bluuebunny/crossref_metadata_2025 huggingface dataset:
Approximately diagonalizing matrices over
C
(
Y
)
Authors: Lin Huaxin
Published: February 2012

Let
X
be a compact metric space which is locally absolutely retract and let
φ
: 
C
(
X
) → 
C
(
Y
,
M

n

) be a unital homomorphism, where
Y
is a compact metric space with dim 
Y
 ≤ 2. It is proved that there exists a sequence of
n
continuous maps
α

i
,
m

: 
Y
 → 
X
(
i
 = 1,2,…,
n
) and a sequence of sets of mutually orthogonal rank-one projections {
p

1,
m

,
p

2,
m

,…,
p

n
,
m

}⊂
C
(
Y
,
M

n

) such that

This is closely related to the Kadison diagonal matrix question. It is also shown that this approximate diagonalization could not hold in general when dim 
Y
≥3.
Female reproductive tract form drives the evolution of complex sperm morphology
Authors: Higginson Dawn M. , Miller Kelly B. , Segraves Kari A. , Pitnick Scott
Published: February 2012

The coevolution of female mate preferences and exaggerated male traits is a fundamental prediction of many sexual selection models, but has largely defied testing due to the challenges of quantifying the sensory and cognitive bases of female preferences. We overcome this difficulty by focusing on postcopulatory sexual selection, where readily quantifiable female reproductive tract structures are capable of biasing paternity in favor of preferred sperm morphologies and thus represent a proximate mechanism of female mate choice when ejaculates from multiple males overlap within the tract. Here, we use phylogenetically controlled generalized least squares and logistic regression to test whether the evolution of female reproductive tract design might have driven the evolution of complex, multivariate sperm form in a family of aquatic beetles. The results indicate that female reproductive tracts have undergone extensive diversification in diving beetles, with remodeling of size and shape of several organs and structures being significantly associated with changes in sperm size, head shape, gains/losses of conjugation and conjugate size. Further, results of Bayesian analyses suggest that the loss of sperm conjugation is driven by elongation of the female reproductive tract. Behavioral and ultrastructural examination of sperm conjugates stored in the female tract indicates that conjugates anchor in optimal positions for fertilization. The results underscore the importance of postcopulatory sexual selection as an agent of diversification.
Impact of cross-protective vaccines on epidemiological and evolutionary dynamics of influenza
Authors: Arinaminpathy Nimalan , Ratmann Oliver , Koelle Katia , Epstein Suzanne L. , Price Graeme E. , Viboud Cecile , Miller Mark A. , Grenfell Bryan T.
Published: February 2012

Large-scale immunization has profoundly impacted control of many infectious diseases such as measles and smallpox because of the ability of vaccination campaigns to maintain long-term herd immunity and, hence, indirect protection of the unvaccinated. In the case of human influenza, such potential benefits of mass vaccination have so far proved elusive. The central difficulty is a considerable viral capacity for immune escape; new pandemic variants, as well as viral escape mutants in seasonal influenza, compromise the buildup of herd immunity from natural infection or deployment of current vaccines. Consequently, most current influenza vaccination programs focus mainly on protection of specific risk groups, rather than mass prophylactic protection. Here, we use epidemiological models to show that emerging vaccine technologies, aimed at broad-spectrum protection, could qualitatively alter this picture. We demonstrate that sustained immunization with such vaccines could—through potentially lowering transmission rates and improving herd immunity—significantly moderate both influenza pandemic and seasonal epidemics. More subtly, phylodynamic models indicate that widespread cross-protective immunization could slow the antigenic evolution of seasonal influenza; these effects have profound implications for a transition to mass vaccination strategies against human influenza, and for the management of antigenically variable viruses in general.
Mutation of A677 in histone methyltransferase EZH2 in human B-cell lymphoma promotes hypertrimethylation of histone H3 on lysine 27 (H3K27)
Authors: McCabe Michael T. , Graves Alan P. , Ganji Gopinath , Diaz Elsie , Halsey Wendy S. , Jiang Yong , Smitheman Kimberly N. , Ott Heidi M. , Pappalardi Melissa B. , Allen Kimberly E. , Chen Stephanie B. , Della Pietra Anthony , Dul Edward , Hughes Ashley M. , Gilbert Seth A. , Thrall Sara H. , Tummino Peter J. , Kruger Ryan G. , Brandt Martin , Schwartz Benjamin , Creasy Caretha L.
Published: February 2012

Trimethylation of histone H3 on lysine 27 (H3K27me3) is a repressive posttranslational modification mediated by the histone methyltransferase EZH2. EZH2 is a component of the polycomb repressive complex 2 and is overexpressed in many cancers. In B-cell lymphomas, its substrate preference is frequently altered through somatic mutation of the EZH2 Y641 residue. Herein, we identify mutation of EZH2 A677 to a glycine (A677G) among lymphoma cell lines and primary tumor specimens. Similar to Y641 mutant cell lines, an A677G mutant cell line revealed aberrantly elevated H3K27me3 and decreased monomethylated H3K27 (H3K27me1) and dimethylated H3K27 (H3K27me2). A677G EZH2 possessed catalytic activity with a substrate specificity that was distinct from those of both WT EZH2 and Y641 mutants. Whereas WT EZH2 displayed a preference for substrates with less methylation [unmethylated H3K27 (H3K27me0):me1:me2
k
cat
/
K
m
ratio = 9:6:1] and Y641 mutants preferred substrates with greater methylation (H3K27me0:me1:me2
k
cat
/
K
m
ratio = 1:2:13), the A677G EZH2 demonstrated nearly equal efficiency for all three substrates (H3K27me0:me1:me2
k
cat
/
K
m
ratio = 1.1:0.6:1). When transiently expressed in cells, A677G EZH2, but not WT EZH2, increased global H3K27me3 and decreased H3K27me2. Structural modeling of WT and mutant EZH2 suggested that the A677G mutation acquires the ability to methylate H3K27me2 through enlargement of the lysine tunnel while preserving activity with H3K27me0/me1 substrates through retention of the Y641 residue that is crucial for orientation of these smaller substrates. This mutation highlights the interplay between Y641 and A677 residues in the substrate specificity of EZH2 and identifies another lymphoma patient population that harbors an activating mutation of EZH2.
Trafficking of gap junction channels at a vertebrate electrical synapse in vivo
Authors: Flores Carmen E. , Nannapaneni Srikant , Davidson Kimberly G. V. , Yasumura Thomas , Bennett Michael V. L. , Rash John E. , Pereda Alberto E.
Published: February 2012

Trafficking and turnover of transmitter receptors required to maintain and modify the strength of chemical synapses have been characterized extensively. In contrast, little is known regarding trafficking of gap junction components at electrical synapses. By combining ultrastructural and in vivo physiological analysis at identified mixed (electrical and chemical) synapses on the goldfish Mauthner cell, we show here that gap junction hemichannels are added at the edges of GJ plaques where they dock with hemichannels in the apposed membrane to form cell–cell channels and, simultaneously, that intact junctional regions are removed from centers of these plaques into either presynaptic axon or postsynaptic dendrite. Moreover, electrical coupling is readily modified by intradendritic application of peptides that interfere with endocytosis or exocytosis, suggesting that the strength of electrical synapses at these terminals is sustained, at least in part, by fast (in minutes) turnover of gap junction channels. A peptide corresponding to a region of the carboxy terminus that is conserved in Cx36 and its two teleost homologs appears to interfere with formation of new gap junction channels, presumably by reducing insertion of hemichannels on the dendritic side. Thus, our data indicate that electrical synapses are dynamic structures and that their channels are turned over actively, suggesting that regulated trafficking of connexons may contribute to the modification of gap junctional conductance.
Capping and in vivo toxicity studies of gold nanoparticles
Authors: Lien Nghiem Thi Ha , Nguyen Thi Tuyen , Fort Emmanuel , Nguyen Thanh Phuong , Nhung Hoang Thi My , Nguyen Thi Quy , Nhung Tran Hong
Published: February 2012

Water-dispersed colloidal gold nanoparticles (AuNPs) with high concentration were synthesized from metal precursor HAuCl
4. The bovine serum albumin (BSA) and heterobiofunctionalized thiol polyethylene glycol acid (HS–PEG–COOH) were used as biofunctionalized layers for the synthesized AuNPs. The BSA and HS–PEG–COOH bound to the AuNPs were characterized qualitatively and quantitatively by transmission electron microscope and UV-VS spectrophotometer. The fabricated BSA and HS–PEG–COOH-capped AuNPs were introduced in mouse to study its toxicity and its availability in the liver.
Rhizoctonia Web Blight—A New Disease on Mint in Israel
Authors: Nitzan Nadav , Chaimovitsh David , Davidovitch-Rekanati Rachel , Sharon Michal , Dudai Nativ
Published: February 2012

Mentha longifolia is produced in and exported from Israel with annual revenue of US$16 million. In 2010, a severe epidemic of unknown etiology reduced growers' returns up to 50%. Disease symptoms included water-soaked lesions, necrosis, and web-like mycelia on plants. Two isolates (JV-1 and BS-1) from randomly selected symptomatic plants were identified as members of Rhizoctonia solani anastomosis groups 1-IB and 4HG-I, respectively. The fitness of JV-1 and BS-1 interacted with temperatures between 17 and 35°C: JV-1 grew faster and was more aggressive (P < 0.05) at lower temperatures (<24°C), BS-1 grew faster and was more aggressive at higher temperatures (>30°C), and the two isolates performed similarly at intermediate temperatures. Disease developed fastest at 24 to 28°C. Yield was reduced between 46 and 100%. In all, 77.5% fewer plants recovered from disease developing at 24 to 28°C than at 17 to 23 or 30 to 35°C. The relationship of disease to relative humidity (RH) fit a quadratic model (P < 0.0015, R2 = 0.98). Disease was most severe at 100% RH, decreasing by 1.3-, 1.9-, 3-, 4.5-, and 10.5-fold with the reduction of RH from 100% to 88, 76, 69, 55, or 49%, respectively. This is the first report of Rhizoctonia web blight in mint in Israel.
First Report of Brown Rot Caused by Monilinia fructicola on Stored Apple in Serbia
Authors: Vasić M. , Duduk N. , Ivanović M. M. , Obradović A. , Ivanović M. S.
Published: February 2012

Monilinia fructicola (G. Winter) Honey is a causal agent of brown rot of stone fruits, occasionally affecting pome fruits as well. The pathogen is commonly present in North and South America, Oceania, and Asia, but listed as a quarantine organism in Europe (4). After its first discovery in France in 2001, its occurrence has been reported in Germany, Hungary, Italy, Poland, Romania, Slovenia, Spain, Switzerland, Austria, and the Slovak Republic (1). In February 2011, during a survey for fungal postharvest pathogens in cold storage conditions, apple fruits (Malus domestica Borkh.) grown and stored in the Grocka Region, Serbia, were collected. All pathogens from symptomatic fruits were isolated on potato dextrose agar (PDA). One isolate from apple fruit cv. Golden Delicious with brown rot symptoms was identified as M. fructicola based on morphological and molecular characters. Colonies cultivated on PDA at 22°C in darkness were colorless, but later became grayish, developing mass of spores in concentric rings. Colony margins were even. Conidia were one-celled, limoniform, hyaline, measured 12.19 to 17.37 (mean 13.8) × 8.62 to 11.43 μm (mean 9.9), and were produced in branched monilioid chains (3). Morphological identification was confirmed by PCR (2) using genomic DNA extracted from the mycelium of pure culture, and an amplified product of 535 bp, specific for the species M. fructicola, was obtained. Sequence of the ribosomal (internal transcribed spacer) ITS1-5.8S-ITS2 region was obtained using primers ITS1 and ITS4 and deposited in GenBank (Accession No. JN176564). Control fruits were inoculated with sterile PDA plugs. After 3 days of incubation in plastic containers with high humidity at room temperature, typical symptoms of brown rot developed on inoculated fruits, while control fruits remained symptomless. The isolate recovered from symptomatic fruits showed the same morphological and molecular features of the original isolate. To our knowledge, this is the first report of M. fructicola in Serbia. Further studies are necessary for estimation of economic importance and geographic distribution of this quarantine organism in Serbia.

References: (1) R. Baker et al. European Food Safety Authority. Online publication. www.efsa.europa.eu/efsajournal . EFSA J. 9(4):2119, 2011. (2) M.-J. Côté et al. Plant Dis. 88:1219, 2004. (3) J. E. M. Mordue. CMI Descriptions of Pathogenic Fungi and Bacteria. No. 616, 1979. (4) OEPP/EPPO. EPPO A2 List of Pests Recommended for Regulation as Quarantine Pests. Online publication. Version 2010-09. Retrieved from http://www.eppo.org/QUARANTINE/listA2.htm , June 27, 2011.
Genetic and Virulence Analysis of Rhizoctonia spp. Associated with Sugar Beet Root and Crown Rot in the Northeast Region of Iran
Authors: Taheri Parissa , Tarighi Saeed
Published: February 2012

Rhizoctonia spp. are the main causal agents of root and crown rot on sugar beet. In this study, isolates of Rhizoctonia spp. were obtained from diseased sugar beet in Iran over 2 years. Of 68 isolates, 61 were R. solani and 7 were R. cerealis. The anastomosis group (AG) of all isolates was determined on glass slides against the testers. Characterization of intraspecific groups (ISGs) of R. solani isolates revealed that, of 61 isolates, 43 were AG2-2 IIIB and 18 were AG2-2 IV. Amplified fragment length polymorphism (AFLP) analyses were used to investigate genetic structure of Rhizoctonia populations. Principal coordinate plots and cluster analysis differentiated R. solani from R. cerealis isolates and separated the R. solani isolates belonging to different ISGs. AFLP data indicated that the R. solani and R. cerealis populations are not clonal. Analysis of molecular variance in AG2-2 IIIB isolates showed that geographic region was the main factor determining genetic structure of the populations. Sampling year had no significant effect on the genotypes. Pathogenicity tests on Beta vulgaris ‘FD0432’ revealed that R. solani AG2-2 IIIB and AG2-2 IV isolates were more virulent than R. cerealis.
Colonization ofVitisspp. Wood by sGFP-TransformedPhaeomoniella chlamydospora, a Tracheomycotic Fungus Involved in Esca Disease
Authors: Landi Lucia , Murolo Sergio , Romanazzi Gianfranco
Published: February 2012

To evaluate wood colonization and interactions with Vitis spp. of Phaeomoniella chlamydospora, a fungal agent involved in Esca disease, isolate CBS 229.95 was transformed using a pCT74 construct which contained the genetic markers for synthetic green fluorescent protein (sGFP) and hygromycin B phosphotransferase. Nine stable P. chlamydospora fungal transformants (Pch-sGFP lines) were obtained using polyethylene-glycol-mediated transformation of protoplasts. These were characterized for sgfp and hygromycin B phosphotransferase (hph) genome insertions and for sGFP fluorescence emission, using quantitative polymerase chain reaction and fluorimetric systems, respectively. No correlation was observed between sgfp copy number genome insertion and sGFP fluorescence expression. Cuttings of Vitis vinifera ‘Montepulciano’, ‘Verdicchio’, ‘Sangiovese’, ‘Biancame’, and ‘Cabernet Sauvignon’; and the grapevine rootstocks ‘Kober 5BB’, ‘SO4’, ‘420A’, ‘1103P’, and V. rupestris were inoculated by immersion in a conidial suspension of the selected fungal Pch-sGFP71 line and incubated at 4 ± 1 and 25 ± 1°C. Wood colonization was estimated through epifluorescence microscopy and was affected by incubation temperature. After 6 months at 4 ± 1°C, the fungal growth was completely inhibited. At 25 ± 1°C, the highest extent of wood colonization was recorded in Montepulciano and Verdicchio, with the lowest in the rootstocks SO4 and V. rupestris. The expression of the Pch-sGFP71 transformed line was localized in the xylem area, primarily around the vessels. The use of sGFP-transformed P. chlamydospora helped to clarify different aspects associated with the location of this pathogen in grapevine tissue, before disease symptom expression.
Delayed song maturation and territorial aggression in a songbird
Authors: Poesel Angelika , Nelson Douglas A.
Published: February 2012

Asymmetries in competitive ability can determine the outcome of social interactions in animals and are often expressed through differences in sexual traits. Competitive ability (resource holding potential, RHP), trait expression and ultimately reproductive success may vary with an individual's age or experience. In some species, reproductively mature males delay acquisition of some adult traits and thereby signal their young age. Theory on animal contests predicts that individuals assess the RHP of an opponent relative to their own, such that escalation is more common between evenly matched opponents. Here, we test predictions from this hypothesis that males respond to a territorial intruder based on their RHP relative to the intruder's RHP. We simulated white-crowned sparrows (
Zonotrichia leucophrys
) intruding into the territory of a recruit or return. Playback of a song repertoire simulating a young male (recruit) elicited a weaker response from established territory holders (return), but a stronger response from recruits. Playback of a single song type simulating an older male elicited the opposite responses. This indicates that males distinguished between simulated young and old intruders based on song, and responded differently depending on their own experience. Our study highlights the possibility that receiver as well as sender traits should be considered when interpreting animal interactions.
Turing's model for biological pattern formation and the robustness problem
Authors: Maini Philip K. , Woolley Thomas E. , Baker Ruth E. , Gaffney Eamonn A. , Lee S. Seirin
Published: February 2012

One of the fundamental questions in developmental biology is how the vast range of pattern and structure we observe in nature emerges from an almost uniformly homogeneous fertilized egg. In particular, the mechanisms by which biological systems maintain robustness, despite being subject to numerous sources of noise, are shrouded in mystery. Postulating plausible theoretical models of biological heterogeneity is not only difficult, but it is also further complicated by the problem of generating robustness, i.e. once we can generate a pattern, how do we ensure that this pattern is consistently reproducible in the face of perturbations to the domain, reaction time scale, boundary conditions and so forth. In this paper, not only do we review the basic properties of Turing's theory, we highlight the successes and pitfalls of using it as a model for biological systems, and discuss emerging developments in the area.
A composite computational model of liver glucose homeostasis. II. Exploring system behaviour
Authors: Sumner T. , Hetherington J. , Seymour R. M. , Li L. , Varela Rey M. , Yamaji S. , Saffrey P. , Margoninski O. , Bogle I. D. L. , Finkelstein A. , Warner A.
Published: February 2012

Using a composite model of the glucose homeostasis system, consisting of seven interconnected submodels, we enumerate the possible behaviours of the model in response to variation of liver insulin sensitivity and dietary glucose variability. The model can reproduce published experimental manipulations of the glucose homeostasis system and clearly illustrates several important properties of glucose homeostasis—boundedness in model parameters of the region of efficient homeostasis, existence of an insulin sensitivity that allows effective homeostatic control and the importance of transient and oscillatory behaviour in characterizing homeostatic failure. Bifurcation analysis shows that the appearance of a stable limit cycle can be identified.
Spatiotemporal dynamics of Spc105 regulates the assembly of theDrosophilakinetochore
Authors: Venkei Zsolt , Przewloka Marcin R. , Ladak Yaseen , Albadri Shahad , Sossick Alex , Juhasz Gabor , Novák Béla , Glover David M.
Published: February 2012

The formation of kinetochores shortly before each cell division is a prerequisite for proper chromosome segregation. The synchronous mitoses ofDrosophilasyncytial embryos have provided an idealin vivosystem to follow kinetochore assembly kinetics and so address the question of how kinetochore formation is regulated. We found that the nuclear exclusion of the Spc105/KNL1 protein during interphase prevents precocious assembly of the Mis12 complex. The nuclear import of Spc105 in early prophase and its immediate association with the Mis12 complex on centromeres are thus the first steps in kinetochore assembly. The cumulative kinetochore levels of Spc105 and Mis12 complex then determine the rate of Ndc80 complex recruitment commencing only after nuclear envelope breakdown. The carboxy-terminal part of Spc105 directs its nuclear import and is sufficient for the assembly of all core kinetochore components and CENP-C, when localized ectopically to centrosomes. Super-resolution microscopy shows that carboxy-terminus of Spc105 lies at the junction of the Mis12 and Ndc80 complexes on stretched kinetochores. Our study thus indicates that physical accessibility of kinetochore components plays a crucial role in the regulation ofDrosophilakinetochore assembly and leads us to a model in which Spc105 is a licensing factor for its onset.
Digital elevation model uncertainty and hazard analysis using a geophysical flow model
Authors: Stefanescu E. R. , Bursik M. , Cordoba G. , Dalbey K. , Jones M. D. , Patra A. K. , Pieri D. C. , Pitman E. B. , Sheridan M. F.
Published: February 2012

This paper describes a new methodology to quantify the variation in the output of a computational fluid dynamics model for block and ash flows, when the digital elevation model (DEM) of the terrain and other inputs are given as a range of possible values with a prescribed uncertainty. Integrating these variations in the possible flows as a function of input uncertainties provides well-defined hazard probabilities at specific locations, i.e. a hazard map. Earlier work provided a methodology for assessing hazards based on variations in flow initiation and friction parameters. This paper extends this approach to include the effect of terrain error and uncertainty. The results are based on potential flows at Mammoth Mountain, CA, and Galeras Volcano, Colombia. The analysis establishes the soundness of the approach and the effect of including the uncertainty in DEMs in the construction of probabilistic hazard maps.
Nuclear translocation of pro‐amphiregulin induces chemoresistance in gastric cancer
Authors: Yoshida Michihiro , Shimura Takaya , Fukuda Shinji , Mizoshita Tsutomu , Tanida Satoshi , Kataoka Hiromi , Kamiya Takeshi , Nakazawa Takahiro , Higashiyama Shigeki , Joh Takashi
Published: February 2012

Amphiregulin (AR) is derived from a membrane‐anchored form (proAR) by ectodomain shedding, and is a ligand that activates epidermal growth factor receptor (EGFR). We have recently shown that proAR translocates from the plasma membrane to the nucleus after truncation of 11 amino acids at the C‐terminus, which is independent of the conventional EGFR signaling pathway. Although proAR immunoreactivity has reportedly been detected in the nucleus of cancer cells, its biological meaning has never been investigated. This study was performed to investigate the roles of proAR nuclear translocation in human gastric cancer. We constructed proAR truncated 11 amino acids at the C‐terminus (proARΔC11) that spontaneously translocates to the nucleus, and established proARΔC11‐expression regulatable gastric cancer cells (MKN45, MKN28) using the tet‐off system. Using these cells, we found that proAR nuclear translocation significantly induced chemoresistance in vitro and in vivo. Analyzing the relationship between immunoreactive localization of proAR and the clinical outcome for 46 advanced gastric cancer cases treated with chemotherapy, median survival time was 311 days in 16 patients with AR‐positive staining in the nucleus and 387 days in 30 patients with AR‐negative staining (P < 0.05). The present study demonstrates that proAR nuclear translocation increases resistance to anti‐cancer drugs, which might be associated with poor prognosis in human gastric cancer. (Cancer Sci 2012; 103: 708–715)
Elevated level of lysine 9‐acetylated histone H3 at the MDR1 promoter in multidrug‐resistant cells
Authors: Toth Monika , Boros Imre M. , Balint Eva
Published: February 2012

Failure of chemotherapy in breast cancer presents a major problem and is often due to elevated expression of ATP binding cassette (ABC)‐type transporters, such as MDR1 protein. It has been shown that MDR1/ABCB1 gene expression is regulated at the chromatin level by DNA methylation and histone acetylation. However, the modified histone residues have not been identified and the role of various histone acetyl transferases (HATs) is not fully understood. By studying a breast carcinoma model cell line and its MDR1‐overexpressing derivative, we show that the histone 3 lysine 9 (H3K9) acetylation level is elevated 100‐fold in the promoter and first exon of the MDR1 gene in the drug‐resistant cell line compared to the drug‐sensitive cell line. The acetylation level of the other examined lysine residues (H3K4, H3K14, H4K8, and H4K12) is weakly or not at all elevated in the MDR1 locus, although their acetylation is generally increased genome‐wide in the drug‐resistant cell. Downregulation of the expression of HATs PCAF and GCN5 by RNAi effectively reduces the expression of MDR1. Unexpectedly, treatment with a p300‐selective inhibitor (HAT inhibitor II) further increases MDR1 expression and drug efflux in the drug‐resistant cells. Our data suggest that repeated exposure to chemotherapy may result in deregulated histone acetylation genome‐wide and in the MDR1 promoter. (Cancer Sci 2012; 103: 659–669)
Accumulation of p62/SQSTM1 is associated with poor prognosis in patients with lung adenocarcinoma
Authors: Inoue Daisuke , Suzuki Takashi , Mitsuishi Yoichiro , Miki Yasuhiro , Suzuki Satoshi , Sugawara Shunichi , Watanabe Mika , Sakurada Akira , Endo Chiaki , Uruno Akira , Sasano Hironobu , Nakagawa Takayuki , Satoh Kennichi , Tanaka Nobuyuki , Kubo Hiroshi , Motohashi Hozumi , Yamamoto Masayuki
Published: February 2012

p62/SQSTM1 is a selective substrate of autophagy, and aberrant accumulation of p62 has been observed in various pathological conditions. To understand the roles p62 plays in non‐small‐cell lung cancer (NSCLC), we carried out immunohistochemical analyses of p62 expression in a cohort of patients with annotated clinicopathological data. As analyses of murine and human hepatocellular carcinomas suggested a correlation between p62 and Nrf2 accumulations, we also examined NRF2 expression in the same cohort. The expression of NRF2 and p62 was examined by immunohistochemical methods in 109 NSCLC cases, which included patients with adenocarcinoma (n = 72), squamous cell carcinoma (n = 31), and large cell carcinoma (n = 6). Accumulation of NRF2 and p62 was detected in 34% and 37% of NSCLC patients, respectively. The accumulations of p62 and NRF2 did not correlate with each other, but both were associated with worse lung cancer‐specific survival (P = 0.0003 for NRF2; P = 0.0130 for p62). NRF2 status had an impact on NSCLC prognosis irrespective of histology types, but p62 status did so particularly in adenocarcinoma (P = 0.037). Multivariate analysis indicated that positive immunoreactivities of NRF2 and p62 were both independent factors predicting worse lung cancer‐specific survival (P < 0.0001 for NRF2 and P = 0.04 for p62). This study revealed that both NRF2 and p62 are independent prognostic factors for NSCLC. The prognostic impact of p62 status was pronounced in adenocarcinoma patients, suggesting that molecular mechanisms underlying cancer evolution differ between adenocarcinoma and squamous cell carcinoma. (Cancer Sci 2012; 103: 760–766)
A new PICTure of nucleolar stress
Authors: Suzuki Akira , Kogo Ryunosuke , Kawahara Kohichi , Sasaki Masato , Nishio Miki , Maehama Tomohiko , Sasaki Takehiko , Mimori Koshi , Mori Masaki
Published: February 2012

Cell growth demands new protein synthesis, which requires nucleolar ribosomal functions. Ribosome biogenesis consumes a large proportion of the cell's resources and energy, and so is tightly regulated through an intricate signaling network to guarantee fidelity. Thus, events that impair ribosome biogenesis cause nucleolar stress. In response to this stress, several nucleolar ribosomal proteins (RPs) translocate to the nucleoplasm and bind to MDM2. MDM2‐mediated ubiquitination and degradation of the tumor suppressor p53 is then blocked, resulting in p53 accumulation and the induction of p53‐dependent cell cycle arrest and apoptosis. Nucleolar stress is therefore a quality control surveillance mechanism that monitors the synthesis and assembly of the rRNA and protein components of ribosomes. Although nucleolar stress signaling pathways have been extensively analyzed, critical questions remain about their regulatory mechanisms. For example, how do RPs translocate from the nucleolus to the nucleoplasm to exert their functions, and do these p53‐regulating RPs influence the prognosis of human cancer patients? Our laboratory recently identified the nucleolar protein PICT1 as a novel regulator of nucleolar stress. PICT1 sequesters the ribosomal protein RPL11 in the nucleolus, preventing it from binding to MDM2. MDM2 is then free to degrade p53, favoring tumor cell growth. Accordingly, the level of PICT1 in a tumor is becoming a useful prognostic marker for human cancers. This review summarizes the evidence that links nucleolar stress to tumorigenesis, and casts PICT1 as an oncogenic player in human cancer biology. (Cancer Sci 2012; 103: 632–637)
Frequent inactivation of the BAP1 gene in epithelioid‐type malignant mesothelioma
Authors: Yoshikawa Yoshie , Sato Ayuko , Tsujimura Tohru , Emi Mitsuru , Morinaga Tomonori , Fukuoka Kazuya , Yamada Shusai , Murakami Aki , Kondo Nobuyuki , Matsumoto Seiji , Okumura Yoshitomo , Tanaka Fumihiro , Hasegawa Seiki , Nakano Takashi , Hashimoto‐Tamaoki Tomoko
Published: February 2012

In the present study, we analyzed genomic alterations of BRCA1‐associated protein 1 (BAP1) in 23 malignant mesotheliomas (MMs), 16 epithelioid and seven non‐epithelioid, consisting of 18 clinical specimens and five established cell lines. In examining these samples for homozygous deletions and sequence‐level mutations, we found biallelic BAP1 gene alterations in 14 of 23 MMs (61%). Seven of these 14 MMs had homozygous deletions of the partial or entire BAP1 gene, another five had sequence‐level mutations, including small deletions, a nonsense mutation, and missense mutations with additional monoallelic deletions, and the remaining two had homozygous mutations without allelic loss. All but one of the 14 BAP1 gene mutations were found in the epithelioid‐type MMs; BAP1 mutations were found in 13 of 16 epithelioid‐type MMs, but in only one of seven non‐epithelioid‐type MMs (13/16 vs 1/7; P = 0.005). There was no BAP1 mRNA expression in MMs with biallelic deletion and repressed expression was confirmed in MM specimens with deletion/mutation as compared with Met5a, SV40‐transformed normal mesothelial cells. Western blot showed that seven of eight epithelioid MMs analyzed were BAP1 negative. Immunostaining with anti‐BAP1 antibody in normal lung tissues revealed clear nuclear staining of normal mesothelial cells. No nuclear staining was observed among BAP1 mutation‐positive MM tumors, whereas nuclear staining was observed among BAP1 mutation‐negative MM tumors. These results suggest that the lack of the tumor suppressor BAP1 may be more specifically involved in the pathogenesis of epithelioid MM rather than non‐epithelioid MM, and would be useful for diagnosis of epithelioid‐type MM. (Cancer Sci 2012; 103: 868–874)
Downregulated Dicer expression predicts poor prognosis in chronic lymphocytic leukemia
Authors: Zhu Dan‐Xia , Fan Lei , Lu Rui‐Nan , Fang Cheng , Shen Wen‐Yi , Zou Zhi‐Jian , Wang Yin‐Hua , Zhu Hua‐Yuan , Miao Kou‐Rong , Liu Peng , Xu Wei , Li Jian‐Yong
Published: February 2012

Chronic lymphocytic leukemia (CLL) is the most common leukemia in the western world. Alterations in microRNAs (miRNAs) expression have been proposed to play a role in CLL pathogenesis. Dicer and Drosha are the main regulators of miRNA biogenesis, and deregulation of their expression has been indicated as a possible cause of miRNA alterations observed in various cancers. To investigate the role of Dicer and Drosha in CLL, we assessed the expression of Dicer and Drosha and their correlation with other prognostic factors, including Binet stages, immunoglobulin heavy chain variable gene (IGHV) mutation status, TP53 mutation status, ZAP‐70 protein and CD38 expression level in 165 CLL patients by using real‐time polymerase chain reaction methods. Patients with unmutated IGHV genes had significantly lower expression of Dicer than patients with IGHV mutations. The lower expression level of Dicer was also significantly associated with higher level of CD38 and ZAP‐70, and more aggressive Binet stage. We also analyzed Dicer expression in different cytogenetic subgroups. Lower Dicer level was found in patients with unfavorable cytogenetic aberrations (deletion in 17p13 or 11q22.3) in contrast to higher level in good risk cytogenetics (deletion in 13q14 as the sole abnormality). Furthermore, the lower expression of Dicer in CLL shows a strong association with shorter overall survival (OS) (P = 0.0046) as well as with reduced treatment free survival (TFS) (P = 0.0006). By contrast, no differences in the expression of Drosha among these groups of patients were observed. Our data suggest that Dicer expression may play an important role in the progression and prognosis of CLL. (Cancer Sci 2012; 103: 875–881)
Tumor‐suppressive microRNA silenced by tumor‐specific DNA hypermethylation in cancer cells
Authors: Kozaki Ken‐ichi , Inazawa Johji
Published: February 2012

MicroRNA (miRNA) genes, located in intergenic or intragenic non‐coding regions of the genome, are transcribed and processed to small non‐protein‐coding RNA of approximately 22 nucleotides negatively regulating gene expression. Some miRNA have already been reported for their genetic alterations, aberrant expression and oncogenic or tumor‐suppressive functions. After 2008, there has been a striking increase in the number of publications reporting tumor‐suppressive miRNA (TS‐miRNA) silenced epigenetically in various types of cancers, suggesting important clinical applications for miRNA‐based molecular diagnosis and therapy for cancers. Here, we introduce a correlation of the gene silencing of TS‐miRNA through CpG island hypermethylation with the genomic distances between intergenic and intragenic miRNA genes or protein‐coding host genes and CpG islands located around these genes. Furthermore, we also discuss the potential of miRNA replacement therapy for cancers using double‐stranded RNA mimicking TS‐miRNA. (Cancer Sci 2012; 103: 837–845)
Body mass index and the risk of obesity in coeliac disease treated with the gluten‐free diet
Authors: Kabbani T. A. , Goldberg A. , Kelly C. P. , Pallav K. , Tariq S. , Peer A. , Hansen J. , Dennis M. , Leffler D. A.
Published: February 2012

Background

Coeliac disease is increasingly diagnosed and weight changes are common after adoption of a gluten‐free diet (GFD), however data on body mass index (BMI) changes are limited.

Aim

To assess changes in BMI after diagnosis in a large coeliac population.

Methods

A total of 1018 patients with biopsy confirmed coeliac disease seen at our centre were studied retrospectively. Initial and follow‐up BMIs were recorded, as was GFD adherence as assessed by an expert dietitian.

Results

A total of 679 patients with at least two recorded BMIs and GFD adherence data were included in the study. Mean follow‐up was 39.5 months. Compared to regional population data, the coeliac cohort was significantly less likely to be overweight or obese (32% vs. 59%, P < 0.0001). Mean BMI increased significantly after GFD initiation (24.0 to 24.6; P < 0.001). 21.8% of patients with normal or high BMI at study entry increased their BMI by more than two points.

Conclusions

Individuals with coeliac disease have lower BMI than the regional population at diagnosis. BMI increases on the GFD, especially in those that adhere closely to the GFD. On the GFD, 15.8% of patients move from a normal or low BMI class into an overweight BMI class, and 22% of patients overweight at diagnosis gain weight. These results indicate that weight maintenance counselling should be an integral part of coeliac dietary education.
A review of postoperative cognitive dysfunction and neuroinflammation associated with cardiac surgery and anaesthesia
Authors: van Harten A. E. , Scheeren T. W. L. , Absalom A. R.
Published: February 2012

Postoperative cognitive dysfunction is receiving increasing attention, particularly as it mainly affects the (growing) elderly population. Until recently, cognitive deficits after cardiac surgery were thought to be caused by physiological disturbances associated with the cardiopulmonary bypass technique. Although the technique of ‘off‐pump’ coronary revascularisation may potentially be associated with improved outcome, long‐term follow‐up studies have failed to demonstrate a significant reduction in the incidence of postoperative cognitive dysfunction. The focus of research is thus shifting from cardiopulmonary bypass to other factors common to both techniques, such as surgery, anaesthesia and patient‐related predisposing factors. Priming of the immune system by ageing and atherosclerosis may result in an exaggerated systemic and cerebral inflammatory response to cardiac surgery and anaesthesia, causing neuronal loss or dysfunction resulting in cognitive dysfunction. We briefly discuss the evidence for cardiopulmonary bypass‐related neuronal injuries in adult cardiac surgery patients, and review the evidence that immune priming is a key factor in the pathogenesis of cognitive dysfunction after cardiac surgery.
Quantitative trait loci associated with chemical composition of the chicken carcass
Authors: Nones K. , Ledur M. C. , Zanella E. L. , Klein C. , Pinto L. F. B. , Moura A. S. A. M. T. , Ruy D. C. , Baron E. E. , Ambo M. , Campos R. L. R. , Boschiero C. , Burt D. W. , Coutinho L. L.
Published: February 2012

Major objectives of the poultry industry are to increase meat production and to reduce carcass fatness, mainly abdominal fat. Information on growth performance and carcass composition are important for the selection of leaner meat chickens. To enhance our understanding of the genetic architecture underlying the chemical composition of chicken carcasses, an F2 population developed from a broiler × layer cross was used to map quantitative trait loci (QTL) affecting protein, fat, water and ash contents in chicken carcasses. Two genetic models were applied in the QTL analysis: the line‐cross and the half‐sib models, both using the regression interval mapping method. Six significant and five suggestive QTL were mapped in the line‐cross analysis, and four significant and six suggestive QTL were mapped in the half‐sib analysis. A total of eleven QTL were mapped for fat (ether extract), five for protein, four for ash and one for water contents in the carcass using both analyses. No study to date has reported QTL for carcass chemical composition in chickens. Some QTL mapped here for carcass fat content match, as expected, QTL regions previously associated with abdominal fat in the same or in different populations, and novel QTL for protein, ash and water contents in the carcass are presented here. The results described here also reinforce the need for fine mapping and to perform multi‐trait analyses to better understand the genetic architecture of these traits.
A novel USP9Y polymorphism allowing a rapid and unambiguous classification of Bos taurus Y chromosomes into haplogroups
Authors: Bonfiglio S. , De Gaetano A. , Tesfaye K. , Grugni V. , Semino O. , Ferretti L.
Published: February 2012

A new sequence‐tagged site (STS) was identified within intron 26 of the bovine USP9Y gene, showing an 81‐base pair insertion (g.76439_76440ins81 in sequence with GenBank accession FJ195366) able to distinguish Y2 and Y3 Bos Y haplogroups from Y1. Moreover, four Y3‐specific sequence variants allow a distinction from haplogroup Y2. The typing of a Bison bison Y chromosome indicates that the ancestral allele for the USP9Y 81‐bp insertion is the short Y1 version. The results from typing the new STS in 1230 cattle Y chromosomes are fully consistent with their classification through standard methods. Thanks to the newly identified STS, it is now possible to assign cattle Y chromosomes to the currently known haplogroups using a single marker.
Differential compaction and early rock fracturing in high‐relief carbonate platforms: numerical modelling of a Triassic case study (Esino Limestone, Central Southern Alps, Italy)
Authors: Berra F. , Carminati E.
Published: February 2012

Numerical models were used to investigate the effects of differential compaction on strain development and early fracturing in an early cemented high‐relief Triassic carbonate platform prograding onto basinal sediments, whose thickness increases basinward. Results show that basinal sediment compaction induces stretching of internal platform and slope strata in prograding platforms. When sediments are early cemented, such extensional strain is accommodated by the generation of syndepositional fractures. The amount of stretching is predicted to increase from the oldest to the youngest layers, due to the thickening of the compactable basinal sequences towards the external parts of the platform. Stretching is also controlled by the characteristics of the basin: the thicker and the more compactable the basinal sediments, the larger will be the stretching. Numerical modelling has been applied to the Ladinian–Early Carnian carbonate platform of the Esino Limestone (Central Southern Alps of Italy). This case study is favourable for numerical modelling, as it is well exposed and both its internal geometry (inner platform, reef and prograding clinostratified slope deposits) and the relationship with the adjacent basin can be fully reconstructed, as the Alpine tectonic overprint is weak in the study area. Evidence for early fracturing (fractures filled by fibrous cements coeval with the platform development) is described and the location, orientation and width of the fractures measured. The fractures are mainly steeply dipping and oriented perpendicularly to the direction of progradation of the platform, mimicking local platform‐margin trends. The integration of numerical models with field data gives the opportunity to quantify the extension triggered by differential compaction and predict the possible distribution of early fractures in carbonate platforms of known geometry and thickness, whereas the interpretation of early fractures as the effects of differential compaction can be supported or rejected by the comparison with the results of ad hoc numerical modelling.
Long‐term macrolide treatment of chronic inflammatory airway diseases: risks, benefits and future developments
Authors: Cameron E. J. , McSharry C. , Chaudhuri R. , Farrow S. , Thomson N. C.
Published: February 2012

Macrolide antibiotics were discovered over 50 years ago and following their use as antimicrobials it became apparent that this group of antibiotics also possessed anti‐inflammatory properties. Subsequent clinical trials showed benefits of macrolides as long‐term adjuncts in the treatment of a spectrum of chronic inflammatory respiratory diseases, particularly diffuse panbronchiolitis, cystic fibrosis, post‐transplant bronchiolitis obliterans and more recently chronic obstructive pulmonary disease (COPD). The evidence for efficacy of macrolides in the long‐term treatment of chronic asthma and bronchiectasis is less well established. The mechanism(s) of action of macrolides in the treatment of these diseases remains unexplained, but may be due to their antibacterial and/or anti‐inflammatory actions, which include reductions in interleukin‐8 production, neutrophil migration and/or function. Macrolides have additional potentially beneficial properties including anti‐viral actions and an ability to restore corticosteroid sensitivity. The increased prescribing of macrolides for long‐term treatment could result in the development of microbial resistance and adverse drug effects. New macrolides have been developed which do not possess any antimicrobial activity and hence lack the ability to produce microbial resistance, but which still retain immunomodulatory effects. Potentially novel macrolides may overcome a significant barrier to the use of this type of drug for the long‐term treatment of chronic inflammatory airway diseases.
Incorporating hydromorphology in strategic approaches to managing flows for salmonids
Authors: NEWSON M. , SEAR D. , SOULSBY C.
Published: February 2012

Abstract  Whilst flow is often seen simplistically as a measurable and manageable variable in rivers, the habitat value of flow is delivered by interactions with channel morphology and substrate. The resulting hydromorphology impacts on all salmonid life stages; its proper understanding requires integration between the sciences of hydrology/hydraulics, geomorphology and freshwater ecology, but this integration is scarce. This study describes those features of river channel morphology and dynamics that are most relevant to hydromorphological status, describes progress in field assessment and outlines practical progress in calibrating in‐channel habitat condition as an aid to setting flows. However, the incorporation of the true spatial and temporal variability of hydromorphology awaits further refinement of survey techniques and the long‐awaited interdisciplinary research on causal process links. Meanwhile, amongst the geomorphological tools available to those setting environmental flows are fluvial audits, the definition and mapping of meso‐scale biotopes and the use of realistic river typologies for the local application of general flow rules.
A prospective randomized study to compare pelvic floor rehabilitation and dapoxetine for treatment of lifelong premature ejaculation
Authors: Pastore A. L. , Palleschi G. , Leto A. , Pacini L. , Iori F. , Leonardo C. , Carbone A.
Published: February 2012

Premature ejaculation (PE) is the most common male sexual disorder. We compared pelvic floor muscle rehabilitation to on‐demand treatment with the selective serotonin reuptake inhibitor dapoxetine in 40 men with lifelong PE (baseline intra‐vaginal ejaculatory latency time (IELT) ≤1 min). Subjects were randomized into the following two treatment groups: (1) PFM rehabilitation or (2) 30 or 60 mg of on‐demand dapoxetine. Total treatment time for both groups was 12 weeks, at the end of which, IELT mean values were calculated to compare the effectiveness of the two different therapeutic approaches. At the end of treatment, 11 of the 19 patients (57%) treated with rehabilitation were able to control the ejaculation reflex, with a mean IELT of 126.6 sec (range: 123.6–152.4 sec). In the dapoxetine group, after 12 weeks of therapy, 5 of 8 (62.5%) patients in the 30 mg subgroup and five of seven (72%) in the 60 mg subgroup had an IELT >180 sec (mean: 178.2 and 202.8 sec, respectively). The results obtained in the group treated with pelvic floor rehabilitation are promising, and this treatment represents an important cost reduction if compared to dapoxetine on‐demand treatment. The present study confirms the data that are previously available in the literature on the efficacy and safety of the new inhibitor of serotonin reuptake, dapoxetine, as well as proposes and evaluates a new type of physical treatment that may be a viable therapeutic option for treatment of PE.