bluuebunny/crossref_metadata_2025 huggingface dataset:
Reduced expression of the
Kinesin-Associated Protein 3
(
KIFAP3
) gene increases survival in sporadic amyotrophic lateral sclerosis
Authors: Landers John E. , Melki Judith , Meininger Vincent , Glass Jonathan D. , van den Berg Leonard H. , van Es Michael A. , Sapp Peter C. , van Vught Paul W. J. , McKenna-Yasek Diane M. , Blauw Hylke M. , Cho Ting-Jan , Polak Meraida , Shi Lijia , Wills Anne-Marie , Broom Wendy J. , Ticozzi Nicola , Silani Vincenzo , Ozoguz Aslihan , Rodriguez-Leyva Ildefonso , Veldink Jan H. , Ivinson Adrian J. , Saris Christiaan G. J. , Hosler Betsy A. , Barnes-Nessa Alayna , Couture Nicole , Wokke John H. J. , Kwiatkowski Thomas J. , Ophoff Roel A. , Cronin Simon , Hardiman Orla , Diekstra Frank P. , Leigh P. Nigel , Shaw Christopher E. , Simpson Claire L. , Hansen Valerie K. , Powell John F. , Corcia Philippe , Salachas François , Heath Simon , Galan Pilar , Georges Franck , Horvitz H. Robert , Lathrop Mark , Purcell Shaun , Al-Chalabi Ammar , Brown Robert H.
Published: May 2009

Amyotrophic lateral sclerosis is a degenerative disorder of motor neurons that typically develops in the 6th decade and is uniformly fatal, usually within 5 years. To identify genetic variants associated with susceptibility and phenotypes in sporadic ALS, we performed a genome-wide SNP analysis in sporadic ALS cases and controls. A total of 288,357 SNPs were screened in a set of 1,821 sporadic ALS cases and 2,258 controls from the U.S. and Europe. Survival analysis was performed using 1,014 deceased sporadic cases. Top results for susceptibility were further screened in an independent sample set of 538 ALS cases and 556 controls. SNP rs1541160 within the
KIFAP3
gene (encoding a kinesin-associated protein) yielded a genome-wide significant result (
P
= 1.84 × 10
−8
) that withstood Bonferroni correction for association with survival. Homozygosity for the favorable allele (CC) conferred a 14.0 months survival advantage. Sequence, genotypic and functional analyses revealed that there is linkage disequilibrium between rs1541160 and SNP rs522444 within the
KIFAP3
promoter and that the favorable alleles of rs1541160 and rs522444 correlate with reduced KIFAP3 expression. No SNPs were associated with risk of sporadic ALS, site of onset, or age of onset. We have identified a variant within the
KIFAP3
gene that is associated with decreased
KIFAP3
expression and increased survival in sporadic ALS. These findings support the view that genetic factors modify phenotypes in this disease and that cellular motor proteins are determinants of motor neuron viability.
Hamiltonella defensa
, genome evolution of protective bacterial endosymbiont from pathogenic ancestors
Authors: Degnan Patrick H. , Yu Yeisoo , Sisneros Nicholas , Wing Rod A. , Moran Nancy A.
Published: May 2009

Eukaryotes engage in a multitude of beneficial and deleterious interactions with bacteria.
Hamiltonella defensa
, an endosymbiont of aphids and other sap-feeding insects, protects its aphid host from attack by parasitoid wasps. Thus
H. defensa
is only conditionally beneficial to hosts, unlike ancient nutritional symbionts, such as
Buchnera
, that are obligate. Similar to pathogenic bacteria,
H. defensa
is able to invade naive hosts and circumvent host immune responses. We have sequenced the genome of
H. defensa
to identify possible mechanisms that underlie its persistence in healthy aphids and protection from parasitoids. The 2.1-Mb genome has undergone significant reduction in size relative to its closest free-living relatives, which include
Yersinia
and
Serratia
species (4.6–5.4 Mb). Auxotrophic for 8 of the 10 essential amino acids,
H. defensa
is reliant upon the essential amino acids produced by
Buchnera
. Despite these losses, the
H. defensa
genome retains more genes and pathways for a variety of cell structures and processes than do obligate symbionts, such as
Buchnera
. Furthermore, putative pathogenicity loci, encoding type-3 secretion systems, and toxin homologs, which are absent in obligate symbionts, are abundant in the
H. defensa
genome, as are regulatory genes that likely control the timing of their expression. The genome is also littered with mobile DNA, including phage-derived genes, plasmids, and insertion-sequence elements, highlighting its dynamic nature and the continued role horizontal gene transfer plays in shaping it.
Proteomic screening of variola virus reveals a unique NF-κB inhibitor that is highly conserved among pathogenic orthopoxviruses
Authors: Mohamed Mohamed R. , Rahman Masmudur M. , Lanchbury Jerry S. , Shattuck Donna , Neff Chris , Dufford Max , van Buuren Nick , Fagan Katharine , Barry Michele , Smith Scott , Damon Inger , McFadden Grant
Published: May 2009

Identification of the binary interactions between viral and host proteins has become a valuable tool for investigating viral tropism and pathogenesis. Here, we present the first systematic protein interaction screening of the unique variola virus proteome by using yeast 2-hybrid screening against a variety of human cDNA libraries. Several protein–protein interactions were identified, including an interaction between variola G1R, an ankryin/F-box containing protein, and human nuclear factor kappa-B1 (NF-κB1)/p105. This represents the first direct interaction between a pathogen-encoded protein and NF-κB1/p105. Orthologs of G1R are present in a variety of pathogenic orthopoxviruses, but not in vaccinia virus, and expression of any one of these viral proteins blocks NF-κB signaling in human cells. Thus, proteomic screening of variola virus has the potential to uncover modulators of the human innate antiviral responses.
Light-transduction in melanopsin-expressing photoreceptors of Amphioxus
Authors: del Pilar Gomez María , Angueyra Juan M. , Nasi Enrico
Published: May 2009

Spatial vision in different organisms is mediated by 2 classes of photoreceptors: microvillar and ciliary. Recently, additional photosensitive cells implicated in nonvisual light-dependent functions have been identified in the mammalian retina. A previously undescribed photopigment, melanopsin, underlies these photoresponses, and it has been proposed that its transduction mechanisms may be akin to the lipid-signaling scheme of invertebrate microvillar receptors, rather than the cyclic-nucleotide cascade of vertebrates. Melanopsin has an ancient origin in deuterostomia, and expresses in 2 morphologically distinct classes of cells in the neural tube of Amphioxus, the most basal extant chordate: pigmented ocelli, and Joseph cells. However, to our knowledge, their physiology and alleged photosensitivity had never been investigated. We dissociated both types of cells, and conclusively demonstrated by patch-electrode recoding that they are primary photoreceptors; their receptor potential is depolarizing, accompanied by an increase in membrane conductance. The action spectrum peaks in the blue region, ≈470 nm, similar to the absorption of melanopsin in vitro. The light-dependent conductance rectifies inwardly; Na and Ca are differentially implicated in the 2 cell types. Fluorescence Ca imaging reveals that photostimulation rapidly mobilizes calcium from internal stores. Intracellular 1,2-bis(2-aminophenoxy)ethane-
N
,
N
,
N
′,
N
′-tetraacetate severely impairs the photoresponse, indicating that light-evoked Ca elevation is an important event in photoexcitation. These observations support the notion that the lineage of microvillar photoreceptors and its associated light-signaling pathway also evolved in the chordates. Thus, Joseph cells and pigmented ocelli of the Amphioxus may represent a link between ancestral rhabdomeric-like light sensors present in prebilaterians and the circadian photoreceptors of higher vertebrates.
A coordinated network of transporters with overlapping specificities provides a robust survival strategy
Authors: Tal Nir , Schuldiner Shimon
Published: May 2009

Multidrug transporters provide a survival strategy for living organisms. As expected given their central role in survival, these transporters are ubiquitous, and in many genomes, several genes coding for putative transporters have been identified. However, in an organism such as
Escherichia coli
mutations in genes coding for transporters other than the major AcrAB-TolC multidrug efflux transporter have only a marginal effect on phenotype. Thus, whether the physiological role of the transporters identified is indeed drug export has been questioned. We show here that the minor effect of single mutations is due to the overlapping functionality of several transporters. This was revealed by generating multiple chromosomal deletion mutations in genes coding for transporters that share the same substrate and testing their effect on the resistance phenotype. In addition, complementation studies imply that AcrAB-TolC confers robust resistance provided that single-component transporters in the plasma membrane are functional. This finding supports the contention that hydrophobic drugs are removed in a 2-stage process: AcrAB-TolC removes substrates from the periplasmic space, while single-component transporters remove them from the cell. The overlapping specificities of the transporters ensure coverage of a wide range of xenobiotics and provide robustness in the response to environmental stress. This strategy also confers evolvability to the organism by reducing constraints on change and allowing the accumulation of nonlethal variation.
Biogenic carbon and anthropogenic pollutants combine to form a cooling haze over the southeastern United States
Authors: Goldstein Allen H. , Koven Charles D. , Heald Colette L. , Fung Inez Y.
Published: May 2009

Remote sensing data over North America document the ubiquity of secondary aerosols resulting from a combination of primary biogenic and anthropogenic emissions. The spatial and temporal distribution of aerosol optical thickness (AOT) over the southeastern United States cannot be explained by anthropogenic aerosols alone, but is consistent with the spatial distribution, seasonal distribution, and temperature dependence of natural biogenic volatile organic compound (BVOC) emissions. These patterns, together with observations of organic aerosol in this region being dominated by modern14C and BVOC oxidation products with summer maxima, indicate nonfossil fuel origins and strongly suggest that the dominant summer AOT signal is caused by secondary aerosol formed from BVOC oxidation. A link between anthropogenic and biogenic emissions forming secondary aerosols that dominate the regional AOT is supported by reports of chemicals in aerosols formed by BVOC oxidation in a NOx- and sulfate-rich environment. Even though ground-based measurements from the IMPROVE network suggest higher sulfate than organic concentrations near the surface in this region, we infer that much of the secondary organic aerosol in the Southeast must occur above the surface layer, consistent with reported observations of the organic fraction of the total aerosol increasing with height and models of the expected vertical distribution of secondary organic aerosols from isoprene oxidation. The observed AOT is large enough in summer to provide regional cooling; thus we conclude that this secondary aerosol source is climatically relevant with significant potential for a regional negative climate feedback as BVOC emissions increase with temperature.
Microcoil embolization through a downsized coaxial catheter system: An experimental study
Authors: Tajima T. , Yoshimitsu K. , Irie H. , Nishie A. , Hirakawa M. , Ishigami K. , Ushijima Y. , Okamoto D. , Honda H.
Published: May 2009

Background: Most of the recently developed microcatheters for abdominal angiography still have large diameters at their trailing ends, and thus cannot be used for microcoil embolization in combination with a 3-French (F) system.

Purpose: To evaluate the in vitro passage of microcoils through a newly developed 2-F microcatheter (Meister Cath Superselective Plus, MC6) that is compatible with a downsized coaxial catheter system (3-F system) in an experimental study.

Material and Methods: We evaluated the passage of microcoils through MC6 within a blood vessel model using the saline flush technique. Six types of microcoils and 17 size variations (maximal curled diameter 2–10 mm, total length 20–140 mm) were used. We evaluated the passage and post-deployment shape of the microcoils as well as the volume of saline required to flush them.

Results: In the experimental study, all microcoils passed through the MC6 and deployed in a satisfactory manner without catheter occlusion. The mean volumes of saline required to flush the TORNADO ( n=1), Reverse TORNADO ( n=6), HILAL ( n=1), Micronester ( n=3), VortX ( n=4), and C-Stopper Coil ( n=2) were 0.7 ml, 0.58±0.20 ml, 0.5 ml, 0.57±0.058 ml, 3.5±1.5 ml, and 0.70±0.14 ml, respectively. There was a statistically significant difference in the mean volume of saline required between the VortX and Reverse TORNADO ( P=0.029), and between the VortX and C-Stopper Coil ( P=0.031). The VortX required the greatest volume of saline.

Conclusion: Microcoil embolization through a 3-F system appears to be feasible for the coils examined in this study.
Magnetic resonance appearance of cerebral cystic echinococcosis: World health organization (WHO) classification
Authors: Razek A. A. K. Abdel , El-Shamam O. , Wahab N. Abdel
Published: May 2009

Background: Cystic echinococcosis (CE) of the brain is an uncommon parasitic infestation. The World Health Organization (WHO) recently published a classification of hepatic CE based upon ultrasonographic findings.

Purpose: To evaluate whether the new WHO classification of hepatic CE can be used in the classification of cerebral CE.

Material and Methods: The magnetic resonance (MR) imaging findings of 17 patients (14 male, three female), aged 10–24 years (mean age 16 years), with pathologically proved cerebral CE, and who underwent pre- and postcontrast MR imaging, were retrospectively evaluated. The cysts were classified according to the new WHO classification and their clinical stages. The MR imaging findings were correlated to the histopathologic findings.

Results: The fertile active cysts ( n=12) that showed protoscoleces appeared as unilocular cysts with no visible wall (cystic lesions; CL), unilocular spherical cysts with a clear visible wall (CE1), or as a unilocular mother cyst with multiple vesicles arranged peripherally along the cyst wall (CE2). The transitional form (CE3) ( n=2) containing scoleces showed multiple daughter cysts entirely filling the maternal cyst. The inactive cysts ( n=3) that had lost their fertility appeared as a “ball of wool” with collapsed membrane or had detached membrane with water-lily sign (CE4) and calcified lesions (CE5).

Conclusion: The WHO classification of hepatic CE can be used in the classification of cerebral CE when evaluated by MRI, as it can differentiate fertile active cysts from the transitional and inactive forms of cerebral cystic echinococcosis. This information is essential for treatment planning.
Accuracy of 3-Tesla magnetic resonance imaging for the staging of prostate cancer in comparison to the partin tables
Authors: Augustin H. , Fritz G. A. , Ehammer T. , Auprich M. , Pummer K.
Published: May 2009

Background: An accurate prediction of final pathological stage is essential for proper patient selection to determine who will experience maximum benefit from radical prostatectomy. In this context, the Partin tables represent one of the most widely used statistical prediction tools.

Purpose: To compare the accuracy in predicting pathological stage in patients intended for radical prostatectomy between 3-Tesla (T) magnetic resonance imaging (MRI) and the Partin tables in a prospective trial.

Material and Methods: 27 men with staging results from 3T MRI using a phased-array coil were compared in terms of staging accuracy with whole-mount-section histopathologic analyses as the standard of reference. Probabilities for pathological stages were estimated according to the Partin tables. Spearman rank correlation and discriminant analysis were calculated to assess relationships.

Results: Histopathological evaluation revealed organ-confined disease (OC) in 21 (77.8%) and extracapsular extension (ECE) in six (22.2%) men. Three-Tesla MRI staging was accurate in all patients with OC and in four out of the six men with ECE. Accuracy of local staging was 85.2% (23 of 27). Sensitivity was 66.7% (95% confidence interval [CI] 0.223–0.957) and specificity 100% (95% CI 0.839–1) for the detection of ECE. Findings of MRI and the Partin tables showed a Spearman rho of 0.780 vs. 0.254 for OC and 0.780 vs. 0.363 for ECE, respectively. Compared to the Partin tables, MRI revealed standardized canonical discriminant function coefficients of 0.992 ( P<0.001) vs. 0.205 ( P=0.432) for OC and 0.965 ( P<0.001) vs. 0.329 ( P=0.197) for ECE, respectively.

Conclusion: 3T MRI showed a high accuracy for the staging of clinically localized prostate cancer, and it was significantly more accurate in predicting the final pathological stage than the Partin tables.
Medial temporal lobe atrophy increases the specificity of cerebrospinal fluid biomarkers in alzheimer disease with minor cerebrovascular changes
Authors: Zhang Y. , Londos E. , Minthon L. , Wattmo C. , Blennow K. , Liu H.J. , Bronge L. , Aspelin P. , Wahlund L.-O.
Published: May 2009

Background: Although cerebrospinal fluid (CSF) biomarkers and medial temporal lobe atrophy (MTA) contribute to the diagnosis of Alzheimer disease (AD), they may not be specific. Relatively little is known about how they correlate with each other.

Purpose: To identify the validity of the radiological linear measurements of brain atrophy in AD diagnosis by examining the correlation with CSF biomarkers and by examining if specificity could be improved in classification of AD from controls, when the linear measurements are combined with the CSF biomarkers.

Material and Methods: 59 controls (20 male/39 female, age 73±8 years), 162 pure AD patients (49/113, 74±7 years), and 86 AD patients with minor cerebrovascular changes (CVC) (31/55, 77±5 years), aged between 52 and 94 years, were recruited from the Malmö Alzheimer Study. AD patients were subgrouped into “pure AD” and “AD + CVC” in order to clarify the possible influence of CVC on atrophy or CSF biomarkers in AD patients. Abeta42, T-tau, and P-tau in CSF were examined. Computed tomography (CT) linear measurements were performed, which included temporal horn ratio and suprasellar cistern ratio that reflect MTA.

Results: Compared with the 14 significant correlations between the CT measurements and three CSF biomarkers in the pure AD group, there was only one significant correlation in the AD + CVC group and one in the control group. In particular, P-tau correlates with temporal horn ratio only in pure AD. When the CT measurements were added with CSF biomarkers as independent variables in discriminant analysis, the percentage of correct classification of AD + CVC from controls increased from 79.5% (only CSF biomarkers) to 84.6% (combined CT measurements with CSF biomarkers). However, little was changed in the pure AD group.

Conclusion: P-tau correlates with the linear CT measure of MTA only in pure AD without CVC. Combined with the measure of MTA, the specificity of CSF biomarkers can be increased, but only in AD + CVC. The linear measurements of MTA are of value in AD diagnosis.
Introduction of endovascular embolization for intracranial aneurysms in a low-volume institution
Authors: Lindekleiv H. M. , Jacobsen E. A. , Kloster R. , Sandell T. , Isaksen J. G. , Romner B. , Ingebrigtsen T. , Bajic R.
Published: May 2009

Background: Studies indicate a relationship between hospital caseload and health outcomes after both surgical and endovascular repair of intracranial aneurysms.

Purpose: To evaluate outcomes after introduction of endovascular embolization for intracranial aneurysms in a low-volume regional university hospital.

Material and Methods: Retrospective study of 243 consecutive patients treated for 284 intracranial aneurysms with endovascular embolization or surgical clipping from 2000 to 2006 at the University Hospital of North Norway. Postoperative complications were registered. The Glasgow Outcome Scale (GOS) was used for assessment of outcome.

Results: The mean annual number of procedures was 39 (microsurgery 23, embolization 16). Seventy-four percent of patients with ruptured aneurysms and all patients with unruptured aneurysms had a favorable outcome (GOS 4 or 5) at 1 year follow-up. Patients with subarachnoid hemorrhage were more likely to experience postoperative complications than patients treated for unruptured aneurysms (42% versus 8% of the patients, P<0.01). The immediate incomplete occlusion rate (Raymond II–III) in the initial embolization procedure was 29%. Ten endovascularly treated patients and one surgically treated patient required retreatments due to residual aneurysm or neck remnants.

Conclusion: The present study indicates that acceptable outcome from aneurysm treatment, both endovascular and microsurgical, is possible in a low-volume institution.
Why did I change when I went to therapy? A qualitative analysis of former patients' conceptions of successful psychotherapy
Authors: Binder Per-Einar , Holgersen Helge , Nielsen Geir Høstmark
Published: May 2009

Aim: Much research has been undertaken to identify significant events and change processes in psychotherapy. Most of these studies use categories and concepts consonant with the researcher's particular theoretical affiliation. But how do patients themselves, retrospectively, give meaning to what they felt most important for their realization of change? The present study sought to identify specific experiences and reflections of former psychotherapy patients who described their previous therapy as successful. Methods: Semi‐structured, qualitative, in‐depth interviews with ten former psychotherapy patients, recruited through an advertisement in a local newspaper. A descriptive and hermeneutically modified phenomenological approach was used to analyse interview transcripts, technically carried out with the assistance of Nvivo 8 software. Findings: The different ways the participants gave meaning to change processes and events clustered around the following themes: (i) Being in a relationship with a wise, warm, and competent professional, (ii) Being in a relationship with continuity when suffering from feelings of inner discontinuity, (iii) Having assumptions and beliefs about oneself and one's relational world corrected, (iv) Creating new meaning and seeing new connections in one's life patterns. Discussion: Relates current findings to those of previous studies and addresses strengths and limitations of the study, including reflections on the possible influence of the researchers' theoretical and professional background. Replications of the study are proposed, with researchers of other theoretical affiliations, and with different groups of former patients.
Psychological experiences of renal transplant patients: A qualitative analysis
Authors: Amerena Penny , Wallace Patti
Published: May 2009

Introduction: Organ‐sourcing developments now permit increasing numbers of renal transplants. Recipients commonly experience negative affect pre‐ and/or post‐transplant yet research on patient experience is lacking. Aims: This study aims to develop theory based on the lived experience of recipients, and to guide psychological and support interventions by counsellors and professional carers for the benefit of patients. Methods: A sample of eight participants was interviewed about their transplant experiences. The interview data were analysed using grounded theory methodology. Uniquely the research was conducted by a renal transplant patient, which potentially adds interpretive insight. Results: The central finding is that the issues facing transplant patients before and after transplant may be summarised as living with paradox and conflict. Thus, recipients may need to juxtapose anger/sadness about losses with an adaptive attitude to making the most of a second chance at life, and negotiate a positive relationship with an ‘alien’ organ. Conclusions/implications: The study offers evidence‐based guidance to counsellors supporting recipients to adjust to a changing sense of self, and to form adaptive relationships with self, others and the new kidney. Finally the research recommends action on improving awareness of and access to counselling and other supports for renal transplantees, and the need for in‐depth experiential research in this expanding area.
A re‐examination of choking in sport
Authors: Hill Denise M. , Hanton Sheldon , Fleming Scott , Matthews Nic
Published: May 2009

The purpose of this study was to re‐examine choking in sport. Using a grounded theory approach (Glaser & Strauss, 1967), qualitative data were gathered from four “experts” of applied sport psychology, who had published within the stress and anxiety literature, and worked extensively with athletes who had performed in highly stressful situations. The experts perceived that the contemporary definitions of choking in sport fail to reflect fully the experiences of “chokers”, and created a more detailed definition in response. They considered the choking process to consist of a stress response that culminates in a significant drop in performance – a choke, which psychologically damages the performer. It was also suggested that the choking process and its consequences were moderated by individual differences and type of sport. Accordingly, they recommended interventions that may alleviate choking and, importantly, generated characteristics that can be used to identify a choker. Such findings offer an extended understanding of choking in sport and provide a framework for future ecologically valid research.
Activated monocytes in peritumoral stroma of hepatocellular carcinoma foster immune privilege and disease progression through PD-L1
Authors: Kuang Dong-Ming , Zhao Qiyi , Peng Chen , Xu Jing , Zhang Jing-Ping , Wu Changyou , Zheng Limin
Published: May 2009

Macrophages (Mϕ) are prominent components of solid tumors and exhibit distinct phenotypes in different microenvironments. We have recently found that tumors can alter the normal developmental process of Mϕ to trigger transient activation of monocytes in peritumoral stroma. We showed that a fraction of monocytes/Mϕ in peritumoral stroma, but not in cancer nests, expresses surface PD-L1 (also termed B7-H1) molecules in tumors from patients with hepatocellular carcinoma (HCC). Monocytes activated by tumors strongly express PD-L1 proteins with kinetics similar to their activation status, and significant correlations were found between the levels of PD-L1+ and HLA-DRhigh on tumor-infiltrating monocytes. Autocrine tumor necrosis factor α and interleukin 10 released from activated monocytes stimulated monocyte expression of PD-L1. The PD-L1+ monocytes effectively suppressed tumor-specific T cell immunity and contributed to the growth of human tumors in vivo; the effect could be reversed by blocking PD-L1 on those monocytes. Moreover, we found that PD-L1 expression on tumor-infiltrating monocytes increased with disease progression, and the intensity of the protein was associated with high mortality and reduced survival in the HCC patients. Thus, expression of PD-L1 on activated monocytes/Mϕ may represent a novel mechanism that links the proinflammatory response to immune tolerance in the tumor milieu.
Deficiency of the DNA repair enzyme ATM in rheumatoid arthritis
Authors: Shao Lan , Fujii Hiroshi , Colmegna Inés , Oishi Hisashi , Goronzy Jörg J. , Weyand Cornelia M.
Published: May 2009

In rheumatoid arthritis (RA), dysfunctional T cells sustain chronic inflammatory immune responses in the synovium. Even unprimed T cells are under excessive replication pressure, suggesting an intrinsic defect in T cell regeneration. In naive CD4 CD45RA+ T cells from RA patients, DNA damage load and apoptosis rates were markedly higher than in controls; repair of radiation-induced DNA breaks was blunted and delayed. DNA damage was highest in newly diagnosed untreated patients. RA T cells failed to produce sufficient transcripts and protein of the DNA repair kinase ataxia telangiectasia (AT) mutated (ATM). NBS1, RAD50, MRE11, and p53 were also repressed. ATM knockdown mimicked the biological effects characteristic for RA T cells. Conversely, ATM overexpression reconstituted DNA repair capabilities, response patterns to genotoxic stress, and production of MRE11 complex components and rescued RA T cells from apoptotic death. In conclusion, ATM deficiency in RA disrupts DNA repair and renders T cells sensitive to apoptosis. Apoptotic attrition of naive T cells imposes lymphopenia-induced proliferation, leading to premature immunosenescence and an autoimmune-biased T cell repertoire. Restoration of DNA repair mechanisms emerges as an important therapeutic target in RA.
iNKT cell development is orchestrated by different branches of TGF-β signaling
Authors: Doisne Jean-Marc , Bartholin Laurent , Yan Kai-Ping , Garcia Céline N. , Duarte Nadia , Le Luduec Jean-Benoît , Vincent David , Cyprian Farhan , Horvat Branka , Martel Sylvie , Rimokh Ruth , Losson Régine , Benlagha Kamel , Marie Julien C.
Published: May 2009

Invariant natural killer T (iNKT) cells constitute a distinct subset of T lymphocytes exhibiting important immune-regulatory functions. Although various steps of their differentiation have been well characterized, the factors controlling their development remain poorly documented. Here, we show that TGF-β controls the differentiation program of iNKT cells. We demonstrate that TGF-β signaling carefully and specifically orchestrates several steps of iNKT cell development. In vivo, this multifaceted role of TGF-β involves the concerted action of different pathways of TGF-β signaling. Whereas the Tif-1γ branch controls lineage expansion, the Smad4 branch maintains the maturation stage that is initially repressed by a Tif-1γ/Smad4-independent branch. Thus, these three different branches of TGF-β signaling function in concert as complementary effectors, allowing TGF-β to fine tune the iNKT cell differentiation program.
General Relativity Needs No Interpretation
Authors: Curiel Erik
Published: May 2009

I argue that, contrary to the recent claims of physicists and philosophers of physics, general relativity requires no interpretation in any substantive sense of the term. I canvass the common reasons given in favor of the alleged need for an interpretation, including the difficulty in coming to grips with the physical significance of diffeomorphism invariance and of singular structure, and the problems faced in the search for a theory of quantum gravity. I find that none of them shows any defect in our comprehension of general relativity as a physical theory. I conclude by comparing general relativity with quantum mechanics, a theory that manifestly does stand in need of an interpretation in an important sense. Although many aspects of the conceptual structure of general relativity remain poorly understood, it suffers no incoherence in its formulation as a physical theory that only an ‘interpretation’ could resolve.
Fast and accurate short read alignment with Burrows–Wheeler transform
Authors: Li Heng , Durbin Richard
Published: May 2009

Motivation: The enormous amount of short reads generated by the new DNA sequencing technologies call for the development of fast and accurate read alignment programs. A first generation of hash table-based methods has been developed, including MAQ, which is accurate, feature rich and fast enough to align short reads from a single individual. However, MAQ does not support gapped alignment for single-end reads, which makes it unsuitable for alignment of longer reads where indels may occur frequently. The speed of MAQ is also a concern when the alignment is scaled up to the resequencing of hundreds of individuals.

Results: We implemented Burrows-Wheeler Alignment tool (BWA), a new read alignment package that is based on backward search with Burrows–Wheeler Transform (BWT), to efficiently align short sequencing reads against a large reference sequence such as the human genome, allowing mismatches and gaps. BWA supports both base space reads, e.g. from Illumina sequencing machines, and color space reads from AB SOLiD machines. Evaluations on both simulated and real data suggest that BWA is ∼10–20× faster than MAQ, while achieving similar accuracy. In addition, BWA outputs alignment in the new standard SAM (Sequence Alignment/Map) format. Variant calling and other downstream analyses after the alignment can be achieved with the open source SAMtools software package.

Availability:  http://maq.sourceforge.net

Contact:  rd@sanger.ac.uk
Isolation, Purification, and Characterization of a Polygalacturonase Produced in Penicillium solitum-Decayed ‘Golden Delicious’ Apple Fruit
Authors: Jurick Wayne M. , Vico Ivana , McEvoy James L. , Whitaker Bruce D. , Janisiewicz Wojciech , Conway William S.
Published: May 2009

Polygalacturonase (PG) was extracted and purified from decayed ‘Golden Delicious’ apple fruit inoculated with Penicillium solitum. Ammonium sulfate, gel filtration, and cation exchange chromatography were used to purify the enzyme. Both chromatographic methods revealed a single peak corresponding to PG activity. The purified PG most likely originates from the fungus because PG activity from healthy and wounded apple tissue was undetectable. Analysis of cation exchange-purified material using sodium dodecyl sulfate polyacrylamide gel electrophoresis revealed a single 50-kDa band. The enzyme was active over a broad pH range (3 to 7), with optimal activity between pH 4 and 5. PG was highly active at 20 and 37°C but was also detectable at 2, 50, and 75°C. Divalent cations affected PG enzyme activity; Mg and Fe increased, whereas Ca and Mn reduced activity in vitro. Thin-layer chromatographic separation of hydrolysis products and data from a PG plate activity assay based on staining with ruthenium red showed that the enzyme exhibits both exo and endo activity. Purified PG incubated with intact apple fruit tissue in vitro caused a 30% reduction in mass after 48 h, suggesting a role in P. solitum-mediated decay of apple fruit.
Fungal Colonization and Host Defense Reactions in Ulmus americana Callus Cultures Inoculated with Ophiostoma novo-ulmi
Authors: Aoun Mirella , Rioux Danny , Simard Marie , Bernier Louis
Published: May 2009

The host–pathogen interaction leading to Dutch elm disease was analyzed using histo- and cyto-chemical tests in an in vitro system. Friable and hard susceptible Ulmus americana callus cultures were inoculated with the highly aggressive pathogen Ophiostoma novo-ulmi. Inoculated callus tissues were compared with water-treated callus tissues and studied with light microscopy (LM), transmission-electron microscopy (TEM), and scanning-electron microscopy (SEM). New aspects of this interaction are described. These include the histological observation, for the first time in plant callus cultures, of suberin with its typical lamellar structure in TEM and the intracellular presence of O. novo-ulmi. Expression of the phenylalanine ammonia lyase gene, monitored by real-time quantitative polymerase chain reaction, was correlated with the accumulation of suberin, phenols, and lignin in infected callus cultures. This study validates the potential use of the in vitro system for genomic analyses aimed at identifying genes expressed during the interaction in the Dutch elm disease pathosystem.
Development of Ramulosis Disease of Cotton Under Controlled Environment and Field Conditions
Authors: Monteiro José Eduardo B. A. , Sentelhas Paulo C. , Gleason Mark L. , Esker Paul D. , Chiavegato Ederaldo J.
Published: May 2009

Colletotrichum gossypii var. cephalosporioides, the fungus that causes ramulosis disease of cotton, is widespread in Brazil and can cause severe yield loss. Because weather conditions greatly affect disease development, the objective of this work was to develop weather-based models to assess disease favorability. Latent period, incidence, and severity of ramulosis symptoms were evaluated in controlled environment experiments using factorial combinations of temperature (15, 20, 25, 30, and 35°C) and leaf wetness duration (0, 4, 8, 16, 32, and 64 h after inoculation). Severity was modeled as an exponential function of leaf wetness duration and temperature. At the optimum temperature of disease development, 27°C, average latent period was 10 days. Maximum ramulosis severity occurred from 20 to 30°C, with sharp decreases at lower and higher temperatures. Ramulosis severity increased as wetness periods were increased from 4 to 32 h. In field experiments at Piracicaba, São Paulo State, Brazil, cotton plots were inoculated (105conidia ml–1) and ramulosis severity was evaluated weekly. The model obtained from the controlled environment study was used to generate a disease favorability index for comparison with disease progress rate in the field. Hourly measurements of solar radiation, temperature, relative humidity, leaf wetness duration, rainfall, and wind speed were also evaluated as possible explanatory variables. Both the disease favorability model and a model based on rainfall explained ramulosis growth rate well, with R2of 0.89 and 0.91, respectively. They are proposed as models of ramulosis development rate on cotton in Brazil, and weather–disease relationships revealed by this work can form the basis of a warning system for ramulosis development.
Occurrence ofErysiphe necatorChasmothecia and Their Natural Parasitism byAmpelomyces quisqualis
Authors: Angeli Dario , Pellegrini Elisabetta , Pertot Ilaria
Published: May 2009

In northern Italy, Erysiphe necator overwinters almost exclusively as chasmothecia. From 2004 to 2008, we investigated the occurrence of natural parasitism of grapevine powdery mildew chasmothecia by Ampelomyces quisqualis in the Trentino-Alto Adige region, in northern Italy. The survey was conducted in 18 vineyards in autumn 2004 and 2005 and in 45 vineyards in autumn 2006 and 2007. The incidence of powdery mildew signs (white powdery mycelia and conidia), the number of chasmothecia and their development pattern, and the incidence of parasitism by A. quisqualis were assessed. The production of E. necator chasmothecia on leaves is related to the incidence and severity of the disease on leaves at the end of the season and is not correlated with the elevation of the vineyard, which is inversely related to the temperature. A limited amount of natural parasitism of E. necator by Ampelomyces spp. (0.17 to 3.51%) was observed in all of the years of the survey. Pycnidia and conidia of Ampelomyces spp. parasitizing E. necator chasmothecia were found in conventional, organically grown, and untreated vineyards. Some of the isolated Ampelomyces strains have conidia that are shaped differently than those of the commercial A. quisqualis strain (AQ10) and are phylogenetically different from AQ10.
Molecular Diversity and Evolutionary Processes of Alternaria solani in Brazil Inferred Using Genealogical and Coalescent Approaches
Authors: Lourenço Valdir , Moya Andrés , González-Candelas Fernando , Carbone Ignazio , Maffia Luiz A. , Mizubuti Eduardo S. G.
Published: May 2009

Alternaria spp. form a heterogeneous group of saprophytic and plant-pathogenic fungi widespread in temperate and tropical regions. However, the relationship between evolutionary processes and genetic diversity with epidemics is unknown for several plant-pathogenic Alternaria spp. The interaction of Alternaria solani populations with potato and tomato plants is an interesting case study for addressing questions related to molecular evolution of an asexual fungus. Gene genealogies based on the coalescent process were used to infer evolutionary processes that shape the A. solani population. Sequences of the rDNA internal transcribed spacer (ITS) region and the genes which encode the allergenic protein alt a 1 (Alt a 1) and glyceraldehyde-3-phosphate dehydrogenase (Gpd) were used to estimate haplotype and nucleotide diversity as well as for the coalescent analyses. The highest number of parsimony informative sites (n = 14), nucleotide diversity (0.007), and the average number of nucleotide differences (3.20) were obtained for Alt a 1. Although the highest number of haplotypes (n = 7) was generated for ITS, haplotype diversity was the lowest (0.148) for this region. Recombination was not detected. Subdivision was inferred from populations associated with hosts but there was no evidence of geographic subdivision, and gene flow is occurring among subpopulations. In the analysis of the Alt a 1, balancing selection and population expansion or purifying selection could have occurred in A. solani subpopulations associated with potato and tomato plants, respectively. There is strong evidence that the subpopulation of A. solani that causes early blight in potato is genetically distinct from the subpopulation that causes early blight in tomato. The population of A. solani is clonal, and gene flow and mutation are the main evolutionary processes shaping its genetic structure.
Infection Dynamics of Fusarium mangiferae, Causal Agent of Mango Malformation Disease
Authors: Gamliel-Atinsky E. , Sztejnberg A. , Maymon M. , Vintal H. , Shtienberg D. , Freeman S.
Published: May 2009

Conditions affecting germination and growth of Fusarium mangiferae, causal agent of mango malformation disease, were studied in vitro. Both conidial germination and colony growth required temperatures >5°C and reached a peak at 28 and 25°C, respectively. A minimum 2-h wetness period was required for conidial germination, reaching a peak after 8 h of wetness. High incidence of fungal colonization in buds, predominantly the apical buds, was detected compared with inoculated leaves. The pathogen was detected in the roots of inoculated soil 19 weeks postinoculation but not in aboveground parts of the plants, and symptoms of the disease were not observed, either. Dry, malformed inflorescence debris serving as a source of inoculum caused significantly higher colonization (52 and 20%) of inoculated buds, compared with that (0%) of the untreated controls. Incidence of sampled leaf disks bearing propagules of F. mangiferae from an infected orchard peaked in June and July and decreased during the following months, whereas airborne infections on 1-month-old branches was the highest in May and June, corresponding with inoculum availability released from infected inflorescences. Colonization pattern, determined in naturally infected vegetative and woody branches, was significantly higher in node sections than in the internode sections. This study sheds light on infection dynamics, colonization patters, and the disease cycle of F. mangiferae in mango.
Evolution of seahorses' upright posture was linked to Oligocene expansion of seagrass habitats
Authors: Teske Peter R. , Beheregaray Luciano B.
Published: May 2009

Seahorses (Syngnathidae:
Hippocampus
) are iconic marine teleosts that are readily identifiable by their upright posture. The fossil record is inadequate to shed light on the evolution of this trait because it lacks transitional forms. There are, however, extant syngnathid species (the pygmy pipehorses) that look like horizontally swimming seahorses and that might represent a surviving evolutionary link between the benthic seahorses and other, free-swimming members of the family Syngnathidae. Using sequence data from five nuclear loci, we confirm the sister taxon relationship between seahorses and pygmy pipehorses. Molecular dating indicates that the two taxa diverged during the Late Oligocene. During this time, tectonic events in the Indo-West Pacific resulted in the formation of vast amounts of new shallow-water areas and associated expansion of seagrass habitats that would have favoured the seahorses’ upright posture by improving their camouflage while not affecting their manoeuvrability negatively. The molecular techniques employed here provide new insights into the evolution of a taxon whose fossil record is incomplete, but whose evolutionary history is so recent that the major stages of morphological evolution are still represented in extant species.
Horizontal gene transfer of an entire metabolic pathway between a eukaryotic alga and its DNA virus
Authors: Monier Adam , Pagarete António , de Vargas Colomban , Allen Michael J. , Read Betsy , Claverie Jean-Michel , Ogata Hiroyuki
Published: May 2009

Interactions between viruses and phytoplankton, the main primary producers in the oceans, affect global biogeochemical cycles and climate. Recent studies are increasingly revealing possible cases of gene transfers between cyanobacteria and phages, which might have played significant roles in the evolution of cyanobacteria/phage systems. However, little has been documented about the occurrence of horizontal gene transfer in eukaryotic phytoplankton/virus systems. Here we report phylogenetic evidence for the transfer of seven genes involved in the sphingolipid biosynthesis pathway between the cosmopolitan eukaryotic microalgaEmiliania huxleyiand its large DNA virus EhV. PCR assays indicate that these genes are prevalent inE. huxleyiand EhV strains isolated from different geographic locations. Patterns of protein and gene sequence conservation support that these genes are functional in bothE. huxleyiand EhV. This is the first clear case of horizontal gene transfer of multiple functionally linked enzymes in a eukaryotic phytoplankton–virus system. We examine arguments for the possible direction of the gene transfer. The virus-to-host direction suggests the existence of ancient viruses that controlled the complex metabolic pathway in order to infect primitive eukaryotic cells. In contrast, the host-to-virus direction suggests that the serial acquisition of genes involved in the same metabolic pathway might have been a strategy for the ancestor of EhVs to stay ahead of their closest relatives in the great evolutionary race for survival.
Structures of K0.05Na0.95NbO3 (50–300 K) and K0.30Na0.70NbO3 (100–200 K)
Authors: Zhang N. , Glazer A. M. , Baker D. , Thomas P. A.
Published: May 2009

Rietveld refinement using neutron powder diffraction data is reported for the potential lead-free piezoelectric material K
x
Na1 − x
NbO3 (x = 0.05, x = 0.3) at low temperatures. The structures were determined to be of rhombohedral symmetry, space group R3c, with the tilt system a
−
a
−
a
− for both compositions. It was found that some of the structural parameters differ significantly in the two structures, and particularly the NbO6 octahedral strains as a function of temperature. The 300 K profile for K0.05Na0.95NbO3 shows the coexistence of rhombohedral and monoclinic phases, which indicates that the phase boundary is close to room temperature; the phase boundary for K0.30Na0.70NbO3 is found to be at approximately 180 K.
Complex ceramic structures. I. Weberites
Authors: Cai Lu , Nino Juan C.
Published: May 2009

The weberite structure (A
2
B
2
X
7) is an anion-deficient fluorite-related superstructure. Compared with fluorites, the reduction in the number of anions leads to a decrease in the coordination number of the B cations (VI coordination) with respect to the A cations (VIII coordination), thus allowing the accommodation of diverse cations. As a result, weberite compounds have a broad range of chemical and physical properties and great technological potential. This article summarizes the structural features of weberite and describes the structure in several different ways. This is the first time that the stacking vector and stacking angle are used to represent the weberite structure. This paper also discusses the crystallographic relationship between weberite, fluorite and pyrochlore (another fluorite-related structure). The cation sublattices of weberite and pyrochlore are correlated by an axial transformation. It has been shown that the different coordination environment of anions is due to the alternating layering of the AB
3 and A
3
B close-packed cation layers. A stability field of weberite oxides is proposed in terms of the ratio of ionic radius of cations and relative bond ionicity. In addition, a selection of weberite compounds with interesting properties is discussed.