bluuebunny/crossref_metadata_2025_split huggingface dataset:
The crystal structure of alanine racemase from Streptococcus pneumoniae, a target for structure-based drug design
Authors: Im Hookang , Sharpe Miriam L , Strych Ulrich , Davlieva Milya , Krause Kurt L 
Published: May 2011

Abstract

Background

Streptococcus pneumoniae is a globally important pathogen. The Gram-positive diplococcus is a leading cause of pneumonia, otitis media, bacteremia, and meningitis, and antibiotic resistant strains have become increasingly common over recent years.Alanine racemase is a ubiquitous enzyme among bacteria and provides the essential cell wall precursor, D-alanine. Since it is absent in humans, this enzyme is an attractive target for the development of drugs against S. pneumoniae and other bacterial pathogens.

Results
Here we report the crystal structure of alanine racemase from S. pneumoniae (AlrSP). Crystals diffracted to a resolution of 2.0 Å and belong to the space group P3121 with the unit cell parameters a = b = 119.97 Å, c = 118.10 Å, α = β = 90° and γ = 120°. Structural comparisons show that AlrSP shares both an overall fold and key active site residues with other bacterial alanine racemases. The active site cavity is similar to other Gram positive alanine racemases, featuring a restricted but conserved entryway.

Conclusions
We have solved the structure of AlrSP, an essential step towards the development of an accurate pharmacophore model of the enzyme, and an important contribution towards our on-going alanine racemase structure-based drug design project. We have identified three regions on the enzyme that could be targeted for inhibitor design, the active site, the dimer interface, and the active site entryway.
Dexamethasone inhibits the Nox-dependent ROS production via suppression of MKP-1-dependent MAPK pathways in activated microglia
Authors: Huo Yingqian , Rangarajan Parakalan , Ling Eng-Ang , Dheen S Thameem 
Published: May 2011

AbstractBackgroundNox-2 (also known as gp91phox), a subunit component of NADPH oxidases, generates reactive oxygen species (ROS). Nox-dependent ROS generation and nitric oxide (NO) release by microglia have been implicated in a variety of diseases in the central nervous system. Dexamethasone (Dex) has been shown to suppress the ROS production, NO release and inflammatory reaction of activated microglial cells. However, the underlying mechanisms remain unclear.ResultsThe present study showed that the increased ROS production and NO release in activated BV-2 microglial cells by LPS were associated with increased expression of Nox-2 and iNOS. Dex suppressed the upregulation of Nox-2 and iNOS, as well as the subsequent ROS production and NO synthesis in activated BV-2 cells. This inhibition caused by Dex appeared to be mediated by upregulation of MAPK phosphatase-1 (MKP-1), which antagonizes the activity of mitogen-activated protein kinases (MAPKs). Dex induced-suppression of Nox-2 and -upregulation of MKP-1 was also evident in the activated microglia from corpus callosum of postnatal rat brains. The overexpression of MKP-1 or inhibition of MAPKs (by specific inhibitors of JNK and p38 MAPKs), were found to downregulate the expression of Nox-2 and iNOS and thereby inhibit the synthesis of ROS and NO in activated BV-2 cells. Moreover, Dex was unable to suppress the LPS-induced synthesis of ROS and NO in BV-2 cells transfected with MKP-1 siRNA. On the other hand, knockdown of Nox-2 in BV-2 cells suppressed the LPS-induced ROS production and NO release.ConclusionIn conclusion, it is suggested that downregulation of Nox-2 and overexpression of MKP-1 that regulate ROS and NO may form the potential therapeutic strategy for the treatment of neuroinflammation in neurodegenerative diseases.
Characterization and analysis of the cotton cyclopropane fatty acid synthase family and their contribution to cyclopropane fatty acid synthesis
Authors: Yu Xiao-Hong , Rawat Richa , Shanklin John 
Published: May 2011

Abstract

Background
Cyclopropane fatty acids (CPA) have been found in certain gymnosperms, Malvales, Litchi and other Sapindales. The presence of their unique strained ring structures confers physical and chemical properties characteristic of unsaturated fatty acids with the oxidative stability displayed by saturated fatty acids making them of considerable industrial interest. While cyclopropenoid fatty acids (CPE) are well-known inhibitors of fatty acid desaturation in animals, CPE can also inhibit the stearoyl-CoA desaturase and interfere with the maturation and reproduction of some insect species suggesting that in addition to their traditional role as storage lipids, CPE can contribute to the protection of plants from herbivory.

Results
Three genes encoding cyclopropane synthase homologues GhCPS1, GhCPS2 and GhCPS3 were identified in cotton. Determination of gene transcript abundance revealed differences among the expression of GhCPS1, 2 and 3 showing high, intermediate and low levels, respectively, of transcripts in roots and stems; whereas GhCPS1 and 2 are both expressed at low levels in seeds. Analyses of fatty acid composition in different tissues indicate that the expression patterns of GhCPS1 and 2 correlate with cyclic fatty acid (CFA) distribution. Deletion of the N-terminal oxidase domain lowered GhCPS's ability to produce cyclopropane fatty acid by approximately 70%. GhCPS1 and 2, but not 3 resulted in the production of cyclopropane fatty acids upon heterologous expression in yeast, tobacco BY2 cell and Arabidopsis seed.

Conclusions
In cotton GhCPS1 and 2 gene expression correlates with the total CFA content in roots, stems and seeds. That GhCPS1 and 2 are expressed at a similar level in seed suggests both of them can be considered potential targets for gene silencing to reduce undesirable seed CPE accumulation. Because GhCPS1 is more active in yeast than the published Sterculia CPS and shows similar activity when expressed in model plant systems, it represents a strong candidate gene for CFA accumulation via heterologous expression in production plants.
Introduction of an electronic monitoring system for monitoring compliance with Moments 1 and 4 of the WHO "My 5 Moments for Hand Hygiene" methodology
Authors: Cheng Vincent CC , Tai Josepha WM , Ho Sara KY , Chan Jasper FW , Hung Kwan Ngai , Ho Pak Leung , Yuen Kwok Yung 
Published: May 2011

Abstract

Background
MedSense is an electronic hand hygiene compliance monitoring system that provides Infection Control Practitioners with continuous access to hand hygiene compliance information by monitoring Moments 1 and 4 of the WHO "My 5 Moments for Hand Hygiene" guidelines. Unlike previous electronic monitoring systems, MedSense operates in open cubicles with multiple beds and does not disrupt existing workflows.

Methods
This study was conducted in a 6-bed neurosurgical intensive care unit with technical development and evaluation phases. Healthcare workers (HCWs) wore an electronic device in the style of an identity badge to detect hand hygiene opportunities and compliance. We compared the compliance determined by the system and an infection control nurse. At the same time, the system assessed compliance by time of day, day of week, work shift, professional category of HCWs, and individual subject, while the workload of HCWs was monitored by measuring the amount of time they spent in patient zones.

Results
During the three-month evaluation phase, the system identified 13,694 hand hygiene opportunities from 17 nurses, 3 physiotherapists, and 1 healthcare assistant, resulting in an overall compliance of 35.1% for the unit. The per-indication compliance for Moment 1, 4, and simultaneous 1 and 4 were 21.3% (95%CI: 19.0, 23.6), 39.6% (95%CI: 37.3, 41.9), and 49.2% (95%CI: 46.6, 51.8), respectively, and were all statistically significantly different (p < 0.001). In the four 20-minute sessions when hand hygiene was monitored concurrently by the system and infection control nurse, the compliance were 88.9% and 95.6% respectively (p = 0.34), and the activity indices were 11.1 and 12.9 opportunities per hour, respectively. The hours from 12:00 to 14:00 had a notably lower compliance (21.3%, 95%CI: 17.2, 25.3) than nearly three quarters of the other periods of the day (p < 0.001). Nurses who used shared badges had significantly (p < 0.01) lower compliance (23.7%, 95%CI: 17.8, 29.6) than both the registered nurses (36.1%, 95%CI: 34.2, 37.9) and nursing officers (34.0%, 95%CI: 31.1, 36.9) who used named badges.

Conclusion
MedSense provides an unobtrusive and objective measurement of hand hygiene compliance. The information is important for staff training by the infection control team and allocation of manpower by hospital administration.
Genetic polymorphisms in folate pathway enzymes, DRD4 and GSTM1 are related to temporomandibular disorder
Authors: Aneiros-Guerrero Angel , Lendinez Ana M , Palomares Arturo R , Perez-Nevot Beatriz , Aguado Lidia , Mayor-Olea Alvaro , Ruiz-Galdon Maximiliano , Reyes-Engel Armando 
Published: May 2011

Abstract

Background
Temporomandibular disorder (TMD) is a multifactorial syndrome related to a critical period of human life. TMD has been associated with psychological dysfunctions, oxidative state and sexual dimorphism with coincidental occurrence along the pubertal development. In this work we study the association between TMD and genetic polymorphisms of folate metabolism, neurotransmission, oxidative and hormonal metabolism. Folate metabolism, which depends on genes variations and diet, is directly involved in genetic and epigenetic variations that can influence the changes of last growing period of development in human and the appearance of the TMD.

Methods
A case-control study was designed to evaluate the impact of genetic polymorphisms above described on TMD. A total of 229 individuals (69% women) were included at the study; 86 were patients with TMD and 143 were healthy control subjects. Subjects underwent to a clinical examination following the guidelines by the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD). Genotyping of 20 Single Nucleotide Polymorphisms (SNPs), divided in two groups, was performed by multiplex minisequencing preceded by multiplex PCR. Other seven genetic polymorphisms different from SNPs (deletions, insertions, tandem repeat, null genotype) were achieved by a multiplex-PCR. A chi-square test was performed to determine the differences in genotype and allelic frequencies between TMD patients and healthy subjects. To estimate TMD risk, in those polymorphisms that shown significant differences, odds ratio (OR) with a 95% of confidence interval were calculated.

Results
Six of the polymorphisms showed statistical associations with TMD. Four of them are related to enzymes of folates metabolism: Allele G of Serine Hydoxymethyltransferase 1 (SHMT1) rs1979277 (OR = 3.99; 95%CI 1.72, 9.25; p = 0.002), allele G of SHMT1 rs638416 (OR = 2.80; 95%CI 1.51, 5.21; p = 0.013), allele T of Methylentetrahydrofolate Dehydrogenase (MTHFD) rs2236225 (OR = 3.09; 95%CI 1.27, 7.50; p = 0.016) and allele A of Methionine Synthase Reductase (MTRR) rs1801394 (OR = 2.35; 95CI 1.10, 5.00; p = 0.037). An inflammatory oxidative stress enzyme, Gluthatione S-Tranferase Mu-1(GSTM1), null allele (OR = 2.21; 95%CI 1.24, 4.36; p = 0.030) and a neurotransmission receptor, Dopamine Receptor D4 (DRD4), long allele of 48 bp-repeat (OR = 3.62; 95%CI 0.76, 17.26; p = 0.161).

Conclusions
Some genetic polymorphisms related to folates metabolism, inflammatory oxidative stress, and neurotransmission responses to pain, has been significantly associated to TMD syndrome
Selected AGXT gene mutations analysis provides a genetic diagnosis in 28% of Tunisian patients with primary hyperoxaluria
Authors: Mbarek Ibtihel Benhaj , Abroug Saoussen , Omezzine Asma , Zellama Dorsaf , Achour Abdellatif , Harbi Abdelaziz , Bouslama Ali 
Published: May 2011

Abstract

Background
Primary hyperoxaluria type I (PH1) is a rare genetic disorder characterized by allelic and clinical heterogeneity. Four mutations (G170R, 33_34insC, I244T and F152I) account for more than 50% of PH1 alleles and form the basis for diagnostic genetic screening for PH1. We aimed to analyze the prevalence of these specific mutations causing PH1, and to provide an accurate tool for diagnosis of presymptomatic patients as well as for prenatal diagnosis in the affected families.

Methods
Polymerase chain reaction/Restriction Fragment Length Polymorphism, were used to detect the four mutations in the AGXT gene in DNA samples from 57 patients belonging to 40 families.

Results
Two mutations causing PH1 were detected in 24 patients (42.1%), with a predominance of the I244T mutation (68% of patients) and 33_34insC (in the remaining 32%). In 92% of cases, mutated alleles were in homozygous state.
The presented clinical features were similar for the two mutations. The age of onset was heterogeneous with a higher frequency of the pediatric age. In 58.3% of cases, the presentation corresponded to advanced renal disease which occurred early (< 5 years) in the two mutations. In adolescents, only the I244T mutation was detected (41.1%). I244T and 33_34insC mutations were observed in adult patients, with 17.6% and 12.5% respectively.

Conclusion
Limited mutation analysis can provide a useful first line investigation for PH1. I244T and 33_34insC presented 28.2% of identified mutations causing disease in our cohort. This identification could provide an accurate tool for prenatal diagnosis in the affected families, for genetic counselling and for detection of presymptomatic individuals.
Overexpression of eIF-5A2 in mice causes accelerated organismal aging by increasing chromosome instability
Authors: Chen Muhan , Huang Jian-Dong , Deng Hong Kui , Dong Suisui , Deng Wen , Tsang Sze Lan , Huen Michael SY , Chen Leilei , Zan Tong , Zhu Gui-Xia , Guan Xin-Yuan 
Published: May 2011

Abstract

Background
Amplification of 3q26 is one of the most frequent genetic alterations in many human malignancies. Recently, we isolated a novel oncogene eIF-5A2 within the 3q26 region. Functional study has demonstrated the oncogenic role of eIF-5A2 in the initiation and progression of human cancers. In the present study, we aim to investigate the physiological and pathological effect of eIF-5A2 in an eIF-5A2 transgenic mouse model.

Methods
An eIF-5A2 transgenic mouse model was generated using human eIF-5A2 cDNA. The eIF-5A2 transgenic mice were characterized by histological and immunohistochemistry analyses. The aging phenotypes were further characterized by wound healing, bone X-ray imaging and calcification analysis. Mouse embryo fibroblasts (MEF) were isolated to further investigate molecular mechanism of eIF-5A2 in aging.

Results
Instead of resulting in spontaneous tumor formation, overexpression of eIF-5A2 accelerated the aging process in adult transgenic mice. This included decreased growth rate and body weight, shortened life span, kyphosis, osteoporosis, delay of wound healing and ossification. Investigation of the correlation between cellular senescence and aging showed that cellular senescence is not required for the aging phenotypes in eIF-5A2 mice. Interestingly, we found that activation of eIF-5A2 repressed p19 level and therefore destabilized p53 in transgenic mouse embryo fibroblast (MEF) cells. This subsequently allowed for the accumulation of chromosomal instability, such as errors in cell dividing during metaphase and anaphase. Additionally, a significantly increase in number of aneuploidy cells (p < 0.05) resulted from an increase in the incidences of misaligned and lagging chromosomal materials, anaphase bridges, and micronuclei in the transgenic mice.

Conclusion
These observations suggest that eIF-5A2 mouse models could accelerate organismal aging by increasing chromosome instability.
Discriminative ability of the generic and condition-specific Child-Oral Impacts on Daily Performances (Child-OIDP) by the Limpopo-Arusha School Health (LASH) Project: A cross-sectional study
Authors: Mbawalla Hawa S , Mtaya Matilda , Masalu Joyce R , Brudvik Pongsri , Astrom Anne N 
Published: May 2011

Abstract

Background
Generic and condition-specific (CS) oral-health-related quality-of-life (OHRQoL) instruments assess the impacts of general oral conditions and specific oral diseases. Focusing schoolchildren from Arusha and Dar es Salaam, in Tanzania, this study compared the discriminative ability of the generic Child OIDP with respect to dental caries and periodontal problems across the study sites. Secondly, the discriminative ability of the generic-and the CS Child OIDP attributed to dental caries, periodontal problems and malocclusion was compared with respect to various oral conditions as part of a construct validation.

Methods
In Arusha, 1077 school children (mean age 14.9 years, range 12-17 years) and 1601 school children in Dar es Salaam (mean age 13.0 years, range 12-14 years) underwent oral clinical examinations and completed the Kiswahili version of the generic and CS Child-OIDP inventories. The discriminative ability was assessed as differences in overall mean and prevalence scores between groups, corresponding effect sizes and odd ratios, OR.

Results
The differences in the prevalence scores and the overall mean generic Child-OIDP scores were significant between the groups with (DMFT > 0) and without (DMFT = 0) caries experience and with (simplified oral hygiene index [OHI-S] > 1) and without periodontal problems (OHI-S ≤ 1) in Arusha and Dar es Salaam. In Dar es Salaam, differences in the generic and CS Child-OIDP scores were observed between the groups with and without dental caries, differences in the generic Child-OIDP scores were observed between the groups with and without periodontal problems, and differences in the CS Child-OIDP scores were observed between malocclusion groups. The adjusted OR for the association between dental caries and the CS Child-OIDP score attributed to dental caries was 5.4. The adjusted OR for the association between malocclusion and CS Child-OIDP attributed to malocclusion varied from 8.8 to 2.5.

Conclusion
The generic Child-OIDP discriminated equally well between children with and without dental caries and periodontal problems across socio-culturally different study sites. Compared with its generic form, the CS Child-OIDP discriminated most strongly between children with and without dental caries and malocclusion. The CS Child OIDP attributed to dental caries and malocclusion seems to be better suited to support clinical indicators when estimating oral health needs among school children in Tanzania.
Methylation levels of the "long interspersed nucleotide element-1" repetitive sequences predict survival of melanoma patients
Authors: Sigalotti Luca , Fratta Elisabetta , Bidoli Ettore , Covre Alessia , Parisi Giulia , Colizzi Francesca , Coral Sandra , Massarut Samuele , Kirkwood John M , Maio Michele 
Published: May 2011

AbstractBackgroundThe prognosis of cutaneous melanoma (CM) differs for patients with identical clinico-pathological stage, and no molecular markers discriminating the prognosis of stage III individuals have been established. Genome-wide alterations in DNA methylation are a common event in cancer. This study aimed to define the prognostic value of genomic DNA methylation levels in stage III CM patients.MethodsOverall level of genomic DNA methylation was measured using bisulfite pyrosequencing at three CpG sites (CpG1, CpG2, CpG3) of theLong Interspersed Nucleotide Element-1(LINE-1) sequences in short-term CM cultures from 42 stage IIIC patients. The impact ofLINE-1methylation on overall survival (OS) was assessed using Cox regression and Kaplan-Meier analysis.ResultsHypomethylation (i.e., methylation below median) at CpG2 and CpG3 sites significantly associated with improved prognosis of CM, CpG3 showing the strongest association. Patients with hypomethylated CpG3 had increased OS (P = 0.01, log-rank = 6.39) by Kaplan-Meyer analysis. Median OS of patients with hypomethylated or hypermethylated CpG3 were 31.9 and 11.5 months, respectively. The 5 year OS for patients with hypomethylated CpG3 was 48% compared to 7% for patients with hypermethylated sequences. Among the variables examined by Cox regression analysis,LINE-1methylation at CpG2 and CpG3 was the only predictor of OS (Hazard Ratio = 2.63, for hypermethylated CpG3; 95% Confidence Interval: 1.21-5.69;P= 0.01).ConclusionLINE-1methylation is identified as a molecular marker of prognosis for CM patients in stage IIIC. Evaluation ofLINE-1promises to represent a key tool for driving the most appropriate clinical management of stage III CM patients.
Allergen-specific T cell quantity in blood is higher in allergic compared to nonallergic individuals
Authors: Ueno-Yamanouchi Aito , Khan Faisal M , Serushago Bazir , Bowen Tom , Lu Cathy , Luider Joanne , Storek Jan 
Published: May 2011

AbstractBackgroundAllergen-specific IgE production is a hallmark of allergic asthma/rhinitis/eczema. Theoretically this could be due to a high number of allergen-specific B cells or allergen-specific T cells helping allergen-specific B cells differentiate into IgE-producing plasma cells. Here, we determined whether the number of allergen-specific B cells or T helper (Th) cells is higher in allergic individuals compared to nonallergic individuals.MethodsA total of 52 allergic individuals and 32 nonallergic individuals were studied. The allergen-specific B and Th cells were enumerated by culturing CFSE-loaded blood mononuclear cells for 7-days with allergen (cat, Timothy or birch), and determining the number of proliferating B or Th cells (diluting CFSE) by flow cytometry. Allergen-specific IgE concentration was determined by fluorescent enzymoimmunoassay (FEIA).ResultsThe quantities of proliferating Th cells but not proliferating B cells specific for cat, Timothy and birch were significantly higher in cat-, Timothy- and birch-allergic individuals compared to nonallergic individuals. The titer of allergen-specific IgE showed significant correlation with allergen-specific Th cells and not with allergen-specific B cells for all 3 allergens.ConclusionsA high number of allergen-specific proliferating Th cells, but not proliferating B cells, may play a role in the pathogenesis of allergic asthma/rhinitis/eczema.