bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacokinetics and Safety of Intravenous Cidofovir for Life-Threatening Viral Infections in Pediatric Hematopoietic Stem Cell Transplant Recipients
Authors: Caruso Brown Amy E. , Cohen Mindy N. , Tong Suhong , Braverman Rebecca S. , Rooney James F. , Giller Roger , Levin Myron J. 
Published: March 2015

ABSTRACT
Children undergoing hematopoietic stem cell transplantation (HSCT) are at risk for life-threatening viral infections. Cidofovir is often used as a first-line agent for adenovirus infections, despite the absence of randomized controlled trials with HSCT patients, and as a second-line agent for resistant herpesvirus infections. The frequency and severity of adverse effects, particularly nephrotoxicity, in pediatric HSCT recipients are unclear, and pharmacokinetics (PK) of cidofovir in children have not previously been reported. This study was an open-label, nonrandomized, single-dose pilot study to determine the safety and PK of cidofovir in pediatric HSCT recipients with symptomatic adenovirus, nucleoside-resistant cytomegalovirus (CMV) or herpes simplex virus (HSV), and/or human papovavirus infections. Subsequent dosing and frequency were determined by clinical response and side effects, as assessed by the treating physician. Blood and urine samples were obtained from patients for PK studies and assessment of toxicity and virologic response. Twelve patients were enrolled (median age, 9 years; 33.5 days posttransplantation). Four of seven patients with adenovirus infection were successfully treated and eventually cleared their infections. Four of twelve patients died of disseminated viral disease and multiorgan failure. Two of twelve patients had evidence of acute kidney injury after the first dose, and one of these patients developed chronic kidney disease; two other patients developed late nephrotoxicity. The mean drug half-life was 9.5 h. There was no correlation between nephrotoxicity and plasma maximum concentration, clearance, or half-life. PK were similar to those reported for adults, although the drug half-life was significantly longer than that for adults. Cidofovir was well tolerated in the majority of patients. However, effective therapeutic strategies are urgently needed to support patients until immune reconstitution is achieved.
Heterogeneity of Genetic Pathways toward Daptomycin Nonsusceptibility in Staphylococcus aureus Determined by Adjunctive Antibiotics
Authors: Berti Andrew D. , Baines Sarah L. , Howden Benjamin P. , Sakoulas George , Nizet Victor , Proctor Richard A. , Rose Warren E. 
Published: March 2015

ABSTRACT

Daptomycin is increasingly used in combination with other antibiotics to enhance antimicrobial efficacy and/or to mitigate the emergence of daptomycin nonsusceptibility (DNS). This study used a clinical methicillin-resistant
Staphylococcus aureus
(MRSA) strain in which DNS emerged upon therapy to examine the influence of antibiotic combinations on the development of mutations in specific genes (
mprF
,
rpoBC
,
dltA
,
cls2
, and
yycFG
) previously associated with DNS. Whole genomes of bacteria obtained following 28 days of
in vitro
exposure to daptomycin with or without adjunctive clarithromycin, linezolid, oxacillin, or trimethoprim-sulfamethoxazole were sequenced, and the sequences were compared to that of the progenitor isolate. The addition of oxacillin to medium containing daptomycin prevented the emergence of
mprF
mutation but did not prevent
rpoBC
mutation (
P
< 0.01). These isolates maintained susceptibility to daptomycin during the combined exposure (median MIC, 1 mg/liter). Daptomycin plus clarithromycin or linezolid resulted in low-level (1.5 to 8 mg/liter) and high-level (12 to 96 mg/liter) DNS, respectively, and did not prevent
mprF
mutation. However, these same combinations prevented
rpoBC
mutation. Daptomycin alone or combined with linezolid or trimethoprim-sulfamethoxazole resulted in high-level DNS and mutations in
mprF
plus
rpoBC
,
cls2
, and
yycFG
. Combining daptomycin with different antimicrobials alters the mutational space available for DNS development, thereby favoring the development of predictable collateral susceptibilities.
CD4
+
T Cell Response Correlates with Naturally Acquired Antibodies against Plasmodium vivax Tryptophan-Rich Antigens
Authors: Zeeshan Mohammad , Tyagi Kriti , Sharma Yagya D. 
Published: March 2015

ABSTRACT

Tryptophan-rich proteins play important biological functions for the
Plasmodium
parasite.
Plasmodium vivax
contains remarkably large numbers of such proteins belonging to the “Pv-fam-a” family that need to be characterized. Earlier, we reported the presence of memory T cells and naturally acquired antibodies against 15 of these proteins in
P. vivax
malaria-exposed individuals (M. Zeeshan, H. Bora, and Y. D. Sharma, J Infect Dis
207:
175–185, 2013,
http://dx.doi.org/10.1093/infdis/jis650
). Here, we sought to characterize and ascertain the cross talk between effector responses of T and B cells in malarial patients against all Pv-fam-a family proteins. Therefore, we expressed the remaining 21 of these proteins in
Escherichia coli
and studied the humoral and cellular immune responses based on the same parameters used in our previous study. Naturally acquired IgG antibodies were detected against all 21 antigens in
P. vivax
patient sera (37.7 to 94.4% seropositivity). These antigens were able to activate the lymphocytes of
P. vivax
-exposed individuals, and the activated CD4
+
T lymphocytes produced higher levels of Th1 (interleukin-2 [IL-2] and gamma interferon [IFN-γ]) and Th2 (IL-4 and IL-10) cytokines than the healthy controls, but the response was Th2 biased. The combined results of present and previous studies seem to suggest a striking link between induction of the CD4
+
T cell response and naturally acquired antibodies against all 36 proteins of the Pv-fam-a family, the majority of them having conserved sequences in the parasite population. Further work is required to utilize this information to develop immunotherapeutic treatments for this disease.
Evidence that Biosynthesis of the Second and Third Sugars of the Archaellin Tetrasaccharide in the Archaeon Methanococcus maripaludis Occurs by the Same Pathway Used by Pseudomonas aeruginosa To Make a Di-N-Acetylated Sugar
Authors: Siu Sarah , Robotham Anna , Logan Susan M. , Kelly John F. , Uchida Kaoru , Aizawa Shin-Ichi , Jarrell Ken F. 
Published: March 2015

ABSTRACTMethanococcus maripaludishas two surface appendages, archaella and type IV pili, which are composed of glycoprotein subunits. Archaellins are modified with an N-linked tetrasaccharide with the structure Sug-1,4-β-ManNAc3NAmA6Thr-1,4-β-GlcNAc3NAcA-1,3-β-GalNAc, where Sug is (5S)-2-acetamido-2,4-dideoxy-5-O-methyl-α-l-erythro-hexos-5-ulo-1,5-pyranose. The pilin glycan has an additional hexose attached to GalNAc. In this study, genes located in two adjacent, divergently transcribed operons (mmp0350-mmp0354andmmp0359-mmp0355) were targeted for study based on annotations suggesting their involvement in biosynthesis of N-glycan sugars. Mutants carrying deletions inmmp0350,mmp0351,mmp0352, ormmp0353were nonarchaellated and synthesized archaellins modified with a 1-sugar glycan, as estimated from Western blots. Mass spectroscopy analysis of pili purified from the Δmmp0352strain confirmed a glycan with only GalNAc, suggestingmmp0350tommp0353were all involved in biosynthesis of the second sugar (GlcNAc3NAcA). The Δmmp0357mutant was archaellated and had archaellins with a 2-sugar glycan, as confirmed by mass spectroscopy of purified archaella, indicating a role for MMP0357 in biosynthesis of the third sugar (ManNAc3NAmA6Thr).M. maripaludismmp0350,mmp0351,mmp0352,mmp0353, andmmp0357are proposed to be functionally equivalent toPseudomonas aeruginosawbpABEDI, involved in converting UDP-N-acetylglucosamine to UDP-2,3-diacetamido-2,3-dideoxy-d-mannuronic acid, an O5-specific antigen sugar. Cross-domain complementation of the final step of theP. aeruginosapathway withmmp0357supports this hypothesis.IMPORTANCEThis work identifies a series of genes in adjacent operons that are shown to encode the enzymes that complete the entire pathway for generation of the second and third sugars of the N-linked tetrasaccharide that modifies archaellins ofMethanococcus maripaludis. This posttranslational modification of archaellins is important, as it is necessary for archaellum assembly. Pilins are modified with a different N-glycan consisting of the archaellin tetrasaccharide but with an additional hexose attached to the linking sugar. Mass spectrometry analysis of the pili of one mutant strain provided insight into how this different glycan might ultimately be assembled. This study includes a rare example of an archaeal gene functionally replacing a bacterial gene in a complex sugar biosynthesis pathway.
Oxygen-Dependent Regulation of Bacterial Lipid Production
Authors: Lemmer Kimberly C. , Dohnalkova Alice C. , Noguera Daniel R. , Donohue Timothy J. 
Published: March 2015

ABSTRACT

Understanding the mechanisms of lipid accumulation in microorganisms is important for several reasons. In addition to providing insight into assembly of biological membranes, lipid accumulation has important applications in the production of renewable fuels and chemicals. The photosynthetic bacterium
Rhodobacter sphaeroides
is an attractive organism to study lipid accumulation, as it has the ability to increase membrane production at low O
2
tensions. Under these conditions,
R. sphaeroides
develops invaginations of the cytoplasmic membrane to increase its membrane surface area for housing of the membrane-bound components of its photosynthetic apparatus. Here we use fatty acid levels as a reporter of membrane lipid content. We show that, under low-O
2
and anaerobic conditions, the total fatty acid content per cell increases 3-fold. We also find that the increases in the amount of fatty acid and photosynthetic pigment per cell are correlated as O
2
tensions or light intensity are changed. To ask if lipid and pigment accumulation were genetically separable, we analyzed strains with mutations in known photosynthetic regulatory pathways. While a strain lacking AppA failed to induce photosynthetic pigment-protein complex accumulation, it increased fatty acid content under low-O
2
conditions. We also found that an intact PrrBA pathway is required for low-O
2
-induced fatty acid accumulation. Our findings suggest a previously unknown role of
R. sphaeroides
transcriptional regulators in increasing fatty acid and phospholipid accumulation in response to decreased O
2
tension.

IMPORTANCE
Lipids serve important functions in living systems, either as structural components of membranes or as a form of carbon storage. Understanding the mechanisms of lipid accumulation in microorganisms is important for providing insight into the assembly of biological membranes and additionally has important applications in the production of renewable fuels and chemicals. In this study, we investigate the ability of
Rhodobacter sphaeroides
to increase membrane production at low O
2
tensions in order to house its photosynthetic apparatus. We demonstrate that this bacterium has a mechanism to increase lipid content in response to decreased O
2
tension and identify a transcription factor necessary for this response. This is significant because it identifies a transcriptional regulatory pathway that can increase microbial lipid content.
Novel Antibacterial Targets and Compounds Revealed by a High-Throughput Cell Wall Reporter Assay
Authors: Nayar Asha S. , Dougherty Thomas J. , Ferguson Keith E. , Granger Brett A. , McWilliams Lisa , Stacey Clare , Leach Lindsey J. , Narita Shin-ichiro , Tokuda Hajime , Miller Alita A. , Brown Dean G. , McLeod Sarah M. 
Published: March 2015

ABSTRACT

A high-throughput phenotypic screen based on a
Citrobacter freundii
AmpC reporter expressed in
Escherichia coli
was executed to discover novel inhibitors of bacterial cell wall synthesis, an attractive, well-validated target for antibiotic intervention. Here we describe the discovery and characterization of sulfonyl piperazine and pyrazole compounds, each with novel mechanisms of action.
E. coli
mutants resistant to these compounds display no cross-resistance to antibiotics of other classes. Resistance to the sulfonyl piperazine maps to LpxH, which catalyzes the fourth step in the synthesis of lipid A, the outer membrane anchor of lipopolysaccharide (LPS). To our knowledge, this compound is the first reported inhibitor of LpxH. Resistance to the pyrazole compound mapped to mutations in either LolC or LolE, components of the essential LolCDE transporter complex, which is required for trafficking of lipoproteins to the outer membrane. Biochemical experiments with
E. coli
spheroplasts showed that the pyrazole compound is capable of inhibiting the release of lipoproteins from the inner membrane. Both of these compounds have significant promise as chemical probes to further interrogate the potential of these novel cell wall components for antimicrobial therapy.

IMPORTANCE
The prevalence of antibacterial resistance, particularly among Gram-negative organisms, signals a need for novel antibacterial agents. A phenotypic screen using AmpC as a sensor for compounds that inhibit processes involved in Gram-negative envelope biogenesis led to the identification of two novel inhibitors with unique mechanisms of action targeting
Escherichia coli
outer membrane biogenesis. One compound inhibits the transport system for lipoprotein transport to the outer membrane, while the other compound inhibits synthesis of lipopolysaccharide. These results indicate that it is still possible to uncover new compounds with intrinsic antibacterial activity that inhibit novel targets related to the cell envelope, suggesting that the Gram-negative cell envelope still has untapped potential for therapeutic intervention.
MCM of Sung Joo Group: An MCM Licensee Wrote a Creation Myth in the Luxury Industry
Authors: Choi Eun Jung 
Published: March 2015

In 1994, Sung Joo International was an international distributor of premium and luxury fashion brands in Korea. During that time, Sung Joo International successfully built partnerships with designers such as Gucci, Sonia Rykiel, Yves Saint Laurent (YSL) and Mode Creations Munich (MCM) until 1999. Due to the premillennial global financial crisis, Sung Joo International strategically terminated all their international distribution agreements in 1999 — except their agreement with MCM. The brand gained notoriety among Korean, female college students within the masstige handbag market. Therefore, Sung Joo International acted as the official MCM licensee in Korea, from 2000 to 2004. Based upon a $4 million increase in sales volume, the Sung Joo Group purchased MCM in 2005 with the intent of transforming it into a full-fledged, global luxury brand. Since 2005, the Sung Joo Group has successfully molded MCM into an emerging, semi-luxury brand of iconic leather goods in China, the United States, Korea and Europe. Several innovative steps, such as new product designs, competitive pricing strategies, remerchandising, retail store expansions and collaborative marketing, preceded their entry into the international market. Such steps have been important for the elevation of MCM's brand prestige. The public image of Sung Joo Kim, founder and chairperson of Sung Joo International, has been vital to the rebuilding of MCM's brand image. Under her leadership, Sung Joo International was officially dubbed the “Sung Joo Group.” Her presence in news media and MCM advertisements has since broadened MCM's aspirational appeal. MCM is currently valued at $320 to $400 million, exceeding the $250 million in sales during MCM's 1993 preacquisition height. Within 5 years, Sung Joo Kim expects MCM to become a luxury brand that will be competitive with more established brands such as Louis Vuitton and Gucci.
Numerical interpretation of gas-injection tests at different scales
Authors: Shao Hua , Xu Wenjie , Marschall Paul , Kolditz Olaf , Hesser Jürgen 
Published: March 2015

Abstract

To investigate gas-migration processes in saturated low-permeability argillaceous rocks, gas-injection tests under different injection pressures were carried out at different scales: on core samples at the laboratory scale; in the packed-off section of boreholes at the borehole scale (HG-B); and in the sealed microtunnel at the tunnel scale (HG-A) – a 1:2 scale experiment at the Mont Terri Rock Laboratory, Switzerland. All three tests at the Mont Terri Rock Laboratory involved Opalinus Clay. A fully coupled hydromechanical model has been developed that takes account of elastic and plastic anisotropies, anisotropic two-phase flow based on the van Genuchten function, and permeability changes when evaluating the experimental data. Two different flow regimes were studied: two-phase flow under low gas-injection pressure and dilatancy-controlled gas flow under high gas-injection pressure above the confining pressure in the laboratory experiment or the minimal principal stress
in situ
. When dealing with the dilatancy-controlled gas-flow regime, special consideration was made by applying two permeability approaches in which (i) the permeability change was pore-gas-pressure dependent and (ii) where the permeability change was deformation dependent.

Using the parameter values determined by laboratory data, the
in situ
borehole tests obtained under well-defined hydromechanical conditions could be analysed accordingly. The gas-flow regime in large-scale experiments, as in the case of HG-A, is mainly governed by experimental circumstances: in this case, the excavation-induced fractures around an opening with a permeability four order of magnitude higher than that in the undisturbed rock mass.
Application of a new method for rapid quality assessment of renewable aggregate resources in alpine regions
Authors: Pfleiderer S. , Heinrich M. , Rabeder J. , Reitner H. , Untersweg T. , Wimmer-Frey I. 
Published: March 2015

Abstract
Alluvial fans, valley fills and debris cones represent economically significant, natural aggregate resources in the alpine regions of Austria. Due to continual erosion they constitute renewable sources of sand and gravel. However, knowledge of their petrographic properties and resulting aggregate quality is scant. An automated evaluation method was developed to estimate petrographic characteristics and predict resource suitability. This method makes use of the fact that the properties of a gravel deposit depend on the morphology and geology of the provenance area. Area percentages of geological units in the source area were expected to mirror the litho-spectrum of the gravel resource. Petrographic analysis of 13 field samples shows that this is indeed the case. Discrepancies amount to 0–10%; larger deviations occur for grain size fractions <2 mm in the presence of soft rock types such as mica-schist or paragneiss. Forecasts of aggregate quality on the basis of lithological composition and grain size characteristics were compared to operational data of five gravel pits. The actual usage of the material agrees with predictions in four out of the five cases.
Adrenomedullin influences magnocellular and parvocellular neurons of paraventricular nucleus via separate mechanisms
Authors: Follwell Matthew J. , Ferguson Alastair V. 
Published: March 2015

We previously reported that adrenomedullin (AM) decreases blood pressure following microinjection into the paraventricular nucleus of the hypothalamus (PVN) of the rat. With the use of whole cell recordings in rat hypothalamic slice preparations, we characterized the effects of AM on electrophysiologically identified PVN neurons and described the membrane events underlying such actions. AM hyperpolarized magnocellular (type I) neurons in a dose-dependent manner, a response associated with an increase in the frequency and amplitude of inhibitory postsynaptic potentials. Blockade of action potentials with tetrodotoxin (TTX) abolished AM effects on membrane potential and synaptic activity in magnocellular neurons, suggesting direct actions on inhibitory interneurons. Furthermore, blockade of inhibitory synaptic transmission with the GABAA receptor antagonist bicuculline methiodide also abolished AM effects on membrane potential in magnocellular neurons. In contrast, parvocellular (type II) neurons depolarized following AM receptor activation. AM effects on parvocellular neurons were dose dependent and were maintained in the presence of TTX, indicating direct effects on this population of neurons. Voltage-clamp recordings from parvocellular neurons showed AM enhances a nonselective cationic conductance, suggesting a potential mechanism through which AM influences membrane potential. These observations show clear population-specific actions of AM on separate identified groups of PVN neurons. Such effects on magnocellular neurons likely contribute to the hypotensive actions of this peptide in PVN. Although the effects on parvocellular neurons may also contribute to such cardiovascular effects of AM, it is more likely that actions on this population of PVN neurons underlie the previously demonstrated activational effects of AM on the hypothalamic-pituitary-adrenal axis.
Host Age Is a Systemic Regulator of Gene Expression Impacting Cancer Progression
Authors: Beheshti Afshin , Benzekry Sébastien , McDonald J. Tyson , Ma Lili , Peluso Michael , Hahnfeldt Philip , Hlatky Lynn 
Published: March 2015

AbstractAging is the major determinant of cancer incidence, which, in turn, is likely dictated in large part by processes that influence the progression of early subclinical (occult) cancers. However, there is little understanding of how aging informs changes in aggregate host signaling that favor cancer progression. In this study, we provide direct evidence that aging can serve as an organizing axis to define cancer progression-modulating processes. As a model system to explore this concept, we employed adolescent (68 days), young adult (143 days), middle-aged (551 days), and old (736 days) C57BL/6 mice as syngeneic hosts for engraftment of Lewis lung cancer to identify signaling and functional processes varying with host age. Older hosts exhibited dysregulated angiogenesis, metabolism, and apoptosis, all of which are associated with cancer progression. TGFβ1, a central player in these systemic processes, was downregulated consistently in older hosts. Our findings directly supported the conclusion of a strong host age dependence in determining the host tumor control dynamic. Furthermore, our results offer initial mechanism-based insights into how aging modulates tumor progression in ways that may be actionable for therapy or prevention. Cancer Res; 75(6); 1134–43. ©2015 AACR.
4DCT Simulation With Synchronized Contrast Injection in Liver SBRT Patients
Authors: Helou Joelle , Karotki Aliaksandr , Milot Laurent , Chu William , Erler Darby , Chung Hans T. 
Published: March 2015

Background/Purpose: Delivering stereotactic body radiotherapy for liver metastases remains a challenge because of respiratory motion and poor visibility without intravenous contrast. The purpose of this article is to describe a novel and simple computed tomography (CT) simulation process of integrating timed intravenous contrast that could overcome the uncertainty of target delineation. Methods and Results: The simulation involves two 4-dimensional CT (4DCT) scans. The first scan only encompasses the immediate region of the tumor and surrounding tissue, which reduces the 4DCT scan time so that it can be optimally timed with intravenous contrast injection. The second 4DCT scan covers a larger volume and is used as the primary CT data set for dose calculation, as well as patient setup verification on the treatment unit. The combination of the two 4DCT scans allows us to optimally visualize liver metastases over all phases of the breathing cycle while simultaneously acquiring a long enough 4DCT data set that is suitable for planning and patient setup verification. Conclusion: This simulation technique allows for a better target definition when treating liver metastases, without being invasive.