
Candida nivariensis
and 3
Candida bracarensis
strains) were evaluated by microdilution and compared with the results from a molecular tool able to detect FKS mutations. No echinocandin resistance was detected. The PCR results coincide with the MIC data in 99.25% of the cases (1
C. glabrata
strain was misidentified as resistant) but were 20 h faster.
C. nivariensis FKS
genes were sequenced and showed differences with
C. glabrata
FKS
genes.
Impaired Inhibition by Avibactam and Resistance to the Ceftazidime-Avibactam Combination Due to the D
179
Y Substitution in the KPC-2 β-Lactamase
Authors: Compain Fabrice , Arthur Michel 
Published: May 2017

ABSTRACT

The ceftazidime-avibactam antibiotic combination was recently shown to be at risk for the emergence of resistance under treatment. To gain insight into the underlying mechanism, we have analyzed the catalytic properties of a
Klebsiella pneumoniae
carbapenemase type 2 (KPC-2) β-lactamase harboring the D
179
Y substitution. We show that impaired inhibition by avibactam combined with significant residual activity for ceftazidime hydrolysis accounts for the resistance. In contrast, the D
179
Y substitution abolished the hydrolysis of aztreonam and imipenem, indicating that these drugs might provide therapeutic alternatives.
NDM-5 and OXA-181 Beta-Lactamases, a Significant Threat Continues To Spread in the Americas
Authors: Rojas Laura J. , Hujer Andrea M. , Rudin Susan D. , Wright Meredith S. , Domitrovic T. Nicholas , Marshall Steven H. , Hujer Kristine M. , Richter Sandra S. , Cober Eric , Perez Federico , Adams Mark D. , van Duin David , Bonomo Robert A. 
Published: May 2017

ABSTRACT

Among Gram-negative bacteria, carbapenem-resistant infections pose a serious and life-threatening challenge. Here, the CRACKLE network reports a sentinel detection and characterization of a carbapenem-resistant
Klebsiella pneumoniae
ST147 isolate harboring
bla
NDM-5
and
bla
OXA-181
from a young man who underwent abdominal surgery in India.
bla
NDM-5
was located on an IncFII plasmid of ≈90 kb, whereas
bla
OXA-181
was chromosomally encoded. Resistome and genome analysis demonstrated multiple copies of the transposable element IS
26
and a “hot-spot region” in the IncFII plasmid.
Crystal Structure of the New Investigational Drug Candidate VT-1598 in Complex with Aspergillus fumigatus Sterol 14α-Demethylase Provides Insights into Its Broad-Spectrum Antifungal Activity
Authors: Hargrove Tatiana Y. , Garvey Edward P. , Hoekstra William J. , Yates Christopher M. , Wawrzak Zdzislaw , Rachakonda Girish , Villalta Fernando , Lepesheva Galina I. 
Published: May 2017

ABSTRACT

Within the past few decades, the incidence and complexity of human fungal infections have increased, and therefore, the need for safer and more efficient, broad-spectrum antifungal agents is high. In the study described here, we characterized the new tetrazole-based drug candidate VT-1598 as an inhibitor of sterol 14α-demethylase (CYP51B) from the filamentous fungus
Aspergillus fumigatus
. VT-1598 displayed a high affinity of binding to the enzyme in solution (dissociation constant, 13 ± 1 nM) and in the reconstituted enzymatic reaction was revealed to have an inhibitory potency stronger than the potencies of all other simultaneously tested antifungal drugs, including fluconazole, voriconazole, ketoconazole, and posaconazole. The X-ray structure of the VT-1598/
A. fumigatus
CYP51 complex was determined and depicts the distinctive binding mode of the inhibitor in the enzyme active site, suggesting the molecular basis of the improved drug potency and broad-spectrum antifungal activity. These data show the formation of an optimized hydrogen bond between the phenoxymethyl oxygen of VT-1598 and the imidazole ring nitrogen of His374, the CYP51 residue that is highly conserved across fungal pathogens and fungus specific. Comparative structural analysis of
A. fumigatus
CYP51/voriconazole and
Candida albicans
CYP51/VT-1161 complexes supports the role of H bonding in fungal CYP51/inhibitor complexes and emphasizes the importance of an optimal distance between this interaction and the inhibitor-heme iron interaction. Cellular experiments using two
A. fumigatus
strains (strains 32820 and 1022) displayed a direct correlation between the effects of the drugs on CYP51B activity and fungal growth inhibition, indicating the noteworthy anti-
A. fumigatus
potency of VT-1598 and confirming its promise as a broad-spectrum antifungal agent.
Population Pharmacokinetic Modeling as a Tool To Characterize the Decrease in Ciprofloxacin Free Interstitial Levels Caused by Pseudomonas aeruginosa Biofilm Lung Infection in Wistar Rats
Authors: Torres Bruna G. S. , Helfer Victória E. , Bernardes Priscila M. , Macedo Alexandre José , Nielsen Elisabet I. , Friberg Lena E. , Dalla Costa Teresa 
Published: May 2017

ABSTRACT

Biofilm formation plays an important role in the persistence of pulmonary infections, for example, in cystic fibrosis patients. So far, little is known about the antimicrobial lung disposition in biofilm-associated pneumonia. This study aimed to evaluate, by microdialysis, ciprofloxacin (CIP) penetration into the lungs of healthy and
Pseudomonas aeruginosa
biofilm-infected rats and to develop a comprehensive model to describe the CIP disposition under both conditions.
P. aeruginosa
was immobilized into alginate beads and intratracheally inoculated 14 days before CIP administration (20 mg/kg of body weight). Plasma and microdialysate were sampled from different animal groups, and the observations were evaluated by noncompartmental analysis (NCA) and population pharmacokinetic (popPK) analysis. The final model that successfully described all data consisted of an arterial and a venous central compartment and two peripheral distribution compartments, and the disposition in the lung was modeled as a two-compartment model structure linked to the venous compartment. Plasma clearance was approximately 32% lower in infected animals, leading to a significantly higher level of plasma CIP exposure (area under the concentration-time curve from time zero to infinity, 27.3 ± 12.1 μg · h/ml and 13.3 ± 3.5 μg · h/ml in infected and healthy rats, respectively). Despite the plasma exposure, infected animals showed a four times lower tissue concentration/plasma concentration ratio (lung penetration factor = 0.44 and 1.69 in infected and healthy rats, respectively), and lung clearance (CL
lung
) was added to the model for these animals (CL
lung
= 0.643 liters/h/kg) to explain the lower tissue concentrations. Our results indicate that
P. aeruginosa
biofilm infection reduces the CIP free interstitial lung concentrations and increases plasma exposure, suggesting that plasma concentrations alone are not a good surrogate of lung concentrations.
Propofol Sedation Exacerbates Kidney Pathology and Dissemination of Bacteria during Staphylococcus aureus Bloodstream Infections
Authors: Visvabharathy Lavanya , Freitag Nancy E. 
Published: May 2017

ABSTRACTMethicillin-resistantStaphylococcus aureus(MRSA) is responsible for large numbers of postsurgical nosocomial infections across the United States and worldwide. Propofol anesthesia is widely used in surgery and in intensive care units, and recent evidence indicates that even brief exposure to propofol can substantially increase host susceptibility to microbial infection. Here, we delineate the impact of propofol sedation on MRSA bloodstream infections in mice in the presence and absence of prophylactic antibiotic treatment. Consistent with previous reports, brief periods of anesthesia with propofol were sufficient to significantly increase bacterial burdens and kidney pathology in mice infected with MRSA. Propofol exposure increased neutrophilic infiltrates into the kidney and enhanced bacterial dissemination throughout kidney tissue. Propofol sedation reduced populations of effector phagocytes and mature dendritic cells within the kidney and led to the apparent expansion of myeloid-derived suppressor cell-like populations. When propofol was coadministered with vancomycin prophylaxis, it dramatically increased kidney abscess formation and bacterial dissemination throughout kidney tissue at early times post-S. aureusinfection compared to antibiotic-treated but nonsedated animals. Taken together, our data indicate that short-term sedation with propofol significantly increases the severity of bloodstream MRSA infection, even when administered in conjunction with vancomycin prophylaxis.
Infection of Hysterectomized Mice with Chlamydia muridarum and Chlamydia trachomatis
Authors: Yang Chunfu , Whitmire William M. , Sturdevant Gail L. , Bock Kevin , Moore Ian , Caldwell Harlan D. 
Published: May 2017

ABSTRACTWe studied infection and immunity of hysterectomized mice infected withChlamydia muridarumandChlamydia trachomatisto determine if there were differences between these species in their ability to infect vaginal squamous epithelial cellsin vivoindependently of proximal upper genital tract tissues. We found thatC. muridarumreadily colonized and infected vaginal squamous epithelial cells, whereasC. trachomatisdid not. Primary infection of the vaginal epithelium withC. muridarumproduced infections of a duration longer than that reported for normal mice. Infection resulted in an inflammatory response in the vagina characterized by neutrophils and infiltrating submucosal plasma cells consisting primarily of T cells. Despite the delayed clearance, rechallengedC. muridarum-infected mice were highly immune. Mice vaginally infected withC. muridarumproduced serum and vaginal wash antibodies and an antigen-specific gamma interferon-dominated Th1-biased T cell response. By comparison, mice vaginally infected withC. trachomatisexhibited transient low-burden infections, produced no detectable tissue inflammatory response, and failed to seroconvert. We discuss how these marked differences in the biology of vaginal infection between these otherwise genetically similar species are possibly linked to pathogen-specific virulence genes and how they may influence pathology and immunity in the upper genital tract.
Phase-Variable Changes in the Position of
O
-Methyl Phosphoramidate Modifications on the Polysaccharide Capsule of Campylobacter jejuni Modulate Serum Resistance
Authors: Pequegnat Brittany , Laird Renee M. , Ewing Cheryl P. , Hill Christina L. , Omari Eman , Poly Frederic , Monteiro Mario A. , Guerry Patricia 
Published: May 2017

ABSTRACT

Campylobacter jejuni
polysaccharide capsules (CPS) are characterized by the presence of nonstoichiometric
O
-methyl phosphoramidate (MeOPN) modifications. The lack of stoichiometry is due to phase variation at homopolymeric tracts within the MeOPN transferase genes.
C. jejuni
strain 81-176 contains two MeOPN transferase genes and has been shown previously to contain MeOPN modifications at the 2 and 6 positions of the galactose (Gal) moiety in the CPS. We demonstrate here that one of the two MeOPN transferases, encoded by CJJ81176_1435, is bifunctional and is responsible for the addition of MeOPN to both the 2 and the 6 positions of Gal. A new MeOPN at the 4 position of Gal was observed in a mutant lacking the CJJ81176_1435 transferase and this was encoded by the CJJ81176_1420 transferase. During routine growth of 81-176, the CJJ81176_1420 transferase was predominantly in an off configuration, while the CJJ81176_1435 transferase was primarily on. However, exposure to normal human serum selected for cells expressing the CJJ81176_1420 transferase. MeOPN modifications appear to block binding of naturally occurring antibodies to the 81-176 CPS. The absence of MeOPN-4-Gal resulted in enhanced sensitivity to serum killing, whereas the loss of MeOPN-2-Gal and MeOPN-6-Gal resulted in enhanced resistance to serum killing, perhaps by allowing more MeOPN to be put onto the 4 position of Gal.

IMPORTANCE
Campylobacter jejuni
undergoes phase variation in genes encoding surface antigens, leading to the concept that a strain of this organism consists of multiple genotypes that are selected for fitness in various environments. Methyl phosphoramidate modifications on the capsule of
C. jejuni
block access of preexisting antibodies in normal human sera to the polysaccharide chain, thus preventing activation of the classical arm of the complement cascade. We show that the capsule of strain 81-176 contains more sites of MeOPN modifications than previously recognized and that one site, on the 4 position of galactose, is more critical to complement resistance than the others. Exposure to normal human serum selects for variants in the population expressing this MeOPN modification.
Glucose-Specific Enzyme IIA of the Phosphoenolpyruvate:Carbohydrate Phosphotransferase System Modulates Chitin Signaling Pathways in Vibrio cholerae
Authors: Yamamoto Shouji , Ohnishi Makoto 
Published: May 2017

ABSTRACT

In
Vibrio cholerae
, the genes required for chitin utilization and natural competence are governed by the chitin-responsive two-component system (TCS) sensor kinase ChiS. In the classical TCS paradigm, a sensor kinase specifically phosphorylates a cognate response regulator to activate gene expression. However, our previous genetic study suggested that ChiS stimulates the non-TCS transcriptional regulator TfoS by using mechanisms distinct from classical phosphorylation reactions (S. Yamamoto, J. Mitobe, T. Ishikawa, S. N. Wai, M. Ohnishi, H. Watanabe, and H. Izumiya, Mol Microbiol 91:326–347, 2014,
https://doi.org/10.1111/mmi.12462
). TfoS specifically activates the transcription of
tfoR
, encoding a small regulatory RNA essential for competence gene expression. Whether ChiS and TfoS interact directly remains unknown. To determine if other factors mediate the communication between ChiS and TfoS, we isolated transposon mutants that turned off
tfoR
::
lacZ
expression but possessed intact
chiS
and
tfoS
genes. We demonstrated an unexpected association of chitin-induced signaling pathways with the glucose-specific enzyme IIA (EIIA
glc
) of the phosphoenolpyruvate:carbohydrate phosphotransferase system (PTS) for carbohydrate uptake and catabolite control of gene expression. Genetic and physiological analyses revealed that dephosphorylated EIIA
glc
inactivated natural competence and
tfoR
transcription. Chitin-induced expression of the
chb
operon, which is required for chitin transport and catabolism, was also repressed by dephosphorylated EIIA
glc
. Furthermore, the regulation of
tfoR
and
chb
expression by EIIA
glc
was dependent on ChiS and intracellular levels of ChiS were not affected by disruption of the gene encoding EIIA
glc
. These results define a previously unknown connection between the PTS and chitin signaling pathways in
V. cholerae
and suggest a strategy whereby this bacterium can physiologically adapt to the existing nutrient status.

IMPORTANCE
The EIIA
glc
protein of the PTS coordinates a wide variety of physiological functions with carbon availability. In this report, we describe an unexpected association of chitin-activated signaling pathways in
V. cholerae
with EIIA
glc
. The signaling pathways are governed by the chitin-responsive TCS sensor kinase ChiS and lead to the induction of chitin utilization and natural competence. We show that dephosphorylated EIIA
glc
inhibits both signaling pathways in a ChiS-dependent manner. This inhibition is different from classical catabolite repression that is caused by lowered levels of cyclic AMP. This work represents a newly identified connection between the PTS and chitin signaling pathways in
V. cholerae
and suggests a strategy whereby this bacterium can physiologically adapt to the existing nutrient status.