bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Stability of a Second Order Linear Periodic System
Authors: Davison E. J. 
Published: November 2011

Necessary and sufficient conditions are obtained for the stability of the following second order linear system: x˙=θ(t)x,θ(t)=θt+∑i=1lTi and θ(t) =A1,0<t<T1=A2,T1<t<T1+T2⋮=Al,∑i=1l−1Ti<t<∑i=1lTi in terms of the eigenvalues and elements of the matrices Ai, i = 1, 2…l. The conditions become very simple for the case that l = 2. An example of a pendulum with a vibrating support is included.
Optimal Bang-Bang Control With Quadratic Performance Index
Authors: Wonham W. M. , Johnson C. D. 
Published: November 2011

The following optimal regulator problem is considered: Find the scalar control function u = u(t) which minimizes the performance index J[u]= 12∫0T〈x(t),Qx(t)〉dt, subject to the conditions x˙=Ax+u(t)f,|u(t)|≦1x(0)=x0(x0isunrestricted)x(T)=0(Tisfree)Q, A are constant n × n-matrices; f is a constant n-vector. It is shown that optimal control includes both a bang-bang mode and a linear mode, the latter arising from the “singular” solutions of the Pontriagin canonical equations. Conditions are given under which nth-order systems are equivalent, for control purposes, to systems of first or second order. One example of a second-order system is worked in detail and some results of an analog computer study are presented.
On a Successive Approximation Technique in Solving Some Control System Optimization Problems
Authors: Aoki Masanao 
Published: November 2011

It has been realized for some time that most realistic optimization problems defy analytical solutions in closed forms and that in most cases it is necessary to resort to judicious combinations of analytical and computational procedures to solve problems. For example, in many optimization problems, one is interested in obtaining structural information on optimal and “good” suboptimal policies. Very often, various analytical as well as computational approximation techniques need be employed to obtain clear understandings of structures of policy spaces. The paper discusses a successive approximation technique to construct minimizing sequences for functionals in extremal problems, and the techniques will be applied, to a class of control optimization problems given by: Minv J(v)=Minv ∫01g(u.v)dt, where du/dt = h(u, v), h(u, v) linear in u and v, and where u and v are, in general, elements of Banach spaces. In Section 2, the minimizing sequences are constructed by approximating g(u, v) by appropriate quadratic expressions with linear constraining differential equations. It is shown that under the stated conditions the functional values converge to the minimal value monotonically. In Section 3, an example is included to illustrate some of the techniques discussed in the paper.
Population Pharmacokinetics of Voriconazole in Adults
Authors: Hope William W. 
Published: November 2011

ABSTRACT

Voriconazole is a first-line agent for the treatment of invasive fungal infections. The pharmacology of voriconazole is characterized by extensive interindividual variability and nonlinear pharmacokinetics. The population pharmacokinetics of voriconazole in 64 adults is described. The patient population consisted of 21 healthy volunteers, who received a range of intravenous (i.v.) and oral voriconazole regimens, and 43 patients with proven or probable invasive aspergillosis, who received the currently licensed dosage. Voriconazole concentrations were measured using high-performance liquid chromatography (HPLC). The pharmacokinetic data were modeled using a nonparametric methodology and with a nonlinear pharmacokinetic structural model. The extent and consequences of pharmacokinetic variability were explored using Monte Carlo simulation. The relationship between drug exposure and clinical response was explored using logistic regression. Optimal sampling times were identified using D-optimal design. The fit of the nonlinear model was acceptable. Data from the healthy volunteers provided robust estimates for

K
m

and the maximum rate of enzyme activity (
V
max
). The Bayesian parameter estimates were more variable and statistically different in patients than in volunteers. There was a linear relationship between the trough concentration and area under the concentration-time curve (AUC
0-12
). There was no relationship between the AUC
0-12
and clinical response. The original parameter values were readily recapitulated using Monte Carlo simulation. Initial i.v. dosing resulted in higher AUC
0-12
and trough concentrations compared with oral dosing. Sample collection times of 1, 2, 3, 4, 8, and 12 h after an i.v. infusion are maximally informative times for future pharmacokinetic studies.
Discovery and Engineered Overproduction of Antimicrobial Nucleoside Antibiotic A201A from the Deep-Sea Marine Actinomycete Marinactinospora thermotolerans SCSIO 00652
Authors: Zhu Qinghua , Li Jun , Ma Junying , Luo Minghe , Wang Bo , Huang Hongbo , Tian Xinpeng , Li Wenjun , Zhang Si , Zhang Changsheng , Ju Jianhua 
Published: November 2011

ABSTRACT

Marinactinospora thermotolerans
SCSIO 00652, originating from a deep-sea marine sediment of the South China Sea, was discovered to produce antimicrobial nucleoside antibiotic A201A. Whole-genome scanning and annotation strategies enabled us to localize the genes responsible for A201A biosynthesis and to experimentally identify the gene cluster; inactivation of
mtdF
, an oxidoreductase gene within the suspected gene cluster, abolished A201A production. Bioinformatics analysis revealed that a gene designated
mtdA
furthest upstream within the A201A biosynthetic gene cluster encodes a GntR family transcriptional regulator. To determine the role of MtdA in regulating A201A production, the
mtdA
gene was inactivated in frame and the resulting Δ
mtdA
mutant was fermented alongside the wild-type strain as a control. High-performance liquid chromatography (HPLC) analyses of fermentation extracts revealed that the Δ
mtdA
mutant produced A201A in a yield ∼25-fold superior to that of the wild-type strain, thereby demonstrating that
MtdA
is a negative transcriptional regulator governing A201A biosynthesis. By virtue of its high production capacity, the Δ
mtdA
mutant constitutes an ideal host for the efficient large-scale production of A201A. These results validate
M. thermotolerans
as an emerging source of antibacterial agents and highlight the efficiency of metabolic engineering for antibiotic titer improvement.
Directed HIV-1 Evolution of Protease Inhibitor Resistance by Second-Generation Short Hairpin RNAs
Authors: Schopman Nick C. T. , Braun Anja , Berkhout Ben 
Published: November 2011

ABSTRACT
Despite the success of antiretroviral drugs in decreasing AIDS-related mortality, a substantial fraction of HIV-infected patients experience therapy failure due to the emergence of drug-resistant virus variants. For durable inhibition of HIV-1 replication, the emergence of such escape viruses must be controlled. In addition to antiretroviral drugs, RNA interference (RNAi)-based gene therapy can be used to inhibit HIV-1 replication by targeting the viral RNA genome. RNAi is an evolutionary conserved gene silencing mechanism that mediates the sequence-specific breakdown of the targeted mRNA. Here we investigated an alternative strategy combining the activity of a protease inhibitor (PI) with second-generation short hairpin RNAs (shRNAs) designed to specifically block the emergence of PI-resistant HIV-1 variants. We demonstrate that dominant viral escape routes can be effectively blocked by second-generation shRNAs and that virus evolution can be redirected toward less-fit variants. These results are of importance for a deeper understanding of HIV-1 evolution under combined drug and RNAi pressure and may be used to design future therapeutic approaches.
Galectin-1-Specific Inhibitors as a New Class of Compounds To Treat HIV-1 Infection
Authors: St-Pierre Christian , Ouellet Michel , Giguère Denis , Ohtake Reiko , Roy René , Sato Sachiko , Tremblay Michel J. 
Published: November 2011

ABSTRACT

Despite significant improvements, antiretroviral therapies against HIV-1 are plagued by a high frequency of therapeutic failures that have been associated with acquisition of drug resistance. We recently reported that HIV-1 exploits a host glycan binding protein, galectin-1, to increase its attachment to host cells, thereby increasing its overall infectivity in susceptible cells. This finding suggests that host molecules such as galectin-1 could reduce the expected efficiency of HIV-1 drugs targeting early steps of the replicative cycle, such as attachment and entry processes. Thus, new classes of drugs that would interfere with galectin-1/HIV-1 interactions could benefit the current antiretroviral therapy. To further explore this possibility, experiments were conducted to discover leading compounds showing specific inhibition of galectin-1 activity in a cellular model of HIV-1 infection. Three lactoside compounds were found to modestly inhibit the interaction of galectin-1 with primary human CD4
+
T cells. Interestingly, these same inhibitors reduced the galectin-1-mediated increase in HIV-1 attachment to target cells in a much more efficient manner. More important, the tested lactoside derivatives also significantly decreased the galectin-1-dependent enhancement of HIV-1 infection. These observations deserve further attention when considering that the development of new drugs to prevent and treat HIV-1 infection remains a priority.
Differential Effects of Linezolid and Ciprofloxacin on Toxin Production by Bacillus anthracis in an
In Vitro
Pharmacodynamic System
Authors: Louie Arnold , VanScoy Brian D. , Heine Henry S. , Liu Weiguo , Abshire Terry , Holman Kari , Kulawy Robert , Brown David L. , Drusano George L. 
Published: November 2011

ABSTRACT

Bacillus anthracis
causes anthrax. Ciprofloxacin is a gold standard for the treatment of anthrax. Previously, using the non-toxin-producing ΔSterne strain of
B. anthracis
, we demonstrated that linezolid was equivalent to ciprofloxacin for reducing the total (vegetative and spore) bacterial population. With ciprofloxacin therapy, the total population consisted of spores. With linezolid therapy, the population consisted primarily of vegetative bacteria. Linezolid is a protein synthesis inhibitor, while ciprofloxacin is not. Since toxins are produced only by vegetative
B. anthracis
, the effect of linezolid and ciprofloxacin on toxin production is of interest. The effect of simulated clinical regimens of ciprofloxacin and linezolid on the vegetative and spore populations and on toxin production was examined in an
in vitro
pharmacodynamic model over 15 days by using the toxin-producing Sterne strain of
B. anthracis
. Ciprofloxacin and linezolid reduced the total Sterne population at similar rates. With ciprofloxacin therapy, the total Sterne population consisted of spores. With linezolid therapy, >90% of the population was vegetative
B. anthracis
. With ciprofloxacin therapy, toxin was first detectable at 3 h and remained detectable for at least 5 h. Toxin was never detected with linezolid therapy. Ciprofloxacin and linezolid reduced the total Sterne population at similar rates. However, the
B. anthracis
population was primarily spores with ciprofloxacin therapy and was primarily vegetative bacteria with linezolid therapy. Toxin production was detected for at least 5 h with ciprofloxacin therapy but was never detected with linezolid treatment. Linezolid may have an advantage over ciprofloxacin for the treatment of
B. anthracis
infections.
Two Strikingly Different Signaling Pathways Are Induced by Meningococcal Type IV Pili on Endothelial and Epithelial Cells
Authors: Lécuyer Hervé , Nassif Xavier , Coureuil Mathieu 
Published: November 2011

ABSTRACT

Following adhesion on brain microvasculature,
Neisseria meningitidis
is able to cross the blood-brain barrier (BBB) by recruiting the polarity complex and the cell junction proteins, thus allowing the opening of the paracellular route. This feature is the consequence of the activation by the type IV pili of the β
2
-adrenergic receptor/β-arrestin signaling pathway. Here, we have extended this observation to primary peripheral endothelial cells, and we report that the interaction of
N. meningitidis
with the epithelium is strikingly different. The recruitment of the junctional components by
N. meningitidis
is indeed restricted to endothelial cell lines, and no alteration of the cell-cell junctions can be seen in epithelial monolayers following meningococcal type IV pilus-mediated colonization. Consistently, the β
2
-adrenergic receptor/β-arrestin pathway was not hijacked by bacteria adhering on epithelial cells. In addition, we showed that the consequences of the bacterial signaling on epithelial cells is different from that of endothelial cells, since
N. meningitidis
-induced signaling which protects the microcolonies from shear stress on endothelial cells is unable to do so on epithelial cells. Finally, we report that the minor pilin PilV, which has been shown to be essential for endothelial cell response, is not a required bacterial determinant to induce an epithelial cell response. These data demonstrate that even though pilus-mediated signaling induces an apparently similar cortical plaque, in epithelial and endothelial cell lineages, the signaling pathways are strikingly different in both models.
Conflicting objectives in trophy trout recreational fisheries: evaluating trade-offs using an individual-based model
Authors: García-Asorey Martín Ignacio , Escati-Peñaloza Gabriela , Parma Ana María , Pascual Miguel Alberto 
Published: November 2011

Standard fisheries models, based on average population metrics, are inadequate for analyzing recreational fisheries where fishing is size-selective and management objectives are related to preserving population size structure. We developed a framework for policy analysis of size-based harvest strategies in recreational fisheries. The framework combines a mixed-effects body growth model and an individual-based harvest model to describe the relationship of growth, mortality, and size structure. Fishery performance is quantified with indicators directly associated to catch-related components of anglers’ satisfaction: yield (kg), population size, and availability of trophy-size fish. We applied our analyses to the steelhead ( Oncorhynchus mykiss ) fishery in the Santa Cruz River (Patagonia, Argentina). Large declines in trophy-size fish are to be expected at fishing mortalities much too low to cause a sizeable decline in recruitment from virgin values. When somatic growth is density-independent, harvest occurs at the expense of other indicators associated with the quality of fishing experienced by individual anglers. Size limits provide a tool to better accommodate harvest without compromising fishing quality. When preserving population size is favored over preserving trophy-size fish, minimum size limits constitute the best policy overall, whereas maximum size limits are best when the emphasis is on preserving trophy-size fish.
Interactions between natural-occurring landscape conditions and land use influencing the abundance of riverine smallmouth bass, Micropterus dolomieu
Authors: Brewer Shannon K. , Rabeni Charles F. 
Published: November 2011

This study examined how interactions between natural landscape features and land use influenced the abundance of smallmouth bass, Micropterus dolomieu , in Missouri, USA, streams. Stream segments were placed into one of four groups based on natural-occurring watershed characteristics (soil texture and soil permeability) predicted to relate to smallmouth bass abundance. Within each group, stream segments were assigned forest (n = 3), pasture (n = 3), or urban (n = 3) designations based on the percentages of land use within each watershed. Analyses of variance indicated smallmouth bass densities differed between land use and natural conditions. Decision tree models indicated abundance was highest in forested stream segments and lowest in urban stream segments, regardless of group designation. Land use explained the most variation in decision tree models, but in-channel features of temperature, flow, and sediment also contributed significantly. These results are unique and indicate the importance of natural-occurring watershed conditions in defining the potential of populations and how finer-scale filters interact with land use to further alter population potential. Smallmouth bass has differing vulnerabilities to land-use attributes, and the better the natural watershed conditions are for population success, the more resilient these populations will be when land conversion occurs.
Microarray profiling reveals microRNAs involving soybean resistance to Phytophthora sojae
Authors: Guo Na , Ye Wen-Wu , Wu Xiao-Ling , Shen Dan-Yu , Wang Yuan-Chao , Xing Han , Dou Dao-Long 
Published: November 2011

MicroRNAs (miRNAs), a group of small noncoding RNAs, may serve as a class of post-transcriptional regulators in plant immune systems. Nevertheless, little is known about their roles in plant immune response to the oomycete pathogens. To identify miRNAs involved in the response of soybean to Phytophthora sojae , we examined expressional patterns of miRNAs upon infection by P. sojae by microarray analysis in three soybean cultivars: Williams (susceptible), Conrad (quantitative resistance), and Williams 82 (qualitative resistance). Expression of a number of miRNAs was significantly altered upon infection and (or) in the different genotypes. qRT–PCR data with some miRNAs further confirmed the microarray results. Comparative analysis of the selected miRNAs and their targeted gene expression datasets uncovered many reciprocally expressed miRNA–target pairs, which could proposed a feedback circuit between miRNA(s) and protein-coding genes. These results may serve as a basis for further in-depth studies of miRNAs involved in soybean resistance to P. sojae.
The complete mitochondrial genome sequence of Euphausia pacifica (Malacostraca: Euphausiacea) reveals a novel gene order and unusual tandem repeats
Authors: Shen Xin , Wang Haiqing , Wang Minxiao , Liu Bin 
Published: November 2011

Euphausiid krill are dominant organisms in the zooplankton population and play a central role in marine ecosystems. Euphausia pacifica (Malacostraca: Euphausiacea) is one of the most important and dominant crustaceans in the North Pacific Ocean. In this paper, we described the gene content, organization, and codon usage of the E. pacifica mitochondrial genome. The mitochondrial genome of E. pacifica is 16 898 bp in length and contains a standard set of 13 protein-coding genes, 2 ribosomal RNA genes, and 22 transfer RNA genes. Translocation of three transfer RNAs (trnL1, trnL2, and trnW) was found in the E. pacifica mitochondrial genome when comparing with the pancrustacean ground pattern. The rate of Ka/Ks in 13 protein-coding genes among three krill is much less than 1, which indicates a strong purifying selection within this group. The largest noncoding region in the E. pacifica mitochondrial genome contains one section with tandem repeats (4.7 × 154 bp), which are the largest tandem repeats found in malacostracan mitochondrial genomes so far. All analyses based on nucleotide and amino acid data strongly support the monophyly of Stomatopoda, Penaeidae, Caridea, Brachyura, and Euphausiacea. The Bayesian analysis of nucleotide and amino acid datasets strongly supports the close relationship between Euphausiacea and Decapoda, which confirms traditional findings. The maximum likelihood analysis based on amino acid data strongly supports the close relationship between Euphausiacea and Penaeidae, which destroys the monophyly of Decapoda.
Stem eccentricity, crown dry mass distribution, and longitudinal growth strain of plantation-grown Eucalyptus nitens after thinning
Authors: Medhurst Jane , Ottenschlaeger Maria , Wood Matthew , Harwood Chris , Beadle Chris , Valencia Juan Carlos 
Published: November 2011

Silvicultural treatments that aim to improve tree growth rates also have the potential to alter physical characteristics of the tree stem and thus affect the recovery of solid-wood products. We tested the hypothesis that manifest crown asymmetry in thinned Eucalyptus nitens (Deane & Maiden) Maiden plantations was affecting the development of stem shape. The crown and stem characteristics of 15 E. nitens trees from a 22-year-old thinning trial in northeastern Tasmania were examined. The trial had been thinned 16 years previously. Lowering the intensity of local intraspecific competition through thinning increased the crown dry mass in the north-facing aspect. No direct link was found between crown dry mass distribution and stem eccentricity. The direction of pith eccentricity at 3.0 m height was confined to the northwest and southeast sectors and averaged 11%; the degree of noncircularity in stems at 3.0 m height was strongly related to the ratio of stem diameter to total height squared. These results suggest that the dynamic loading from wind exposure plays a greater role in determining the extent and direction of pith eccentricity and stem cross-sectional circularity in E. nitens than does the static load from asymmetrical crown dry mass distribution.
Activated STAT5 Promotes Long-Lived Cytotoxic CD8+ T Cells That Induce Regression of Autochthonous Melanoma
Authors: Grange Magali , Buferne Michel , Verdeil Grégory , Leserman Lee , Schmitt-Verhulst Anne-Marie , Auphan-Anezin Nathalie 
Published: November 2011

Abstract
Immunotherapy based on adoptive transfer of tumor antigen-specific CD8+ T cell (TC) is generally limited by poor in vivo expansion and tumor infiltration. In this study, we report that activated STAT5 transcription factors (STAT5CA) confer high efficiency on CD8+ effector T cells (eTC) for host colonization after adoptive transfer. Engineered expression of STAT5CA in antigen-experienced TCs with poor replicative potential was also sufficient to convert them into long-lived antigen-responsive eTCs. In transplanted mastocytoma- or melanoma-bearing hosts, STAT5CA greatly enhanced the ability of eTCs to accumulate in tumors, become activated by tumor antigens, and to express the cytolytic factor granzyme B. Taken together, these properties contributed to an increase in tumor regression by STAT5CA-transduced, as compared with untransduced, TCs including when the latter control cells were combined with infusion of interleukin (IL)-2/anti–IL-2 complexes. In tumors arising in the autochthonous TiRP transgenic model of melanoma associated with systemic chronic inflammation, endogenous CD8+ TCs were nonfunctional. In this setting, adoptive transfer of STAT5CA-transduced TCs produced superior antitumor effects compared with nontransduced TCs. Our findings imply that STAT5CA expression can render TCs resistant to the immunosuppressive environment of melanoma tumors, enhancing their ability to home to tumors and to maintain high granzyme B expression, as well as their capacity to stimulate granzyme B expression in endogenous TCs. Cancer Res; 72(1); 76–87. ©2011 AACR.
BEAMing Sheds Light on Drug Resistance
Authors: Lauring Josh , Park Ben Ho 
Published: November 2011

Abstract
Targeted therapies against somatically altered genes are currently used for the treatment of many human cancers. The nascent technology known as BEAMing has the potential to increase the clinical utility of these agents because it allows for the detection of cancer mutations in peripheral blood, providing a rapid assessment of tumor mutation status. Clin Cancer Res; 17(24); 7508–10. ©2011 AACR.