bluuebunny/crossref_metadata_2025_split huggingface dataset:
A generalized 2D pencil beam scaling algorithm for proton dose calculation in heterogeneous slab geometries
Authors: Westerly David C. , Mo Xiaohu , Tomé Wolfgang A. , Mackie Thomas R. , DeLuca Paul M. 
Published: May 2013

Purpose:Pencil beam algorithms are commonly used for proton therapy dose calculations. Szymanowski and Oelfke [“Two‐dimensional pencil beam scaling: An improved proton dose algorithm for heterogeneous media,” Phys. Med. Biol. 47, – (2002) ] developed a two‐dimensional (2D) scaling algorithm which accurately models the radial pencil beam width as a function of depth in heterogeneous slab geometries using a scaled expression for the radial kernel width in water as a function of depth and kinetic energy. However, an assumption made in the derivation of the technique limits its range of validity to cases where the input expression for the radial kernel width in water is derived from a local scattering power model. The goal of this work is to derive a generalized form of 2D pencil beam scaling that is independent of the scattering power model and appropriate for use with any expression for the radial kernel width in water as a function of depth.Methods:Using Fermi‐Eyges transport theory, the authors derive an expression for the radial pencil beam width in heterogeneous slab geometries which is independent of the proton scattering power and related quantities. The authors then perform test calculations in homogeneous and heterogeneous slab phantoms using both the original 2D scaling model and the new model with expressions for the radial kernel width in water computed from both local and nonlocal scattering power models, as well as a nonlocal parameterization of Molière scattering theory. In addition to kernel width calculations, dose calculations are also performed for a narrow Gaussian proton beam.Results:Pencil beam width calculations indicate that both 2D scaling formalisms perform well when the radial kernel width in water is derived from a local scattering power model. Computing the radial kernel width from a nonlocal scattering model results in the local 2D scaling formula under‐predicting the pencil beam width by as much as 1.4 mm (21%) at the depth of the Bragg peak for a 220 MeV proton beam in homogeneous water. This translates into a 32% dose discrepancy for a 5 mm Gaussian proton beam. Similar trends were observed for calculations made in heterogeneous slab phantoms where it was also noted that errors tend to increase with greater beam penetration. The generalized 2D scaling model performs well in all situations, with a maximum dose error of 0.3% at the Bragg peak in a heterogeneous phantom containing 3 cm of hard bone.Conclusions:The authors have derived a generalized form of 2D pencil beam scaling which is independent of the proton scattering power model and robust to the functional form of the radial kernel width in water used for the calculations. Sample calculations made with this model show excellent agreement with expected values in both homogeneous water and heterogeneous phantoms.
Identification of Critical Genes for Growth in Olive Brine by Transposon Mutagenesis of Lactobacillus pentosus C11
Authors: Perpetuini G. , Scornec H. , Tofalo R. , Serror P. , Schirone M. , Suzzi G. , Corsetti A. , Cavin J. F. , Licandro-Seraut H. 
Published: May 2013

ABSTRACT

Olive brine represents a stressful environment due to the high NaCl concentration, presence of phenolic compounds known as antimicrobials, and low availability of nutrients. Thus, only a few strains of lactic acid bacteria (LAB) are adapted to grow in and ferment table olives. To identify the mechanisms by which these few strains are able to grow in olive brine,
Lactobacillus pentosus
C11, a particularly resistant strain isolated from naturally fermented table olives, was mutagenized by random transposition using the P
junc
-TpaseIS
1223
system (H. Licandro-Seraut, S. Brinster, M. van de Guchte, H. Scornec, E. Maguin, P. Sansonetti, J. F. Cavin, and P. Serror, Appl. Environ. Microbiol. 78:5417–5423, 2012). A library of 6,000 mutants was generated and screened for adaptation and subsequent growth in a medium, named BSM (brine screening medium), which presents the stressful conditions encountered in olive brine. Five transposition mutants impaired in growth on BSM were identified. Transposition occurred in two open reading frames and in three transcription terminators affecting stability of transcripts. Thus, several essential genes for adaptation and growth of
L. pentosus
C11 in olive brine were identified.
Neurospora crassa NKIN2, a Kinesin-3 Motor, Transports Early Endosomes and Is Required for Polarized Growth
Authors: Seidel Constanze , Moreno-Velásquez Sergio David , Riquelme Meritxell , Fischer Reinhard 
Published: May 2013

ABSTRACT

Biological motors are molecular nanomachines, which convert chemical energy into mechanical forces. The combination of mechanoenzymes with structural components, such as the cytoskeleton, enables eukaryotic cells to overcome entropy, generate molecular gradients, and establish polarity. Hyphae of filamentous fungi are among the most polarized cells, and polarity defects are most obvious. Here, we studied the role of the kinesin-3 motor, NKIN2, in
Neurospora crassa
. We found that NKIN2 localizes as fast-moving spots in the cytoplasm of mature hyphae. To test whether the spots represented early endosomes, the Rab5 GTPase YPT52 was used as an endosomal marker. NKIN2 colocalized with YPT52. Deletion of
nkin2
caused strongly reduced endosomal movement. Combined, these results confirm the involvement of NKIN2 in early endosome transport. Introduction of a rigor mutation into NKIN2 labeled with green fluorescent protein (GFP) resulted in decoration of microtubules. Interestingly, NKIN2
rigor
was associated with a subpopulation of microtubules, as had been shown earlier for the
Aspergillus nidulans
orthologue UncA. Other kinesins did not show this specificity.
A SAS-6-Like Protein Suggests that the Toxoplasma Conoid Complex Evolved from Flagellar Components
Authors: de Leon Jessica Cruz , Scheumann Nicole , Beatty Wandy , Beck Josh R. , Tran Johnson Q. , Yau Candace , Bradley Peter J. , Gull Keith , Wickstead Bill , Morrissette Naomi S. 
Published: May 2013

ABSTRACTSAS-6 is required for centriole biogenesis in diverse eukaryotes. Here, we describe a novel family of SAS-6-like (SAS6L) proteins that share an N-terminal domain with SAS-6 but lack coiled-coil tails. SAS6L proteins are found in a subset of eukaryotes that contain SAS-6, including diverse protozoa and green algae. In the apicomplexan parasiteToxoplasma gondii, SAS-6 localizes to the centriole but SAS6L is found above the conoid, an enigmatic tubulin-containing structure found at the apex of a subset of alveolate organisms. Loss of SAS6L causes reduced fitness inToxoplasma. TheTrypanosoma bruceihomolog of SAS6L localizes to the basal-plate region, the site in the axoneme where the central-pair microtubules are nucleated. When endogenous SAS6L is overexpressed inToxoplasmatachyzoites orTrypanosomatrypomastigotes, it forms prominent filaments that extend through the cell cytoplasm, indicating that it retains a capacity to form higher-order structures despite lacking a coiled-coil domain. We conclude that although SAS6L proteins share a conserved domain with SAS-6, they are a functionally distinct family that predates the last common ancestor of eukaryotes. Moreover, the distinct localization of the SAS6L protein inTrypanosomaandToxoplasmaadds weight to the hypothesis that the conoid complex evolved from flagellar components.
Gene Expression and Physiological Role of Pseudomonas aeruginosa Methionine Sulfoxide Reductases during Oxidative Stress
Authors: Romsang Adisak , Atichartpongkul Sopapan , Trinachartvanit Wachareeporn , Vattanaviboon Paiboon , Mongkolsuk Skorn 
Published: May 2013

ABSTRACT

Pseudomonas aeruginosa
PAO1 has two differentially expressed methionine sulfoxide reductase genes:
msrA
(PA5018) and
msrB
(PA2827). The
msrA
gene is expressed constitutively at a high level throughout all growth phases, whereas
msrB
expression is highly induced by oxidative stress, such as sodium hypochlorite (NaOCl) treatment. Inactivation of either
msrA
or
msrB
or both genes (
msrA msrB
mutant) rendered the mutants less resistant than the parental PAO1 strain to oxidants such as NaOCl and H
2
O
2
. Unexpectedly,
msr
mutants have disparate resistance patterns when exposed to paraquat, a superoxide generator. The
msrA
mutant had a higher paraquat resistance level than the
msrB
mutant, which had a lower paraquat resistance level than the PAO1 strain. The expression levels of
msrA
showed an inverse correlation with the paraquat resistance level, and this atypical paraquat resistance pattern was not observed with
msrB
. Virulence testing using a
Drosophila melanogaster
model revealed that the
msrA
,
msrB
, and, to a greater extent,
msrA msrB
double mutants had an attenuated virulence phenotype. The data indicate that
msrA
and
msrB
are essential genes for oxidative stress protection and bacterial virulence. The pattern of expression and mutant phenotypes of
P. aeruginosa
msrA
and
msrB
differ from previously characterized
msr
genes from other bacteria. Thus, as highly conserved genes, the
msrA
and
msrB
have diverse expression patterns and physiological roles that depend on the environmental niche where the bacteria thrive.
BB0172, a Borrelia burgdorferi Outer Membrane Protein That Binds Integrin α
3
β
1
Authors: Wood Elaine , Tamborero Silvia , Mingarro Ismael , Esteve-Gassent Maria D. 
Published: May 2013

ABSTRACT

Lyme disease is a multisystemic disorder caused by
Borrelia burgdorferi
infection. Upon infection, some
B. burgdorferi
genes are upregulated, including members of the microbial surface components recognizing adhesive matrix molecule (MSCRAMM) protein family, which facilitate
B. burgdorferi
adherence to extracellular matrix components of the host. Comparative genome analysis has revealed a new family of
B. burgdorferi
proteins containing the von Willebrand factor A (vWFA) domain. In the present study, we characterized the expression and membrane association of the vWFA domain-containing protein BB0172 by using
in vitro
transcription/translation systems in the presence of microsomal membranes and with detergent phase separation assays. Our results showed evidence of BB0172 localization in the outer membrane, the orientation of the vWFA domain to the extracellular environment, and its function as a metal ion-dependent integrin-binding protein. This is the first report of a borrelial adhesin with a metal ion-dependent adhesion site (MIDAS) motif that is similar to those observed in eukaryotic integrins and has a similar function.
Role of Polyphosphate in Thermophilic Synechococcus sp. from Microbial Mats
Authors: Gomez-Garcia Maria R. , Fazeli Fariba , Grote Alexandra , Grossman Arthur R. , Bhaya Devaki 
Published: May 2013

ABSTRACT

Synechococcus
OS-B′, a thermophilic unicellular cyanobacterium, recently isolated from the microbial mats in Octopus Spring (Yellowstone National Park), induces a suite of genes, including phosphatases and transporters, in response to phosphorus (P) starvation. Here we describe two different approaches to examine the ability of
Synechococcus
OS-B′ to synthesize and break down polyphosphate (poly P), a key storage compound in many prokaryotes. First, we developed a transformation protocol to create mutants in the polyphosphate kinase (
ppk
), the major enzyme responsible for the synthesis of poly P. The
ppk
mutant exhibited a pleiotropic phenotype with defects in poly P accumulation, aberrant levels of Pho regulon transcripts, growth defects, and changes in cell size and exopolysaccharide levels, among others. Second, we measured transcripts of
ppk
and
ppx
(encoding the polyphosphatase) directly from mat samples and found that the levels varied dramatically over a diel cycle. We also used Western blot analysis to quantify levels of PPK and PPX and found that these enzymes differentially accumulated during the diel cycle. Levels of polyphosphate kinase peaked at night, while polyphosphatase levels were highest during the early morning hours. We hypothesize that the opposing activities of these two enzymes allow cells to store and utilize poly P to optimize growth over a diel cycle.
A Differential Fluorescence-Based Genetic Screen Identifies Listeria monocytogenes Determinants Required for Intracellular Replication
Authors: Perry Kyle J. , Higgins Darren E. 
Published: May 2013

ABSTRACT

Listeria monocytogenes
is a Gram-positive, facultative intracellular pathogen capable of causing severe invasive disease with high mortality rates in humans. While previous studies have largely elucidated the bacterial and host cell mechanisms necessary for invasion, vacuolar escape, and subsequent cell-to-cell spread, the
L. monocytogenes
factors required for rapid replication within the restrictive environment of the host cell cytosol are poorly understood. In this report, we describe a differential fluorescence-based genetic screen utilizing fluorescence-activated cell sorting (FACS) and high-throughput microscopy to identify
L. monocytogenes
mutants defective in optimal intracellular replication. Bacteria harboring deletions within the identified gene
menD
or
pepP
were defective for growth in primary murine macrophages and plaque formation in monolayers of L2 fibroblasts, thus validating the ability of the screening method to identify intracellular replication-defective mutants. Genetic complementation of the
menD
and
pepP
deletion strains rescued the
in vitro
intracellular infection defects. Furthermore, the
menD
deletion strain displayed a general extracellular replication defect that could be complemented by growth under anaerobic conditions, while the intracellular growth defect of this strain could be complemented by the addition of exogenous menaquinone. As prior studies have indicated the importance of aerobic metabolism for
L. monocytogenes
infection, these findings provide further evidence for the importance of menaquinone and aerobic metabolism for
L. monocytogenes
pathogenesis. Lastly, both the
menD
and
pepP
deletion strains were attenuated during
in vivo
infection of mice. These findings demonstrate that the differential fluorescence-based screening approach provides a powerful tool for the identification of intracellular replication determinants in multiple bacterial systems.
Mutational Analysis of the Multiple-Antibiotic Resistance Regulator MarR Reveals a Ligand Binding Pocket at the Interface between the Dimerization and DNA Binding Domains
Authors: Duval Valérie , McMurry Laura M. , Foster Kimberly , Head James F. , Levy Stuart B. 
Published: May 2013

ABSTRACT

The
Escherichia coli
regulator MarR represses the multiple-antibiotic resistance operon
marRAB
and responds to phenolic compounds, including sodium salicylate, which inhibit its activity. Crystals obtained in the presence of a high concentration of salicylate indicated two possible salicylate sites, SAL-A and SAL-B. However, it was unclear whether these sites were physiologically significant or were simply a result of the crystallization conditions. A study carried out on MarR homologue MTH313 suggested the presence of a salicylate binding site buried at the interface between the dimerization and the DNA-binding domains. Interestingly, the authors of the study indicated a similar pocket conserved in the MarR structure. Since no mutagenesis analysis had been performed to test which amino acids were essential in salicylate binding, we examined the role of residues that could potentially interact with salicylate. We demonstrated that mutations in residues shown as interacting with salicylate at SAL-A and SAL-B in the MarR-salicylate structure had no effect on salicylate binding, indicating that these sites were not the physiological regulatory sites. However, some of these residues (P57, R86, M74, and R77) were important for DNA binding. Furthermore, mutations in residues R16, D26, and K44 significantly reduced binding to both salicylate and 2,4-dinitrophenol, while a mutation in residue H19 impaired the binding to 2,4-dinitrophenol only. These findings indicate, as for MTH313, the presence of a ligand binding pocket located between the dimerization and DNA binding domains.
Anastomotic leakage as an outcome measure for quality of colorectal cancer surgery
Authors: Snijders H S , Henneman D , van Leersum N L , ten Berge M , Fiocco M , Karsten T M , Havenga K , Wiggers T , Dekker J W , Tollenaar R A E M , Wouters M W J M 
Published: May 2013

IntroductionWhen comparing mortality rates between hospitals to explore hospital performance, there is an important role for adjustment for differences in case-mix. Identifying outcome measures that are less influenced by differences in case-mix may be valuable. The main goal of this study was to explore whether hospital differences in anastomotic leakage (AL) and postoperative mortality are due to differences in case-mix or to differences in treatment factors.MethodsData of the Dutch Surgical Colorectal Audit were used. Case-mix factors and treatment-related factors were identified from the literature and their association with AL and mortality were analysed with logistic regression. Hospital differences in observed AL and mortality rates, and adjusted rates based on the logistic regression models were shown. The reduction in hospital variance after adjustment was analysed with Levene's test for equality of variances.Results17 of 22 case-mix factors and 4 of 11 treatment factors related to AL derived from the literature were available in the database. Variation in observed AL rates between hospitals was large with a maximum rate of 17%. This variation could not be attributed to differences in case-mix but more to differences in treatment factors. Hospital variation in observed mortality rates was significantly reduced after adjustment for differences in case-mix.ConclusionsHospital variation in AL is relatively independent of differences in case-mix. In contrast to ‘postoperative mortality’ the observed AL rates of hospitals evaluated in our study were only slightly affected after adjustment for case-mix factors. Therefore, AL rates may be suitable as an outcome indicator for measurement of surgical quality of care.
Understanding risk factors for perioperative ischemic events with carotid stenting: is patient age over 80 years or is unfavorable arch anatomy to blame?
Authors: Dumont Travis M , Mokin Maxim , Wach Michael M , Drummond Patrick S , Siddiqui Adnan H , Levy Elad I , Hopkins L Nelson 
Published: May 2013

ObjectiveSeveral studies have reported increased perioperative risk after carotid artery stenting (CAS) for patients ≥80 years of age; however, most have not considered unfavorable anatomic features noted more frequently in this population as a confounding variable. The purpose of this study was to show a correlation between poor aortic arch anatomy and perioperative ischemic complications after CAS.MethodsOur prospectively maintained database was queried for all CAS procedures performed on symptomatic patients between 2009 and 2011. Retrospective analysis of consecutive CAS procedures was performed. The primary endpoint was perioperative (within 30 days) ischemic events (stroke, transient ischemic attack (TIA)). Event incidence was compared between groups dichotomized by age and anatomical features. Incidence of unfavorable arch (acute angle between aortic arch and treated common carotid artery) was compared between age groups.ResultsPerioperative ischemic events included four ischemic strokes and three TIAs (all events ipsilateral to the treated vessel). Event incidence was more frequent in patients with unfavorable arch anatomy (7.9%) than in those with favorable aortic arch features (0.7%) (p=0.0073). Event incidence in patients ≥80 years of age (4.5%) was not statistically different than that in patients <80 years (2.3%) (p=0.428). Unfavorable aortic arch anatomy was increased in frequency in patients aged 80 years and over (<80 years, 29%; ≥80 years, 52%; p<0.001).ConclusionsIn the present series, the incidence of perioperative complications was increased in patients with unfavorable aortic arch anatomy but not in patients ≥80 years. CAS represents a revascularization option for patients of all ages; however, patients with unfavorable aortic arch anatomy may represent a group at relatively high risk for periprocedural ischemic events.
Metformin Decreases Glucose Oxidation and Increases the Dependency of Prostate Cancer Cells on Reductive Glutamine Metabolism
Authors: Fendt Sarah-Maria , Bell Eric L. , Keibler Mark A. , Davidson Shawn M. , Wirth Gregory J. , Fiske Brian , Mayers Jared R. , Schwab Matthias , Bellinger Gary , Csibi Alfredo , Patnaik Akash , Blouin Marie Jose , Cantley Lewis C. , Guarente Leonard , Blenis John , Pollak Michael N. , Olumi Aria F. , Vander Heiden Matthew G. , Stephanopoulos Gregory 
Published: May 2013

Abstract
Metformin inhibits cancer cell proliferation, and epidemiology studies suggest an association with increased survival in patients with cancer taking metformin; however, the mechanism by which metformin improves cancer outcomes remains controversial. To explore how metformin might directly affect cancer cells, we analyzed how metformin altered the metabolism of prostate cancer cells and tumors. We found that metformin decreased glucose oxidation and increased dependency on reductive glutamine metabolism in both cancer cell lines and in a mouse model of prostate cancer. Inhibition of glutamine anaplerosis in the presence of metformin further attenuated proliferation, whereas increasing glutamine metabolism rescued the proliferative defect induced by metformin. These data suggest that interfering with glutamine may synergize with metformin to improve outcomes in patients with prostate cancer. Cancer Res; 73(14); 4429–38. ©2013 AACR.
Exploiting Tumor Vulnerabilities: Epigenetics, Cancer Metabolism and the mTOR Pathway in the Era of Personalized Medicine
Authors: Muñoz-Pinedo Cristina , González-Suárez Eva , Portela Anna , Gentilella Antonio , Esteller Manel 
Published: May 2013

Abstract
Patient stratification according to drug responses, together with the discovery of novel antitumor targets, is leading to a new era of personalized cancer treatments. With the aim of identifying emerging pathways and the challenges faced by clinicians during clinical trials, the IDIBELL Cancer Conference on Personalized Cancer Medicine took place in Barcelona on December 3–4, 2012. This conference brought together speakers working in different areas of cancer research (epigenetics, metabolism and the mTOR pathway, cell death and the immune system, clinical oncology) to discuss the latest developments in personalized cancer medicine. Cancer Res; 73(14); 4185–9. ©2013 AACR.