bluuebunny/crossref_metadata_2025_split huggingface dataset:
Systematic Review and Meta-analysis of the Pharmacokinetics of Benznidazole in the Treatment of Chagas Disease
Authors: Wiens Matthew O. , Kanters Steve , Mills Edward , Peregrina Lucano Alejandro A. , Gold Silvia , Ayers Dieter , Ferrero Luis , Krolewiecki Alejandro 
Published: August 2016

ABSTRACT

Chagas disease is a neglected parasitic illness affecting approximately 8 million people, predominantly in Latin America. Benznidazole is the drug of choice for treatment, although its availability has been limited. A paucity of knowledge of the pharmacokinetic properties of this drug has contributed to its limited availability in several jurisdictions. The objective of this study was to conduct a systematic literature review and a Bayesian meta-analysis of pharmacokinetic studies to improve estimates of the basic pharmacokinetic properties of benznidazole. A systematic search of the Embase, Medline, LILACS, and SciELO (Scientific Electronic Library Online) databases was conducted. Eligible studies reported patient-level data from single-100-mg-dose pharmacokinetic evaluations of benznidazole in adults or otherwise provided data relevant to the estimation of pharmacokinetic parameters which could be derived from such studies. A Bayesian hierarchical model was used for analysis. Secondary data (i.e., data from studies that did not include patient-level, single-100-mg-dose data) were used for the generation of empirical priors for the Bayesian analysis. The systematic search identified nine studies for inclusion. Nine pharmacokinetic parameters were estimated, including the area under the concentration-time curve (AUC), the maximum concentration of drug in plasma (
C
max
), the time to
C
max
, the elimination rate constant (
k
el
), the absorption rate constant (

K
a

), the absorption and elimination half-lives, the apparent oral clearance, and the apparent oral volume of distribution. The results showed consistency across studies. AUC and
C
max
were 51.31 mg · h/liter (95% credible interval [CrI], 45.01, 60.28 mg · h/liter) and 2.19 mg/liter (95% CrI, 2.06, 2.33 mg/liter), respectively.

K
a

and
k
el
were 1.16 h
−1
(95% CrI, 0.59, 1.76 h
−1
) and 0.052 h
−1
(95% CrI, 0.045, 0.059 h
−1
), respectively, with the corresponding absorption and elimination half-lives being 0.60 h (95% CrI, 0.38, 1.11 h) and 13.27 h (95% CrI, 11.79, 15.42 h), respectively. The oral clearance and volume of distribution were 2.04 liters/h (95% CrI, 1.77, 2.32 liters/h) and 39.19 liters (95% CrI, 36.58, 42.17 liters), respectively. A Bayesian meta-analysis was used to improve the estimates of the standard pharmacokinetic parameters of benznidazole. These data can inform clinicians and policy makers as access to this drug increases.
Rapid Detection of
FKS
-Associated Echinocandin Resistance in Candida glabrata
Authors: Zhao Yanan , Nagasaki Yoji , Kordalewska Milena , Press Ellen G. , Shields Ryan K. , Nguyen M. Hong , Clancy Cornelius J. , Perlin David S. 
Published: August 2016

ABSTRACT

A novel and highly accurate diagnostic assay platform was established for rapid identification of
FKS
mutations associated with echinocandin resistance in
Candida glabrata
. The assay platform uses allele-specific molecular beacon and DNA melt analysis following asymmetric PCR. A dual assay for
FKS1
and
FKS2
was developed to identify within 3 h the most common and clinically relevant resistance-associated mutations, including 8
FKS1
HS1 (wild type [WT], S629P, F625S, D632Y, D632E [T1896G], D632E [T1896A], I634V, and F625F) and 7
FKS2
HS1 (WT, F659del, F659S, F659V, F659L, S663P, and S663F) genotypes. A blinded panel of 188
C. glabrata
clinical isolates was tested by both assays. The molecular diagnostic results from the dual assay were 100% concordant with data obtained from DNA sequencing. This platform has the potential to overcome the deficiencies of existing
in vitro
susceptibility-based assays to identify echinocandin-resistant
C. glabrata
and holds promise as a surrogate diagnostic method to better direct echinocandin therapy.
Gene
bb0318
Is Critical for the Oxidative Stress Response and Infectivity of Borrelia burgdorferi
Authors: Showman Adrienne C. , Aranjuez George , Adams Philip P. , Jewett Mollie W. 
Published: August 2016

ABSTRACT

A greater understanding of the molecular mechanisms that
Borrelia burgdorferi
uses to survive during mammalian infection is critical for the development of novel diagnostic and therapeutic tools to improve the clinical management of Lyme disease. By use of an
in vivo
expression technology (IVET)-based approach to identify
B. burgdorferi
genes expressed
in vivo
, we discovered the
bb0318
gene, which is thought to encode the ATPase component of a putative riboflavin ABC transport system. Riboflavin is a critical metabolite enabling all organisms to maintain redox homeostasis.
B. burgdorferi
appears to lack the metabolic capacity for
de novo
synthesis of riboflavin and so likely relies on scavenging riboflavin from the host environment. In this study, we sought to investigate the role of
bb0318
in
B. burgdorferi
pathogenesis. No
in vitro
growth defect was observed for the Δ
bb0318
clone. However, the mutant spirochetes displayed reduced levels of survival when exposed to exogenous hydrogen peroxide or murine macrophages. Spirochetes lacking
bb0318
were found to have a 100-fold-higher 50% infectious dose than spirochetes containing
bb0318
. In addition, at a high inoculum dose,
bb0318
was found to be important for effective spirochete dissemination to deep tissues for as long as 3 weeks postinoculation and to be critical for
B. burgdorferi
infection of mouse hearts. Together, these data implicate
bb0318
in the oxidative stress response of
B. burgdorferi
and indicate the contribution of
bb0318
to
B. burgdorferi
mammalian infectivity.
Vibrio cholerae LeuO Links the ToxR Regulon to Expression of Lipid A Remodeling Genes
Authors: Bina X. Renee , Howard Mondraya F. , Ante Vanessa M. , Bina James E. 
Published: August 2016

ABSTRACT

Vibrio cholerae
is an intestinal pathogen that causes the diarrheal disease cholera. Colonization of the intestine depends upon the expression of genes that allow
V. cholerae
to overcome host barriers, including low pH, bile acids, and the innate immune system. ToxR is a major contributor to this process. ToxR is a membrane-spanning transcription factor that coordinates gene expression in response to environmental cues. In previous work we showed that ToxR upregulated
leuO
expression in response to bile salts. LeuO is a LysR family transcription factor that contributes to acid tolerance, bile resistance, and biofilm formation in
V. cholerae
. Here, we investigated the function of ToxR and LeuO in cationic antimicrobial peptide (CAMP) resistance. We report that ToxR and LeuO contribute to CAMP resistance by regulating
carRS
transcription. CarRS is a two-component regulatory system that positively regulates
almEFG
expression. AlmEFG confers CAMP resistance by glycinylation of lipid A. We found that the expression of
carRS
and
almEFG
and the polymyxin B MIC increased in mutants lacking
toxRS
or
leuO
. Conversely,
leuO
overexpression decreased the polymyxin B MIC. Furthermore, we found that LeuO directly bound to the
carRS
promoter and that ToxR-dependent activation of
leuO
transcription regulated
carRS
transcription in response to bile salts. Our results suggest that LeuO functions downstream of ToxR to modulate
carRS
expression in response to environmental cues. This study extends the functional role of ToxR and LeuO in environmental adaptation to include cell surface remodeling and CAMP resistance.
Impact of LytR-CpsA-Psr Proteins on Cell Wall Biosynthesis in Corynebacterium glutamicum
Authors: Baumgart Meike , Schubert Karin , Bramkamp Marc , Frunzke Julia 
Published: August 2016

ABSTRACTProteins of the LCP (LytR, CpsA, Psr) family have been shown to inherit important roles in bacterial cell wall biosynthesis. However, their exact function in the formation of the complex cell wall structures of theCorynebacteriales, including the prominent pathogensMycobacterium tuberculosisandCorynebacterium diphtheriae, remains unclear. Here, we analyzed the role of the LCP proteins LcpA and LcpB ofCorynebacterium glutamicum, both of which localize at regions of nascent cell wall biosynthesis. A strain lackinglcpBdid not show any growth-related or morphological phenotype under the tested conditions. In contrast, conditional silencing of the essentiallcpAgene resulted in severe growth defects and drastic morphological changes. Compared to the wild-type cell wall, the cell wall of this mutant contained significantly less mycolic acids and a reduced amount of arabinogalactan. In particular, rhamnose, a specific sugar component of the linker that connects arabinogalactan and peptidoglycan, was decreased. Complementation studies of thelcpA-silencing strain with several mutated and truncated LcpA variants suggested that both periplasmic domains are essential for function whereas the cytoplasmic N-terminal part is dispensable. Successful complementation experiments with proteins ofM. tuberculosisandC. diphtheriaerevealed a conserved function of LCP proteins in these species. Finally, pyrophosphatase activity of LcpA was shown in anin vitroassay. Taken together, our results suggest that LCP proteins are responsible for the transfer of arabinogalactan onto peptidoglycan in actinobacterial species and support a crucial function of a so-far-uncharacterized C-terminal domain (LytR_C domain) which is frequently found at the C terminus of the LCP domain in this prokaryotic phylum.IMPORTANCEAbout one-third of the world's population is infected withMycobacterium tuberculosis, and multiple-antibiotic resistance provokes the demand for novel antibiotics. The special cell wall architecture ofCorynebacterialesis critical for treatments because it is either a direct target or a barrier that the drug has to cross. Here, we present the analysis of LcpA and LcpB of the closely relatedCorynebacterium glutamicum, the first of which is an essential protein involved in cell wall biogenesis. Our work provides a comprehensive characterization of the impact of LCP proteins on cell wall biogenesis in this medically and biotechnologically important class of bacteria. Special focus is set on the two periplasmic LcpA domains and their contributions to physiological function.
Circuitry Linking the Catabolite Repression and Csr Global Regulatory Systems of Escherichia coli
Authors: Pannuri Archana , Vakulskas Christopher A. , Zere Tesfalem , McGibbon Louise C. , Edwards Adrianne N. , Georgellis Dimitris , Babitzke Paul , Romeo Tony 
Published: August 2016

ABSTRACT

Cyclic AMP (cAMP) and the cAMP receptor protein (cAMP-CRP) and CsrA are the principal regulators of the catabolite repression and carbon storage global regulatory systems, respectively. cAMP-CRP controls the transcription of genes for carbohydrate metabolism and other processes in response to carbon nutritional status, while CsrA binds to diverse mRNAs and regulates translation, RNA stability, and/or transcription elongation. CsrA also binds to the regulatory small RNAs (sRNAs) CsrB and CsrC, which antagonize its activity. The BarA-UvrY two-component signal transduction system (TCS) directly activates
csrB
and
csrC
(
csrB
/
C
) transcription, while CsrA does so indirectly. We show that cAMP-CRP inhibits
csrB
/
C
transcription without negatively regulating phosphorylated UvrY (P-UvrY) or CsrA levels. A
crp
deletion caused an elevation in CsrB/C levels in the stationary phase of growth and increased the expression of
csrB-lacZ
and
csrC-lacZ
transcriptional fusions, although modest stimulation of CsrB/C turnover by the
crp
deletion partially masked the former effects. DNase I footprinting and other studies demonstrated that cAMP-CRP bound specifically to three sites located upstream from the
csrC
promoter, two of which overlapped the P-UvrY binding site. These two proteins competed for binding at the overlapping sites.
In vitro
transcription-translation experiments confirmed direct repression of
csrC-lacZ
expression by cAMP-CRP. In contrast, cAMP-CRP effects on
csrB
transcription may be mediated indirectly, as it bound nonspecifically to
csrB
DNA. In the reciprocal direction, CsrA bound to
crp
mRNA with high affinity and specificity and yet exhibited only modest, conditional effects on expression. Our findings are incorporated into an emerging model for the response of Csr circuitry to carbon nutritional status.

IMPORTANCE
Csr (Rsm) noncoding small RNAs (sRNAs) CsrB and CsrC of
Escherichia coli
use molecular mimicry to sequester the RNA binding protein CsrA (RsmA) away from lower-affinity mRNA targets, thus eliciting major shifts in the bacterial lifestyle. CsrB/C transcription and turnover are activated by carbon metabolism products (e.g., formate and acetate) and by a preferred carbon source (glucose), respectively. We show that cAMP-CRP, a mediator of classical catabolite repression, inhibits
csrC
transcription by binding to the upstream region of this gene and also inhibits
csrB
transcription, apparently indirectly. We propose that glucose availability activates pathways for both synthesis and turnover of CsrB/C, thus shaping the dynamics of global signaling in response to the nutritional environment by poising CsrB/C sRNA levels for rapid response.
Carotenoid Biosynthetic Pathways Are Regulated by a Network of Multiple Cascades of Alternative Sigma Factors in Azospirillum brasilense Sp7
Authors: Rai Ashutosh Kumar , Dubey Ashutosh Prakash , Kumar Santosh , Dutta Debashis , Mishra Mukti Nath , Singh Bhupendra Narain , Tripathi Anil Kumar 
Published: August 2016

ABSTRACT

Carotenoids constitute an important component of the defense system against photooxidative stress in bacteria. In
Azospirillum brasilense
Sp7, a nonphotosynthetic rhizobacterium, carotenoid synthesis is controlled by a pair of extracytoplasmic function sigma factors (RpoEs) and their cognate zinc-binding anti-sigma factors (ChrRs). Its genome harbors two copies of the gene encoding geranylgeranyl pyrophosphate synthase (CrtE), the first critical step in the carotenoid biosynthetic pathway in bacteria. Inactivation of each of two
crtE
paralogs found in
A. brasilense
caused reduction in carotenoid content, suggesting their involvement in carotenoid synthesis. However, the effect of
crtE1
deletion was more pronounced than that of
crtE2
deletion. Out of the five paralogs of
rpoH
in
A. brasilense
, overexpression of
rpoH1
and
rpoH2
enhanced carotenoid synthesis. Promoters of
crtE2
and
rpoH2
were found to be dependent on RpoH2 and RpoE1, respectively. Using a two-plasmid system in
Escherichia coli
, we have shown that the
crtE2
gene of
A. brasilense
Sp7 is regulated by two cascades of sigma factors: one consisting of RpoE1and RpoH2 and the other consisting of RpoE2 and RpoH1. In addition, expression of
crtE1
was upregulated indirectly by RpoE1 and RpoE2. This study shows, for the first time in any carotenoid-producing bacterium, that the regulation of carotenoid biosynthetic pathway involves a network of multiple cascades of alternative sigma factors.

IMPORTANCE
Carotenoids play a very important role in coping with photooxidative stress in prokaryotes and eukaryotes. Although extracytoplasmic function (ECF) sigma factors are known to directly regulate the expression of carotenoid biosynthetic genes in bacteria, regulation of carotenoid biosynthesis by one or multiple cascades of sigma factors had not been reported. This study provides the first evidence of the involvement of multiple cascades of sigma factors in the regulation of carotenoid synthesis in any bacterium by showing the regulation of a gene encoding geranylgeranyl pyrophosphate synthase (
crtE2
) by RpoE1→RpoH2→CrtE2 and RpoE2→RpoH1→CrtE2 cascades in
A. brasilense
. It also provides an insight into existence of an additional cascade or cascades regulating expression of another paralog of
crtE
.
Predictors of fever-related admissions to a paediatric assessment unit, ward and reattendances in a South London emergency department: the CABIN 2 study
Authors: Bustinduy Amaya L , Chis Ster Irina , Shaw Rebecca , Irwin Adam , Thiagarajan Jaiganesh , Beynon Rhys , Ladhani Shamez , Sharland Mike 
Published: August 2016

ObjectiveTo explore the risk factors for ward and paediatric assessment unit (PAU) admissions from the emergency department (ED).DesignProspective observational study.Setting and patientsFebrile children attending a large tertiary care ED during the winter of 2014–2015.Main outcome measuresWard and PAU admissions, National Institute for Health and Care Excellence (NICE) guidelines classification, reattendance to the ED within 28 days and antibiotic use.ResultsA total of 1097 children attending the children's ED with fever were analysed. Risk factors for PAU admission were tachycardia (RR=1.1, 95% CI (1 to 1.1)), ill-appearance (RR=2.2, 95% CI (1.2 to 4.2)), abnormal chest findings (RR=2.1, 95% CI (1.2 to 4.3)), categorised as NICE amber (RR 1.7 95% CI (1.2 to 2.5)). There was a 30% discordance between NICE categorisation at triage and statistical internal validation. Predictors of ward admission were a systemic (RR=6.9, 95% CI (2.4 to 19.8)) or gastrointestinal illness (RR=3.8, 95% (1.4 to 10.4)) and categorised as NICE Red (RR=5.9, 95% CI (2.2 to 15.3)). Only 51 children had probable bacterial pneumonia (4.6%), 52 children had a proven urinary tract infection (4.2%), with just 2 (0.2%) positive blood cultures out of 485 (44%) children who received an antibiotic. 15% of all children reattended by 28 days and were more likely to have been categorised as Amber and had investigations on initial visit.ConclusionsRisk factors for PAU and ward admissions are different in this setting with high reattendance rates and very low proportion of confirmed/probable serious bacterial infections. Future studies need to focus on reducing avoidable admissions and antibiotic treatment.
First-principles study of zinc-blende BxAlyIn1−x−yN quaternary alloy: Alchemical mixing approximation approach
Authors: Bamgbose M. K. , Adebambo P. O. , Badmus B. S. , Dare E. O. , Akinlami J. O. , Adebayo G. A. 
Published: August 2016

Detailed first-principle calculations of properties in zinc blende quaternary alloy [Formula: see text] at various concentrations are investigated using density functional theory (DFT) within virtual crystal approximation (VCA) implemented in alchemical mixing approximation. The calculated bandgaps show direct transitions at [Formula: see text]–[Formula: see text] and indirect transitions at [Formula: see text]–[Formula: see text], which are opened by increasing boron concentration. The density of state (DOS) revealed upper valence band (VB1) domination by [Formula: see text]-states atoms, while [Formula: see text]-states dominate the lower valence band (VB2); also, the DOS shows the contribution of [Formula: see text]-states to the conduction band. The first critical point in the dielectric constant ranges between 0.07–4.47 eV and is due to the first threshold optical transitions in the energy bandgap. Calculated static dielectric function (DF) [Formula: see text] is between 5.15 and 10.35, an indication that small energy bandgaps yield large static DFs. The present results indicate [Formula: see text]-[Formula: see text] alloys are suitable candidates of deep ultraviolet light emitting diodes (LEDs), laser diodes (LDs) and modern solar cell since the concentrations [Formula: see text] and [Formula: see text] make the bandgap and lattice constant of [Formula: see text]-[Formula: see text] quaternary alloys tunable to desirable values.
Prospects for primordial gravitational waves in string inflation
Authors: Parameswaran Susha L. , Zavala Ivonne 
Published: August 2016

Assuming that the early universe had (i) a description using perturbative string theory and its field theory limit, (ii) an epoch of slow-roll inflation within a four-dimensional effective field theory and a hierarchy of scales [Formula: see text] that keeps the latter under control, we derive an upper bound on the amplitude of primordial gravitational waves. The bound is very sensitive to mild changes in numerical coefficients and the expansion parameters. For example, allowing couplings and mass-squared hierarchies [Formula: see text] implies [Formula: see text], but asking more safely for hierarchies [Formula: see text], the bound becomes [Formula: see text]. Moreover, large volumes — typically used in string models to keep backreaction and moduli stabilization under control — drive [Formula: see text] down. Consequently, any detection of inflationary gravitational waves would present an interesting but difficult challenge for string theory.
Grepafloxacin in Patients with Acute Bacterial Exacerbations of Chronic Bronchitis ‐ a Question of Speed in Bacterial Killing
Authors: Schentag Jerome J 
Published: August 2016

OBJECTIVE: To characterize the population pharmacokinetics and pharmacodynamics of oral grepafloxacin in patients with acute bacterial exacerbations of chronic bronchitis (ABECB), with particular attention to the speed of bacterial killing. This was possible because the study design incorporated daily cultures of the patients’ sputum.PATIENTS AND METHODS: The study group included 76 patients (43 male, 33 female) between 23 and 81 years of age who were part of a multicentre, randomized, double‐blind, dose‐response study. Patients were randomly assigned to receive oral regimens of grepafloxacin ‐ 200, 400 or 600 mg ‐ each administered once daily for 14 days. Daily cultures and quantitative Gram stains from serial 24 h collections of sputum were used to determine the days to eradication of each strain of bacteria. Grepafloxacin plasma concentration profiles were best fit by a pharmacokinetic model with first order absorption following a lag time between administration of the dose and onset of systemic absorption. Pharmacodynamic analysis was performed for three measures of antibacterial response: probability of bacteriological cure and probability of clinical cure, and time to eradication.RESULTS: All three measures of response were strongly related to the 24 h area under the inhibitory curve (AUIC) (area under the curve/minimum inhibitory concentration). At an AUIC below of 75/serum inhibiting titre (SIT) x 24 h, the percentage probability of clinical cure was 71 %; at an AUIC between 75 and 175, it was 80% (P<0.05); and, at an AUTC above 175, it was 98% (P<0.01).CONCLUSION: The speed of bacterial killing for grepafloxacin in ABECB patients was highly related to AUIC; values below 75 appear inadequate, and values greater than 175 were optimal.