bluuebunny/crossref_metadata_2025_split huggingface dataset:
Loss of Kindlin-3 in LAD-III eliminates LFA-1 but not VLA-4 adhesiveness developed under shear flow conditions
Authors: Manevich-Mendelson Eugenia , Feigelson Sara W. , Pasvolsky Ronit , Aker Memet , Grabovsky Valentin , Shulman Ziv , Kilic Sara Sebnem , Rosenthal-Allieri Maria Alessandra , Ben-Dor Shifra , Mory Adi , Bernard Alain , Moser Markus , Etzioni Amos , Alon Ronen 
Published: July 2009

Abstract
Leukocyte adhesion deficiency (LAD)–III is associated with homozygous stop codon mutations in Kindlin-3, the hematopoietic member of the Kindlin family of integrin coactivators. In addition, a subgroup of LAD-III patients has a homozygous splice junction mutation in and reduced expression of the Rap-1 guanine nucleotide exchange factor, CalDAG-GEFI (CDGI). In this study, we compared the adhesive properties of the leukocyte function-associated antigen-1 (LFA-1) and very late activation antigen-4 (VLA-4) integrins in both primary and activated leukocytes derived from these 2 LAD-III subgroups. Primary lymphocytes lacking both Kindlin-3 and CDGI lost all firm T-cell receptor–stimulated LFA-1 adhesiveness, in contrast to LAD-III lymphocytes deficient in Kindlin-3 alone. Effector T cells expanded from all tested LAD-III variants expressed normal CDGI, but lacked Kindlin-3. These Kindlin-3–null effector T cells exhibited total loss of inside-out LFA-1 activation by chemokine signals as well as abrogated intrinsic LFA-1 adhesiveness. Surprisingly, VLA-4 in Kindlin-3–null resting or effector lymphocytes retained intrinsic rolling adhesions to vascular cell adhesion molecule-1 and exhibited only partial defects in chemokine-stimulated adhesiveness to vascular cell adhesion molecule-1. Deletion of the putative β1 Kindlin-3 binding site also retained VLA-4 adhesiveness. Thus, our study provides the first evidence that Kindlin-3 is more critical to LFA-1 than to VLA-4–adhesive functions in human lymphocytes.
Cross-recognition of HLA DR4 alloantigen by virus-specific CD8+ T cells: a new paradigm for self-/nonself-recognition
Authors: Rist Michael , Smith Corey , Bell Melissa J. , Burrows Scott R. , Khanna Rajiv 
Published: July 2009

AbstractThe ability of CD8+ T cells to engage a diverse range of peptide–major histocompatibility complex (MHC) complexes can also lead to cross-recognition of self and nonself peptide-MHC complexes and thus directly contribute toward allograft rejection or autoimmunity. Here we present a novel form of cross-recognition by herpes virus–specific CD8+ cytotoxic T cells that challenges the current paradigm of self/non-self recognition. Functional characterization of a human leukocyte antigen (HLA) Cw*0602-restricted cytomegalovirus-specific CD8+ T-cell response revealed an unusual dual specificity toward a pp65 epitope and the alloantigen HLA DR4. This cross-recognition of HLA DR4 alloantigen was critically dependent on the coexpression of HLA DM and was preferentially directed toward the B-cell lineage. Furthermore, allostimulation of peripheral blood lymphocytes with HLA DRB*0401-expressing cells rapidly expanded CD8+ T cells, which recognized the pp65 epitope in the context of HLA Cw*0602. T-cell repertoire analysis revealed 2 dominant populations expressing T-cell receptor beta variable (TRBV)4-3 or TRBV13, with cross-reactivity exclusively mediated by the TRBV13+ clonotypes. More importantly, cross-reactive TRBV13+ clonotypes displayed markedly lower T-cell receptor binding affinity and a distinct pattern of peptide recognition, presumably mimicking a structure presented on the HLA DR4 allotype. These results illustrate a novel mechanism whereby virus-specific CD8+ T cells can cross-recognize HLA class II molecules and may contribute toward allograft rejection and/or autoimmunity.
Genomic island excisions in Bordetella petrii
Authors: Lechner Melanie , Schmitt Karin , Bauer Susanne , Hot David , Hubans Christine , Levillain Erwan , Locht Camille , Lemoine Yves , Gross Roy 
Published: July 2009

Abstract

Background
Among the members of the genus Bordetella B. petrii is unique, since it is the only species isolated from the environment, while the pathogenic Bordetellae are obligately associated with host organisms. Another feature distinguishing B. petrii from the other sequenced Bordetellae is the presence of a large number of mobile genetic elements including several large genomic regions with typical characteristics of genomic islands collectively known as integrative and conjugative elements (ICEs). These elements mainly encode accessory metabolic factors enabling this bacterium to grow on a large repertoire of aromatic compounds.

Results
During in vitro culture of Bordetella petrii colony variants appear frequently. We show that this variability can be attributed to the presence of a large number of metastable mobile genetic elements on its chromosome. In fact, the genome sequence of B. petrii revealed the presence of at least seven large genomic islands mostly encoding accessory metabolic functions involved in the degradation of aromatic compounds and detoxification of heavy metals. Four of these islands (termed GI1 to GI3 and GI6) are highly related to ICEclc of Pseudomonas knackmussii sp. strain B13. Here we present first data about the molecular characterization of these islands. We defined the exact borders of each island and we show that during standard culture of the bacteria these islands get excised from the chromosome. For all but one of these islands (GI5) we could detect circular intermediates. For the clc-like elements GI1 to GI3 of B. petrii we provide evidence that tandem insertion of these islands which all encode highly related integrases and attachment sites may also lead to incorporation of genomic DNA which originally was not part of the island and to the formation of huge composite islands. By integration of a tetracycline resistance cassette into GI3 we found this island to be rather unstable and to be lost from the bacterial population within about 100 consecutive generations. Furthermore, we show that GI3 is self transmissible and by conjugation can be transferred to B. bronchiseptica thus proving it to be an active integrative and conjugative element

Conclusion
The results show that phenotypic variation of B. petrii is correlated with the presence of genomic islands. Tandem integration of related islands may contribute to island evolution by the acquisition of genes originally belonging to the bacterial core genome. In conclusion, B. petrii appears to be the first member of the genus in which horizontal gene transfer events have massively shaped its genome structure.
Type 2 diabetes gene TCF7L2polymorphism is not associated with fetal and postnatal growth in two birth cohort studies
Authors: Mook-Kanamori Dennis O , de Kort Sandra WK , van Duijn Cornelia M , Uitterlinden Andre G , Hofman Albert , Moll Henriëtte A , Steegers Eric AP , Hokken-Koelega Anita CS , Jaddoe Vincent WV 
Published: July 2009

Abstract

Background
An inverse association between birth weight and the risk of developing type 2 diabetes (T2D) in adulthood has been reported. This association may be explained by common genetic variants related to insulin secretion and resistance, since insulin is the most important growth factor in fetal life. The objective of this study was to examine whether T2D gene polymorphism TCF7L2 rs7903146 is associated with growth patterns from fetal life until infancy.

Methods
This study was performed in two independent birth cohort studies, one prospective population-based (Generation R), and one of subjects born small-for-gestational-age (SGA cohort). Fetal growth was assessed by ultrasounds in second and third trimesters of pregnancy in Generation R. Growth in infancy was assessed in both cohorts at birth and at 6, 12 and 24 months postnatally. TCF7L2 genotype was determined in 3,419 subjects in Generation R and in 566 subjects in the SGA cohort.

Results
Minor allele frequency did not differ significantly (p = 0.47) between Generation R (T-allele: 28.7%) and the SGA cohort (T-allele: 29.8%). No differences at birth were found in gestational age or size (head circumference, length, weight) between the genotypes in either cohort. TCF7L2 genotype was also not associated with any pre- or postnatal growth characteristic in either Generation R or the SGA cohort.

Conclusion
We found no evidence for an association between TCF7L2 genotype and fetal and early postnatal growth. Furthermore, this TCF7L2 polymorphism was not associated with an increased risk of SGA.
No association of CDK5 genetic variants with Alzheimer's disease risk
Authors: Vázquez-Higuera José Luis , Mateo Ignacio , Sánchez-Juan Pascual , Rodríguez-Rodríguez Eloy , Infante Jon , Berciano José , Combarros Onofre 
Published: July 2009

Abstract

Background
As cyclin-dependent kinase 5 (CDK5) has been implicated in the abnormal hyperphosphorylation of tau in Alzheimer's disease (AD) brain, and the development of neurofibrillary tangles, we examined the contribution of this gene to the susceptibility for AD.

Methods
We examined genetic variations of CDK5 by genotyping haplotype tagging SNPs (htSNPs) (rs9278, rs2069459, rs891507, rs2069454, rs1549759 and rs2069442) in a group of 408 Spanish AD cases and 444 controls.

Results
There were no differences in the genotypic, allelic or haplotypic distributions between cases and controls in the overall analysis or after stratification by APOE ε4 allele.

Conclusion
Our negative findings in the Spanish population argue against the hypothesis that CDK5 genetic variations are causally related to AD risk. Still, additional studies using different sets of patients and control subjects deserve further attention, since supporting evidence for association between CDK5 gene and AD risk in the Dutch population exists.
Regulation of MYCNexpression in human neuroblastoma cells
Authors: Jacobs Joannes FM , van Bokhoven Hans , van Leeuwen Frank N , Hulsbergen-van de Kaa Christina A , de Vries I Jolanda M , Adema Gosse J , Hoogerbrugge Peter M , de Brouwer Arjan PM 
Published: July 2009

Abstract

Background
Amplification of the MYCN gene in neuroblastoma (NB) is associated with a poor prognosis. However, MYCN-amplification does not automatically result in higher expression of MYCN in children with NB. We hypothesized that the discrepancy between MYCN gene expression and prognosis in these children might be explained by the expression of either MYCN-opposite strand (MYCNOS) or the shortened MYCN-isoform (ΔMYCN) that was recently identified in fetal tissues. Both MYCNOS and ΔMYCN are potential inhibitors of MYCN either at the mRNA or at the protein level.

Methods
Expression of MYCN, MYCNOS and ΔMYCN was measured in human NB tissues of different stages. Transcript levels were quantified using a real-time reverse transcriptase polymerase chain reaction assay (QPCR). In addition, relative expression of these three transcripts was compared to the number of MYCN copies, which was determined by genomic real-time PCR (gQPCR).

Results
Both ΔMYCN and MYCNOS are expressed in all NBs examined. In NBs with MYCN-amplification, these transcripts are significantly higher expressed. The ratio of MYCN:ΔMYCN expression was identical in all tested NBs. This indicates that ΔMYCN and MYCN are co-regulated, which suggests that ΔMYCN is not a regulator of MYCN in NB. However, the ratio of MYCNOS:MYCN expression is directly correlated with NB disease stage (p = 0.007). In the more advanced NB stages and NBs with MYCN-amplification, relatively more MYCNOS is present as compared to MYCN. Expression of the antisense gene MYCNOS might be relevant to the progression of NB, potentially by directly inhibiting MYCN transcription by transcriptional interference at the DNA level.

Conclusion
The MYCNOS:MYCN-ratio in NBs is significantly correlated with both MYCN-amplification and NB-stage. Our data indicate that in NB, MYCN expression levels might be influenced by MYCNOS but not by ΔMYCN.
Concentration of the genera Aspergillus, Eurotium and Penicillium in 63-μm house dust fraction as a method to predict hidden moisture damage in homes
Authors: Baudisch Christoph , Assadian Ojan , Kramer Axel 
Published: July 2009

Abstract

Background
Quantitative measurements of mould enrichment of indoor air or house dust might be suitable surrogates to evaluate present but hidden moisture damage. Our intent was to develop a house-dust monitoring method to detect hidden moisture damage excluding the influence of outdoor air, accumulated old dust, and dust swirled up from room surfaces.

Methods
Based on standardized measurement of mould spores in the 63-μm fraction of house dust yielded by carpets, the background concentrations were determined and compared to simultaneously obtained colony numbers and total spore numbers of the indoor air in 80 non-mouldy living areas during summer and winter periods. Additionally, sampling with a vacuum-cleaner or manual sieve was compared to sampling with a filter holder or sieving machine, and the evaluative power of an established two-step assessment model (lower and upper limits) was compared to that of a one-step model (one limit) in order to derive concentration limits for mould load in house dust.

Results
Comparison with existing evaluation procedures proved the developed method to be the most reliable means of evaluating hidden moisture damage, yielding the lowest false-positive results (specificity 98.7%). Background measurements and measurements in 14 mouldy rooms show that even by evaluating just the indicator genera in summer and winter, a relatively certain assessment of mould infestation is possible.

Conclusion
A one-step evaluation is finally possible for house dust. The house-dust evaluation method is based on analysis of the indicator genera Aspergillus, Eurotium and Penicillium spp., which depend on the total fungal count. Inclusion of further moisture indicators currently appears questionable, because of outdoor air influence and the paucity of measurements.
Depression during pregnancy: views on antidepressant use and information sources of general practitioners and pharmacists
Authors: Ververs Tessa , van Dijk Liset , Yousofi Somaye , Schobben Fred , Visser Gerard HA 
Published: July 2009

Abstract

Background
The use of antidepressants during pregnancy has increased in recent years. In the Netherlands, almost 2% of all pregnant women are exposed to antidepressants. Although guidelines have been developed on considerations that should be taken into account, prescribing antidepressants during pregnancy is still a subject of debate. Physicians and pharmacists may have opposing views on using medication during pregnancy and may give contradictory advice on whether or not to take medication for depression and anxiety disorders during pregnancy. In this study, we investigated information sources used by general practitioners (GPs) and pharmacists and their common practices.

Methods
A questionnaire on the use of information sources and the general approach when managing depression during pregnancy was sent out to 1400 health care professionals to assess information sources on drug safety during pregnancy and also the factors that influence decision-making. The questionnaires consisted predominantly of closed multiple-choice questions.

Results
A total of 130 GPs (19%) and 144 pharmacists (21%) responded. The most popular source of information on the safety of drug use during pregnancy is the Dutch National Health Insurance System Formulary, while a minority of respondents contacts the Dutch national Teratology Information Service (TIS). The majority of GPs contact the pharmacy with questions concerning drug use during pregnancy. There is no clear line with regard to treatment or consensus between GPs on the best therapeutic strategy, nor do practitioners agree upon the drug of first choice. GPs have different views on stopping or continuing antidepressants during pregnancy or applying alternative treatment options. The debate appears to be ongoing as to whether or not specialised care for mother and child is indicated in cases of gestational antidepressant use.

Conclusion
Primary health care workers are not univocal concerning therapy for pregnant women with depression. Although more research is needed to account for all safety issues, local or national policies are indispensable in order to avoid undesirable practices, such as giving contradictory advice. GPs and pharmacists should address the subject during their regular pharmacotherapeutic consensus meetings, preferably in collaboration with the TIS or other professionals in the field.
An integrated approach of community health worker support for HIV/AIDS and TB care in Angónia district, Mozambique
Authors: Simon Sandrine , Chu Kathryn , Frieden Marthe , Candrinho Baltazar , Ford Nathan , Schneider Helen , Biot Marc 
Published: July 2009

Abstract

Background
The need to scale up treatment for HIV/AIDS has led to a revival in community health workers to help alleviate the health human resource crisis in sub-Saharan Africa. Community health workers have been employed in Mozambique since the 1970s, performing disparate and fragmented activities, with mixed results.

Methods
A participant-observer description of the evolution of community health worker support to the health services in Angónia district, Mozambique.

Results
An integrated community health team approach, established jointly by the Ministry of Health and Médecins Sans Frontières in 2007, has improved accountability, relevance, and geographical access for basic health services.

Conclusion
The community health team has several advantages over 'disease-specific' community health worker approaches in terms of accountability, acceptability, and expanded access to care.
Study of RNA interference inhibiting rat ovarian androgen biosynthesis by depressing 17alpha-hydroxylase/17, 20-lyase activity in vivo
Authors: Li Yi , Liang Xiao-yan , Wei Li-na , Xiong Yong-lao , Yang Xing , Shi Hui-gan , Yang Zi-hong 
Published: July 2009

Abstract

Background
17alpha-hydroxylase/17, 20-lyase encoded by CYP17 is the key enzyme in androgen biosynthesis pathway. Previous studies demonstrated the accentuation of the enzyme in patients with polycystic ovary syndrome (PCOS) was the most important mechanism of androgen excess. We chose CYP17 as the therapeutic target, trying to suppress the activity of 17alpha-hydroxylase/17, 20-lyase and inhibit androgen biosynthesis by silencing the expression of CYP17 in the rat ovary.

Methods
Three CYP17-targeting and one negative control oligonucleotides were designed and used in the present study. The silence efficiency of lentivirus shRNA was assessed by qRT-PCR, Western blotting and hormone assay. After subcapsular injection of lentivirus shRNA in rat ovary, the delivery efficiency was evaluated by GFP fluorescence and qPCR. Total RNA was extracted from rat ovary for CYP17 mRNA determination and rat serum was collected for hormone measurement.

Results
In total, three CYP17-targeting lentivirus shRNAs were synthesized. The results showed that all of them had a silencing effect on CYP17 mRNA and protein. Moreover, androstenedione secreted by rat theca interstitial cells (TIC) in the RNAi group declined significantly compared with that in the control group. Two weeks after rat ovarian subcapsular injection of chosen CYP17 shRNA, the GFP fluorescence of frozen ovarian sections could be seen clearly under fluorescence microscope. It also showed that the GFP DNA level increased significantly, and its relative expression level was 7.42 times higher than that in the control group. Simultaneously, shRNA treatment significantly decreased CYP17 mRNA and protein levels at 61% and 54%, respectively. Hormone assay showed that all the levels of androstenedione, 17-hydroxyprogesterone and testosterone declined to a certain degree, but progesterone levels declined significantly.

Conclusion
The present study proves for the first time that ovarian androgen biosynthesis can be inhibited by silencing CYP17 expression. It may provide a novel strategy for therapy of hyperandrogenism diseases, and also set an example for the use of RNAi technology in endocrine diseases.
Comparing the performance of the EQ-5D and SF-6D when measuring the benefits of alleviating knee pain
Authors: Barton Garry R , Sach Tracey H , Avery Anthony J , Doherty Michael , Jenkinson Claire , Muir Kenneth R 
Published: July 2009

AbstractObjectiveTo assess the practicality, validity and responsiveness of using each of two utility measures (the EQ-5D and SF-6D) to measure the benefits of alleviating knee pain.MethodsParticipants in a randomised controlled trial, which was designed to compare four different interventions for people with self-reported knee pain, were asked to complete the EQ-5D, SF-6D, and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) at both pre- and post-intervention. For both utility measures, we assessed their practicality (completion rate), construct validity (ability to discriminate between baseline WOMAC severity levels), and responsiveness (ability to discriminate between three groups: those whose total WOMAC score, i) did not improve, ii) improved by <20%, and iii) improved by ≥20%).ResultsThe EQ-5D was completed by 97.7% of the 389 participants, compared to 93.3% for the SF-6D. Both the EQ-5D and SF-6D were able to discriminate between participants with different levels of WOMAC severity (p < 0.001). The mean EQ-5D change was -0.036 for group i), 0.091 for group ii), and 0.127 for group iii), compared to 0.021, 0.023 and 0.053 on the SF-6D. These change scores were significantly different according to the EQ-5D (p < 0.001), but not the SF-6D.ConclusionThe EQ-5D and SF-6D had largely comparable practicality and construct validity. However, in contrast to the EQ-5D, the SF-6D could not discriminate between those who improved post-intervention, and those who did not. This suggests that it is more appropriate to use the EQ-5D in future cost-effectiveness analyses of interventions which are designed to alleviate knee pain.Trial registrationCurrent Controlled Trials ISRCTN93206785