bluuebunny/crossref_metadata_2025_split huggingface dataset:
Searching for the Optimal Predictor of Ciprofloxacin Resistance in Klebsiella pneumoniae by Using
In Vitro
Dynamic Models
Authors: Strukova Elena N. , Portnoy Yury A. , Romanov Andrey V. , Edelstein Mikhail V. , Zinner Stephen H. , Firsov Alexander A. 
Published: December 2015

ABSTRACT

There is growing evidence of applicability of the hypothesis of the mutant selection window (MSW), i.e., the range between the MIC and the mutant prevention concentration (MPC), within which the enrichment of resistant mutants is most probable. However, it is not clear if MPC-based pharmacokinetic variables are preferable to the respective MIC-based variables as interstrain predictors of resistance. To examine the predictive power of the ratios of the area under the curve (AUC
24
) to the MPC and to the MIC, the selection of ciprofloxacin-resistant mutants of three
Klebsiella pneumoniae
strains with different MPC/MIC ratios was studied. Each organism was exposed to twice-daily ciprofloxacin for 3 days at AUC
24
/MIC ratios that provide peak antibiotic concentrations close to the MIC, between the MIC and the MPC, and above the MPC. Resistant
K. pneumoniae
mutants were intensively enriched at an AUC
24
/MIC ratio of 60 to 360 h (AUC
24
/MPC ratio from 2.5 to 15 h) but not at the lower or higher AUC
24
/MIC and AUC
24
/MPC ratios, in accordance with the MSW hypothesis. AUC
24
/MPC and AUC
24
/MIC relationships with areas under the time courses of ciprofloxacin-resistant
K. pneumoniae
(AUBC
M
) were bell shaped. These relationships predict highly variable “antimutant” AUC
24
/MPC ratios (20 to 290 h) compared to AUC
24
/MIC ratios (1,310 to 2,610 h). These findings suggest that the potential of the AUC
24
/MPC ratio as an interstrain predictor of
K. pneumoniae
resistance is lower than that of the AUC
24
/MIC ratio.
Characterization of Polymyxin B Biodistribution and Disposition in an Animal Model
Authors: Manchandani Pooja , Zhou Jian , Ledesma Kimberly R. , Truong Luan D. , Chow Diana S.-L. , Eriksen Jason L. , Tam Vincent H. 
Published: December 2015

ABSTRACT
Despite dose-limiting nephrotoxicity concerns, polymyxin B has resurged as the treatment of last resort for multidrug-resistant Gram-negative bacterial infections. However, the pharmacokinetic, pharmacodynamic, and nephrotoxic properties of polymyxin B still are not thoroughly understood. The objective of this study was to provide additional insights into the overall biodistribution and disposition of polymyxin B in an animal model. Sprague-Dawley rats were dosed with intravenous polymyxin B (3 mg/kg of body weight). Drug concentrations in the serum, urine, bile, and tissue (brain, heart, lungs, liver, spleen, kidneys, and skeletal muscle) samples over time were assayed by a validated methodology. Among all the organs evaluated, polymyxin B distribution was highest in the kidneys. The mean renal tissue/serum polymyxin B concentration ratios were 7.45 (95% confidence interval [CI], 4.63 to 10.27) at 3 h and 19.62 (95% CI, 5.02 to 34.22) at 6 h postdose. Intrarenal drug distribution was examined by immunostaining. Using a ratiometric analysis, proximal tubular cells showed the highest accumulation of polymyxin B (Mander's overlap coefficient, 0.998) among all cell types evaluated. Less than 5% of the administered dose was recovered in urine over 48 h, but all 4 major polymyxin B components were detected in the bile over 4 h. These findings corroborate previous results that polymyxin B is highly accumulated in the kidneys, but the elimination likely is via a nonrenal route. Biliary excretion could be one of the routes of polymyxin B elimination, and this should be further explored. The elucidation of mechanism(s) of drug uptake in proximal tubular cells is ongoing.
Analysis of Hepatitis C Virus Genotype 1b Resistance Variants in Japanese Patients Treated with Paritaprevir-Ritonavir and Ombitasvir
Authors: Krishnan Preethi , Schnell Gretja , Tripathi Rakesh , Beyer Jill , Reisch Thomas , Zhang Xinyan , Setze Carolyn , Rodrigues Lino , Burroughs Margaret , Redman Rebecca , Chayama Kazuaki , Kumada Hiromitsu , Collins Christine , Pilot-Matias Tami 
Published: December 2015

ABSTRACT

Treatment of HCV genotype 1b (GT1b)-infected Japanese patients with paritaprevir (NS3/4A inhibitor boosted with ritonavir) and ombitasvir (NS5A inhibitor) in studies M12-536 and GIFT-I demonstrated high sustained virologic response (SVR) rates. The virologic failure rate was 3% (13/436) across the two studies. Analyses were conducted to evaluate the impact of baseline resistance-associated variants (RAVs) on treatment outcome and the emergence and persistence of RAVs in patients experiencing virologic failure. Baseline paritaprevir resistance-conferring variants in NS3 were infrequent, while Y93H in NS5A was the most prevalent ombitasvir resistance-conferring variant at baseline. A comparison of baseline prevalence of polymorphisms in Japanese and western patients showed that Q80L and S122G in NS3 and L28M, R30Q, and Y93H in NS5A were significantly more prevalent in Japanese patients. In the GIFT-I study, the prevalence of Y93H in NS5A varied between 13% and 21% depending on the deep-sequencing detection threshold. Among patients with Y93H comprising <1%, 1 to 40%, or >40% of their preexisting viral population, the 24-week SVR (SVR
24
) rates were >99% (276/277), 93% (38/41), and 76% (25/33), respectively, indicating that the prevalence of Y93H within a patient's viral population is a good predictor of treatment response. The predominant RAVs at the time of virologic failure were D168A/V in NS3 and Y93H alone or in combination with other variants in NS5A. While levels of NS3 RAVs declined over time, NS5A RAVs persisted through posttreatment week 48. Results from these analyses are informative in understanding the resistance profile of an ombitasvir- plus paritaprevir/ritonavir-based regimen in Japanese GT1b-infected patients.
Modification of the 1-Phosphate Group during Biosynthesis of Capnocytophaga canimorsus Lipid A
Authors: Renzi Francesco , Zähringer Ulrich , Chandler Courtney E. , Ernst Robert K. , Cornelis Guy R. , Ittig Simon J. 
Published: December 2015

ABSTRACT

Capnocytophaga canimorsus
, a commensal bacterium of dog's mouth flora causing severe infections in humans after dog bites or scratches, has a lipopolysaccharide (LPS) (endotoxin) with low-inflammatory lipid A. In particular, it contains a phosphoethanolamine (
P
-Etn) instead of a free phosphate group at the C-1 position of the lipid A backbone, usually present in highly toxic enterobacterial Gram-negative lipid A. Here we show that the
C. canimorsus
genome comprises a single operon encoding a lipid A 1-phosphatase (LpxE) and a lipid A 1
P
-Etn transferase (EptA). This suggests that lipid A is modified during biosynthesis after completing acylation of the backbone by removal of the 1-phosphate and subsequent addition of an
P
-Etn group. As endotoxicity of lipid A is known to depend largely on the degree of unsubstituted or unmodified phosphate residues, deletion of
lpxE
or
eptA
led to mutants lacking the
P
-Etn group, with consequently increased endotoxicity and decreased resistance to cationic antimicrobial peptides (CAMP). Consistent with the proposed sequential biosynthetic mechanism, the endotoxicity and CAMP resistance of a double deletion mutant of
lpxE-eptA
was similar to that of a single
lpxE
mutant. Finally, the proposed enzymatic activities of LpxE and EptA based on sequence similarity could be successfully validated by mass spectrometry (MS)-based analysis of lipid A isolated from the corresponding deletion mutant strains.
Mycobacterium-Specific γ9δ2T Cells Mediate Both Pathogen-Inhibitory and CD40 Ligand-Dependent Antigen Presentation Effects Important for Tuberculosis Immunity
Authors: Abate Getahun , Spencer Charles T. , Hamzabegovic Fahreta , Blazevic Azra , Xia Mei , Hoft Daniel F. 
Published: December 2015

ABSTRACTNumerous pathogens, includingMycobacterium tuberculosis, can activate human γ9δ2T cells to proliferate and express effector mechanisms. γ9δ2T cells can directly inhibit the growth of intracellular mycobacteria and may also act as antigen-presenting cells (APC). Despite evidence for γδ T cells having the capacity to function as APC, the mechanisms involved and importance of these effects on overall tuberculosis (TB) immunity are unknown. We preparedM. tuberculosis-specific γ9δ2T cell lines to study their direct protective effects and APC functions forM. tuberculosis-specific αβ T cells. The direct inhibitory effects on intracellular mycobacteria were measured, and the enhancing effects on proliferative and effector responses of αβ T cells assessed. Furthermore, the importance of cell-to-cell contact and soluble products for γ9δ2T cell effector responses and APC functions were investigated. We demonstrate, in addition to direct inhibitory effects on intracellular mycobacteria, the following: (i) γ9δ2T cells enhance the expansion ofM. tuberculosis-specific αβ T cells and increase the ability of αβ T cells to inhibit intracellular mycobacteria; (ii) although soluble mediators are critical for the direct inhibitory effects of γ9δ2T cells, their APC functions do not require soluble mediators; (iii) the APC functions of γ9δ2T cells involve cell-to-cell contact that is dependent on CD40-CD40 ligand (CD40L) interactions; and (iv) fully activated CD4+αβ T cells and γ9δ2T cells provide similar immune enhancing/APC functions forM. tuberculosis-specific T cells. These effector and helper effects of γ9δ2T cells further indicate that these T cells should be considered important new targets for new TB vaccines.
Mycobacterium tuberculosis Coinfection Has No Impact on Plasmodium berghei ANKA-Induced Experimental Cerebral Malaria in C57BL/6 Mice
Authors: Blank Jannike , Behrends Jochen , Jacobs Thomas , Schneider Bianca E. 
Published: December 2015

ABSTRACTCerebral malaria (CM) is the most severe complication of human infection withPlasmodium falciparum. The mechanisms predisposing to CM are still not fully understood. Proinflammatory immune responses are required for the control of blood-stage malaria infection but are also implicated in the pathogenesis of CM. A fine balance between pro- and anti-inflammatory immune responses is required for parasite clearance without the induction of host pathology. The most accepted experimental model to study human CM isPlasmodium bergheiANKA (PbANKA) infection in C57BL/6 mice that leads to the development of a complex neurological syndrome which shares many characteristics with the human disease. We applied this model to study the outcome ofPbANKA infection in mice previously infected withMycobacterium tuberculosis, the causative agent of tuberculosis. Tuberculosis is coendemic with malaria in large regions in the tropics, and mycobacteria have been reported to confer some degree of unspecific protection against rodentPlasmodiumparasites in experimental coinfection models. We found that concomitantM. tuberculosisinfection did not change the clinical course ofPbANKA-induced experimental cerebral malaria (ECM) in C57BL/6 mice. The immunological environments in spleen and brain did not differ between singly infected and coinfected animals; instead, the overall cytokine and T cell responses in coinfected mice were comparable to those in animals solely infected withPbANKA. Our data suggest thatM. tuberculosiscoinfection is not able to change the outcome ofPbANKA-induced disease, most likely because the inflammatory response induced by the parasite rapidly dominates in mice previously infected withM. tuberculosis.
Nonredundant Roles of Iron Acquisition Systems in Vibrio cholerae
Authors: Peng Eric D. , Wyckoff Elizabeth E. , Mey Alexandra R. , Fisher Carolyn R. , Payne Shelley M. 
Published: December 2015

ABSTRACT

Vibrio cholerae
, the causative agent of the severe diarrheal disease cholera, thrives in both marine environments and the human host. To do so, it must encode the tools necessary to acquire essential nutrients, including iron, under these vastly different conditions. A number of
V. cholerae
iron acquisition systems have been identified; however, the precise role of each system is not fully understood. To test the roles of individual systems, we generated a series of mutants in which only one of the four systems that support iron acquisition on unsupplemented LB agar, Feo, Fbp, Vct, and Vib, remains functional. Analysis of these mutants under different growth conditions showed that these systems are not redundant. The strain carrying only the ferrous iron transporter Feo grew well at acidic, but not alkaline, pH, whereas the ferric iron transporter Fbp promoted better growth at alkaline than at acidic pH. A strain defective in all four systems (null mutant) had a severe growth defect under aerobic conditions but accumulated iron and grew as well as the wild type in the absence of oxygen, suggesting the presence of an additional, unidentified iron transporter in
V. cholerae
. In support of this, the null mutant was only moderately attenuated in an infant mouse model of infection. While the null mutant used heme as an iron source
in vitro
, we demonstrate that heme is not available to
V. cholerae
in the infant mouse intestine.
Antisocial
luxO
Mutants Provide a Stationary-Phase Survival Advantage in Vibrio fischeri ES114
Authors: Kimbrough John H. , Stabb Eric V. 
Published: December 2015

ABSTRACT

The squid light organ symbiont
Vibrio fischeri
controls bioluminescence using two acyl-homoserine lactone pheromone-signaling (PS) systems. The first of these systems to be activated during host colonization, AinS/AinR, produces and responds to
N
-octanoyl homoserine lactone (C
8
-AHL). We screened activity of a P

ainS

-
lacZ
transcriptional reporter in a transposon mutant library and found three mutants with decreased reporter activity, low C
8
-AHL output, and other traits consistent with low
ainS
expression. However, the transposon insertions were unrelated to these phenotypes, and genome resequencing revealed that each mutant had a distinct point mutation in
luxO
. In the wild type, LuxO is phosphorylated by LuxU and then activates transcription of the small RNA (sRNA) Qrr, which represses
ainS
indirectly by repressing its activator LitR. The
luxO
mutants identified here encode LuxU-independent, constitutively active LuxO* proteins. The repeated appearance of these
luxO
mutants suggested that they had some fitness advantage during construction and/or storage of the transposon mutant library, and we found that
luxO
* mutants survived better and outcompeted the wild type in prolonged stationary-phase cultures. From such cultures we isolated additional
luxO
* mutants. In all, we isolated LuxO* allelic variants with the mutations P41L, A91D, F94C, P98L, P98Q, V106A, V106G, T107R, V108G, R114P, L205F, H319R, H324R, and T335I. Based on the current model of the
V. fischeri
PS circuit,
litR
knockout mutants should resemble
luxO
* mutants; however,
luxO
* mutants outcompeted
litR
mutants in prolonged culture and had much poorer host colonization competitiveness than is reported for
litR
mutants, illustrating additional complexities in this regulatory circuit.

IMPORTANCE
Our results provide novel insight into the function of LuxO, which is a key component of pheromone signaling (PS) cascades in several members of the
Vibrionaceae
. Our results also contribute to an increasingly appreciated aspect of bacterial behavior and evolution whereby mutants that do not respond to a signal from like cells have a selective advantage. In this case, although “antisocial” mutants locked in the PS signal-off mode can outcompete parents, their survival advantage does not require wild-type cells to exploit. Finally, this work strikes a note of caution for those conducting or interpreting experiments in
V. fischeri
, as it illustrates how pleiotropic mutants could easily and inadvertently be enriched in this bacterium during prolonged culturing.
Statistical Characteristic of Heavy Rainfall Associated with Typhoons near Taiwan Based on High-Density Automatic Rain Gauge Data
Authors: Wu Chun-Chieh , Yen Tzu-Hsiung , Huang Yi-Hsuan , Yu Cheng-Ku , Chen Shin-Gan 
Published: December 2015

Abstract
This study utilizes data compiled over 21 years (1993–2013) from the Central Weather Bureau of Taiwan to investigate the statistical characteristics of typhoon-induced rainfall for 53 typhoons that have impacted Taiwan. In this work the data are grouped into two datasets: one includes 21 selected conventional weather stations (referred to as Con-ST), and the other contains all the available rain gauges (250–500 gauges, mostly automatic ones; referred to as All-ST). The primary aim of this study is to understand the potential impacts of the different gauge distributions between All-ST and Con-ST on the statistical characteristics of typhoon-induced rainfall. The analyses indicate that although the average rainfall amount calculated with Con-ST is statistically similar to that with All-ST, the former cannot identify the precipitation extremes and rainfall distribution appropriately, especially in mountainous areas. Because very few conventional stations are located over the mountainous regions, the cumulative frequency obtained solely from Con-ST is not representative. As compared to the results from All-ST, the extreme rainfall assessed from Con-ST is, on average, underestimated by 23%–44% for typhoons approaching different portions of Taiwan. The uneven distribution of Con-ST, with only three stations located in the mountains higher than 1000 m, is likely to cause significant biases in the interpretation of rainfall patterns. This study illustrates the importance of the increase in the number of available stations in assessing the long-term rainfall characteristic of typhoon-associated heavy rainfall in Taiwan.
Characteristics of Long-Term Climate Change and the Ecological Responses in Central China
Authors: Lin Aiwen , Zhu Hongji , Wang Lunche , Gong Wei , Zou Ling 
Published: December 2015

AbstractMeasurements of air temperature and precipitation at 35 stations in Hubei Province, China, during 1962–2011 are used to investigate the regional climate change. There is an increasing trend for observed air temperature (0.23°C decade−1), which is slightly higher than that from multiple model simulations/predictions [phase 5 of CMIP (CMIP5) datasets] (0.16°C decade−1). The observed precipitation increases at the rate of 11.4 mm decade−1, while the CMIP5 results indicate a much lower decreasing trend (0.8 mm decade−1) in this region. To examine the ecological responses to the climate changes in Hubei Province, annual gross primary productivity (GPP) and net primary productivity (NPP) products during 2000–10 and leaf area index (LAI) products during 1981–2011 are also analyzed. It is discovered that GPP, NPP, and LAI increase at the rate of 1.8 TgC yr−1 yr−1, 1.1 TgC yr−1 yr−1, and 0.14 m2 m−2 decade−1, respectively. A linear model is further used to conduct the correlation analyses between climatic parameters (i.e., air temperature and precipitation) and ecological indicators (i.e., GPP, NPP, and LAI). The results indicate that the air temperature has a significant positive correlation with LAI (R2 = 0.311) and GPP (R2 = 0.189); precipitation is positively correlated with NPP (R2 = 0.209). Thus, it is concluded that the air temperature exerts a stronger effect on the ecosystem than precipitation in Hubei Province over the past decades.
Empirical Relationships of Sea Surface Temperature and Vegetation Activity with Summer Rainfall Variability over the Sahel*
Authors: He Yaqian , Lee Eungul 
Published: December 2015

Abstract
Regional land surface and remote ocean variables have been considered as primary forcings altering the variability of summer rainfall over the Sahel. However, previous studies usually examined the two components separately. In this study, the authors apply statistical methods including correlation, multivariate linear regression, and Granger causality analyses to investigate the relative roles of spring–summer sea surface temperature (SST) and vegetation activity in explaining the Sahel summer rainfall variability from 1982 to 2006. The remotely sensed normalized difference vegetation index (NDVI) is used as an indicator of land surface forcing. This study shows that spring and summer SSTs over the subtropical North Atlantic have significant positive correlations with summer rainfall. The spring and summer NDVIs over the Sahel have significant negative and positive correlations, respectively, with summer rainfall. Based on the multivariate linear regression analysis, the adjusted R2 for the integrated model with both the land and ocean variables is 0.70. It is around 2 times larger than the model with SST alone (adjusted R2 = 0.36). To further investigate the causal relationships of summer rainfall with the SST and NDVI variables selected in the integrated multivariate model, the authors perform a Granger causality test. This study finds that summer NDVI over the Sahel does Granger cause summer rainfall over the Sahel, while the summer SST over the subtropical North Atlantic does not Granger cause the summer rainfall. The results indicate that the regional land surface forcing has a relatively strong contribution to Sahel summer rainfall, compared to the remote ocean forcing, during the recent decades.
Variability in Severe Coastal Flooding, Associated Storms, and Death Tolls in Southeastern Australia since the Mid–Nineteenth Century
Authors: Power Scott B. , Callaghan Jeff 
Published: December 2015

AbstractThe variability in the number of severe floods that occurred in coastal catchments in southeastern Australia since the mid–nineteenth century, along with the variability in both the frequency of the weather types that triggered the floods and the associated death tolls, is analyzed. Previous research has shown that all of the severe floods identified were associated with one of two major weather types: east coast lows (ECLs) and tropical interactions (TIs). El Niño–Southern Oscillation (ENSO) is shown to strongly modulate the frequency of severe coastal flooding, weather types, and the number of associated deaths. The analysis presented herein, which examines links over more than a century, provides one of very few known statistically significant links between ENSO and death tolls anywhere in the world. Over the period 1876/77–2013/14 the average numbers of coastal floods, ECLs, TIs, and deaths associated with freshwater drowning in La Niña years are 92%, 55%, 150%, and 220% higher than the corresponding averages in El Niño years. The average number of deaths per flood in La Niña years is 3.2, which is 66% higher than the average in El Niño years. Death tolls of 10 or more occurred in only 5% of El Niño years, but in 27% of La Niña years. The interdecadal Pacific oscillation also modulates the frequency of severe floods, weather types, and death tolls. The results of this study are consistent with earlier research over shorter periods and broader regions, using less-complete datasets.