bluuebunny/crossref_metadata_2025_split huggingface dataset:
Population Pharmacokinetic Analyses for Rezafungin (CD101) Efficacy Using Phase 1 Data
Authors: Lakota Elizabeth A. , Ong Voon , Flanagan Shawn , Rubino Christopher M. 
Published: March 2018

ABSTRACT

Rezafungin (CD101) is a novel echinocandin antifungal agent currently in clinical development for the treatment of candidemia and invasive candidiasis. Rezafungin has potent
in vitro
activity against
Candida albicans
and
Candida glabrata
, including azole- and echinocandin-resistant isolates. The objective of this analysis was to develop a population pharmacokinetic (PK) model to characterize the disposition of rezafungin in plasma following intravenous (i.v.) administration. Data from two phase 1 studies, a single-ascending-dose study and a multiple-ascending-dose study, were available. Candidate population PK models were fit to the pooled data using the Monte Carlo parametric expectation maximization algorithm in S-ADAPT. The data were best described using a linear four-compartment model with zero-order drug input via i.v. infusion and first-order elimination. In order to account for the relationships between the structural PK parameters and subject body weight, all parameters in the model were scaled to subject body weight using standard allometric coefficients (a power of 0.75 for the clearance terms and 1.0 for the volume terms). The final model fit the observed data with very little bias and excellent precision. The prediction-corrected visual predictive check demonstrated that the final model could accurately simulate both the central tendency and the variability of observed rezafungin plasma concentrations. Given this, the final rezafungin population PK model is expected to provide reliable simulated concentration-time profiles and can provide dose selection decision support for future clinical studies.
Clinical Assessment of a Nocardia PCR-Based Assay for Diagnosis of Nocardiosis
Authors: Rouzaud Claire , Rodriguez-Nava Véronica , Catherinot Emilie , Méchaï Frédéric , Bergeron Emmanuelle , Farfour Eric , Scemla Anne , Poirée Sylvain , Delavaud Christophe , Mathieu Daniel , Durupt Stéphane , Larosa Fabrice , Lengelé Jean-Philippe , Christophe Jean-Louis , Suarez Felipe , Lortholary Olivier , Lebeaux David 
Published: March 2018

ABSTRACT

The diagnosis of nocardiosis, a severe opportunistic infection, is challenging. We assessed the specificity and sensitivity of a 16S rRNA
Nocardia
PCR-based assay performed on clinical samples. In this multicenter study (January 2014 to April 2015), patients who were admitted to three hospitals and had an underlying condition favoring nocardiosis, clinical and radiological signs consistent with nocardiosis, and a
Nocardia
PCR assay result for a clinical sample were included. Patients were classified as negative control (NC) (negative
Nocardia
culture results and proven alternative diagnosis or improvement at 6 months without anti-
Nocardia
treatment), positive control (PC) (positive
Nocardia
culture results), or probable nocardiosis (positive
Nocardia
PCR results, negative
Nocardia
culture results, and no alternative diagnosis). Sixty-eight patients were included; 47 were classified as NC, 8 as PC, and 13 as probable nocardiosis. PCR results were negative for 35/47 NC patients (74%). For the 12 NC patients with positive PCR results, the PCR assay had been performed with respiratory samples. These NC patients had chronic bronchopulmonary disease more frequently than did the NC patients with negative PCR results (8/12 patients [67%] versus 11/35 patients [31%];
P
= 0.044). PCR results were positive for 7/8 PC patients (88%). There were 13 cases of probable nocardiosis, diagnosed solely using the PCR results; 9 of those patients (69%) had lung involvement (consolidation or nodule).
Nocardia
PCR testing had a specificity of 74% and a sensitivity of 88% for the diagnosis of nocardiosis.
Nocardia
PCR testing may be helpful for the diagnosis of nocardiosis in immunocompromised patients but interpretation of PCR results from respiratory samples is difficult, because the PCR assay may also detect colonization.
Monitoring Shedding of Five Genotypes of RotaTeq Vaccine Viruses by Genotype-Specific Real-Time Reverse Transcription-PCR Assays
Authors: Higashimoto Yuki , Ihira Masaru , Miyazaki Yu , Kuboshiki Ayumi , Yoshinaga Sayaka , Hiramatsu Hiroyuki , Suzuki Ryota , Miyata Masafumi , Miura Hiroki , Komoto Satoshi , Yukitake Jun , Taniguchi Koki , Kawamura Yoshiki , Yoshikawa Tetsushi 
Published: March 2018

ABSTRACT
RotaTeq (RV5) is a widely used live attenuated pentavalent rotavirus (RV) vaccine. Although fecal shedding of RV vaccine strains persists for long time periods, it is unclear how each vaccine strain replicates in intestinal tissue and is excreted in stool. To examine this issue, we established RV5 genotype-specific real-time reverse transcription-PCR (RT-PCR) assays. Five real-time RT-PCR assays were designed for the VP7 gene in genotypes G1, G2, G3, G4, and G6. All assays exhibited excellent linearity, and the detection limit was 1 infectious unit (IU)/reaction for G2, G4, and G6 and 10 IUs/reaction for G1 and G3. No cross-reactivity was observed among G genotypes. The inter- and intra-assay coefficients of variation were less than 3%. The assays were used to examine 129 stool samples collected from eight infants who received RV5. In cases 1 and 2, who received three rounds of vaccination, RV shedding decreased gradually with the number of vaccinations. G1 and G6 shedding appeared to be predominant in comparison to shedding of the other genotypes. Patterns of fecal shedding of the five genotypes of vaccine viruses differed between the eight vaccine recipients. RV5 genotype-specific real-time RT-PCR assays will be useful to study the molecular biology of RV5 replication in infants and experimental animals.
TgTKL1 Is a Unique Plant-Like Nuclear Kinase That Plays an Essential Role in Acute Toxoplasmosis
Authors: Varberg Joseph M. , Coppens Isabelle , Arrizabalaga Gustavo , Gaji Rajshekhar Y. 
Published: March 2018

ABSTRACT

In the protozoan parasite
Toxoplasma gondii
, protein kinases have been shown to play key roles in regulating parasite motility, invasion, replication, egress, and survival within the host. The tyrosine kinase-like (TKL) family of proteins are an unexplored set of kinases in
Toxoplasma
. Of the eight annotated TKLs in the
Toxoplasma
genome, a recent genome-wide loss-of-function screen showed that six are important for tachyzoite fitness. By utilizing an endogenous tagging approach, we showed that these six
T. gondii
TKLs (TgTKLs) localize to various subcellular compartments, including the nucleus, the cytosol, the inner membrane complex, and the Golgi apparatus. To gain insight into the function of TKLs in
Toxoplasma
, we first characterized TgTKL1, which contains the plant-like enhanced disease resistance 1 (EDR1) domain and localizes to the nucleus. TgTKL1 knockout parasites displayed significant defects in progression through the lytic cycle; we show that the defects were due to specific impairment of host cell attachment. Transcriptomics analysis identified over 200 genes of diverse functions that were differentially expressed in TgTKL1 knockout parasites. Importantly, numerous genes implicated in host cell attachment and invasion were among those most significantly downregulated, resulting in defects in microneme secretion and processing. Significantly, all of the mice inoculated intraperitoneally with TgTKL1 knockout parasites survived the infection, suggesting that TgTKL1 plays an essential role in acute toxoplasmosis. Together, these findings suggest that TgTKL1 mediates a signaling pathway that regulates the expression of multiple factors required for parasite virulence, underscoring the potential of this kinase as a novel therapeutic target.

IMPORTANCE
Toxoplasma gondii
is a protozoan parasite that can cause chronic and life-threatening disease in mammals; new drugs are greatly needed for treatment. One attractive group of drug targets consists of parasite kinases containing unique features that distinguish them from host proteins. In this report, we identify and characterize a previously unstudied kinase, TgTKL1, that localizes to the nucleus and contains a domain architecture unique to plants and protozoa. By disrupting TgTKL1, we showed that this kinase is required for the proper expression of hundreds of genes, including many that are required for the parasite to gain entry into the host cell. Specifically, parasites lacking TgTKL1 have defects in host cell attachment, resulting in impaired growth
in vitro
and a complete loss of virulence in mice. This report provides insight into the importance of the parasite tyrosine kinase-like kinases and establishes TgTKL1 as a novel and essential virulence factor in
Toxoplasma
.
Hitting with a BAM: Selective Killing by Lectin-Like Bacteriocins
Authors: Ghequire Maarten G. K. , Swings Toon , Michiels Jan , Buchanan Susan K. , De Mot René 
Published: March 2018

ABSTRACT

Lectin-like bacteriocins (LlpAs) are secreted by proteobacteria and selectively kill strains of their own or related species, and they are composed of two B-lectin domains with divergent sequences. In
Pseudomonas
spp., initial binding of these antibacterial proteins to cells is mediated by the carboxy-terminal domain through
d
-rhamnose residues present in the common polysaccharide antigen of their lipopolysaccharide, whereas the amino-terminal domain accounts for strain selectivity of killing. Here, we show that spontaneous LlpA-resistant mutants carry mutations in one of three surface-exposed moieties of the essential β-barrel outer membrane protein insertase BamA, the core component of the BAM complex. Polymorphism of this loop in different
Pseudomonas
groups is linked to LlpA susceptibility, and targeted cells all share the same signature motif in this loop. Since heterologous expression of such a
bamA
gene confers LlpA susceptibility upon a resistant strain, BamA represents the primary bacteriocin selectivity determinant in pseudomonads. Contrary to modular bacteriocins that require uptake via the Tol or Ton system, parasitism of BamA as an LlpA receptor advocates a novel bacteriocin killing mechanism initiated by impairment of the BAM machinery.

IMPORTANCE
Bacteria secrete a variety of molecules to eliminate microbial rivals. Bacteriocins are a pivotal group of peptides and proteins that assist in this fight, specifically killing related bacteria. In Gram-negative bacteria, these antibacterial proteins often comprise distinct domains for initial binding to a target cell’s surface and subsequent killing via enzymatic or pore-forming activity. Here, we show that lectin-like bacteriocins, a family of bacteriocins that lack the prototypical modular toxin architecture, also stand out by parasitizing BamA, the core component of the outer membrane protein assembly machinery. A particular surface-exposed loop of BamA, critical for its function, serves as a key discriminant for cellular recognition, and polymorphisms in this loop determine whether a strain is susceptible or immune to a particular bacteriocin. These findings suggest a novel mechanism of contact-dependent killing that does not require cellular uptake. The evolutionary advantage of piracy of an essential cellular compound is highlighted by the observation that contact-dependent growth inhibition, a distinct antagonistic system, can equally take advantage of this receptor.
Prevalence and factors associated with the use of antibiotics in non-bloody diarrhoea in children under 5 years of age in sub-Saharan Africa
Authors: Auta Asa , Ogbonna Brian O , Adewuyi Emmanuel O , Adeloye Davies , Strickland-Hodge Barry 
Published: March 2018

ObjectivesTo estimate the prevalence and determine the factors associated with the use of antibiotics in the management of non-bloody diarrhoea in children under 5 years of age in sub-Saharan Africa (SSA).MethodsWe conducted a meta-analysis of demographic and health survey data sets from 30 countries in SSA. Pooled prevalence estimates were calculated using random effects model. Χ2 tests were employed to determine the factors associated with the antibiotic use.ResultsThe pooled prevalence of antibiotic use among cases of non-bloody diarrhoea in children under 5 years of age was 23.1% (95% CI 19.5 to 26.7). The use of antibiotics in children with non-bloody diarrhoea in SSA was associated with (p<0.05) the source of care, place of residence, wealth index, maternal education and breastfeeding status.ConclusionWe found an unacceptably high use of antibiotics to treat episodes of non-bloody diarrhoea in children under the age of 5 in SSA.
Efficacy of foot orthoses for the treatment of plantar heel pain: a systematic review and meta-analysis
Authors: Rasenberg Nadine , Riel Henrik , Rathleff Michael S , Bierma-Zeinstra Sita M A , van Middelkoop Marienke 
Published: March 2018

BackgroundPlantar heel pain (PHP) is common. Foot orthoses are often applied as treatment for PHP, even though there is little evidence to support this.ObjectiveTo investigate the effects of different orthoses on pain, function and self-reported recovery in patients with PHP and compare them with other conservative interventions.DesignSystematic review and meta-analysis.Data sourcesA systematic literature search was conducted in MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Web of Science, CINAHL and Google Scholar up to January 2017.Eligibility criteria for selecting studiesRandomised controlled trials comparing foot orthoses with a control (defined as no intervention, sham or other type of conservative treatment) reporting on pain, function or self-reported recovery in patients with PHP.ResultsTwenty studies investigating eight different types of foot orthoses were included in the review. Most studies were of high quality. Pooled data from six studies showed no difference between prefabricated orthoses and sham orthoses for pain at short term (mean difference (MD) of 0.26 (95% CI −0.09 to 0.60)). No difference was found between sham orthoses and custom orthoses for pain at short term (MD 0.22 (95% CI −0.05 to 0.50)), nor was there a difference between prefabricated orthoses and custom orthoses for pain at short term (MD 0.03 (95% CI −0.15 to 0.22)). For the majority of other interventions, no significant differences were found.ConclusionsFoot orthoses are not superior for improving pain and function compared with sham or other conservative treatment in patients with PHP.PROSPERO registration numberCRD42015029659.
Control of glyphosate-resistant giant ragweed (Ambrosia trifida L.) with premix of iodosulfuron/thiencarbazone applied alone or in tank mixtures in no-till corn (Zea mays L.)
Authors: Kaur Simranpreet , Jhala Amit J. 
Published: March 2018

The objectives of this study were to evaluate the efficacy of a new premix of iodosulfuron (6%)/thiencarbazone (45%) applied alone or tank-mixed with 2,4-D, dicamba, glyphosate, or metribuzin in the fall and (or) early spring followed by preemergence (PRE) and postemergence (POST) herbicide applications for control of glyphosate-resistant giant ragweed and their effect on corn yield. Field experiments were conducted in no-till corn fields infested with glyphosate-resistant giant ragweed (20–30 plants m−2) near Clay Center and McCool Junction, NE, in 2013 and 2014, respectively. A premix of iodosulfuron/thiencarbazone applied alone or in split applications in the fall and early spring controlled glyphosate-resistant giant ragweed <60% and resulted in a density of 14 giant ragweed plants m−2, which was comparable to the untreated control at 28 d after early spring treatment (DAEST). Metribuzin or 2,4-D applied alone resulted in <75% giant ragweed control at 28 DAEST; however, 2,4-D or dicamba tank-mixed with iodosulfuron/thiencarbazone provided ≥92% control. Treatments including 2,4-D or dicamba led to 85%–98% reduction in giant ragweed biomass at 28 DAEST. A follow-up application of a premix of isoxaflutole/thiencarbazone tank-mixed with atrazine applied PRE was not effective, although a POST application of tembotrione + atrazine resulted in >91% control at 28 d after postemergence treatment. The premix applied alone did not provide effective control of giant ragweed in corn primarily because lack of residual activity.
Electronic structure near Fermi level in few-layer films of FeSe
Authors: Mustre de León J. , Mulato-Gómez D. F. 
Published: March 2018

The electronic density of states of one- and two-layer FeSe-thin films deposited on SrTiO3 was calculated using a Real Space Density Functional Theory method. This method has been previously used to calculate X-ray absorption near edge spectroscopy (XANES) and Resonant X-ray Inelastic Scattering (RIXS) in the system FeSe[Formula: see text]Te[Formula: see text], finding agreement with experimental spectra. In that system, we also found the same trend in the calculated density of states at the Fermi level and the behavior of T[Formula: see text] with varying Te content. In the present case, we find non-negligible contributions of Ti-3d states in the vicinity of the Fermi level, and qualitative differences in the density of states between calculations that assume antiferromagnetic order of the FeSe layers compared with those that assume non-magnetic order. In the magnetic-order calculation, we obtain the highest density of states for the one-layer system, compared with the two-layer or bulk FeSe. Such a trend does not correlate with the experimentally reported increase from T[Formula: see text]=8 K in bulk FeSe to T[Formula: see text]=65 K for one-layer FeSe, and absence of superconductivity in two-layer FeSe.
The square-freeness of the offset equation to a rational planar curve, computed via resultants
Authors: Alcázar Juan Gerardo , Caravantes Jorge , Diaz–Toca Gema M. 
Published: March 2018

It is well known [Algebraic properties of plane offset curves, Comput. Aided Geom. Des. 7 (1990) 101–127] that an implicit equation of the offset to a rational planar curve can be computed by removing the extraneous components of the resultant of two certain polynomials computed from the parametrization of the curve. Furthermore, it is also well known that the implicit equation provided by the nonextraneous component of this resultant has at most two irreducible factors [Algebraic analysis of offsets to hypersurfaces, Math. Z. 234 (2000) 697–719]. In this paper, we complete the algebraic description of this resultant by showing that the multiplicity of the factors corresponding to the offset can be computed in advance. In particular, when the parametrization is proper, i.e. when the curve is just traced once by the parametrization, we prove that any factor corresponding to a simple component of the offset has multiplicity 1, while the factor corresponding to the special component, if any, has multiplicity 2. Hence, if the parametrization is proper and there is no special component, the nonextraneous part of the resultant is square-free. In fact, this condition is proven to be also sufficient. Therefore, this result provides a simple test to check whether or not the offset of a given rational curve has a special component, and in turn, whether a given rational curve is the offset of another curve.
Sedimentary record of Early Permian deglaciation in southern Gondwana from the Falkland Islands
Authors: Horan Kate , Stone Philip , Crowhurst Simon J. 
Published: March 2018

Abstract
The deglaciation of southern Gondwana during the Early Permian was preceded by waxing and waning of the south polar ice sheet. The fluctuations in ice extent are recorded in the sedimentary record by strata separating thick deposits of glacial diamictite from post-glacial mudrock. These deposits span across all of the major Gondwana fragments, now recognized as South Africa, South America, India, Antarctica and Australia, and also occur on the Falklands and Ellsworth Mountains microplates created during break-up of the supercontinent in the Mesozoic. We present sedimentary evidence for the progression of deglaciation from the Falkland Islands microplate using a series of borehole core runs acquired during onshore mineral exploration. Glacial advance and retreat phases are inferred from the Hells Kitchen Member of the Port Sussex Formation; the rock succession that conformably overlies the main body of glacial diamictite known locally as the Fitzroy Tillite Formation. The pulsated nature of the transition to fully post-glacial conditions was accompanied by an intricate interplay of sedimentary processes, including soft sediment deformation, meltwater pulses and turbidity currents. The Falkland Islands core data lend insight into the evolving Early Permian environment and offer an unusually complete view of continental margin deglaciation preserved in the ancient sedimentary record.
Multiplexed Optical Imaging of Energy Substrates Reveals That Left Ventricular Hypertrophy Is Associated With Brown Adipose Tissue Activation
Authors: Panagia Marcello , Chen Howard H. , Croteau Dominique , Iris Chen Yin-Ching , Ran Chongzhao , Luptak Ivan , Josephson Lee , Colucci Wilson S. , Sosnovik David E. 
Published: March 2018

Background—
Substrate utilization in tissues with high energetic requirements could play an important role in cardiometabolic disease. Current techniques to assess energetics are limited by high cost, low throughput, and the inability to resolve multiple readouts simultaneously. Consequently, we aimed to develop a multiplexed optical imaging platform to simultaneously assess energetics in multiple organs in a high throughput fashion.

Methods and Results—

The detection of 18F-Fluordeoxyglucose uptake via Cerenkov luminescence and free fatty acid uptake with a fluorescent C
16
free fatty acid was tested. Simultaneous uptake of these agents was measured in the myocardium, brown/white adipose tissue, and skeletal muscle in mice with/without thoracic aortic banding. Within 5 weeks of thoracic aortic banding, mice developed left ventricular hypertrophy and brown adipose tissue activation with upregulation of β
3
AR (β
3
adrenergic receptors) and increased natriuretic peptide receptor ratio. Imaging of brown adipose tissue 15 weeks post thoracic aortic banding revealed an increase in glucose (
P
<0.01) and free fatty acid (
P
<0.001) uptake versus controls and an increase in uncoupling protein-1 (
P
<0.01). Similar but less robust changes were seen in skeletal muscle, while substrate uptake in white adipose tissue remained unchanged. Myocardial glucose uptake was increased post-thoracic aortic banding but free fatty acid uptake trended to decrease.

Conclusions—
A multiplexed optical imaging technique is presented that allows substrate uptake to be simultaneously quantified in multiple tissues in a high throughput manner. The activation of brown adipose tissue occurs early in the onset of left ventricular hypertrophy, which produces tissue-specific changes in substrate uptake that may play a role in the systemic response to cardiac pressure overload.