bluuebunny/crossref_metadata_2025 huggingface dataset:
Transcriptome and Metabolite Profiling Show That APETALA2a Is a Major Regulator of Tomato Fruit Ripening
Authors: Karlova Rumyana , Rosin Faye M. , Busscher-Lange Jacqueline , Parapunova Violeta , Do Phuc T. , Fernie Alisdair R. , Fraser Paul D. , Baxter Charles , Angenent Gerco C. , de Maagd Ruud A.
Published: March 2011

Fruit ripening in tomato (Solanum lycopersicum) requires the coordination of both developmental cues as well as the plant hormone ethylene. Although the role of ethylene in mediating climacteric ripening has been established, knowledge regarding the developmental regulators that modulate the involvement of ethylene in tomato fruit ripening is still lacking. Here, we show that the tomato APETALA2a (AP2a) transcription factor regulates fruit ripening via regulation of ethylene biosynthesis and signaling. RNA interference (RNAi)-mediated repression of AP2a resulted in alterations in fruit shape, orange ripe fruits, and altered carotenoid accumulation. Microarray expression analyses of the ripe AP2 RNAi fruits showed altered expression of genes involved in various metabolic pathways, such as the phenylpropanoid and carotenoid pathways, as well as in hormone synthesis and perception. Genes involved in chromoplast differentiation and other ripening-associated processes were also differentially expressed, but softening and ethylene biosynthesis occurred in the transgenic plants. Ripening regulators RIPENING-INHIBITOR, NON-RIPENING, and COLORLESS NON-RIPENING (CNR) function upstream of AP2a and positively regulate its expression. In the pericarp of AP2 RNAi fruits, mRNA levels of CNR were elevated, indicating that AP2a and CNR are part of a negative feedback loop in the regulation of ripening. Moreover, we demonstrated that CNR binds to the promoter of AP2a in vitro.
The MYB96 Transcription Factor Regulates Cuticular Wax Biosynthesis under Drought Conditions inArabidopsis
Authors: Seo Pil Joon , Lee Saet Buyl , Suh Mi Chung , Park Mi-Jeong , Go Young Sam , Park Chung-Mo
Published: March 2011

Drought stress activates several defense responses in plants, such as stomatal closure, maintenance of root water uptake, and synthesis of osmoprotectants. Accumulating evidence suggests that deposition of cuticular waxes is also associated with plant responses to cellular dehydration. Yet, how cuticular wax biosynthesis is regulated in response to drought is unknown. We have recently reported that an Arabidopsis thaliana abscisic acid (ABA)–responsive R2R3-type MYB transcription factor, MYB96, promotes drought resistance. Here, we show that transcriptional activation of cuticular wax biosynthesis by MYB96 contributes to drought resistance. Microarray assays showed that a group of wax biosynthetic genes is upregulated in the activation-tagged myb96-1D mutant but downregulated in the MYB96-deficient myb96-1 mutant. Cuticular wax accumulation was altered accordingly in the mutants. In addition, activation of cuticular wax biosynthesis by drought and ABA requires MYB96. By contrast, biosynthesis of cutin monomers was only marginally affected in the mutants. Notably, the MYB96 protein acts as a transcriptional activator of genes encoding very-long-chain fatty acid–condensing enzymes involved in cuticular wax biosynthesis by directly binding to conserved sequence motifs present in the gene promoters. These results demonstrate that ABA-mediated MYB96 activation of cuticular wax biosynthesis serves as a drought resistance mechanism.
A new disulfide‐linked dimer of a single‐chain antibody fragment against human CD47 induces apoptosis in lymphoid malignant cells via the hypoxia inducible factor‐1α pathway
Authors: Sagawa Morihiko , Shimizu Takatsune , Fukushima Naoshi , Kinoshita Yasuko , Ohizumi Iwao , Uno Shinsuke , Kikuchi Yasufumi , Ikeda Yasuo , Yamada‐Okabe Hisafumi , Kizaki Masahiro
Published: March 2011

CD47 belongs to the immunoglobulin superfamily and is associated with β‐integrins. Recently it was reported that CD47 ligation rapidly induces apoptosis in B‐chronic lymphocytic leukemia (CLL) cells. Chronic lymphocytic leukemia is still an incurable hematological malignancy even with the novel therapeutic agents; therefore, new and effective agents for the treatment of CLL in clinical settings are urgently needed. We generated a murine monoclonal antibody against an extracellular domain of human CD47 (designated MABL). Subsequently, we created a disulfide‐stabilized dimer of a single‐chain antibody fragment of MABL (S‐S diabody) to get rid of the adverse effect of MABL such as hemagglutination. In this study, we analyzed the effects of this new antibody on cellular proliferation, and the molecular mechanism of CD47‐mediated apoptosis in human lymphoid malignant cells. Treatment with S‐S diabody alone induced apoptosis of CD47‐positive primary B‐CLL and leukemic cells (MOLT‐4 and JOK‐1). In addition, administration of S‐S diabody significantly prolonged the survival of severe combined immunodeficiency (SCID) mice inoculated with JOK‐1 cells. In gene expression profiling of the S‐S diabody‐treated MOLT‐4 cells, hypoxia inducible factor (HIF)‐1α downstream genes (RTP801 and BNIP3) were upregulated, and the mRNA expression levels of HIF‐1α, RTP801 and BNIP3 were increased. Knockdown of HIF‐1α by siRNA repressed S‐S diabody‐induced apoptosis in MOLT4 cells. In conclusion, CD47 will be a molecular target for the treatment of lymphoid malignancies, and S‐S diabody might have potential as a novel therapeutic agent for B‐CLL. (Cancer Sci 2011; 102: 1208–1215)
Critical role of aquaporin 3 on growth of human esophageal and oral squamous cell carcinoma
Authors: Kusayama Morio , Wada Koichiro , Nagata Masahide , Ishimoto Shunsuke , Takahashi Hirokazu , Yoneda Masato , Nakajima Atsushi , Okura Masaya , Kogo Mikihiko , Kamisaki Yoshinori
Published: March 2011

Aquaporins (AQP) play important roles in water and glycerol transport. We examined whether AQP3 is expressed in primary squamous cell carcinoma (SCC) such as esophageal and oral cancer and lymph node metastasis, and whether AQP3 is a potential target for tumor therapy. A high level expression of AQP3 was observed in tumor areas of human primary SCC such as esophageal and lingual cancers, and lymph node metastasis, but was not observed in normal areas. Treatment with pan‐AQP inhibitor caused apoptotic cell death on the SCC cell lines in a concentration‐dependent manner. Small interfering RNA (siRNA) specific for AQP3 also inhibited cell adhesion and growth of SCC, but not those of adenocarcinoma cell lines and fibroblasts. Expression of integrin α5 and β1, counter adhesion molecules for fibronectin, was inhibited by treatment with AQP3‐siRNA. The phosphorylation of focal adhesion kinase (FAK) was decreased by treatment with AQP3‐siRNA, which then caused decreases in phosphorylation of Erk and MAPK. These results indicate that the decreases in integrins and the inhibition of cell adhesion might cause inhibition of the FAK signaling pathways. Combination of AQP3‐siRNA with cisplatin, a major anti‐cancer drug, strongly inhibited the growth of SCC. Cell death caused by the inhibition of AQP3 was a result of direct interference with cell adhesion involving intracellular FAK‐MAPK signaling pathways. These results imply a potentially important and novel role for the inhibition of AQP3 function via the use of specific siRNA in the treatment of SCC. (Cancer Sci 2011; 102: 1128–1136)
hOGG1 Ser326Cys polymorphism and risk of childhood acute lymphoblastic leukemia in a Chinese population
Authors: Li Qian , Huang Lizhen , Rong Liucheng , Xue Yao , Lu Qin , Rui Yaoyao , Li Jie , Tong Na , Wang Meilin , Zhang Zhengdong , Fang Yongjun
Published: March 2011

Oxidative DNA damage caused by reactive oxygen species can produce 8‐oxoguanine (8‐oxoG) in DNA, which is misread and leads to G:C→T:A transversions. This can be carcinogenic. Repair of 8‐oxoG by the base excision repair pathway involves the activity of human 8‐oxoG DNA glycosylase 1 (hOGG1). Accumulating evidence suggests that the hOGG1 Ser326Cys polymorphism affects the activity of hOGG1 and might serve as a genetic marker for susceptibility to several cancers. To determine whether this polymorphism is associated with risk of childhood acute lymphoblastic leukemia (ALL) in Chinese children, we genotyped the hOGG1 Ser326Cys polymorphism (rs1052133) in a case–control study including 415 cases and 511 controls. We found that there was a significant difference in the genotype distributions of the hOGG1 Ser326Cys polymorphism between cases and controls (P = 0.046), and the combined genotypes Ser/Ser and Ser/Cys were associated with a statistically significantly decreased risk of ALL (adjusted odds ratio [OR] = 0.66, 95% confidence interval [CI] = 0.49–0.88, P = 0.005). Furthermore, we found a decreased risk for high risk ALL (adjusted OR = 0.60, 95% CI = 0.40–0.88, P = 0.005), low risk ALL (adjusted OR = 0.68, 95% CI = 0.47–0.99, P = 0.042), and B‐phenotype ALL (adjusted OR = 0.63, 95% CI = 0.46–0.86, P = 0.003) among children with the Ser/Ser and Ser/Cys genotypes. Our results suggest that the hOGG1 Ser326Cys polymorphism is associated with susceptibility to childhood ALL in a Chinese population. (Cancer Sci 2011; 102: 1123–1127)
Persistent vascular normalization as an alternative goal of anti‐angiogenic cancer therapy
Authors: Sato Yasufumi
Published: March 2011

Angiogenesis is recognized as one of the principal hallmarks of cancers. Cancers contain newly formed immature vessels devoid of firm coverage by pericytes. Several drugs targeting vascular endothelial growth factor signals are now in clinical use for anti‐angiogenic cancer treatment. Those drugs transiently normalize tumor vessels and ultimately provoke vascular regression. This regression causes tumor hypoxia, which could trigger certain cancer cells to become more invasive and metastatic. Normalized vessels do not induce tumor hypoxia, and may protect from cancer cell intravasation and enhance anticancer treatment with chemotherapeutic agents, radiation, or immune therapy. Thus, persistent vascular normalization could be an alternative goal of anti‐angiogenic cancer treatment. (Cancer Sci 2011; 102: 1253–1256)
What impact have tobacco control policies, cigarette price and tobacco control programme funding had on Australian adolescents' smoking? Findings over a 15‐year period
Authors: White Victoria M. , Warne Charles D. , Spittal Matthew J. , Durkin Sarah , Purcell Kate , Wakefield Melanie A.
Published: March 2011

Aims  To assess the impact of tobacco control policies relating to youth access, clean indoor air and tobacco advertising at point‐of‐sale and outdoors, in addition to cigarette price and per capita tobacco control spending, on adolescent smoking prevalence.

Design  Repeated cross‐sectional surveys. Logistic regression analyses examined association between policies and smoking prevalence.

Setting  Australia, 1990–2005.

Participants  A nationally representative sample of secondary students (aged 12–17 years) participating in a triennial survey (sample size per survey range: 20 560 to 27 480).

Measurements  Students' report of past‐month smoking. In each jurisdiction, extent of implementation of the three policies for the year of the survey was determined. For each survey year, national per capita tobacco control spending was determined and jurisdiction‐specific 12‐month change in cigarette price obtained.

Findings  Extent of implementation of the three policy areas varied between states and over the survey years. Multivariate analyses that adjusted for demographic factors, year and all tobacco control variables showed that 12‐month cigarette price increases [odds ratio (OR): 0.98, 95% confidence interval (CI): 0.97–0.99], greater per capita tobacco control spending (OR: 0.99, 95% CI: 0.98–0.99) and stronger implementation of clean indoor air policies (OR: 0.93, 95% CI: 0.92–0.94) were associated with reduced smoking prevalence.

Conclusions  Adult‐directed, population‐based tobacco control policies such as clean indoor air laws and increased prices of cigarettes, implemented as part of a well‐funded comprehensive tobacco control programme are associated with lower adolescent smoking.
Resuscitation in massive obstetric haemorrhage using an intraosseous needle*
Authors: Chatterjee D. J. , Bukunola B. , Samuels T. L. , Induruwage L. , Uncles D. R.
Published: March 2011

A 38‐year‐old woman experienced a massive postpartum haemorrhage 30 minutes after emergency caesarean delivery. The patient became severely haemodynamically compromised with an unrecordable blood pressure. Rapid fluid resuscitation was limited by the capacity of the intravenous cannula in place at the time and inability to establish additional vascular access using conventional routes in a timely manner. An intraosseous needle was inserted in the proximal humerus at the first attempt and administration of resuscitation fluid by this route subsequently enabled successful placement of further intravenous lines. Blood and blood products were deployed in conjunction with intra‐operative cell salvage and transoesophageal Doppler cardiac output monitoring was used to assess adequacy of volume replacement. Haemorrhage control was finally achieved with the use of recombinant factor VIIa and hysterectomy.
The effect of combining dexamethasone with ondansetron for nausea and vomiting associated with fentanyl‐based intravenous patient‐controlled analgesia*
Authors: Song J. W. , Park E. Y. , Lee J. G. , Park Y. S. , Kang B. C. , Shim Y. H.
Published: March 2011

We investigated whether combined dexamethasone and ondansetron is more effective than ondansetron alone in preventing postoperative nausea and vomiting in patients with fentanyl‐based intravenous patient‐controlled analgesia. One hundred and thirty patients undergoing video‐assisted thoracoscopic surgery were assigned to either an ondansetron group or a dexamethasone and ondansetron group. In all patients, ondansetron 4 mg was administered at the end of surgery and 12 mg was added to the patient‐controlled analgesia solution. The dexamethasone and ondansetron group received dexamethasone 8 mg at the induction of anaesthesia. The overall incidence of nausea and vomiting during the first 48 h postoperatively did not differ between groups (34/61 (56%) vs 28/62 (45%) in the ondansetron group and dexamethasone and ondansetron groups, respectively). The incidence of severe nausea and vomiting (≥ 7 nausea on an 11‐point verbal numerical rating scale, retching or vomiting) was higher in the ondansetron group than in the dexamethasone and ondansetron group (15/61 (25%) vs 6/62 (10%, respectively, p = 0.028). Combined dexamethasone and ondansetron is more effective in reducing severe nausea and vomiting than ondansetron alone in patients receiving fentanyl‐based intravenous patient‐controlled analgesia.
Genome‐wide association mapping in Norwegian Red cattle identifies quantitative trait loci for fertility and milk production on BTA12
Authors: Olsen H. G. , Hayes B. J. , Kent M. P. , Nome T. , Svendsen M. , Larsgard A. G. , Lien S.
Published: March 2011

Reproductive performance is a critical trait in dairy cattle. Poor reproductive performance leads to prolonged calving intervals, higher culling rates and extra expenses related to multiple inseminations, veterinary treatments and replacements. Genetic gain for improved reproduction through traditional selection is often slow because of low heritability and negative correlations with production traits. Detection of DNA markers associated with improved reproductive performance through genome‐wide association studies could lead to genetic gain that is more balanced between fertility and production. Norwegian Red cattle are well suited for such studies, as very large numbers of detailed reproduction records are available. We conducted a genome‐wide association study for non‐return rate, fertility treatments and retained placenta using almost 1 million records on these traits and 17 343 genome‐wide single‐nucleotide polymorphisms. Genotyping costs were minimized by genotyping the sires of the cows recorded and by using daughter averages as phenotypes. The genotyped sires were assigned to either a discovery or a validation population. Associations were only considered to be validated if they were significant in both groups. Strong associations were found and validated on chromosomes 1, 5, 8, 9, 11 and 12. Several of these were highly supported by findings in other studies. The most important result was an association for non‐return rate in heifers in a region of BTA12 where several associations for milk production traits have previously been found. Subsequent fine‐mapping verified the presence of a quantitative trait loci (QTL) having opposing effects on non‐return rate and milk production at 18 Mb. The other reproduction QTL did not have pleiotropic effects on milk production, and these are therefore of considerable interest for use in marker‐assisted selection.
Effect of Lactobacillus paracasei ST11 on a nasal provocation test with grass pollen in allergic rhinitis
Authors: Wassenberg J. , Nutten S. , Audran R. , Barbier N. , Aubert V. , Moulin J. , Mercenier A. , Spertini F.
Published: March 2011

Cite this as: J. Wassenberg, S. Nutten, R. Audran, N. Barbier, V. Aubert, J. Moulin, A. Mercenier and F. Spertini, Clinical & Experimental Allergy, 2011 (41) 565–573.

Background
Probiotics have been associated with prevention and improvement of symptoms in atopic diseases such as atopic dermatitis. However, few studies exist that document their efficacy for upper airways allergies such as allergic rhinitis.

Objective
To investigate the effect of short‐term oral administration of Lactobacillus paracasei ST11 on a nasal provocation test (NPT) with grass pollen.

Methods
Thirty‐one adult volunteers with allergic rhinitis were enrolled in a randomized, double‐blind, placebo‐controlled study, based on two 4‐week cross‐over periods of product consumption (ST11‐fermented milk vs. placebo), separated by a wash‐out period of 6–8 weeks. Objective and subjective clinical parameters of NPT as well as systemic and nasal immunological parameters were compared between the two treatment periods (registration number: NCT 011 50 253).

Results
Subjects that received ST11‐fermented milk had lower nasal congestion than subjects under placebo (visual analogical scale; P<0.05). Nasal pruritus followed the same trend. However, no significant change in combined nasal reaction threshold was observed between the two periods. IL‐5 secretion by peripheral blood mononuclear cells and serum allergen‐specific IgG4 were significantly lower in ST11‐fermented milk group compared to placebo group. IL‐8 and IL‐10 secretion followed the same trend.

Conclusion and Clinical Relevance
Short‐term treatment with ST11‐fermented milk before NPT significantly improved a clinical marker of NPT (subjective nasal congestion) and down‐regulated systemic immune markers (IL‐5 from peripheral blood mononuclear cells and serum IgG4). These data strongly suggest that probiotics may down modulate key parameters of allergic rhinitis and warrant future evaluation in seasonal trials.
Asthma in the elderly … Their time is right now
Authors: Olivenstein R. , Hamid Q.
Published: March 2011

Cite this as: R. Olivenstein and Q. Hamid, Clinical & Experimental Allergy, 2011 (41) 457–458.
Airway eosinophilia in occupational asthma
Authors: Maestrelli P.
Published: March 2011

Cite this as: P. Maestrelli, Clinical & Experimental Allergy, 2011 (41) 454–456.
Online version of the food allergy quality of life questionnaire–adult form: validity, feasibility and cross‐cultural comparison
Authors: Goossens N. J. , Flokstra‐de Blok B. M. J. , Vlieg‐Boerstra B. J. , Duiverman E. J. , Weiss C. C. , Furlong T. J. , Dubois A. E. J.
Published: March 2011

Cite this as: N. J. Goossens, B. M. J. Flokstra‐de Blok, B. J. Vlieg‐Boerstra, E. J. Duiverman, C. C. Weiss, T. J. Furlong and A. E. J. Dubois, Clinical & Experimental Allergy, 2011 (41) 574–581.

Background
Food‐allergic reactions occur in 3–4% of the adult population in Western countries. It has been shown that food allergy may impair health‐related quality of life (HRQL). Food allergy quality of life questionnaires (FAQLQs) have been developed and validated, including an adult form (FAQLQ‐AF). These questionnaires may be particularly useful for cross‐cultural comparisons.

Objectives
The aims of this study were to translate the FAQLQ‐AF from Dutch into English and validate an online version in the United States. Additionally, HRQL of American and Dutch food‐allergic adults was compared.

Methods
The Dutch FAQLQ‐AF was translated into English as set out by the World Health Organization and converted to an electronic online format. Participants (food allergic American adults) were recruited through the ‘Food Allergy and Anaphylaxis Network’ website and completed the questionnaire online. Construct validity, internal consistency, discriminative ability and feasibility were analysed. A cross‐cultural comparison was made using the Dutch FAQLQ‐AF scores.

Results
Data from 180 American participants were analysed. The online FAQLQ‐AF had a good construct validity (correlation with FAIM: ρ=0.72; P<0.001), internal consistency (Cronbach's α=0.95) and was discriminative for ‘anaphylaxis’ vs. ‘no anaphylaxis’ and ‘number of food allergies’. The most striking finding was a significantly greater impairment in HRQL in the American participants, as compared with their Dutch counterparts (the total FAQLQ‐AF scores were 4.3 vs. 3.5, respectively; P<0.001, where 1 signifies no impairment and 7 signifies extreme impairment in HRQL).

Conclusions and Clinical Relevance
The online American FAQLQ‐AF is a valid instrument to measure HRQL in food‐allergic patients in the United States. Additionally, HRQL of American food‐allergic adults may be more impaired than Dutch food‐allergic adults. The FAQLQ‐AF can now be used to determine the HRQL in American food‐allergic adults and can assist clinicians in optimizing management strategies for food‐allergic patients.
Oxidative stress‐induced glucocorticoid resistance is prevented by dual PDE3/PDE4 inhibition in human alveolar macrophages
Authors: Milara J. , Navarro A. , Almudéver P. , Lluch J. , Morcillo E. J. , Cortijo J.
Published: March 2011

Background
Oxidative stress is present in airway diseases such as severe asthma or Chronic Obstructive Pulmonary Disease and contributes to the low response to glucocorticoids through the down‐regulation of histone deacetylase (HDAC) activity.

Objective
To study the effects of the phosphodiesterase (PDE)‐3 and 4 inhibitors and their combination vs. glucocorticoids in a model of lipopolysaccharide (LPS)‐induced cytokine release in alveolar macrophages under oxidative stress conditions.

Methods
Differentiated U937 or human alveolar macrophages were stimulated with H2O2 (10–1000 μm) or cigarette smoke extract (CSE, 0–15%) for 4 h before LPS (0.5 μg/mL, 24 h) addition. In other experiments, cells were pre‐treated with dexamethasone or budesonide (10−9–10−6 m), with the PDE4 inhibitor rolipram (10−9–10−5 m), PDE3 inhibitor motapizone (10 μm), 3′,5′‐cyclic monophosphate enhancer PGE2 (10 nm), or with the combination of rolipram (10−6 m)+PGE2 (10 nm)+motapizone (10 μm) 15 min before oxidants. IL‐8 and TNF‐α were measured by ELISA and HDAC activity by a colorimetric assay.

Results
Budesonide and dexamethasone produced a concentration‐dependent inhibition of the LPS‐induced IL‐8 and TNF‐α secretion with an Emax about 90% of inhibition, which was reduced by approximately 30% in the presence of H2O2 or CSE. Pre‐treatment with rolipram, motapizone or PGE2 only reached about 20% of inhibition but was not affected by oxidative stress. In contrast, PDE4/PDE3 combination in presence of PGE2 effectively inhibited the LPS‐induced cytokine secretion by about 90% and was not affected by oxidative stress. Combined PDE4 and PDE3 inhibition reversed glucocorticoid resistance under oxidative stress conditions. HDAC activity was reduced in the presence of oxidative stress, and in contrast to glucocorticoids, pre‐treatment with PDE4/PDE3 combination was able to prevent HDAC inactivity.

Conclusions & Clinical Relevance
This study shows that the combination of the PDE3/PDE4 inhibitors prevents alveolar macrophage activation in those situations of glucocorticoid resistance, which may be of potential interest to develop new effective anti‐inflammatory drugs in airway diseases.

Cite this as: J. Milara, A. Navarro, P. Almudéver, J. Lluch, E. J. Morcillo and J. Cortijo, Clinical & Experimental Allergy, 2011 (41) 535–546.
Does regular paracetamol ingestion increase the risk of developing asthma?
Authors: Dharmage S. C. , Allen K. J.
Published: March 2011

Cite this as: S. C. Dharmage and K. J. Allen, Clinical & Experimental Allergy, 2011 (41) 459–460.
Asthma and ageing: an end user's perspective ‐ the perception and problems with the management of asthma in the elderly
Authors: Jones S. C. , Iverson D. , Burns P. , Evers U. , Caputi P. , Morgan S.
Published: March 2011

Cite this as: S. C. Jones, D. Iverson, P. Burns, U. Evers, P. Caputi and S. Morgan, Clinical & Experimental Allergy, 2011 (41) 471–481.

Despite the high prevalence of asthma in the elderly, its development, diagnosis, and treatment are under‐researched. This paper provides a comprehensive review of the current state of knowledge in relation to management of asthma in the elderly – focusing on barriers to diagnosis and treatment and the central role of self‐management. Asthma prevalence increases with age, as does the risk of dying from asthma, and with the ageing of the population and increasing life expectancy, the prevalence of (diagnosed and undiagnosed) asthma in older adults is expected to increase drastically, placing an increasing burden on sufferers, the community and health budgets. Asthma sufferers are more likely to be psychologically distressed and at a higher risk of anxiety and depression, more likely to experience a sense of lack of control over their health and to have lower self‐reported quality of life. Asthma is under‐diagnosed, and under‐treated, in the elderly, further exacerbating these negative consequences. The review concludes, among other things, that there is a need to better understand the development and impact of asthma in the elderly, to increase community awareness of asthma in the elderly, to improve both ‘medical management’ and ‘self‐management’ in this population and to develop more effective tools for diagnosis and treatment of asthma in the elderly. The paper concludes with key recommendations for future research and practice in this area.
Epitope specificity of myeloperoxidase antibodies: identification of candidate human immunodominant epitopes
Authors: Bruner B F , Vista E S , Wynn D M , James J A
Published: March 2011

Anti-neutrophil cytoplasmic autoantibodies (ANCA) are a common feature of systemic vasculitides and have been classified as autoimmune conditions based, in part, on these autoantibodies. ANCA are subdivided further based on their primary target: cytoplasm (c-ANCA) or perinuclear region (p-ANCA). p-ANCAs commonly target myeloperoxidase (MPO), an enzyme with microbicidal and degradative activity. MPO antibodies are non-specific for any single disease and found in a variety of vasculitides, most commonly microscopic polyangiitis. Despite their prevalence, their role in human disease pathogenesis remains undefined. We sought to characterize the sequential antigenic determinants of MPO in vasculitis patients with p-ANCA. Of 68 patients with significant levels of p-ANCA, 12 have significant levels of MPO antibodies and were selected for fine specificity epitope mapping. Sequential antigenic targets, including those containing amino acids (aa) 213–222 (WTPGVKRNGF) and aa 511–522 (RLDNRYQPMEPN), were commonly targeted with a prevalence ranging from 33% to 58%. Subsequent analysis of autoantibody binding to the RLDNRYQPMEPN peptide was assessed using a confirmatory enzyme-linked immunosorbent assay format, with six patients displaying significant binding using this method. Antibodies against this epitope, along with four others (aa 393–402, aa 437–446, aa 479–488 and aa 717–726), were reactive to the heavy chain structure of the MPO protein. One epitope, GSASPMELLS (aa 91–100), was within the pro-peptide structure of MPO. B cell epitope prediction algorithms identified all or part of the seven epitopes defined. These results provide major common human anti-MPO immunodominant antigenic targets which can be used to examine further the potential pathogenic mechanisms for these autoantibodies.
The tumour necrosis factor/TNF receptor superfamily: therapeutic targets in autoimmune diseases
Authors: Vinay D S , Kwon B S
Published: March 2011

Autoimmune diseases are characterized by the body's ability to mount immune attacks on self. This results from recognition of self-proteins and leads to organ damage due to increased production of pathogenic inflammatory molecules and autoantibodies. Over the years, several new potential therapeutic targets have been identified in autoimmune diseases, notable among which are members of the tumour necrosis factor (TNF) superfamily. Here, we review the evidence that certain key members of this superfamily can augment/suppress autoimmune diseases.
Extracapsular extension but not the tumour burden of lymph node metastases is an independent adverse risk factor in lymph node‐positive bladder cancer
Authors: Seiler Roland , von Gunten Michael , Thalmann George N. , Fleischmann Achim
Published: March 2011

Seiler R, von Gunten M, Thalmann G N & Fleischmann A (2011) Histopathology 58, 571–578 Extracapsular extension but not the tumour burden of lymph node metastases is an independent adverse risk factor in lymph node‐positive bladder cancer

Aims:  To evaluate risk factors in lymph node‐positive bladder cancer.

Methods and results:  Lymph node‐positive bladder cancer patients (n = 162), preoperatively staged N0M0, underwent cystectomy and standardized extended lymphadenectomy. Five‐year overall survival of the cohort was 33%. In univariate analysis, tumour stage (P < 0.006), extracapsular extension of lymph node metastases (P < 0.001), total diameter of metastases (P < 0.04) and lymph node stage (P < 0.03) were significantly correlated with overall survival (OS), disease‐specific survival (DSS) and recurrence‐free survival (RFS). On multivariate analysis, only extracapsular extension (OS, P < 0.002; DSS, P < 0.02; RFS, P = 0.058) and primary tumour stage (OS, P = 0.058; DSS, P < 0.02; RFS, P < 0.02) added independent prognostic information. Extracapsular extension of lymph node metastases did not correlate with a specific recurrence pattern; patients with organ‐confined tumours (pT1/2) never had pelvic relapse.

Conclusions:  Extracapsular extension of lymph node metastases but not lymph node tumour burden adds independent prognostic information in lymph node‐positive bladder cancer. These biological differences in lymph node‐positive bladder cancer are not reflected in the sixth, and challenge future, TNM classification.
Detection of CHK1 and CCND1 gene copy number changes in breast cancer with dual‐colour fluorescence in‐situ hybridization
Authors: Mu Kun , Li Li , Yang Qingrui , Zhang Tingguo , Gao Peng , Meng Bin , Liu Zhiyan , Wang Yan , Zhou Gengyin
Published: March 2011

Mu K, Li L, Yang Q, Zhang T, Gao P, Meng B, Liu Z, Wang Y & Zhou G (2011) Histopathology 58, 601–607 Detection of CHK1 and CCND1 gene copy number changes in breast cancer with dual‐colour fluorescence in‐situ hybridization

Aims:  To investigate the correlation between CCND1 amplification and CHK1 deletion in breast cancer, and to explore their role in tumorigenesis and progression, a comparative study of the gene copy number changes of CCND1 and CHK1 was performed with dual‐colour fluorescence in‐situ hybridization (FISH).

Methods and results:  Sixty‐one infiltrating ductal breast carcinomas with foci of ductal carcinoma in situ (DCIS) components were selected for dual‐colour FISH. A strong correlation was found between CCND1 amplification and CHK1 deletion (P < 0.0001). Fourteen cases were detected that demonstrated both CCND1 amplification and CHK1 deletion. Interestingly, when comparing the infiltrating and non‐invasive areas for the same tumour, we found three cases with CCND1 amplification in the infiltrating areas but not in the DCIS areas. We did not find a CHK1 gene profile difference between infiltrating and DCIS areas in the same lesions.

Conclusions:  Our findings suggest that CCND1 amplification and CHK1 deletion are common events in breast cancer, and that the two genetic alterations often coexist. Our data also suggest that CHK1 deletion is an early genetic event in the development of breast cancer and can be detected at the DCIS stage, whereas CCND1 amplification is more likely to be associated with tumour progression.
Determining appropriate goals for restoration of imperilled communities and species
Authors: Thorpe Andrea S. , Stanley Amanda G.
Published: March 2011

1. Conservation and restoration practitioners often struggle to define appropriate targets for restoration. Frequently, ‘pre‐settlement conditions’ (the conditions that are believed to have existed prior to European settlement) are used. In this review, we draw on our experiences working with land‐managers to restore native ecosystems in the Pacific Northwest (USA) to discuss some of the challenges in using pre‐settlement conditions as a restoration target.

2. We have found that information on the structure and composition of pre‐settlement communities does not exist in sufficient detail to set quantitative restoration targets.

3. The systems we work in have been so altered from the historic condition (as we best understand it), that mimicking the anthropogenic and ‘natural’ disturbances that shaped these communities is both difficult and unlikely to guarantee success.

4. Furthermore, the pre‐settlement condition may not be an appropriate restoration goal given on‐going global changes, including species invasions, habitat loss, and climate change.

5. Synthesis and applications. We suggest that rather than focusing on historic benchmarks, restoration goals should be based on ecological principles that will lead to resilient, functioning ecosystems. We provide real‐world examples for how scientists and managers can work together to define and test appropriate and effective restoration methods and targets.
Post‐stroke aphasia prognosis: a review of patient‐related and stroke‐related factors
Authors: Plowman Emily , Hentz Brecken , Ellis Charles
Published: March 2011

Rationale, aims and objectives  Recovery of language function in individuals with post‐stroke aphasia is associated with a variety of patient and stroke‐related indices. Amidst a complex interaction of a multitude of variables, clinicians are faced with the arduous challenge of predicting aphasia recovery patterns and subsequently, long‐term outcomes in these individuals. Unfortunately, predictive factors are highly variable making prognosis of aphasia recovery difficult. Therefore, the objective of this review was to assess the influence of patient‐related and stroke‐related factors on language recovery in individuals with post‐stroke aphasia.

Methods  We completed a literature review to assess and identify evidence‐based patient and stroke‐related variables shown to be influential in aphasia recovery.

Results  A range of patient‐related (gender, handedness, age, education, socio‐economic status and intelligence) and stroke‐related indices (initial severity, lesion site and lesion size) were identified as potential influential factors to post‐stroke aphasia recovery. Initial severity of aphasia emerged as the factor most predictive of long‐term aphasia recovery. Other influential factors of post‐stroke language recovery included lesion site and size.

Conclusions  Stroke‐related factors, including aphasia severity, lesion site and lesion size, appear most critical to post‐stroke aphasia recovery. The findings presented in this review offer clinicians an evidenced‐based framework to assist in prediction of post‐stroke aphasia recovery patterns and subsequent long‐term functional communication outcomes.
Serial HBV DNA levels in patients with persistently normal transaminase over 10 years following spontaneous HBeAg seroconversion
Authors: Chen Y.‐C. , Huang S.‐F. , Chu C.‐M. , Liaw Y.‐F.
Published: March 2011

Summary.  Earlier studies addressing the hepatitis B virus (HBV) DNA cut‐off level for inactive chronic HBV infection largely involved patients with normal alanine aminotransferase (ALT) for only 1–2 years and based on a single time HBV DNA assay. This study was conducted to address this issue using serial HBV DNA assays in patients with persistently normal ALT (PNALT) over 10 years following spontaneous hepatitis B e antigen (HBeAg) seroconversion. Serial serum specimens (mean 9 samples per patient) of 62 patients with PNALT and no disease progression over 10 years (median 18.1 years) after spontaneous HBeAg seroconversion were assayed for HBV DNA. Excluding assays within 1 year after HBeAg seroconversion, 21% and 82.3% of the patients with PNALT had HBV DNA levels persistently lower than 4 log10 and 5 log10 copies/mL, respectively, and only 8% had a level ≥5 log10 copies/mL in at least two assays. Of the 27 patients with PNALT defined by ALT <30 U/L for male and <19 U/L for female, only 33% had serum HBV DNA level persistently <4 log10 copies/mL. There was no significant difference in the serial HBV DNA changes among patients with different gender, HBV genotype or age at HBeAg seroconversion. Liver biopsy in nine patients invariably showed minimal necroinflammation and one showed Ishak fibrosis score 4. These results suggest that 5 log10 copies/mL (20 000 IU/mL) is a more appropriate cut‐off HBV DNA level for inactive chronic HBV infection in the setting of PNALT.
Phylogenetic ecology of widespread uncultured clades of the Kingdom Euryarchaeota
Authors: BARBERÁN ALBERT , FERNÁNDEZ‐GUERRA ANTONI , AUGUET JEAN‐CHRISTOPHE , GALAND PIERRE E. , CASAMAYOR EMILIO O.
Published: March 2011

Despite its widespread distribution and high levels of phylogenetic diversity, microbes are poorly understood creatures. We applied a phylogenetic ecology approach in the Kingdom Euryarchaeota (Archaea) to gain insight into the environmental distribution and evolutionary history of one of the most ubiquitous and largely unknown microbial groups. We compiled 16S rRNA gene sequences from our own sequence libraries and public genetic databases for two of the most widespread mesophilic Euryarchaeota clades, Lake Dagow Sediment (LDS) and Rice Cluster‐V (RC‐V). The inferred population history indicated that both groups have undergone specific nonrandom evolution within environments, with several noteworthy habitat transition events. Remarkably, the LDS and RC‐V groups had enormous levels of genetic diversity when compared with other microbial groups, and proliferation of sequences within each single clade was accompanied by significant ecological differentiation. Additionally, the freshwater Euryarchaeota counterparts unexpectedly showed high phylogenetic diversity, possibly promoted by their environmental adaptability and the heterogeneous nature of freshwater ecosystems. The temporal phylogenetic diversification pattern of these freshwater Euryarchaeota was concentrated both in early times and recently, similarly to other much less diverse but deeply sampled archaeal groups, further stressing that their genetic diversity is a function of environment plasticity. For the vast majority of living beings on Earth (i.e. the uncultured microorganisms), how they differ in the genetic or physiological traits used to exploit the environmental resources is largely unknown. Inferring population history from 16S rRNA gene‐based molecular phylogenies under an ecological perspective may shed light on the intriguing relationships between lineage, environment, evolution and diversity in the microbial world.
Species‐specific levels of ant attendance mediate performance costs in a facultative myrmecophilous butterfly
Authors: KAMINSKI LUCAS A. , RODRIGUES DANIELA
Published: March 2011

Trophobiont butterfly larvae offer caloric rewards to ants through specialised glands and, in return, gain ant‐derived protection from natural enemies. Thus, from the larva's perspective, the major cost of myrmecophily comprises the reward production. Larvae of the butterflyParrhasius polibetes(Stoll) (Lycaenidae) are facultatively tended by several ant species, which might differ in the intensity of tending behaviour. The performance costs (development time, survival, pupal mass and adult dry mass) ofP. polibetesare examined when tended by two ant species differing in size and foraging strategies (Camponotus melanoticusEmery andCamponotus crassusMayr), along with the corresponding intensity of tending behaviour towards late instars. Untended larvae serve as controls. Larvae tended byC. melanoticustake longer to pupate compared with bothC. crassusand control larvae. By contrast, pupae whose larvae are tended byC. crassusare lighter than control larvae but do not differ from those tended byC. melanoticus. No differences are found in the adult stage, indicating compensation in all cases. Both at short‐ and long‐term scales,C. melanoticustends larvae ofP. polibetesmore intensely thanC. crassus. The increase in tending activity ofC. melanoticuspresumably delays the development time of larvae tended by this ant species. The results of the present study show that tending intensity varies depending on the ant species, and thatP. polibeteshas compensatory mechanisms to minimise myrmecophily costs, regardless of tending intensity. To the authors' knowledge, this is the first experimental evidence that intensity of ant‐tending behaviour is species‐specific and affects performance in a trophobiont insect.
Interplay of SLIM1 and miR395 in the regulation of sulfate assimilation in Arabidopsis
Authors: Kawashima Cintia G. , Matthewman Colette A. , Huang Siqi , Lee Bok‐Rye , Yoshimoto Naoko , Koprivova Anna , Rubio‐Somoza Ignacio , Todesco Marco , Rathjen Tina , Saito Kazuki , Takahashi Hideki , Dalmay Tamas , Kopriva Stanislav
Published: March 2011

MicroRNAs play a key role in the control of plant development and response to adverse environmental conditions. For example, microRNA395 (miR395), which targets three out of four isoforms of ATP sulfurylase, the first enzyme of sulfate assimilation, as well as a low‐affinity sulfate transporter, SULTR2;1, is strongly induced by sulfate deficiency. However, other components of sulfate assimilation are induced by sulfate starvation, so that the role of miR395 is counterintuitive. Here, we describe the regulation of miR395 and its targets by sulfate starvation. We show that miR395 is important for the increased translocation of sulfate to the shoots during sulfate starvation. MiR395 together with the SULFUR LIMITATION 1 transcription factor maintain optimal levels of ATP sulfurylase transcripts to enable increased flux through the sulfate assimilation pathway in sulfate‐deficient plants. Reduced expression of ATP sulfurylase (ATPS) alone affects both sulfate translocation and flux, but SULTR2;1 is important for the full rate of sulfate translocation to the shoots. Thus, miR395 is an integral part of the regulatory circuit controlling plant sulfate assimilation with a complex mechanism of action.
Functional interaction of the circadian clock and UV RESISTANCE LOCUS 8‐controlled UV‐B signaling pathways in Arabidopsis thaliana
Authors: Fehér Balázs , Kozma‐Bognár László , Kevei Éva , Hajdu Anita , Binkert Melanie , Davis Seth Jon , Schäfer Eberhard , Ulm Roman , Nagy Ferenc
Published: March 2011

Circadian clocks regulate many molecular and physiological processes in Arabidopsis (Arabidopsis thaliana), allowing the timing of these processes to occur at the most appropriate time of the day in a 24‐h period. The accuracy of timing relies on the synchrony of the clock and the environmental day/night cycle. Visible light is the most potent signal for such synchronization, but light‐induced responses are also rhythmically attenuated (gated) by the clock. Here, we report a similar mutual interaction of the circadian clock and non‐damaging photomorphogenic UV‐B light. We show that low‐intensity UV‐B radiation acts as entraining signal for the clock. UV RESISTANCE LOCUS 8 (UVR8) and CONSTITUTIVELY PHOTOMORPHOGENIC 1 (COP1) are required, but ELONGATED HYPOCOTYL 5 (HY5) and HY5 HOMOLOG (HYH) are dispensable for this process. UV‐B responsiveness of clock gene expression suggests that photomorphogenic UV‐B entrains the plant clock through transcriptional activation. We also demonstrate that UV‐B induction of gene expression under these conditions is gated by the clock in a HY5/HYH‐independent manner. The arrhythmic early flowering 3–4 mutant showed non‐gated, high‐level gene induction by UV‐B, yet displayed no increased tolerance to UV‐B stress. Thus, the temporal restriction of UV‐B responsiveness by the circadian clock can be considered as saving resources during acclimation without losing fitness.
Genetic identification of Arabidopsis RID2 as an essential factor involved in pre‐rRNA processing
Authors: Ohbayashi Iwai , Konishi Mineko , Ebine Kazuo , Sugiyama Munetaka
Published: March 2011

A temperature‐sensitive mutant of Arabidopsis, root initiation defective 2‐1 (rid2‐1), is characterized by peculiar defects in callus formation. To gain insights into the requirements for the reactivation of cell division, we analyzed this mutant and isolated the gene responsible, RID2. The phenotypes of rid2‐1 in tissue culture and in seedlings indicated that the rid2 mutation has various (acute and non‐acute) inhibitory effects on different aspects of cell proliferation. This suggests that the RID2 function is not directly involved in every cycle of cell division, but is related to ‘vitality’, supporting cell proliferation. The rid2‐1 mutation was shown to cause nucleolar vacuolation and excessive accumulation of various intermediates of pre‐rRNA processing. Positional cloning of the RID2 gene revealed that it encodes an evolutionarily conserved methyltransferase‐like protein, which was found to localize in the nucleus, with accumulation being most evident in the nucleolus. It can be inferred from these findings that RID2 contributes to the nucleolar activity for pre‐rRNA processing, probably through some methylation reaction.
Bundle‐sheath cell regulation of xylem‐mesophyll water transport via aquaporins under drought stress: a target of xylem‐borne ABA?
Authors: Shatil‐Cohen Arava , Attia Ziv , Moshelion Menachem
Published: March 2011

The hydraulic conductivity of the leaf vascular system (Kleaf) is dynamic and decreases rapidly under drought stress, possibly in response to the stress phytohormone ABA, which increases sharply in the xylem sap (ABAxyl) during periods of drought. Vascular bundle‐sheath cells (BSCs; a layer of parenchymatous cells tightly enwrapping the entire leaf vasculature) have been hypothesized to control Kleaf via the specific activity of BSC aquaporins (AQPs). We examined this hypothesis and provide evidence for drought‐induced ABAxyl diminishing BSC osmotic water permeability (Pf) via downregulated activity of their AQPs. ABA fed to the leaf via the xylem (petiole) both decreased Kleaf and led to stomatal closure, replicating the effect of drought. In contrast, smearing ABA on the leaf blade, while also closing stomata, did not decrease Kleaf within 2–3 h of application, demonstrating that Kleaf does not depend entirely on stomatal closure. GFP‐labeled BSCs showed decreased Pf in response to ‘drought’ and ABA treatment, and a reversible decrease with HgCl2 (an AQP blocker). These Pf responses, absent in mesophyll cells, suggest stress‐regulated AQP activity specific to BSCs, and imply a role for these cells in decreasing Kleaf via a reduction in Pf. Our results support the above hypothesis and highlight the BSCs as hitherto overlooked vasculature sensor compartments, extending throughout the leaf and functioning as ‘stress‐regulated valves’ converting vasculature chemical signals (possibly ABAxyl) into leaf hydraulic signals.