bluuebunny/crossref_metadata_2025_split huggingface dataset:
The association between polymorphisms in the DNA nucleotide excision repair genes and RRM1 gene and lung cancer risk
Authors: Li Xuefei , Zhang Jie , Su Chunxia , Zhao Xinping , Tang Liang , Zhou Caicun 
Published: January 2012

AbstractBackground  Although numerous studies have investigated the association between DNA repair gene variants and lung cancer risk, the results remain inconclusive and incomplete.Methods  We examined variants in seven nucleotide excision repair (NER) and RRM1 genes in association with primary lung cancer risk among 385 patients with newly diagnosed primary non‐small cell lung cancer and 208 cancer‐free controls collected from 2007 to 2009 in east China. The relationship between single nucleotide polymorphisms and risk of lung cancer was assessed by logistic regression and stratification analysis.Results  The rs17655GG (ERCC5) and rs5744751CT (POLE) were associated with increased risk of lung cancer (adjusted odds ratio [OR], 2.32, 95% confidence interval [CI], 1.41–3.83; adjusted OR, 2.84, 95% CI, 1.70–4.74]. In stratification analysis, we found the increased effect of rs17655GG on the risk of lung cancer was observed among female, older subjects, or non‐smokers. The heterozygote computed tomography (CT) of rs5744751 had a stronger unprotective effect on lung cancer among male, older subjects, or heavy smokers.Conclusion  These results suggest that rs17655GG and rs5744751CT may be associated with lung cancer susceptibility in the Chinese population. However, these findings still need to be verified in larger confirmatory studies.
Validation of a portable hand‐held whole‐blood ketone meter for use in cats
Authors: Weingart Christiane , Lotz Fabian , Kohn Barbara 
Published: January 2012

BackgroundUrinary dipsticks are the most frequent method used for screening of ketones in animals, but this method has many drawbacks. In human medicine, portable meters that measure ketones in whole blood have largely replaced urinary dipsticks.ObjectiveThe aim of this prospective study was to validate a portable whole‐blood ketone meter for use in cats.MethodsSixty‐two cats (11 clinically healthy, 51 with diabetes mellitus) were included in the study. The concentration of β‐hydroxybuyrate (β‐HB) was measured in venous and capillary blood with a hand‐held ketone meter (PrecisionXceed; assay range 0–8 mmol/L) and compared with a spectrophotometric method. Precision, accuracy, and the effects of hematocrit and anticoagulants were evaluated.ResultsBetween‐run precision using low‐ and high‐concentration control solutions was 8.1% and 2.6%, respectively; within‐run coefficient of variation determined using 12 feline blood samples was 2.8%. In the 62 cats, β‐HBconcentrations measured with the portable ketone meter ranged from 0–7.4 mmol/L (median 0.9 mmol/L). When β‐HBconcentrations measured by the portable meter were < 4.0 mmol/L there was good agreement with the reference method, but concentrations > 4.0 mmol/L were lower than those obtained by the reference method in 20 of 24 cats (83%). There was good correlation between capillary and venous measurements. Results were not affected by hematocrits from 0.17 to 0.50 L/L, butEDTAwas not a suitable anticoagulant.ConclusionMeasurement of β‐HBconcentration in peripheral or capillary blood by an easy‐to‐use portable ketone meter was suitable for detecting ketonemia in cats. Underestimation of β‐HBconcentration was observed at higher values, but results were sufficiently high to aid in diagnosing diabetic ketoacidosis.
Imaging diagnosis and clinical presentation of a Chiari malformation in a Thoroughbred foal
Authors: Lempe A. , Heine M. , Bosch B. , Mueller K. , Brehm W. 
Published: January 2012

SummaryA newborn Thoroughbred foal was presented to the clinic with ambiguous neurological deficits, spinal anomalies and a soft tissue swelling dorsal to the lumbar vertebral column. The foal was alert but unable to rise and stand. With radiography, ultrasonography, computed tomography (CT) and magnetic resonance imaging (MRI) a lumbar dysraphic anomaly, cerebellar herniation and coincidental skeletal abnormalities were documented. Finally, a meningomyelocele was defined and, in context with the cerebellar herniation through theforamen magnum, the foal was diagnosed to have a Chiari malformation. The MRI examination corresponded best with thepost mortemfindings. Although 3‐dimensional imaging methods have been considered superior regarding full and detailed assessment of the congenital malformation, radiography and ultrasonography also provide essential information to diagnose dysraphic lesions at reduced costs and efforts. A Chiari malformation should be considered as a differential diagnosis in foals with neurological deficits.
Complications associated with transurethral endoscopic‐assisted electrohydraulic lithotripsy for treatment of a bladder calculus in a gelding
Authors: Reichelt U. , Lischer C. 
Published: January 2012

SummaryA cystic calculus approximately 6 cm in diameter was diagnosed by ultrasonography and endoscopy in a 12‐year‐old Trakehner gelding with a history of haematuria and dysuria. Transurethral endoscopic lithotripsy with electrohydraulic shock waves was performed as a minimally invasive treatment option. Fragmentation of the calculus was achieved, the fragments of the calculus left in the bladder and excretion assisted by infusion of Ringer's solution. Twenty‐four hours after the third lithotripsy, the horse suffered a recurrence of dysuria and pollakiuria due to partial obstruction of the urethra by the calculus fragments. The treatment was repeated within the urethra until clearance of the fragments was achieved. The sharp fragments had produced a zone of urethral mucosal trauma, approximately 10 cm in length. At the follow‐up visit 4 weeks later, the patient had developed inflammation and swelling of the urethral mucosa, which was successfully treated with a 14 day course of anti‐inflammatory drugs. This resulted in normal urination. At the last follow‐up, the horse had been recurrence‐free for 12 months.
A Genomewide Screen in Schizosaccharomyces pombe for Genes Affecting the Sensitivity of Antifungal Drugs That Target Ergosterol Biosynthesis
Authors: Fang Yue , Hu Lingling , Zhou Xin , Jaiseng Wurentuya , Zhang Ben , Takami Tomonori , Kuno Takayoshi 
Published: January 2012

ABSTRACT

We performed a genomewide screen for altered sensitivity to antifungal drugs, including clotrimazole and terbinafine, that target ergosterol biosynthesis using a
Schizosaccharomyces pombe
gene deletion library consisting of 3,004 nonessential haploid deletion mutants. We identified 109 mutants that were hypersensitive and 11 mutants that were resistant to these antifungals. Proteins whose absence rendered cells sensitive to these antifungals were classified into various functional categories, including ergosterol biosynthesis, membrane trafficking, histone acetylation and deacetylation, ubiquitination, signal transduction, ribosome biosynthesis and assembly, regulation of transcription and translation, cell wall organization and biogenesis, mitochondrion function, amino acid metabolism, nucleic acid metabolism, lipid metabolism, meiosis, and other functions. Also, proteins whose absence rendered cells resistant to these antifungals were classified into functional categories including mitochondrion function, ubiquitination, membrane trafficking, cell polarity, chromatin remodeling, and some unknown functions. Furthermore, the 109 sensitive mutants were tested for sensitivity to micafungin, another antifungal drug that inhibits (1,3)-β-
d
-glucan synthase, and 57 hypersensitive mutants were identified, suggesting that these mutants were defective in cell wall integrity. Altogether, our findings in fission yeast have shed light on molecular pathways associated with the cellular response to ergosterol biosynthesis inhibitors and may provide useful information for developing strategies aimed at sensitizing cells to these drugs.
S279 Point Mutations in Candida albicans Sterol 14-α Demethylase (CYP51) Reduce
In Vitro
Inhibition by Fluconazole
Authors: Warrilow Andrew G. S. , Mullins Jonathan G. L. , Hull Claire M. , Parker Josie E. , Lamb David C. , Kelly Diane E. , Kelly Steven L. 
Published: January 2012

ABSTRACT

The effects of S279F and S279Y point mutations in
Candida albicans
CYP51 (CaCYP51) on protein activity and on substrate (lanosterol) and azole antifungal binding were investigated. Both S279F and S279Y mutants bound lanosterol with 2-fold increased affinities (

K
s

, 7.1 and 8.0 μM, respectively) compared to the wild-type CaCYP51 protein (

K
s

, 13.5 μM). The S279F and S279Y mutants and the wild-type CaCYP51 protein bound fluconazole, voriconazole, and itraconazole tightly, producing typical type II binding spectra. However, the S279F and S279Y mutants had 4- to 5-fold lower affinities for fluconazole, 3.5-fold lower affinities for voriconazole, and 3.5- to 4-fold lower affinities for itraconazole than the wild-type CaCYP51 protein. The S279F and S279Y mutants gave 2.3- and 2.8-fold higher 50% inhibitory concentrations (IC
50
s) for fluconazole in a CYP51 reconstitution assay than the wild-type protein did. The increased fluconazole resistance conferred by the S279F and S279Y point mutations appeared to be mediated through a combination of a higher affinity for substrate and a lower affinity for fluconazole. In addition, lanosterol displaced fluconazole from the S279F and S279Y mutants but not from the wild-type protein. Molecular modeling of the wild-type protein indicated that the oxygen atom of S507 interacts with the second triazole ring of fluconazole, assisting in orientating fluconazole so that a more favorable binding conformation to heme is achieved. In contrast, in the two S279 mutant proteins, this S507-fluconazole interaction is absent, providing an explanation for the higher
K
d
values observed.
NagZ-Dependent and NagZ-Independent Mechanisms for β-Lactamase Expression in Stenotrophomonas maltophilia
Authors: Huang Yi-Wei , Hu Rouh-Mei , Lin Cheng-Wen , Chung Tung-Ching , Yang Tsuey-Ching 
Published: January 2012

ABSTRACT

β-
N
-Acetylglucosaminidase (NagZ), encoded by the
nagZ
gene, is a critical enzyme for basal-level
ampC
derepression (
ampC
expression in the absence of β-lactam challenge) in
ampD
and
dacB
mutants of
Pseudomonas aeruginosa
. Three mutants with a phenotype of basal-level L1 and L2 β-lactamase derepression in
Stenotrophomonas maltophilia
have been reported, including KJΔDI (

ampD
I

mutant), KJΔmrcA (
mrcA
mutant), and KJΔDIΔmrcA (

ampD
I

and
mrcA
double mutant). In this study,
nagZ
of
S. maltophilia
was characterized, and its roles in basal-level β-lactamase derepression, induced β-lactamase activities, and β-lactam resistance of KJΔDI, KJΔmrcA, and KJΔDIΔmrcA were evaluated. Expression of the
nagZ
gene was constitutive and not regulated by AmpR, AmpD
I
, AmpN, AmpG, PBP1a, and NagZ. Introduction of Δ
nagZ
into KJΔDI nearly abolished basal-level derepressed β-lactamase activity; conversely, introduction of Δ
nagZ
into KJΔmrcA did not affect it. At least two activator ligands (ALs) are thus considered responsible for β-lactamase expression in the
S. maltophilia
system, specifically, the NagZ-dependent (AL1) and NagZ-independent (AL2) ligands responsible for the basal-level derepressed β-lactamase activities of KJΔDI and KJΔmrcA, respectively. The contributions of AL1 and AL2 to the induced β-lactamase activities may vary with the types of β-lactams.
nagZ
inactivation did not affect aztreonam-, cefoxitin-, and carbenicillin-induced β-lactamase activities, but it attenuated cefuroxime- and piperacillin-induced β-lactamase activities. Introduction of Δ
nagZ
into KJ, KJΔDI, KJΔmrcA, and KJΔDIΔmrcA did not significantly change the MICs of the β-lactams tested except that the MICs of cefuroxime and piperacillin moderately decreased in strains KJΔZ and KJΔDIΔZ (
nagZ
mutants).
SQ109 Targets MmpL3, a Membrane Transporter of Trehalose Monomycolate Involved in Mycolic Acid Donation to the Cell Wall Core of Mycobacterium tuberculosis
Authors: Tahlan Kapil , Wilson Regina , Kastrinsky David B. , Arora Kriti , Nair Vinod , Fischer Elizabeth , Barnes S. Whitney , Walker John R. , Alland David , Barry Clifton E. , Boshoff Helena I. 
Published: January 2012

ABSTRACT

SQ109, a 1,2-diamine related to ethambutol, is currently in clinical trials for the treatment of tuberculosis, but its mode of action remains unclear. Here, we demonstrate that SQ109 disrupts cell wall assembly, as evidenced by macromolecular incorporation assays and ultrastructural analyses. SQ109 interferes with the assembly of mycolic acids into the cell wall core of
Mycobacterium tuberculosis
, as bacilli exposed to SQ109 show immediate inhibition of trehalose dimycolate (TDM) production and fail to attach mycolates to the cell wall arabinogalactan. These effects were not due to inhibition of mycolate synthesis, since total mycolate levels were unaffected, but instead resulted in the accumulation of trehalose monomycolate (TMM), the precursor of TDM and cell wall mycolates.
In vitro
assays using purified enzymes showed that this was not due to inhibition of the secreted Ag85 mycolyltransferases. We were unable to achieve spontaneous generation of SQ109-resistant mutants; however, analogs of this compound that resulted in similar shutdown of TDM synthesis with concomitant TMM accumulation were used to spontaneously generate resistant mutants that were also cross-resistant to SQ109. Whole-genome sequencing of these mutants showed that these all had mutations in the essential
mmpL3
gene, which encodes a transmembrane transporter. Our results suggest that MmpL3 is the target of SQ109 and that MmpL3 is a transporter of mycobacterial TMM.
Azole Resistance by Loss of Function of the Sterol Δ
5,6
-Desaturase Gene (
ERG3
) in Candida albicans Does Not Necessarily Decrease Virulence
Authors: Vale-Silva L. A. , Coste A. T. , Ischer F. , Parker J. E. , Kelly S. L. , Pinto E. , Sanglard D. 
Published: January 2012

ABSTRACT

The inactivation of
ERG3
, a gene encoding sterol Δ
5,6
-desaturase (essential for ergosterol biosynthesis), is a known mechanism of
in vitro
resistance to azole antifungal drugs in the human pathogen
Candida albicans. ERG3
inactivation typically results in loss of filamentation and attenuated virulence in animal models of disseminated candidiasis. In this work, we identified a
C. albicans
clinical isolate (VSY2) with high-level resistance to azole drugs
in vitro
and an absence of ergosterol but normal filamentation. Sequencing of
ERG3
in VSY2 revealed a double base deletion leading to a premature stop codon and thus a nonfunctional enzyme. The reversion of the double base deletion in the mutant allele (
erg3-1
) restored ergosterol biosynthesis and full fluconazole susceptibility in VSY2, confirming that
ERG3
inactivation was the mechanism of azole resistance. Additionally, the replacement of both
ERG3
alleles by
erg3-1
in the wild-type strain SC5314 led to the absence of ergosterol and to fluconazole resistance without affecting filamentation. In a mouse model of disseminated candidiasis, the clinical
ERG3
mutant VSY2 produced kidney fungal burdens and mouse survival comparable to those obtained with the wild-type control. Interestingly, while VSY2 was resistant to fluconazole both
in vitro
and
in vivo
, the
ERG3
-derived mutant of SC5314 was resistant only
in vitro
and was less virulent than the wild type. This suggests that VSY2 compensated for the
in vivo
fitness defect of
ERG3
inactivation by a still unknown mechanism(s). Taken together, our results provide evidence that contrary to previous reports inactivation of
ERG3
does not necessarily affect filamentation and virulence.
A Semimechanistic Pharmacokinetic-Enzyme Turnover Model for Rifampin Autoinduction in Adult Tuberculosis Patients
Authors: Smythe Wynand , Khandelwal Akash , Merle Corinne , Rustomjee Roxana , Gninafon Martin , Bocar Lo Mame , Sow Oumou Bah , Olliaro Piero L. , Lienhardt Christian , Horton John , Smith Peter , McIlleron Helen , Simonsson Ulrika S. H. 
Published: January 2012

ABSTRACT

The currently recommended doses of rifampin are believed to be at the lower end of the dose-response curve. Rifampin induces its own metabolism, although the effect of dose on the extent of autoinduction is not known. This study aimed to investigate rifampin autoinduction using a semimechanistic pharmacokinetic-enzyme turnover model. Four different structural basic models were explored to assess whether different scaling methods affected the final covariate selection procedure. Covariates were selected by using a linearized approach. The final model included the allometric scaling of oral clearance and apparent volume of distribution. Although HIV infection was associated with a 30% increase in the apparent volume of distribution, simulations demonstrated that the effect of HIV on rifampin exposure was slight. Model-based simulations showed close-to-maximum induction achieved after 450-mg daily dosing, since negligible increases in oral clearance were observed following the 600-mg/day regimen. Thus, dosing above 600 mg/day is unlikely to result in higher magnitudes of autoinduction. In a typical 55-kg male without HIV infection, the oral clearance, which was 7.76 liters · h
−1
at the first dose, increased 1.82- and 1.85-fold at steady state after daily dosing with 450 and 600 mg, respectively. Corresponding reductions of 41 and 42%, respectively, in the area under the concentration-versus-time curve from 0 to 24 h were estimated. The turnover of the inducible process was estimated to have a half-life of approximately 8 days in a typical patient. Assuming 5 half-lives to steady state, this corresponds to a duration of approximately 40 days to reach the induced state for rifampin autoinduction.
pJIE137 Carrying
bla
CTX-M-62
Is Closely Related to p271A Carrying
bla
NDM-1
Authors: Partridge Sally R. , Paulsen Ian T. , Iredell Jonathan R. 
Published: January 2012

ABSTRACT

Complete sequencing of pJIE137 revealed a backbone closely related to p271A, encoding a novel RepA protein but with a similar organization and up to ∼70% nucleotide identity to IncN plasmids. A region in pJIE137 resembling the IncN CUP regulon is mostly missing from p271A, presumably due to recombination. The class 1 In/Tn and IS
Ecp1-bla
CTX-M-62
transposition unit in pJIE137 and a putative transposon carrying
bla
NDM-1
in p271A are inserted in different locations in the plasmid backbone.
In Vitro
and
In Vivo
Antimalarial Activities of T-2307, a Novel Arylamidine
Authors: Kimura Akiko , Nishikawa Hiroshi , Nomura Nobuhiko , Mitsuyama Junichi , Fukumoto Shinya , Inoue Noboru , Kawazu Shin-ichiro 
Published: January 2012

ABSTRACT

T-2307, a novel arylamidine, has been shown to exhibit broad-spectrum antifungal activities against clinically significant pathogens. Here, we evaluated the
in vitro
and
in vivo
antimalarial activity of T-2307. The 50% inhibitory concentrations (IC
50
s) of T-2307 against
Plasmodium falciparum
FCR-3 and K-1 strains were 0.47 and 0.17 μM, respectively. T-2307 at 2.5 to 10 mg/kg of body weight/day exhibited activity against blood stage and liver stage parasites in rodent malaria models. In conclusion, T-2307 exhibited
in vitro
and
in vivo
antimalarial activity.
The Natural Antimicrobial Peptide Subtilosin Acts Synergistically with Glycerol Monolaurate, Lauric Arginate, and ε-Poly-
l
-Lysine against Bacterial Vaginosis-Associated Pathogens but Not Human Lactobacilli
Authors: Sutyak Noll Katia , Prichard Mark N. , Khaykin Arkady , Sinko Patrick J. , Chikindas Michael L. 
Published: January 2012

ABSTRACT

Subtilosin is a cyclical antimicrobial peptide produced by
Bacillus amyloliquefaciens
that has antimicrobial activity against the bacterial vaginosis-associated human pathogen
Gardnerella vaginalis
. The ability of subtilosin to inhibit
G. vaginalis
alone and in combination with the natural antimicrobial agents glycerol monolaurate (Lauricidin), lauric arginate, and ε-poly-
l
-lysine was tested using a checkerboard approach. Subtilosin was found to act synergistically with all of the chosen antimicrobials. These promising results indicate that lower concentrations of subtilosin in combination with other compounds could effectively be used to inhibit growth of the pathogen, thereby decreasing the risk of developed antimicrobial resistance. This is the first report on the effects of subtilosin combined with other natural antimicrobials against
G. vaginalis
.
Interleukin-17 Drives Pulmonary Eosinophilia following Repeated Exposure to Aspergillus fumigatus Conidia
Authors: Murdock Benjamin J. , Falkowski Nicole R. , Shreiner Andrew B. , Sadighi Akha Amir A. , McDonald Roderick A. , White Eric S. , Toews Galen B. , Huffnagle Gary B. 
Published: January 2012

ABSTRACTPrevious research in our laboratory has demonstrated that repeated intranasal exposure toAspergillus fumigatusconidia in C57BL/6 mice results in a chronic pulmonary inflammatory response that reaches its maximal level after four challenges. The inflammatory response is characterized by eosinophilia, goblet cell metaplasia, and T helper TH2 cytokine production, which is accompanied by sustained interleukin-17 (IL-17) expression that persists even after the TH2 response has begun to resolve. TH17 cells could develop in mice deficient in gamma interferon (IFN-γ), IL-4, or IL-10. In the lungs of IL-17 knockout mice repeatedly challenged withA. fumigatusconidia, inflammation was attenuated (with the most significant decrease occurring in eosinophils), conidial clearance was enhanced, and the early transient peak of CD4+CD25+FoxP3+cells blunted. IL-17 appeared to play only a minor role in eosinophil differentiation in the bone marrow but a central role in eosinophil extravasation from the blood into the lungs. These observations point to an expanded role for IL-17 in driving TH2-type inflammation to repeated inhalation of fungal conidia.
Protective Role ofd-Amino Acid Oxidase against Staphylococcus aureus Infection
Authors: Nakamura Hideaki , Fang Jun , Maeda Hiroshi 
Published: January 2012

ABSTRACTd-Amino acid oxidase (DAO) is a hydrogen peroxide-generating enzyme that uses ad-amino acid as a substrate. We hypothesized that DAO may protect against bacterial infection, because hydrogen peroxide is one of the most important molecules in the antibacterial defense systems in mammals. We show here that DAO suppressed the growth ofStaphylococcus aureusin a manner that depended on the concentration of DAO andd-amino acidin vitro. Addition of catalase abolished the bacteriostatic activity of DAO. Although DAO plusd-Ala showed less bactericidal activity, addition of myeloperoxidase (MPO) greatly enhanced the bactericidal activity of DAO. Furthermore, DAO was able to utilize bacterial lysate, which containsd-Ala derived from peptidoglycan; this could produce hydrogen peroxide with, in the presence of myeloperoxidase, formation of hypochlorous acid. This concerted reaction of DAO and MPO led to the bactericidal action.In vivoexperiments showed that DAO−/−(mutant) mice were more susceptible toS. aureusinfection than were DAO+/+(wild-type) mice. These results suggest that DAO, together with myeloperoxidase, may play an important role in antibacterial systems in mammals.