bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of critical functional determinants of kainate receptor modulation by auxiliary protein Neto2
Authors: Griffith Theanne N. , Swanson Geoffrey T. 
Published: August 2015

Key points
Kainate receptors (KARs) are ionotropic glutamate receptors (iGluRs) that modulate synaptic transmission and intrinsic neuronal excitability.
KARs associate with the auxiliary proteins neuropilin‐ and tolloid‐like 1 and 2 (Neto1 and Neto2), which act as allosteric modulators of receptor function impacting all biophysical properties of these receptors studied to date.
M3–S2 linkers play a critical role in KAR gating; we found that individual residues in these linkers bidirectionally influence Neto2 modulation of KAR desensitization in an agonist specific manner.
We also identify the D1 dimer interface as a novel site of Neto2 modulation and functionally correlate the actions of Neto2 modulation of desensitization with modulation of cation sensitivity.
We identify these domains as determinants of Neto2 modulation. Thus, our work contributes to the understanding of auxiliary subunit modulation of KAR function and could aid the development of KAR‐specific modulators to alter receptor function.
AbstractKainate receptors (KARs) are important modulators of synaptic transmission and intrinsic neuronal excitability in the CNS. Their activity is shaped by the auxiliary proteins Neto1 and Neto2, which impact KAR gating in a receptor subunit‐ and Neto isoform‐specific manner. The structural basis for Neto modulation of KAR gating is unknown. Here we identify the M3–S2 gating linker as a critical determinant contributing to Neto2 modulation of KARs. M3–S2 linkers control both the valence and magnitude of Neto2 modulation of homomeric GluK2 receptors. Furthermore, a single mutation in this domain abolishes Neto2 modulation of heteromeric receptor desensitization. Additionally, we found that cation sensitivity of KAR gating is altered by Neto2 association, suggesting that stability of the D1 dimer interface in the ligand‐binding domain (LBD) is an important determinant of Neto2 actions. Moreover, modulation of cation sensitivity was eliminated by mutations in the M3–S2 linkers, thereby correlating the action of Neto2 at these structurally discrete sites on receptor subunits. These results demonstrate that the KAR M3–S2 linkers and LBD dimer interface are critical determinants for Neto2 modulation of receptor function and identify these domains as potential sites of action for the targeted development of KAR‐specific modulators that alter the function of auxiliary proteins in native receptors.
Outbreak Caused by Enterobacteriaceae Harboring NDM-1 Metallo-β-Lactamase Carried in an IncFII Plasmid in a Tertiary Care Hospital in Mexico City
Authors: Torres-González Pedro , Bobadilla-del Valle Miriam , Tovar-Calderón Estrella , Leal-Vega Francisco , Hernández-Cruz Araceli , Martínez-Gamboa Areli , Niembro-Ortega María Dolores , Sifuentes-Osornio José , Ponce-de-León Alfredo 
Published: August 2015

ABSTRACT

Carbapenem-resistant
Enterobacteriaceae
carrying New Delhi metallo-β-lactamase 1 (NDM-1) have rarely been reported in Latin America. We report of an outbreak caused by a
bla
NDM-1
-harboring plasmid spread through different bacterial species, including
Escherichia coli
(ST617) and
Enterobacter cloacae
(ST182) isolates from the same patient and three
Klebsiella pneumoniae
isolates (ST22) derived from three epidemiologically related patients. IncFII plasmids were found in all strains. Measures to control the outbreak were applied successfully.
Targeting the Parasite's DNA with Methyltriazenyl Purine Analogs Is a Safe, Selective, and Efficacious Antitrypanosomal Strategy
Authors: Rodenko Boris , Wanner Martin J. , Alkhaldi Abdulsalam A. M. , Ebiloma Godwin U. , Barnes Rebecca L. , Kaiser Marcel , Brun Reto , McCulloch Richard , Koomen Gerrit-Jan , de Koning Harry P. 
Published: August 2015

ABSTRACT

The human and veterinary disease complex known as African trypanosomiasis continues to inflict significant global morbidity, mortality, and economic hardship. Drug resistance and toxic side effects of old drugs call for novel and unorthodox strategies for new and safe treatment options. We designed methyltriazenyl purine prodrugs to be rapidly and selectively internalized by the parasite, after which they disintegrate into a nontoxic and naturally occurring purine nucleobase, a simple triazene-stabilizing group, and the active toxin: a methyldiazonium cation capable of damaging DNA by alkylation. We identified 2-(3-acetyl-3-methyltriazen-1-yl)-6-hydroxypurine (compound 1) as a new lead compound, which showed submicromolar potency against
Trypanosoma brucei
, with a selectivity index of >500, and it demonstrated a curative effect in animal models of acute trypanosomiasis. We investigated the mechanism of action of this lead compound and showed that this molecule has significantly higher affinity for parasites over mammalian nucleobase transporters, and it does not show cross-resistance with current first-line drugs. Once selectively accumulated inside the parasite, the prodrug releases a DNA-damaging methyldiazonium cation. We propose that ensuing futile cycles of attempted mismatch repair then lead to G
2
/M phase arrest and eventually cell death, as evidenced by the reduced efficacy of this purine analog against a mismatch repair-deficient (
MSH2
−/−
) trypanosome cell line. The observed absence of genotoxicity, hepatotoxicity, and cytotoxicity against mammalian cells revitalizes the idea of pursuing parasite-selective DNA alkylators as a safe chemotherapeutic option for the treatment of human and animal trypanosomiasis.
Phospholipase A1 Modulates the Cell Envelope Phospholipid Content of Brucella melitensis, Contributing to Polymyxin Resistance and Pathogenicity
Authors: Kerrinnes Tobias , Young Briana M. , Leon Carlos , Roux Christelle M. , Tran Lisa , Atluri Vidya L. , Winter Maria G. , Tsolis Renée M. 
Published: August 2015

ABSTRACT

A subset of bacterial pathogens, including the zoonotic
Brucella
species, are highly resistant against polymyxin antibiotics. Bacterial polymyxin resistance has been attributed primarily to the modification of lipopolysaccharide; however, it is unknown what additional mechanisms mediate high-level resistance against this class of drugs. This work identified a role for the
Brucella melitensis
gene
bveA
(
BMEII0681
), encoding a predicted esterase, in the resistance of
B. melitensis
to polymyxin B. Characterization of the enzymatic activity of BveA demonstrated that it is a phospholipase A1 with specificity for phosphatidylethanolamine (PE). Further, lipidomic analysis of
B. melitensis
revealed an excess of PE lipids in the bacterial membranes isolated from the
bveA
mutant. These results suggest that by lowering the PE content of the cell envelope, BveA increases the resistance of
B. melitensis
to polymyxin B. BveA was required for survival and replication of
B. melitensis
in macrophages and for persistent infection in mice. BveA family esterases are encoded in the genomes of the alphaproteobacterial species that coexist with the polymyxin-producing bacteria in the rhizosphere, suggesting that maintenance of a low PE content in the bacterial cell envelope may be a shared persistence strategy for association with plant and mammalian hosts.
Population Pharmacokinetics of Peramivir in Healthy Volunteers and Influenza Patients
Authors: Matsuo Yumiko , Ishibashi Toru , Hollister Alan S. , Wajima Toshihiro 
Published: August 2015

ABSTRACT
Peramivir is an intravenous anti-influenza agent that inhibits viral growth by selectively inhibiting neuraminidase in human influenza A and B viruses. To characterize its pharmacokinetics, a population pharmacokinetic analysis of peramivir was performed using 3,199 plasma concentration data samples from 332 subjects in six clinical studies in Japan and the United States, including studies with renal impairment subjects, elderly subjects, and influenza patients. A three-compartment model well described the plasma concentration data for peramivir, and creatinine clearance was found to be the most important factor influencing clearance. Age and body weight were also found to be covariates for clearance and the volume of distribution, respectively. No difference in pharmacokinetics was found between genders or between Japanese and U.S. subjects. Small differences in pharmacokinetics were observed between uninfected subjects and influenza patients (clearance was 18% higher and the volume of distribution was 6% lower in influenza patients). Monte Carlo simulations indicated that single adjusted doses of 1/3- and 1/6-fold for patients with moderate and severe renal impairment, respectively, would give areas under the curve comparable to those for patients with normal renal function. The population pharmacokinetic model developed for peramivir should be useful for understanding its pharmacokinetic characteristics and for dose adjustment on the basis of renal function.
Investigating Clinically Adequate Concentrations of Oseltamivir Carboxylate in End-Stage Renal Disease Patients Undergoing Hemodialysis Using a Population Pharmacokinetic Approach
Authors: Kamal Mohamed A. , Lien Kayla Yi Ting , Robson Richard , Subramoney Vishak , Clinch Barry , Rayner Craig R. , Gibiansky Leonid 
Published: August 2015

ABSTRACT
End-stage renal disease (ESRD) patients receiving hemodialysis (HD) are at heightened risk for influenza, but the optimal oseltamivir dosage regimen for treating or preventing influenza in this high-risk population is still uncertain. Pharmacokinetic data for 24 adults with ESRD were pooled from a single-dose and a multiple-dose study to develop a population pharmacokinetic model using nonlinear mixed-effects modeling. The final model comprised five compartments, two each to describe the systemic pharmacokinetics of oseltamivir phosphate and its metabolite, oseltamivir carboxylate (OC), and a delay compartment to describe oseltamivir metabolism. Estimated OC clearance in the model was markedly faster during HD sessions (7.43 liters/min) than at other times (0.19 liter/min). Model simulations showed that 30 mg oseltamivir given after every HD session is the most suitable regimen for influenza treatment, producing trough OC concentrations above the median value achieved with the 75-mg twice-daily regimen in patients with normal renal function and peak concentrations below the highest oseltamivir exposures known to be well tolerated (median exposures after twice-daily dosing of 450 mg). Administration of the first dose following diagnosis of influenza need not wait until after the next HD session: addition of a single 30-mg dose during the 12 h before the next HD session raises OC exposures quickly without posing any safety risk. Further simulation showed that 30 mg oseltamivir given after every other HD session is the most suitable regimen for influenza prophylaxis.
Population Pharmacokinetic Analysis of Isoniazid, Acetylisoniazid, and Isonicotinic Acid in Healthy Volunteers
Authors: Seng Kok-Yong , Hee Kim-Hor , Soon Gaik-Hong , Chew Nicholas , Khoo Saye H. , Lee Lawrence Soon-U 
Published: August 2015

ABSTRACT

In this study, we aimed to quantify the effects of the
N
-acetyltransferase 2 (NAT2) phenotype on isoniazid (INH) metabolism
in vivo
and identify other sources of pharmacokinetic variability following single-dose administration in healthy Asian adults. The concentrations of INH and its metabolites acetylisoniazid (AcINH) and isonicotinic acid (INA) in plasma were evaluated in 33 healthy Asians who were also given efavirenz and rifampin. The pharmacokinetics of INH, AcINH, and INA were analyzed using nonlinear mixed-effects modeling (NONMEM) to estimate the population pharmacokinetic parameters and evaluate the relationships between the parameters and the elimination status (fast, intermediate, and slow acetylators), demographic status, and measures of renal and hepatic function. A two-compartment model with first-order absorption best described the INH pharmacokinetics. AcINH and INA data were best described by a two- and a one-compartment model, respectively, linked to the INH model. In the final model for INH, the derived metabolic phenotypes for NAT2 were identified as a significant covariate in the INH clearance, reducing its interindividual variability from 86% to 14%. The INH clearance in fast eliminators was 1.9- and 7.7-fold higher than in intermediate and slow eliminators, respectively (65 versus 35 and 8 liters/h). Creatinine clearance was confirmed as a significant covariate for AcINH clearance. Simulations suggested that the current dosing guidelines (200 mg for 30 to 45 kg and 300 mg for >45 kg) may be suboptimal (3 mg/liter ≤
C
max
≤ 6 mg/liter) irrespective of the acetylator class. The analysis established a model that adequately characterizes INH, AcINH, and INA pharmacokinetics in healthy Asians. Our results refine the NAT2 phenotype-based predictions of the pharmacokinetics for INH.
Multicenter Study of Epidemiological Cutoff Values and Detection of Resistance in Candida spp. to Anidulafungin, Caspofungin, and Micafungin Using the Sensititre YeastOne Colorimetric Method
Authors: Espinel-Ingroff A. , Alvarez-Fernandez M. , Cantón E. , Carver P. L. , Chen S. C.-A. , Eschenauer G. , Getsinger D. L. , Gonzalez G. M. , Govender N. P. , Grancini A. , Hanson K. E. , Kidd S. E. , Klinker K. , Kubin C. J. , Kus J. V. , Lockhart S. R. , Meletiadis J. , Morris A. J. , Pelaez T. , Quindós G. , Rodriguez-Iglesias M. , Sánchez-Reus F. , Shoham S. , Wengenack N. L. , Borrell Solé N. , Echeverria J. , Esperalba J. , Gómez-G. de la Pedrosa E. , García García I. , Linares M. J. , Marco F. , Merino P. , Pemán J. , Pérez del Molino L. , Roselló Mayans E. , Rubio Calvo C. , Ruiz Pérez de Pipaon M. , Yagüe G. , Garcia-Effron G. , Guinea J. , Perlin D. S. , Sanguinetti M. , Shields R. , Turnidge J. 
Published: August 2015

ABSTRACTNeither breakpoints (BPs) nor epidemiological cutoff values (ECVs) have been established forCandidaspp. with anidulafungin, caspofungin, and micafungin when using the Sensititre YeastOne (SYO) broth dilution colorimetric method. In addition, reference caspofungin MICs have so far proven to be unreliable.Candidaspecies wild-type (WT) MIC distributions (for microorganisms in a species/drug combination with no detectable phenotypic resistance) were established for 6,007Candida albicans, 186C. dubliniensis, 3,188C. glabratacomplex, 119C. guilliermondii, 493C. krusei, 205C. lusitaniae, 3,136C. parapsilosiscomplex, and 1,016C. tropicalisisolates. SYO MIC data gathered from 38 laboratories in Australia, Canada, Europe, Mexico, New Zealand, South Africa, and the United States were pooled to statistically define SYO ECVs. ECVs for anidulafungin, caspofungin, and micafungin encompassing ≥97.5% of the statistically modeled population were, respectively, 0.12, 0.25, and 0.06 μg/ml forC. albicans, 0.12, 0.25, and 0.03 μg/ml forC. glabratacomplex, 4, 2, and 4 μg/ml forC. parapsilosiscomplex, 0.5, 0.25, and 0.06 μg/ml forC. tropicalis, 0.25, 1, and 0.25 μg/ml forC. krusei, 0.25, 1, and 0.12 μg/ml forC. lusitaniae, 4, 2, and 2 μg/ml forC. guilliermondii, and 0.25, 0.25, and 0.12 μg/ml forC. dubliniensis. Species-specific SYO ECVs for anidulafungin, caspofungin, and micafungin correctly classified 72 (88.9%), 74 (91.4%), 76 (93.8%), respectively, of 81Candidaisolates with identifiedfksmutations. SYO ECVs may aid in detecting non-WT isolates with reduced susceptibility to anidulafungin, micafungin, and especially caspofungin, since testing the susceptibilities ofCandidaspp. to caspofungin by reference methodologies is not recommended.
Case-Control Study and Case Series of Pseudohyperphosphatemia during Exposure to Liposomal Amphotericin B
Authors: Bohm Nicole M. , Hoover Katherine C. , Wahlquist Amy E. , Zhu Yusheng , Velez Juan Carlos Q. 
Published: August 2015

ABSTRACT

Pseudohyperphosphatemia due to an interaction between liposomal amphotericin B and the Beckman Coulter PHOSm assay occurs sporadically and remains underrecognized in clinical practice. This retrospective case-control study compares the incidences of hyperphosphatemia in adult inpatients exposed to liposomal amphotericin B or a triazole. A case series of patients with confirmed pseudohyperphosphatemia is described. A total of 80 exposures to liposomal amphotericin B and 726 exposures to triazoles were identified. Among subjects without chronic kidney disease and no concomitant acute kidney injury, hyperphosphatemia occurred more often during liposomal amphotericin B therapy than during triazole therapy (40% [14/35 cases] versus 10% [47/475 cases] of cases;
P
< 0.01; adjusted odds ratio, 5.2 [95% confidence interval {CI}, 2.3 to 11.9]). Among individuals with chronic kidney disease and no concomitant acute kidney injury, hyperphosphatemia also occurred more often during liposomal amphotericin B exposure (59% [10/17 cases] versus 20% [34/172 cases] of cases;
P
< 0.01; adjusted odds ratio, 6.0 [95% CI, 2.0 to 18.0]). When acute kidney injury occurred during antifungal exposure, the frequencies of hyperphosphatemia were not different between treatments. Seven episodes of unexpected hyperphosphatemia during liposomal amphotericin B exposure prompted a confirmatory test using an endpoint-based assay that found lower serum phosphorus levels (median difference of 2.5 mg/dl [range, 0.6 to 3.6 mg/dl]). Liposomal amphotericin B exposure confers a higher likelihood of developing hyperphosphatemia than that with exposure to a triazole antifungal, which is likely attributable to pseudohyperphosphatemia. Elevated phosphorus levels in patients receiving liposomal amphotericin B at institutions using the Beckman Coulter PHOSm assay should be interpreted cautiously.
Emtricitabine Seminal Plasma and Blood Plasma Population Pharmacokinetics in HIV-Infected Men in the EVARIST ANRS-EP 49 Study
Authors: Valade Elodie , Tréluyer Jean-Marc , Illamola Silvia M. , Bouazza Naïm , Foissac Frantz , De Sousa Mendes Maïlys , Lui Gabrielle , Chenevier-Gobeaux Camille , Suzan-Monti Marie , Rouzioux Christine , Assoumou Lambert , Viard Jean-Paul , Hirt Déborah , Urien Saïk , Ghosn Jade 
Published: August 2015

ABSTRACT

We aimed to describe blood plasma (BP) and seminal plasma (SP) pharmacokinetics of emtricitabine (FTC) in HIV-1-infected men, assess its penetration in the male genital tract, and evaluate its impact on seminal plasma HIV load (spVL) detection. Men from the EVARIST ANRS EP49 study receiving combined antiretroviral therapy with FTC and with suppressed BP viral load were included in the study. A total of 236 and 209 FTC BP and SP concentrations, respectively, were available. A population pharmacokinetic model was developed with Monolix 4.1.4. The impact of FTC seminal exposure on spVL detection was explored by receiver operating characteristic (ROC) curves and mixed-effects logistic regressions. FTC BP pharmacokinetics was described by a two-compartment model. The addition of an effect compartment with different input and output constants best described FTC SP pharmacokinetics. No covariates were found to explain the variability in SP. FTC exposures (area under the concentration-time curve from 0 to 24 h [AUC
0–24
]) were higher in SP than in BP (median AUC
0–24
, 38.04 and 12.95 mg · liter
−1
· h, respectively). The median (range) SP-to-BP AUC
0–24
ratio was 2.91 (0.84 to 10.08). Less than 1% of FTC AUC
0–24
ratios were lower than 1. The impact of FTC SP AUC
0–24
or FTC SP-to-BP AUC
0–24
ratio on spVL detection was not significant (
P
= 0.943 or 0.893, respectively). This is the first population model describing FTC pharmacokinetics simultaneously in both BP and SP. FTC distributes well in the male genital tract with higher FTC concentrations in SP than in BP. FTC seminal plasma exposures were considered efficient in the majority of men.
Ceftolozane-Tazobactam Activity against Phylogenetically Diverse Clostridium difficile Strains
Authors: Gonzalez Mark D. , Wallace Meghan A. , Hink Tiffany , Dubberke Erik R. , Burnham Carey-Ann D. 
Published: August 2015

ABSTRACT

Ceftolozane-tazobactam (C/T) is approved for the treatment of complicated intra-abdominal and urinary tract infections and has varied activity against anaerobic bacteria. Here, we evaluate the activity of C/T against a phylogenetically diverse collection of
Clostridium difficile
isolates and report uniformly high MICs (≥256 μg/ml) to C/T.
Conservation of the Host-Interacting Proteins Tp0750 and Pallilysin among Treponemes and Restriction of Proteolytic Capacity to Treponema pallidum
Authors: Houston Simon , Taylor John S. , Denchev Yavor , Hof Rebecca , Zuerner Richard L. , Cameron Caroline E. 
Published: August 2015

ABSTRACT

The spirochete
Treponema pallidum
subsp.
pallidum
is the causative agent of syphilis, a chronic, sexually transmitted infection characterized by multiple symptomatic and asymptomatic stages. Although several other species in the genus are able to cause or contribute to disease,
T. pallidum
differs in that it is able to rapidly disseminate via the bloodstream to tissue sites distant from the site of initial infection. It is also the only
Treponema
species able to cross both the blood-brain and placental barriers. Previously, the
T. pallidum
proteins, Tp0750 and Tp0751 (also called pallilysin), were shown to degrade host proteins central to blood coagulation and basement membrane integrity, suggesting a role for these proteins in
T. pallidum
dissemination and tissue invasion. In the present study, we characterized Tp0750 and Tp0751 sequence variation in a diversity of pathogenic and nonpathogenic treponemes. We also determined the proteolytic potential of the orthologs from the less invasive species
Treponema denticola
and
Treponema phagedenis
. These analyses showed high levels of sequence similarity among Tp0750 orthologs from pathogenic species. For pallilysin, lower levels of sequence conservation were observed between this protein and orthologs from other treponemes, except for the ortholog from the highly invasive rabbit venereal syphilis-causing
Treponema paraluiscuniculi
.
In vitro
host component binding and degradation assays demonstrated that pallilysin and Tp0750 orthologs from the less invasive treponemes tested were not capable of binding or degrading host proteins. The results show that pallilysin and Tp0750 host protein binding and degradative capability is positively correlated with treponemal invasiveness.