bluuebunny/crossref_metadata_2025 huggingface dataset:
Localization of eukaryote-specific ribosomal proteins in a 5.5-Å cryo-EM map of the 80S eukaryotic ribosome
Authors: Armache Jean-Paul , Jarasch Alexander , Anger Andreas M. , Villa Elizabeth , Becker Thomas , Bhushan Shashi , Jossinet Fabrice , Habeck Michael , Dindar Gülcin , Franckenberg Sibylle , Marquez Viter , Mielke Thorsten , Thomm Michael , Berninghausen Otto , Beatrix Birgitta , Söding Johannes , Westhof Eric , Wilson Daniel N. , Beckmann Roland
Published: October 2010

Protein synthesis in all living organisms occurs on ribonucleoprotein particles, called ribosomes. Despite the universality of this process, eukaryotic ribosomes are significantly larger in size than their bacterial counterparts due in part to the presence of 80 r proteins rather than 54 in bacteria. Using cryoelectron microscopy reconstructions of a translating plant (
Triticum aestivum
) 80S ribosome at 5.5-Å resolution, together with a 6.1-Å map of a translating
Saccharomyces cerevisiae
80S ribosome, we have localized and modeled 74/80 (92.5%) of the ribosomal proteins, encompassing 12 archaeal/eukaryote-specific small subunit proteins as well as the complete complement of the ribosomal proteins of the eukaryotic large subunit. Near-complete atomic models of the 80S ribosome provide insights into the structure, function, and evolution of the eukaryotic translational apparatus.
Spectral quality of light modulates emotional brain responses in humans
Authors: Vandewalle G. , Schwartz S. , Grandjean D. , Wuillaume C. , Balteau E. , Degueldre C. , Schabus M. , Phillips C. , Luxen A. , Dijk D. J. , Maquet P.
Published: October 2010

Light therapy can be an effective treatment for mood disorders, suggesting that light is able to affect mood state in the long term. As a first step to understand this effect, we hypothesized that light might also acutely influence emotion and tested whether short exposures to light modulate emotional brain responses. During functional magnetic resonance imaging, 17 healthy volunteers listened to emotional and neutral vocal stimuli while being exposed to alternating 40-s periods of blue or green ambient light. Blue (relative to green) light increased responses to emotional stimuli in the voice area of the temporal cortex and in the hippocampus. During emotional processing, the functional connectivity between the voice area, the amygdala, and the hypothalamus was selectively enhanced in the context of blue illumination, which shows that responses to emotional stimulation in the hypothalamus and amygdala are influenced by both the decoding of vocal information in the voice area and the spectral quality of ambient light. These results demonstrate the acute influence of light and its spectral quality on emotional brain processing and identify a unique network merging affective and ambient light information.
Crystal structure of prethrombin-1
Authors: Chen Zhiwei , Pelc Leslie A. , Di Cera Enrico
Published: October 2010

Prothrombin is the zymogen precursor of the clotting enzyme thrombin, which is generated by two sequential cleavages at R271 and R320 by the prothrombinase complex. The structure of prothrombin is currently unknown. Prethrombin-1 differs from prothrombin for the absence of 155 residues in the N-terminal domain and is composed of a single polypeptide chain containing fragment 2 (residues 156–271), A chain (residues 272–320), and B chain (residues 321–579). The X-ray crystal structure of prethrombin-1 solved at 2.2-Å resolution shows an overall conformation significantly different (rmsd = 3.6 
Å
) from that of its active form meizothrombin desF1 carrying a cleavage at R320. Fragment 2 is rotated around the
y
axis by 29° and makes only few contacts with the B chain. In the B chain, the oxyanion hole is disrupted due to absence of the I16-D194 ion pair and the Na
+
binding site and adjacent primary specificity pocket are highly perturbed. A remarkable feature of the structure is that the autolysis loop assumes a helical conformation enabling W148 and W215, located 17 Å apart in meizothrombin desF1, to come within 3.3 Å of each other and completely occlude access to the active site. These findings suggest that the zymogen form of thrombin possesses conformational plasticity comparable to that of the mature enzyme and have significant implications for the mechanism of prothrombin activation and the zymogen → protease conversion in trypsin-like proteases.
Convergent recombination shapes the clonotypic landscape of the naïve T-cell repertoire
Authors: Quigley Máire F. , Greenaway Hui Yee , Venturi Vanessa , Lindsay Ross , Quinn Kylie M. , Seder Robert A. , Douek Daniel C. , Davenport Miles P. , Price David A.
Published: October 2010

Adaptive T-cell immunity relies on the recruitment of antigen-specific clonotypes, each defined by the expression of a distinct T-cell receptor (TCR), from an array of naïve T-cell precursors. Despite the enormous clonotypic diversity that resides within the naïve T-cell pool, interindividual sharing of TCR sequences has been observed within mobilized T-cell responses specific for certain peptide–major histocompatibility complex (pMHC) antigens. The mechanisms that underlie this phenomenon have not been fully elucidated, however. A mechanism of convergent recombination has been proposed to account for the occurrence of shared, or “public,” TCRs in specific memory T-cell populations. According to this model, TCR sharing between individuals is directly related to TCR production frequency; this, in turn, is determined on a probabilistic basis by the relative generation efficiency of particular nucleotide and amino acid sequences during the recombination process. Here, we tested the key predictions of convergent recombination in a comprehensive evaluation of the naïve CD8
+
TCRβ repertoire in mice. Within defined segments of the naïve CD8
+
T-cell repertoire, TCRβ sequences with convergent features were (
i
) present at higher copy numbers within individual mice and (
ii
) shared between individual mice. Thus, the naïve CD8
+
T-cell repertoire is not flat, but comprises a hierarchy of recurrence rates for individual clonotypes that is determined by relative production frequencies. These findings provide a framework for understanding the early mobilization of public CD8
+
T-cell clonotypes, which can exert profound biological effects during acute infectious processes.
Cytokine-dependent but acquired immunity-independent arthritis caused by DNA escaped from degradation
Authors: Kawane Kohki , Tanaka Hiromi , Kitahara Yusuke , Shimaoka Shin , Nagata Shigekazu
Published: October 2010

DNase II digests the chromosomal DNA in macrophages after apoptotic cells and nuclei from erythroid precursors are engulfed. The DNase II-null mice develop a polyarthritis that resembles rheumatoid arthritis. Here, we showed that when bone marrow cells from the DNase II-deficient mice were transferred to the wild-type mice, they developed arthritis. A deficiency of Rag2 or a lack of lymphocytes accelerated arthritis of the DNase II-null mice, suggesting that the DNase II
−/−
macrophages were responsible for triggering arthritis, and their lymphocytes worked protectively. A high level of TNFα, IL-1β, and IL-6 was found in the affected joints of the DNase II-null mice, suggesting an inflammatory-skewed cytokine storm was established in the joints. A lack of TNFα, IL-1β, or IL-6 gene blocked the expression of the other cytokine genes as well and inhibited the development of arthritis. Neutralization of TNFα, IL-1β, or IL-6 had a therapeutic effect on the developed arthritis of the DNase II-null mice, indicating that the cytokine storm was essential for the maintenance of arthritis in the DNase II-deficient mice. Methotrexate, an antimetabolite that is often used to treat patients with rheumatoid arthritis, had a therapeutic effect with the DNase II-null mice. These properties of arthritis in the DNase II-null mice were similar to those found in human systemic-onset juvenile idiopathic arthritis or Still's disease, indicating that the DNase II-null mice are a good animal model of this type of arthritis.
Genome analysis of
Bifidobacterium bifidum
PRL2010 reveals metabolic pathways for host-derived glycan foraging
Authors: Turroni Francesca , Bottacini Francesca , Foroni Elena , Mulder Imke , Kim Jae-Han , Zomer Aldert , Sánchez Borja , Bidossi Alessandro , Ferrarini Alberto , Giubellini Vanessa , Delledonne Massimo , Henrissat Bernard , Coutinho Pedro , Oggioni Marco , Fitzgerald Gerald F. , Mills David , Margolles Abelardo , Kelly Denise , van Sinderen Douwe , Ventura Marco
Published: October 2010

The human intestine is densely populated by a microbial consortium whose metabolic activities are influenced by, among others, bifidobacteria. However, the genetic basis of adaptation of bifidobacteria to the human gut is poorly understood. Analysis of the 2,214,650-bp genome of
Bifidobacterium bifidum
PRL2010, a strain isolated from infant stool, revealed a nutrient-acquisition strategy that targets host-derived glycans, such as those present in mucin. Proteome and transcriptome profiling revealed a set of chromosomal loci responsible for mucin metabolism that appear to be under common transcriptional control and with predicted functions that allow degradation of various O-linked glycans in mucin. Conservation of the latter gene clusters in various
B. bifidum
strains supports the notion that host-derived glycan catabolism is an important colonization factor for
B. bifidum
with concomitant impact on intestinal microbiota ecology.
brca2
in zebrafish ovarian development, spermatogenesis, and tumorigenesis
Authors: Shive Heather R. , West Robert R. , Embree Lisa J. , Azuma Mizuki , Sood Raman , Liu Paul , Hickstein Dennis D.
Published: October 2010

Humans with inherited mutations in
BRCA2
are at increased risk for developing breast and ovarian cancer; however, the relationship between
BRCA2
mutation and these cancers is not understood. Studies of
Brca2
mutation by gene targeting in mice are limited, given that homozygous
Brca2
mutation typically leads to early embryonic lethality. We established a zebrafish line with a nonsense mutation in
brca2
exon 11 (
brca2
Q658X
), a mutation similar in location and type to
BRCA2
mutations found in humans with hereditary breast and ovarian cancer.
brca2
Q658X
homozygous zebrafish are viable and survive to adulthood; however, juvenile homozygotes fail to develop ovaries during sexual differentiation. Instead,
brca2
Q658X
homozygotes develop as infertile males with meiotic arrest in spermatocytes. Germ cell migration to the embryonic gonadal ridge is unimpaired in
brca2
Q658X
homozygotes; thus, failure of ovarian development is not due to defects in early establishment of the embryonic gonad. Homozygous
tp53
mutation rescues ovarian development in
brca2
Q658X
homozygous zebrafish, reflecting the importance of germ cell apoptosis in gonad morphogenesis. Adult
brca2
Q658X
homozygous zebrafish are predisposed to testicular neoplasias. In addition, tumorigenesis in multiple tissues is significantly accelerated in combination with homozygous
tp53
mutation in both
brca2
Q658X
homozygous and
brca2
Q658X
heterozygous zebrafish. These studies reveal critical roles for
brca2
in ovarian development and tumorigenesis in reproductive tissues.
Sarco(endo)plasmic reticulum Ca
2+
-ATPase 2b is a major regulator of endoplasmic reticulum stress and glucose homeostasis in obesity
Authors: Park Sang Won , Zhou Yingjiang , Lee Jaemin , Lee Justin , Ozcan Umut
Published: October 2010

Increased endoplasmic reticulum (ER) stress is one of the central mechanisms that lead to dysregulated metabolic homeostasis in obesity. It is thus crucial to understand the underpinnings of the mechanisms that lead to the development of ER stress. A high level of ER Ca
2+
is imperative for maintenance of normal ER function and this high Ca
2+
concentration of ER is maintained by sarco(endo)plasmic reticulum Ca
2+
-ATPase (SERCA). Here, we show that SERCA2b protein and mRNA levels are dramatically reduced in the liver of obese mice and restoration of SERCA2b in the liver of obese and diabetic mice alleviates ER stress, increases glucose tolerance, and significantly reduces the blood glucose levels. Furthermore, overexpression of SERCA2b in the liver of obese mice significantly reduces the lipogenic gene expression and the triglyceride content in the liver. Our results document the importance of SERCA2b in dysregulated glucose and lipid homeostasis in the liver of obese mice and suggest development of drugs to increase SERCA2b activity for treatment of type 2 diabetes and nonalcoholic steatohepatitis.
Generation of induced pluripotent stem cells using site-specific integration with phage integrase
Authors: Ye Lin , Chang Judy C. , Lin Chin , Qi Zhongxia , Yu Jingwei , Kan Yuet Wai
Published: October 2010

To date, a large number of reports have described reprogramming many somatic cell types into induced pluripotent stem (iPS) cells, using different numbers of transcription factors and devising alternate methods of introducing the transcription factor genes or proteins into the somatic cells. Here, we describe a method using bacteriophage ΦC31 integrase to reprogram mouse embryonic fibroblasts and human amniotic fluid cells into iPS cells. These iPS cells showed morphology, surface antigens, gene expression, and epigenetic states similar to ES cells and formed teratomas with three germ layers in nonobese diabetic/severely compromised immunodeficient mice. Importantly, these iPS cells have only a single integration site in each cell line. The locations of integration favor the intergenic regions, and their distances from the adjacent genes extended from several hundred to >1 million bp. The effect of the insertion on the expression of these genes can be studied by RT-PCR. No insertion into microRNA gene loci was detected. Hence, it is possible to select cells in which adjacent gene functions are not affected, or the inserts can be removed if necessary. We conclude that phage integrase-mediated site-specific recombination can produce iPS cells that have undisturbed endogenous gene function and could be safe for future human therapeutic application.
Domain structure of the DEMETER 5-methylcytosine DNA glycosylase
Authors: Mok Young Geun , Uzawa Rie , Lee Jiyoon , Weiner Gregory M. , Eichman Brandt F. , Fischer Robert L. , Huh Jin Hoe
Published: October 2010

DNA glycosylases initiate the base excision repair (BER) pathway by excising damaged, mismatched, or otherwise modified bases. Animals and plants independently evolved active BER-dependent DNA demethylation mechanisms important for epigenetic reprogramming. One such DNA demethylation mechanism is uniquely initiated in plants by DEMETER (DME)-class DNA glycosylases. Arabidopsis DME family glycosylases contain a conserved helix–hairpin–helix domain present in both prokaryotic and eukaryotic DNA glycosylases as well as two domains A and B of unknown function that are unique to this family. Here, we employed a mutagenesis approach to screen for DME residues critical for DNA glycosylase activity. This analysis revealed that amino acids clustered in all three domains, but not in the intervening variable regions, are required for in vitro 5-methylcytosine excision activity. Amino acids in domain A were found to be required for nonspecific DNA binding, a prerequisite for 5-methylcytosine excision. In addition, mutational analysis confirmed the importance of the iron-sulfur cluster motif to base excision activity. Thus, the DME DNA glycosylase has a unique structure composed of three essential domains that all function in 5-methylcytosine excision.
Human remains from Zhirendong, South China, and modern human emergence in East Asia
Authors: Liu Wu , Jin Chang-Zhu , Zhang Ying-Qi , Cai Yan-Jun , Xing Song , Wu Xiu-Jie , Cheng Hai , Edwards R. Lawrence , Pan Wen-Shi , Qin Da-Gong , An Zhi-Sheng , Trinkaus Erik , Wu Xin-Zhi
Published: October 2010

The 2007 discovery of fragmentary human remains (two molars and an anterior mandible) at Zhirendong (Zhiren Cave) in South China provides insight in the processes involved in the establishment of modern humans in eastern Eurasia. The human remains are securely dated by U-series on overlying flowstones and a rich associated faunal sample to the initial Late Pleistocene, >100 kya. As such, they are the oldest modern human fossils in East Asia and predate by >60,000 y the oldest previously known modern human remains in the region. The Zhiren 3 mandible in particular presents derived modern human anterior symphyseal morphology, with a projecting tuber symphyseos, distinct mental fossae, modest lateral tubercles, and a vertical symphysis; it is separate from any known late archaic human mandible. However, it also exhibits a lingual symphyseal morphology and corpus robustness that place it close to later Pleistocene archaic humans. The age and morphology of the Zhiren Cave human remains support a modern human emergence scenario for East Asia involving dispersal with assimilation or populational continuity with gene flow. It also places the Late Pleistocene Asian emergence of modern humans in a pre-Upper Paleolithic context and raises issues concerning the long-term Late Pleistocene coexistence of late archaic and early modern humans across Eurasia.
Linking differential domain functions of the GS3 protein to natural variation of grain size in rice
Authors: Mao Hailiang , Sun Shengyuan , Yao Jialing , Wang Chongrong , Yu Sibin , Xu Caiguo , Li Xianghua , Zhang Qifa
Published: October 2010

Grain yield in many cereal crops is largely determined by grain size. Here we report the genetic and molecular characterization of
GS3
, a major quantitative trait locus for grain size. It functions as a negative regulator of grain size and organ size. The wild-type isoform is composed of four putative domains: a plant-specific organ size regulation (OSR) domain in the N terminus, a transmembrane domain, a tumor necrosis factor receptor/nerve growth factor receptor (TNFR/NGFR) family cysteine-rich domain, and a von Willebrand factor type C (VWFC) in the C terminus. These domains function differentially in grain size regulation. The OSR domain is both necessary and sufficient for functioning as a negative regulator. The wild-type allele corresponds to medium grain. Loss of function of OSR results in long grain. The C-terminal TNFR/NGFR and VWFC domains show an inhibitory effect on the OSR function; loss-of-function mutations of these domains produced very short grain. This study linked the functional domains of the GS3 protein to natural variation of grain size in rice.
Integrated biochemical and mechanical signals regulate multifaceted human embryonic stem cell functions
Authors: Li Dong , Zhou Jiaxi , Wang Lu , Shin Myung Eun , Su Pei , Lei Xiaohua , Kuang Haibin , Guo Weixiang , Yang Hong , Cheng Linzhao , Tanaka Tetsuya S. , Leckband Deborah E. , Reynolds Albert B. , Duan Enkui , Wang Fei
Published: October 2010

Human embryonic stem cells (ESCs [hESCs]) proliferate as colonies wherein individual cells are strongly adhered to one another. This architecture is linked to hESC self-renewal, pluripotency, and survival and depends on epithelial cadherin (E-cadherin), NMMIIA (nonmuscle myosin IIA), and p120-catenin. E-cadherin and p120-catenin work within a positive feedback loop that promotes localized accumulation of E-cadherin at intercellular junctions. NMMIIA stabilizes p120-catenin protein and controls E-cadherin–mediated intercellular adhesion. Perturbations of this signaling network disrupt colony formation, destabilize the transcriptional regulatory circuitry for pluripotency, and impair long-term survival of hESCs. Furthermore, depletion of E-cadherin markedly reduces the efficiency of reprogramming of human somatic cells to an ESC-like state. The feedback regulation and mechanical–biochemical integration provide mechanistic insights for the regulation of intercellular adhesion and cellular architecture in hESCs during long-term self-renewal. Our findings also contribute to the understanding of microenvironmental regulation of hESC identity and somatic reprogramming.
Revolving movement of a dynamic cluster of actin filaments during mitosis
Authors: Mitsushima Masaru , Aoki Kazuhiro , Ebisuya Miki , Matsumura Shigeru , Yamamoto Takuya , Matsuda Michiyuki , Toyoshima Fumiko , Nishida Eisuke
Published: October 2010

The actin cytoskeleton undergoes rapid changes in its architecture during mitosis. Here, we demonstrate novel actin assembly dynamics in M phase. An amorphous cluster of actin filaments appears during prometaphase, revolves horizontally along the cell cortex at a constant angular speed, and fuses into the contractile ring after three to four revolutions. Cdk1 activity is required for the formation of this mitotic actin cluster and its revolving movement. Rapid turnover of actin in the filaments takes place everywhere in the cluster and is also required for its cluster rotation during mitosis. Knockdown of Arp3, a component of the actin filament–nucleating Arp2/3 complex, inhibits the formation of the mitotic actin cluster without affecting other actin structures. These results identify Arp2/3 complex as a key factor in the generation of the dynamic actin cluster during mitosis.
IκBβ is an essential co-activator for LPS-induced IL-1β transcription in vivo
Authors: Scheibel Melanie , Klein Bettina , Merkle Heidrun , Schulz Manon , Fritsch Ralph , Greten Florian R. , Arkan Melek C. , Schneider Günter , Schmid Roland M.
Published: October 2010

Inhibitor of κB (IκB) β (IκBβ) represents one of the major primary regulators of NF-κB in mammals. In contrast to the defined regulatory interplay between NF-κB and IκBα, much less is known about the biological function of IκBβ. To elucidate the physiological role of IκBβ in NF-κB signaling in vivo, we generated IκBβ-deficient mice. These animals proved to be highly refractory to LPS-induced lethality, accompanied by a strong reduction in sepsis-associated cytokine production. In response to LPS, IκBβ is recruited to the IL-1β promoter forming a complex with the NF-κB subunits RelA/c-Rel required for IL-1β transcription. Further transcriptome analysis of LPS-stimulated wild-type and IκBβ-deficient BM-derived macrophages revealed several other genes with known regulatory functions in innate immunity arguing that a subset of NF-κB target genes is under control of IκBβ. Collectively, these findings provide an essential proinflammatory role for IκBβ in vivo, and establish a critical function for IκBβ as a transcriptional coactivator under inflammatory conditions.
Functional Analysis of the Asian Soybean Rust Resistance Pathway Mediated by Rpp2
Authors: Pandey Ajay K. , Yang Chunling , Zhang Chunquan , Graham Michelle A. , Horstman Heidi D. , Lee Yeunsook , Zabotina Olga A. , Hill John H. , Pedley Kerry F. , Whitham Steven A.
Published: October 2010

Asian soybean rust is an aggressive foliar disease caused by the obligate biotrophic fungus Phakopsora pachyrhizi. On susceptible plants, the pathogen penetrates and colonizes leaf tissue, resulting in the formation of necrotic lesions and the development of numerous uredinia. The soybean Rpp2 gene confers resistance to specific isolates of P. pachyrhizi. Rpp2-mediated resistance limits the growth of the pathogen and is characterized by the formation of reddish-brown lesions and few uredinia. Using virus-induced gene silencing, we screened 140 candidate genes to identify those that play a role in Rpp2 resistance toward P. pachyrhizi. Candidate genes included putative orthologs to known defense-signaling genes, transcription factors, and genes previously found to be upregulated during the Rpp2 resistance response. We identified 11 genes that compromised Rpp2-mediated resistance when silenced, including GmEDS1, GmNPR1, GmPAD4, GmPAL1, five predicted transcription factors, an O-methyl transferase, and a cytochrome P450 monooxygenase. Together, our results provide new insight into the signaling and biochemical pathways required for resistance against P. pachyrhizi.
The Evolutionary History of Beet necrotic yellow vein virus Deduced from Genetic Variation, Geographical Origin and Spread, and the Breaking of Host Resistance
Authors: Chiba Soutaro , Kondo Hideki , Miyanishi Masaki , Andika Ida Bagus , Han Chenggui , Tamada Tetsuo
Published: October 2010

Beet necrotic yellow vein virus (BNYVV) is an economically important pathogen of sugar beet and has been found worldwide, probably as the result of recent worldwide spread. The BNYVV genome consists of four or five RNA components. Here, we report analysis of sequence variation in the RNA3-p25, RNA4-p31, RNA2-CP, and RNA5-p26 genes of 73 worldwide isolates. The RNA3-p25 gene encodes virulence and avirulence factors. These four sets of gene sequences each fell into two to four groups, of which the three groups of p25 formed eight subgroups with different geographical distributions. Each of these subgroup isolates (strains) could have arisen from four original BNYVV population and their mixed infections. The genetic diversity for BNYVV was relatively small. Selection pressure varied greatly depending on the BNYVV gene and geographical location. Isolates of the Italy strain, in which p25 was subject to the strongest positive selection, were able to overcome the Rz1-host resistance gene to differing degrees, whereas other geographically limited strains could not. Resistance-breaking variants were generated by p25 amino acid changes at positions 67 and 68. Our studies suggest that BNYVV originally evolved in East Asia and has recently become a pathogen of cultivated sugar beet followed by the emergence of new resistance-breaking variants.
Reassessing the Role of N-Hydroxytryptamine in Auxin Biosynthesis
Authors: Tivendale Nathan D. , Davies Noel W. , Molesworth Peter P. , Davidson Sandra E. , Smith Jason A. , Lowe Edwin K. , Reid James B. , Ross John J.
Published: October 2010

The tryptamine pathway is one of five proposed pathways for the biosynthesis of indole-3-acetic acid (IAA), the primary auxin in plants. The enzymes AtYUC1 (Arabidopsis thaliana), FZY (Solanum lycopersicum), and ZmYUC (Zea mays) are reported to catalyze the conversion of tryptamine to N-hydroxytryptamine, putatively a rate-limiting step of the tryptamine pathway for IAA biosynthesis. This conclusion was based on in vitro assays followed by mass spectrometry or HPLC analyses. However, there are major inconsistencies between the mass spectra reported for the reaction products. Here, we present mass spectral data for authentic N-hydroxytryptamine, 5-hydroxytryptamine (serotonin), and tryptamine to demonstrate that at least some of the published mass spectral data for the YUC in vitro product are not consistent with N-hydroxytryptamine. We also show that tryptamine is not metabolized to IAA in pea (Pisum sativum) seeds, even though a PsYUC-like gene is strongly expressed in these organs. Combining these findings, we propose that at present there is insufficient evidence to consider N-hydroxytryptamine an intermediate for IAA biosynthesis.
C4GEM, a Genome-Scale Metabolic Model to Study C4 Plant Metabolism
Authors: de Oliveira Dal’Molin Cristiana Gomes , Quek Lake-Ee , Palfreyman Robin William , Brumbley Stevens Michael , Nielsen Lars Keld
Published: October 2010

Leaves of C4 grasses (such as maize [Zea mays], sugarcane [Saccharum officinarum], and sorghum [Sorghum bicolor]) form a classical Kranz leaf anatomy. Unlike C3 plants, where photosynthetic CO2 fixation proceeds in the mesophyll (M), the fixation process in C4 plants is distributed between two cell types, the M cell and the bundle sheath (BS) cell. Here, we develop a C4 genome-scale model (C4GEM) for the investigation of flux distribution in M and BS cells during C4 photosynthesis. C4GEM, to our knowledge, is the first large-scale metabolic model that encapsulates metabolic interactions between two different cell types. C4GEM is based on the Arabidopsis (Arabidopsis thaliana) model (AraGEM) but has been extended by adding reactions and transporters responsible to represent three different C4 subtypes (NADP-ME [for malic enzyme], NAD-ME, and phosphoenolpyruvate carboxykinase). C4GEM has been validated for its ability to synthesize 47 biomass components and consists of 1,588 unique reactions, 1,755 metabolites, 83 interorganelle transporters, and 29 external transporters (including transport through plasmodesmata). Reactions in the common C4 model have been associated with well-annotated C4 species (NADP-ME subtypes): 3,557 genes in sorghum, 11,623 genes in maize, and 3,881 genes in sugarcane. The number of essential reactions not assigned to genes is 131, 135, and 156 in sorghum, maize, and sugarcane, respectively. Flux balance analysis was used to assess the metabolic activity in M and BS cells during C4 photosynthesis. Our simulations were consistent with chloroplast proteomic studies, and C4GEM predicted the classical C4 photosynthesis pathway and its major effect in organelle function in M and BS. The model also highlights differences in metabolic activities around photosystem I and photosystem II for three different C4 subtypes. Effects of CO2 leakage were also explored. C4GEM is a viable framework for in silico analysis of cell cooperation between M and BS cells during photosynthesis and can be used to explore C4 plant metabolism.
Analysis of rainbow troutOncorhynchus mykissepidermal mucus and evaluation of semiochemical activity for polar filament discharge inMyxobolus cerebralisactinospores
Authors: Kallert D. M. , Ponader S. , Adelt S. , Kaese P. , Geyer R. , Haas W. , El‐Matbouli M.
Published: October 2010

As myxozoan actinospores are stimulated by fish epidermal mucus to attach to their hostsviaextrusion of filaments from specialized organelles, the polar capsules, mucus components were tested for discharge triggering activity onMyxobolus cerebralisactinospores. Using various methodological approaches, a selective exclusion of candidate substances based on experimental outcome is provided and the physiochemical traits of the putative agents are explored to create a basis for the isolation of the host recognition chemostimuli. Activity was detected in compounds that can be characterized as small molecular, amphiphilic to slightly hydrophobic organic substances. They were separable by chromatographic methods using reversed phase C18 supports. An active fraction was isolated by solid phase extraction comprising at least nine UV‐detectable constituents as shown by thin‐layer chromatography. By means of biochemical fractionation and analysis of host fish mucus, non‐volatile inorganic electrolytes, all volatiles, free L‐amino acids, glycoproteins, bound and free hexoses, sialic acids, glycans, proteins, urea, amines and inositols were shown not to trigger polar filament discharge. The results contribute to the identification of the attachment host cues and enable a more focused laboratory activation of myxozoan actinospores.
Age validation and growth of bluenose Hyperoglyphe antarctica using the bomb chronometer method of radiocarbon ageing
Authors: Horn P. L. , Neil H. L. , Paul L. J. , Marriott P.
Published: October 2010

Age validation of bluenose Hyperoglyphe antarctica was sought using the independent bomb chronometer procedure. Radiocarbon (14C) levels were measured in core micro‐samples from 12 otoliths that had been aged using a zone count method. The core 14C measurement for each fish was compared with the value on a surface water reference curve for the calculated birth year of the fish. There was good agreement, indicating that the line‐count ageing method described here is not substantially biased. A second micro‐sample was also taken near the edge of nine of the otolith cross‐sections to help define a bomb‐carbon curve for waters deeper than 200–300 m. There appears to be a 10 to 15 year lag in the time it takes the 14C to reach the waters where adult H. antarctica are concentrated. The maximum estimated age of this species was 76 years, and females grow significantly larger than males. Von Bertalanffy growth curves were estimated, and although they fit the available data reasonably well, the lack of aged juvenile fish results in the K and t0 parameters being biologically meaningless. Consequently, curves that are likely to better represent population growth were estimated by forcing t0 to be −0·5.
Promise and progress in environmental genomics: a status report on the applications of gene expression‐based microarray studies in ecologically relevant fish species
Authors: Hook S. E.
Published: October 2010

The advent of any new technology is typically met with great excitement. So it was a few years ago, when the combination of advances in sequencing technology and the development of microarray technology made measurements of global gene expression in ecologically relevant species possible. Many of the review papers published around that time promised that these new technologies would revolutionize environmental biology as they had revolutionized medicine and related fields. A few years have passed since these technological advancements have been made, and the use of microarray studies in non‐model fish species has been adopted in many laboratories internationally. Has the relatively widespread adoption of this technology really revolutionized the fields of environmental biology, including ecotoxicology, aquaculture and ecology, as promised? Or have these studies merely become a novelty and a potential distraction for scientists addressing environmentally relevant questions? In this review, the promises made in early review papers, in particular about the advances that the use of microarrays would enable, are summarized; these claims are compared to the results of recent studies to determine whether the forecasted changes have materialized. Some applications, as discussed in the paper, have been realized and have led to advances in their field, others are still under development.
Dual roles of a variable number of tandem repeat polymorphism in the TERT gene in lung cancer
Authors: Jin Guang , Yoo Seung Soo , Cho Sukki , Jeon Hyo‐Sung , Lee Won‐Kee , Kang Hyo‐Gyoung , Choi Yi Young , Choi Jin Eun , Cha Sung‐Ick , Lee Eung Bae , Kim Chang Ho , Jung Tae Hoon , Kim Young Tae , Park Jae Yong
Published: October 2010

This study was conducted to determine the impact of a functional tandem repeat minisatellite (MNS16A) polymorphism in the telomerase reverse transcriptase (TERT) gene on the risk of lung cancer, as well as on survival of patients with non‐small‐cell lung cancer (NSCLC). The effect of the MNS16A variable number of tandem repeat (VNTR) polymorphism on the risk of lung cancer was evaluated in a case–control study that consisted of 937 lung cancer patients and 943 healthy controls. The effect of the polymorphism on survival outcome was evaluated in 703 patients with surgically resected NSCLC. Compared with the VNTR‐302 allele, the VNTR‐243 allele was associated with a significantly increased risk of lung cancer (adjusted odds ratio, 1.55; 95% confidence interval [CI], 1.07–2.25; P = 0.02). In addition, the genotypes carrying at least one VNTR‐243 allele were associated with a significantly increased risk of lung cancer compared with the genotypes with no VNTR‐243 allele (adjusted odds ratio, 1.61; 95% CI, 1.09–2.38; P = 0.02). In contrast to the effect of the polymorphism on the risk of lung cancer, the genotypes carrying at least one VNTR‐243 allele were associated with a significantly better overall survival in patients with surgically resected NSCLC (adjusted hazard ratio, 0.51; 95% CI, 0.28–0.93; P = 0.03). These findings suggest that the MNS16A VNTR polymorphism in the TERT gene has dual, conflicting roles in lung carcinogenesis. This polymorphism may increase the risk of lung cancer development, and may improve survival in lung cancer patients. (Cancer Sci 2011; 102: 144–149)
Enhanced expression of nuclear factor I/B in oxaliplatin‐resistant human cancer cell lines
Authors: Kashiwagi Eiji , Izumi Hiroto , Yasuniwa Yoshihiro , Baba Ryoko , Doi Yoshiaki , Kidani Akihiko , Arao Tokuzo , Nishio Kazuto , Naito Seiji , Kohno Kimitoshi
Published: October 2010

Oxaliplatin is a third‐generation platinum drug that has favorable activity in cisplatin‐resistant cells. However, the molecular mechanisms underlying oxaliplatin resistance are not well understood. To investigate the molecular mechanisms involved, resistant cell lines were independently derived from colon cancer (DLD1) and bladder cancer (T24) cells. Oxaliplatin‐resistant DLD1 OX1 and DLD1 OX2 cell lines were approximately 16.3‐fold and 17.8‐fold more resistant to oxaliplatin than the parent cell lines, respectively, and had 1.7‐ and 2.2‐fold higher cross‐resistance to cisplatin, respectively. Oxaliplatin‐resistant T24 OX2 and T24 OX3 cell lines were approximately 5.0‐fold more resistant to oxaliplatin than the parent cell line and had 1.9‐fold higher cross‐resistance to cisplatin. One hundred and fifty‐eight genes commonly upregulated in both DLD1 OX1 and DLD1 OX2 were identified by microarray analysis. These genes were mainly involved in the function of transcriptional regulators (14.6%), metabolic molecules (14.6%), and transporters (9.5%). Of these, nuclear factor I/B (NFIB) was upregulated in all oxaliplatin‐resistant cells. Downregulation of NFIB rendered cells sensitive to oxaliplatin, but not to cisplatin. Forced expression of NFIB induced resistance to oxaliplatin, but not to cisplatin. Taken together, these results suggest that NFIB is a novel and specific biomarker for oxaliplatin resistance in human cancers. (Cancer Sci 2011; 102: 382–386)
Oral cavity cancer risk in relation to tobacco chewing and bidi smoking among men in Karunagappally, Kerala, India: Karunagappally cohort study
Authors: Jayalekshmi Padmavaty Amma , Gangadharan Paleth , Akiba Suminori , Koriyama Chihaya , Nair Raghu Ram K.
Published: October 2010

The Karunagapally cohort in Kerala, India was established in the 1990s. The present study examined oral cancer risk among 66 277 men aged 30–84 years in the cohort, using Poisson regression analysis of grouped data, stratified on attained age, calendar time, education, and family income. By the end of 2005, 160 oral cancer cases were identified by the Karunagapally Cancer Registry. Tobacco chewing increased oral cancer risk (P < 0.001). Particularly increased was the risk of cancers of the gum and mouth (relative risk [RR] = 4.7; 95% confidence interval [CI] = 2.8–7.9), which increased with higher daily frequencies (P < 0.001) and longer duration (P < 0.001) of tobacco chewing. Alcohol drinking was not significantly related to oral cancer risk regardless of tobacco chewing. Bidi smoking significantly increased oral cancer risk (RR = 2.6; 95%CI = 1.4–4.9) only among men without tobacco chewing habits. The risk increased with higher daily consumption (P < 0.001), longer duration (P = 0.001), and younger age at start of bidi smoking (P = 0.007). In location‐specific analysis, bidi smoking was significantly associated with cancer of the gum and mouth (RR = 3.6; 95%CI = 1.1–12.1), and its risk significantly increased with larger daily consumption of bidis (P = 0.013) and younger age at the start of smoking (P = 0.044). Tongue cancer risk was significantly increased among men who smoked bidis for 30 years or longer, and men started bidi smoking at 18 years old or younger. The present study is the first cohort study showing that tobacco chewing increases cancers of the gum and mouth among men keeping chewing tobacco in the cheek, and that bidi smoking strongly increased oral cancer risk among men without a tobacco chewing habit. (Cancer Sci 2011; 102: 460–467)
Residual neurocognitive features of long‐term ecstasy users with minimal exposure to other drugs
Authors: Halpern John H. , Sherwood Andrea R. , Hudson James I. , Gruber Staci , Kozin David , Pope Jr Harrison G.
Published: October 2010

Aims  In field studies assessing cognitive function in illicit ecstasy users, there are several frequent confounding factors that might plausibly bias the findings toward an overestimate of ecstasy‐induced neurocognitive toxicity. We designed an investigation seeking to minimize these possible sources of bias.

Design  We compared illicit ecstasy users and non‐users while (1) excluding individuals with significant life‐time exposure to other illicit drugs or alcohol; (2) requiring that all participants be members of the ‘rave’ subculture; and (3) testing all participants with breath, urine and hair samples at the time of evaluation to exclude possible surreptitious substance use. We compared groups with adjustment for age, gender, race/ethnicity, family‐of‐origin variables and childhood history of conduct disorder and attention deficit hyperactivity disorder. We provide significance levels without correction for multiple comparisons.

Setting  Field study.

Participants  Fifty‐two illicit ecstasy users and 59 non‐users, aged 18–45 years.

Measurements   Battery of 15 neuropsychological tests tapping a range of cognitive functions.

Findings  We found little evidence of decreased cognitive performance in ecstasy users, save for poorer strategic self‐regulation, possibly reflecting increased impulsivity. However, this finding might have reflected a pre‐morbid attribute of ecstasy users, rather than a residual neurotoxic effect of the drug.

Conclusions  In a study designed to minimize limitations found in many prior investigations, we failed to demonstrate marked residual cognitive effects in ecstasy users. This finding contrasts with many previous findings—including our own—and emphasizes the need for continued caution in interpreting field studies of cognitive function in illicit ecstasy users.
Randomised clinical trial: MiraLAX vs. Golytely – a controlled study of efficacy and patient tolerability in bowel preparation for colonoscopy
Authors: Enestvedt B. K. , Fennerty M. B. , Eisen G. M.
Published: October 2010

Aliment Pharmacol Ther 2011; 33: 33–40

Background  MiraLAX is gaining acceptance as a bowel cleanser for colonoscopy. We hypothesize that MiraLAX/Gatorade is as efficacious for bowel cleansing as Golytely and is more tolerable for patients undergoing screening colonoscopy.

Aim  To compare bowel preparation scores of MiraLAX/Gatorade vs. Golytely and examine differences in patient tolerability.

Methods  Patients undergoing screening colonoscopy were randomized to 4 L Golytely or 238 g MiraLAX in 64 ounces Golytely and four bisacodyl tablets. Efficacy in bowel cleansing was assessed using the Boston Bowel Preparation Scale (BPPS). Subjects completed a brief survey assessing patient tolerability.

Results  A total of 190 patients were enrolled (85 male, 105 female; mean age 56.9 years, s.d. 6.3); 87 were randomized to MiraLAX, 103 to Golytely. There was no difference in age, gender or timing of colonoscopy between the bowel preparation groups. Golytely’s median total BBPS score was significantly higher than that of MiraLAX [9 (IQR 7–9) vs. 8 (IQR 6–9), P = 0.034]. Golytely had a higher rate of an excellent equivalent BBPS score of 8 or 9 than MiraLAX (70% vs. 55%, P = 0.036). There was no difference in patient tolerability (P = 0.857).

Conclusions  Golytely was more efficacious than MiraLAX/Gatorade in bowel cleansing; both preparations were equally tolerated by patients.
A novel class of miniature inverted repeat transposable elements (MITEs) that contain hitchhiking (GTCY)n microsatellites
Authors: Coates B. S. , Kroemer J. A. , Sumerford D. V. , Hellmich R. L.
Published: October 2010

The movement of miniature inverted repeat transposable elements (MITEs) modifies genome structure and function. We describe the microsatellite‐associated interspersed nuclear element 2 (MINE‐2), that integrates at consensus WTTTT target sites, creates dinucleotide TT target site duplications (TSDs), and forms predicted MITE‐like secondary structures; a 5′ subterminal inverted repeat (SIR; AGGGTTCCGTAG) that is partially complementary to a 5′ inverted repeat (IR; ACGAAGCCCT) and 3′‐SIRs (TTACGGAACCCT). A (GTCY)n microsatellite is hitchhiking downstream of conserved 5′MINE‐2 secondary structures, causing flanking sequence similarity amongst mobile microsatellite loci. Transfection of insect cell lines indicates that MITE‐like secondary structures are sufficient to mediate genome integration, and provides insight into the transposition mechanism used by MINE‐2s.
Clinical judgement and the medical profession
Authors: Kienle Gunver S , Kiene Helmut
Published: October 2010

Objectives Clinical judgment is a central element of the medical profession, essential for the performance of the doctor, and potentially generating information also for other clinicians and for scientists and health care managers. The recently renewed interest in clinical judgement is primarily engaged with its role in communication, diagnosis and decision making. Beyond this issue, the present article highlights the interrelations between clinical judgement, therapy assessment and medical professionalism.

Methods Literature review and theory development.

Results The article presents different methodologicalapproaches to causality assessmentin clinical studies and in clinical judgement, and offers criteria for clinicalsingle case causality. The article outlines models of medical professionalism such astechnical rationalityandpractice epistemology, and characterizes features of professional expertise such astacit knowledge,reflection in action, andgestalt cognition.

Conclusions Consequences of a methodological and logistical advancement of clinical judgment are discussed, both in regard to medical progress and to the renewel of the cognitive basis of the medical profession.
Social science, behavioural medicine, and the tomato effect
Authors: Mostofsky David I.
Published: October 2010

‘Behavioural medicine’ is poised to contribute to the quality of health to the benefit of patients and physicians. There is a need for medical students and residents to better understand the field of behavioural medicine, and for practising physicians to incorporate it in medical education and clinical practice. This paper seeks to correct an erroneous conceptualization of behavioural medicine as being limited to psychosocial and mental health adjustments, and to provide examples of selected applications for medical conditions, including those that are not primarily regarded as requiring changes in lifestyle or psychotherapy. In fact, there are dramatic treatment and intervention protocols available that employ behavioural procedures that can provide relief for patients in all medical and dental specialties and that deserve to be considered along with conventional treatment protocols.
Impact of initial pattern of care on hospital costs in a cohort of incident lung cancer cases
Authors: Pagano Eva , Gregori Dario , Filippini Claudia , Di Cuonzo Daniela , Ruffini Enrico , Zanetti Roberto , Rosso Stefano , Bertetto Oscar , Merletti Franco , Ciccone Giovannino
Published: October 2010

Rationale, aims and objectives  Lung cancer is a disease with high consumption of health care resources. The aim of this study was to describe hospital costs due to lung cancer care from diagnosis until death or end of the study follow‐up, in a cohort of incident cases, by using administrative data.

Methods  Particular attention was given to the determinants of total costs and the impact of the initial treatment approach on the process of costs accumulation. Incident cases were identified by the local Cancer Registry (January 2000–December 2003) among the residents of Turin (Italy). Per patient hospital care has been determined from administrative databases (outpatient radiotherapy records and hospital discharge records). Costs determinants were identified via a multivariable generalized linear model (GLM), with a Gamma cost distribution and a logarithmic link function. To assess the time effect over the cost accumulation process for non‐small‐cell lung cancer cases, the same GLM Gamma model was repeated at different follow‐up periods. Analyses were stratified by cancer histotype.

Results  Results evidenced the relevant role of initial patterns of care on the cost accumulation process, with increased midterm costs associated with curative patterns of care.

Conclusion  The use of administrative data enabled hospital lung cancer care to be described, and related costs to be estimated.