bluuebunny/crossref_metadata_2025_split huggingface dataset:
Generalized ‘second Ritt theorem’ and explicit solution of the polynomial moment problem
Authors: Pakovich F. 
Published: January 2013

AbstractIn the recent paper by Pakovich and Muzychuk [Solution of the polynomial moment problem, Proc. Lond. Math. Soc. (3) 99 (2009), 633–657] it was shown that any solution of ‘the polynomial moment problem’, which asks to describe polynomials $Q$ orthogonal to all powers of a given polynomial $P$ on a segment, may be obtained as a sum of so-called ‘reducible’ solutions related to different decompositions of $P$ into a composition of two polynomials of lower degrees. However, the methods of that paper do not permit us to estimate the number of necessary reducible solutions or to describe them explicitly. In this paper we provide a description of polynomial solutions of the functional equation $P_1\circ W_1=P_2\circ W_2=\cdots =P_r\circ W_r,$and on this base describe solutions of the polynomial moment problem in an explicit form suitable for applications.
Fibre type‐specific change in FXYD1 phosphorylation during acute intense exercise in humans
Authors: Thomassen Martin , Murphy Robyn M. , Bangsbo Jens 
Published: January 2013

Key points
Most human experiments examine proteins at the whole muscle level, and knowledge of fibre type specificity is mainly obtained in animal muscles. We used a new methodology and provide novel findings at the single fibre level.
Potassium changes across muscle cell membranes may be important for development of fatigue during exercise. The Na+–K+ pump with the regulatory phospholemman (FXYD1) subunit and the ATP‐dependent K+ channel Kir6.2 play crucial roles in potassium regulation.
We show that in humans Na+–K+ pump α2 is expressed to a greater extent in type II than in type I fibres and Kir6.2 is expressed primarily in type I fibres. During exercise, phosphorylation of FXYD1 serine 68 is increased only in type II fibres, indicating differences in Na+–K+ pump activity.
These results show that human Kir6.2 and Na+–K+ pump subunit expression and FXYD1 phosphorylation are fibre type specific, which may influence exercise‐induced potassium regulation and fatigue development.
Abstract  The aim of the present study was to examine fibre type‐specific Na+–K+ pump subunit expression and exercise‐induced alterations in phospholemman (FXYD1) phosphorylation in humans. Segments of human skeletal muscle fibres were dissected and fibre typed, and protein expression was determined by Western blotting. The protein expression of the Na+–K+ pump α2 isoform was lower in type I than in type II fibres (0.63 ± 0.04 a.u. vs. 1.00 ± 0.07 a.u., P < 0.001), while protein expression of the Na+–K+ pump α1 and β1 isoforms was not different. Protein expression of the ATP‐dependent potassium channel Kir6.2 was higher in type I compared with type II fibres. In both type I (P < 0.01) and type II fibres (P < 0.001) the AB_FXYD1 signal was lower after exercise compared with rest, indicating an increase in unspecific FXYD1 phosphorylation. The FXYD1 serine 68 phosphorylation was higher (P < 0.001) after exercise compared with rest in type II fibres (1.90 ± 0.25 vs. 1.00 ± 0.08) and not changed in type I fibres. Total FXYD1 was not expressed in a fibre type‐specific manner. Expression of phosphofructokinase was lower (P < 0.001) in type I than in type II fibres, whereas citrate synthase and 3‐hydroxyacyl‐CoA dehydrogenase were more abundant (P < 0.001) in type I fibres. In conclusion, FXYD1 phosphorylation at serine 68 increased after an acute bout of intense exercise in human type II fibres, while AB_FXYD1 signal intensity was lower in both type I and type II fibres, indicating fibre type‐specific differences in FXYD1 phosphorylation on serine 63, serine 68 and threonine 69. This, together with the observation of a higher abundance of the Na+–K+ pump α2 isoform protein in type II fibres, is likely to have importance for the exercise‐induced human Na+–K+ pump activity in the different fibre types.
Investigation on the Effort Transmission in Planar Parallel
Manipulators
Authors: Briot Sébastien , Glazunov Victor , Arakelian Vigen 
Published: January 2013

Abstract
In the design of a mechanism, the quality of effort transmission is a key issue. Traditionally, the effort transmissivity of a mechanism is defined as the quantitative measure of the power flowing effectiveness from the input link(s) to the output link(s). Many researchers have focused their work on the study of the effort transmission in mechanisms and diverse indices have been defined. However, the developed indices have exclusively dealt with the studies of the ratio between the input and output powers and they do not seem to have been devoted to the studies of the admissible reactions in passive joints. However, the observations show that it is possible for a mechanism to reach positions in which the transmission indices will have admissible values but the reaction(s) in passive joint(s) can reach excessively high values leading to the breakdown of the mechanism. In the present paper, a method is developed to ensure the admissible values of reactions in passive joints of planar parallel manipulators. It is shown that the increase of reactions in passive joints of a planar parallel manipulator depends not only on the transmission angle but also on the position of the instantaneous center of rotation of the platform. It allows the determination of the maximal reachable workspace of planar parallel manipulators taking into account the admissible reactions in its passive joints. The suggested method is illustrated via a 5R planar parallel mechanism and a planar 3-RPR parallel manipulator.
Complete Sequence of the IncT-Type Plasmid pT-OXA-181 Carrying the
bla
OXA-181
Carbapenemase Gene from Citrobacter freundii
Authors: Villa Laura , Carattoli Alessandra , Nordmann Patrice , Carta Claudio , Poirel Laurent 
Published: January 2013

ABSTRACT

The gene encoding the carbapenemase OXA-181 (an OXA-48 variant) was identified from a
Citrobacter freundii
isolate coproducing NDM-1. The whole sequence of plasmid pT-OXA-181 bearing the
bla
OXA-181
gene was determined and revealed a 84-kb mobilizable but non-self-conjugative IncT-type plasmid. It totally differs from the 7.6-kb ColE-type and
bla
OXA-181
-bearing plasmid recently identified in a
Klebsiella pneumoniae
isolate. However, in both plasmids, insertion sequence IS
Ecp1
might have played a role in acquisition of the
bla
OXA-181
gene.
Outbreak of NDM-1-Producing Klebsiella pneumoniae in a Neonatal Unit in Colombia
Authors: Escobar Pérez Javier Antonio , Olarte Escobar Narda María , Castro-Cardozo Betsy , Valderrama Márquez Ismael Alberto , Garzón Aguilar Martha Isabel , Martinez de la Barrera Leslie , Barrero Barreto Esther Rocio , Marquez-Ortiz Ricaurte Alejandro , Moncada Guayazán Maria Victoria , Vanegas Gómez Natasha 
Published: January 2013

ABSTRACT

Six multiresistant, NDM-1-producing
Klebsiella pneumoniae
strains were recovered from an outbreak that affected six neonatal patients in a Colombian hospital. Molecular analysis showed that all of the isolates harbored the
bla
NDM-1
,
qnrA
, and
intI1
genes and were clonally related. Multilocus sequence typing showed that the isolates belonged to a new sequence type (ST1043) that was different from the sequence types that had previously been reported. This is the first report of NDM-1-producing isolates in South America.
A Physiologically Based Pharmacokinetic Model of Rifampin in Mice
Authors: Lyons Michael A. , Reisfeld Brad , Yang Raymond S. H. , Lenaerts Anne J. 
Published: January 2013

ABSTRACT

One problem associated with regimen-based development of antituberculosis (anti-TB) drugs is the difficulty of a systematic and thorough
in vivo
evaluation of the large number of possible regimens that arise from consideration of multiple drugs tested together. A mathematical model capable of simulating the pharmacokinetics and pharmacodynamics of experimental combination chemotherapy of TB offers a way to mitigate this problem by extending the use of available data to investigate regimens that are not initially tested. In order to increase the available mathematical tools needed to support such a model for preclinical anti-TB drug development, we constructed a preliminary whole-body physiologically based pharmacokinetic (PBPK) model of rifampin in mice, using data from the literature. Interindividual variability was approximated using Monte Carlo (MC) simulation with assigned probability distributions for the model parameters. An MC sensitivity analysis was also performed to determine correlations between model parameters and plasma concentration to inform future model development. Model predictions for rifampin concentrations in plasma, liver, kidneys, and lungs, following oral administration, were generally in agreement with published experimental data from multiple studies. Sensitive model parameters included those descriptive of oral absorption, total clearance, and partitioning of rifampin between blood and muscle. This PBPK model can serve as a starting point for the integration of rifampin pharmacokinetics in mice into a larger mathematical framework, including the immune response to
Mycobacterium tuberculosis
infection, and pharmacokinetic models for other anti-TB drugs.
A Novel Mechanism Underlies the Hepatotoxicity of Pyrazinamide
Authors: Shih Tung-Yuan , Pai Chien-Yi , Yang Ping , Chang Wen-Liang , Wang Ning-Chi , Hu Oliver Yoa-Pu 
Published: January 2013

ABSTRACT

Relatively little is known about the hepatotoxicity of pyrazinamide (PZA). PZA requires activation by amidase to form pyrazinoic acid (PA). Xanthine oxidase then hydroxylates PA to form 5-hydroxypyrazinoic acid (5-OH-PA). PZA can also be directly oxidized to form 5-OH-PZA. Before this study, it was unclear which metabolic pathway or PZA metabolites led to hepatotoxicity. This study determines whether PZA metabolites are responsible for PZA-induced hepatotoxicity. PZA metabolites were identified and cytotoxicity in HepG2 cells was assessed. Potential PZA and PA hepatotoxicity was then tested in rats. Urine specimens were collected from 153 tuberculosis (TB) patients, and the results were evaluated to confirm whether a correlation existed between PZA metabolite concentrations and hepatotoxicity. This led to the hypothesis that coadministration of amidase inhibitor (bis-
p
-nitrophenyl phosphate [BNPP]) decreases or prevents PZA- and PZA metabolite-induced hepatotoxicity in rats. PA and 5-OH-PA are more toxic than PZA. Electron microscopy showed that PZA and PA treatment of rats significantly increases aspartate transaminase (AST) and alanine aminotransferase (ALT) activity and galactose single-point (GSP) levels (
P
< 0.005). PA and 5-OH-PA levels are also significantly correlated with hepatotoxicity in the urine of TB patients (
P
< 0.005). Amidase inhibitor, BNPP, decreases PZA-induced, but not PA-induced, hepatotoxicity. This is the first report of a cell line, animal, and clinical trial confirming that the metabolite 5-OH-PA is responsible for PZA-induced hepatotoxicity.
Pathogenicity of Yersinia pestis Synthesis of 1-Dephosphorylated Lipid A
Authors: Sun Wei , Six David A. , Reynolds C. Michael , Chung Hak Suk , Raetz Christian R. H. , Curtiss Roy 
Published: January 2013

ABSTRACT

Synthesis of
Escherichia coli
LpxL, which transfers a secondary laurate chain to the 2′ position of lipid A, in
Yersinia pestis
produced bisphosphoryl hexa-acylated lipid A at 37°C, leading to significant attenuation of virulence. Our previous observations also indicated that strain χ10015(pCD1Ap) (Δ
lpxP32
::P
lpxL
lpxL
) stimulated a strong inflammatory reaction but sickened mice before recovery and retained virulence via intranasal (i.n.) infection. The development of live, attenuated
Y. pestis
vaccines may be facilitated by detoxification of its lipopolysaccharide (LPS). Heterologous expression of the lipid A 1-phosphatase, LpxE, from
Francisella tularensis
in
Y. pestis
yields predominantly 1-dephosphorylated lipid A, as confirmed by mass spectrometry. Results indicated that expression of LpxE on top of LpxL provided no significant reduction in virulence of
Y. pestis
in mice when it was administered i.n. but actually reduced the 50% lethal dose (LD
50
) by 3 orders of magnitude when the strain was administered subcutaneously (s.c.). Additionally, LpxE synthesis in wild-type
Y. pestis
KIM6+(pCD1Ap) led to slight attenuation by s.c. inoculation but no virulence change by i.n. inoculation in mice. In contrast to
Salmonella enterica
, expression of LpxE does not attenuate the virulence of
Y. pestis
.
RfaL Is Required for Yersinia pestis Type III Secretion and Virulence
Authors: Houppert Andrew S. , Bohman Lesley , Merritt Peter M. , Cole Christopher B. , Caulfield Adam J. , Lathem Wyndham W. , Marketon Melanie M. 
Published: January 2013

ABSTRACT

Yersinia pestis
, the causative agent of plague, uses a type III secretion system (T3SS) to inject cytotoxic Yop proteins directly into the cytosol of mammalian host cells. The T3SS can also be activated
in vitro
at 37°C in the absence of calcium. The chromosomal gene
rfaL
(
waaL
) was recently identified as a virulence factor required for proper function of the T3SS. RfaL functions as a ligase that adds the terminal
N
-acetylglucosamine to the lipooligosaccharide core of
Y. pestis
. We previously showed that deletion of
rfaL
prevents secretion of Yops
in vitro
. Here we show that the divalent cations calcium, strontium, and magnesium can partially or fully rescue Yop secretion
in vitro
, indicating that the secretion phenotype of the
rfaL
mutant may be due to structural changes in the outer membrane and the corresponding feedback inhibition on the T3SS. In support of this, we found that the defect can be overcome by deleting the regulatory gene
lcrQ
. Consistent with a defective T3SS, the
rfaL
mutant is less virulent than the wild type. We show here that the virulence defect of the mutant correlates with a decrease in both T3SS gene expression and ability to inject innate immune cells, combined with an increased sensitivity to cationic antimicrobial peptides.
Infective endocarditis developing serious multiple complications
Authors: Guler Selma , Sokmen Abdullah , Mese Bulent , Bozoglan Orhan 
Published: January 2013

A 20-year-old female patient with no history of heart disease presented to the hospital with high fever, cough and sputum. On the third day of hospitalisation, left facial paralysis developed and cranial revealed an infarct in the right frontoparietotemporal lobe. Transthoracic echocardiography revealed 1.5×2 cm-sized vegetation on the mitral valve and severe mitral regurgitation. On the 11th day of hospitalisation, multiple emboli were shown to be present in the left iliac artery. Since the patient had recurrent septic emboli despite 3 weeks of treatment, a surgical intervention was planned. The vegetation was removed and the mitral valve was replaced by mechanical prostheses. During the postoperative period, acute renal failure developed in the patient. The treatment was completed in 6 weeks with full recovery. This case confirms that infective endocarditis may present with various clinical situations, and that a high index of suspicion and surgical intervention, in addition to aggressive antibiotic therapy, is lifesaving.
Reducing Interleaving Semantics Redundancy in Reachability Analysis of Time Petri Nets
Authors: Boucheneb Hanifa , Barkaoui Kamel 
Published: January 2013

The main problem of verification techniques based on exploration of (reachable) state space is the state explosion problem. In timed models, abstract states reached by different interleavings of the same set of transitions are, in general, different and their union is not necessarily an abstract state. To attenuate this state explosion, it would be interesting to reduce the redundancy caused by the interleaving semantics by agglomerating all these abstract states whenever their union is an abstract state.
This article considers the time Petri net model and establishes some sufficient conditions that ensure that this union is an abstract state. In addition, it proposes a procedure to compute this union without computing beforehand intermediate abstract states. Finally, it shows how to use this result to improve the reachability analysis.
Overcoming the Response Plateau in Multiple Myeloma: A Novel Bortezomib-Based Strategy for Secondary Induction and High-Yield CD34+ Stem Cell Mobilization
Authors: Niesvizky Ruben , Mark Tomer M. , Ward Maureen , Jayabalan David S. , Pearse Roger N. , Manco Megan , Stern Jessica , Christos Paul J. , Mathews Lena , Shore Tsiporah B. , Zafar Faiza , Pekle Karen , Xiang Zhaoying , Ely Scott , Skerret Donna , Chen-Kiang Selina , Coleman Morton , Lane Maureen E. 
Published: January 2013

Abstract
Purpose: This phase II study evaluated bortezomib-based secondary induction and stem cell mobilization in 38 transplant-eligible patients with myeloma who had an incomplete and stalled response to, or had relapsed after, previous immunomodulatory drug-based induction.
Experimental Design: Patients received up to six 21-day cycles of bortezomib plus dexamethasone, with added liposomal doxorubicin for patients not achieving partial response or better by cycle 2 or very good partial response or better (≥VGPR) by cycle 4 (DoVeD), followed by bortezomib, high-dose cyclophosphamide, and filgrastim mobilization. Gene expression/signaling pathway analyses were conducted in purified CD34+ cells after bortezomib-based mobilization and compared against patients who received only filgrastim ± cyclophosphamide. Plasma samples were similarly analyzed for quantification of associated protein markers.
Results: The response rate to DoVeD relative to the pre-DoVeD baseline was 61%, including 39% ≥VGPR. Deeper responses were achieved in 10 of 27 patients who received bortezomib-based mobilization; postmobilization response rate was 96%, including 48% ≥VGPR, relative to the pre-DoVeD baseline. Median CD34+ cell yield was 23.2 × 106 cells/kg (median of 1 apheresis session). After a median follow-up of 46.6 months, median progression-free survival was 47.1 months from DoVeD initiation; 5-year overall survival rate was 76.4%. Grade ≥3 adverse events included thrombocytopenia (13%), hand–foot syndrome (11%), peripheral neuropathy (8%), and neutropenia (5%). Bortezomib-based mobilization was associated with modulated expression of genes involved in stem cell migration.
Conclusion: Bortezomib-based secondary induction and mobilization could represent an alternative strategy for elimination of tumor burden in immunomodulatory drug-resistant patients that does not impact stem cell yield. Clin Cancer Res; 19(6); 1534–46. ©2013 AACR.
Synergistic Activity of Bortezomib and HDACi in Preclinical Models of B-cell Precursor Acute Lymphoblastic Leukemia via Modulation of p53, PI3K/AKT, and NF-κB
Authors: Bastian Lorenz , Hof Jana , Pfau Madlen , Fichtner Iduna , Eckert Cornelia , Henze Günter , Prada Javier , von Stackelberg Arend , Seeger Karl , Shalapour Shabnam 
Published: January 2013

Abstract
Purpose: Relapse of disease and subsequent resistance to established therapies remains a major challenge in the treatment of childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL). New therapeutic options, such as proteasome and histone deacetylase inhibitors (HDACi) with a toxicity profile differing from that of conventional cytotoxic agents, are needed for these extensively pretreated patients.
Experimental Design: Antiproliferative and proapoptotic effects of combined HDACi/proteasome inhibitor treatments were analyzed using BCP-ALL monocultures, cocultures with primary mesenchymal stroma cells from patients with ALL, and xenograft mouse models. The underlying molecular mechanisms associated with combined treatment were determined by gene expression profiling and protein validation.
Results: We identified the proteasome inhibitor bortezomib as a promising combination partner for HDACi due to the substantial synergistic antileukemic activity in BCP-ALL cells after concomitant application. This effect was maintained or even increased in the presence of chemotherapeutic agents. The synergistic effect of combined HDACi/BTZ treatment was associated with the regulation of genes involved in cell cycle, JUN/MAPK, PI3K/AKT, p53, ubiquitin/proteasome, and NF-κB pathways. We observed an activation of NF-κB after bortezomib treatment and the induction of apoptosis-related NF-κB target genes such as TNFαRs after concomitant treatment, indicating a possible involvement of NF-κB as proapoptotic mediator. In this context, significantly lower NF-κB subunits gene expression was detected in leukemia cells from patients who developed a relapse during frontline chemotherapy, compared with those who relapsed after cessation of frontline therapy.
Conclusion: These results provide a rationale for the integration of HDACi/BTZ combinations into current childhood BCP-ALL treatment protocols. Clin Cancer Res; 19(6); 1445–57. ©2013 AACR.
First-in-Humans Trial of an RNA Interference Therapeutic Targeting VEGF and KSP in Cancer Patients with Liver Involvement
Authors: Tabernero Josep , Shapiro Geoffrey I. , LoRusso Patricia M. , Cervantes Andres , Schwartz Gary K. , Weiss Glen J. , Paz-Ares Luis , Cho Daniel C. , Infante Jeffrey R. , Alsina Maria , Gounder Mrinal M. , Falzone Rick , Harrop Jamie , White Amy C. Seila , Toudjarska Iva , Bumcrot David , Meyers Rachel E. , Hinkle Gregory , Svrzikapa Nenad , Hutabarat Renta M. , Clausen Valerie A. , Cehelsky Jeffrey , Nochur Saraswathy V. , Gamba-Vitalo Christina , Vaishnaw Akshay K. , Sah Dinah W.Y. , Gollob Jared A. , Burris Howard A. 
Published: January 2013

Abstract
RNA interference (RNAi) is a potent and specific mechanism for regulating gene expression. Harnessing RNAi to silence genes involved in disease holds promise for the development of a new class of therapeutics. Delivery is key to realizing the potential of RNAi, and lipid nanoparticles (LNP) have proved effective in delivery of siRNAs to the liver and to tumors in animals. To examine the activity and safety of LNP-formulated siRNAs in humans, we initiated a trial of ALN-VSP, an LNP formulation of siRNAs targeting VEGF and kinesin spindle protein (KSP), in patients with cancer. Here, we show detection of drug in tumor biopsies, siRNA-mediated mRNA cleavage in the liver, pharmacodynamics suggestive of target downregulation, and antitumor activity, including complete regression of liver metastases in endometrial cancer. In addition, we show that biweekly intravenous administration of ALN-VSP was safe and well tolerated. These data provide proof-of-concept for RNAi therapeutics in humans and form the basis for further development in cancer.
Significance: The findings in this report show safety, pharmacokinetics, RNAi mechanism of action, and clinical activity with a novel first-in-class LNP-formulated RNAi therapeutic in patients with cancer. The ability to harness RNAi to facilitate specific multitargeting, as well as increase the number of druggable targets, has important implications for future drug development in oncology. Cancer Discov; 3(4); 406–17. ©2012 AACR.
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