bluuebunny/crossref_metadata_2025 huggingface dataset:
Allosteric gating mechanism underlies the flexible gating of KCNQ1 potassium channels
Authors: Osteen Jeremiah D. , Barro-Soria Rene , Robey Seth , Sampson Kevin J. , Kass Robert S. , Larsson H. Peter
Published: April 2012

KCNQ1 (Kv7.1) is a unique member of the superfamily of voltage-gated K
+
channels in that it displays a remarkable range of gating behaviors tuned by coassembly with different β subunits of the KCNE family of proteins. To better understand the basis for the biophysical diversity of KCNQ1 channels, we here investigate the basis of KCNQ1 gating in the absence of β subunits using voltage-clamp fluorometry (VCF). In our previous study, we found the kinetics and voltage dependence of voltage-sensor movements are very similar to those of the channel gate, as if multiple voltage-sensor movements are not required to precede gate opening. Here, we have tested two different hypotheses to explain KCNQ1 gating: (
i
) KCNQ1 voltage sensors undergo a single concerted movement that leads to channel opening, or (
ii
) individual voltage-sensor movements lead to channel opening before all voltage sensors have moved. Here, we find that KCNQ1 voltage sensors move relatively independently, but that the channel can conduct before all voltage sensors have activated. We explore a KCNQ1 point mutation that causes some channels to transition to the open state even in the absence of voltage-sensor movement. To interpret these results, we adopt an allosteric gating scheme wherein KCNQ1 is able to transition to the open state after zero to four voltage-sensor movements. This model allows for widely varying gating behavior, depending on the relative strength of the opening transition, and suggests how KCNQ1 could be controlled by coassembly with different KCNE family members.
General anesthesia alters time perception by phase shifting the circadian clock
Authors: Cheeseman James F. , Winnebeck Eva C. , Millar Craig D. , Kirkland Lisa S. , Sleigh James , Goodwin Mark , Pawley Matt D. M. , Bloch Guy , Lehmann Konstantin , Menzel Randolf , Warman Guy R.
Published: April 2012

Following general anesthesia, people are often confused about the time of day and experience sleep disruption and fatigue. It has been hypothesized that these symptoms may be caused by general anesthesia affecting the circadian clock. The circadian clock is fundamental to our well-being because it regulates almost all aspects of our daily biochemistry, physiology, and behavior. Here, we investigated the effects of the most common general anesthetic, isoflurane, on time perception and the circadian clock using the honeybee (
Apis mellifera)
as a model. A 6-h daytime anesthetic systematically altered the time-compensated sun compass orientation of the bees, with a mean anticlockwise shift in vanishing bearing of 87° in the Southern Hemisphere and a clockwise shift in flight direction of 58° in the Northern Hemisphere. Using the same 6-h anesthetic treatment, time-trained bees showed a delay in the start of foraging of 3.3 h, and whole-hive locomotor-activity rhythms were delayed by an average of 4.3 h. We show that these effects are all attributable to a phase delay in the core molecular clockwork. mRNA oscillations of the central clock genes
cryptochrome
-m
and
period
were delayed by 4.9 and 4.3 h, respectively. However, this effect is dependent on the time of day of administration, as is common for clock effects, and nighttime anesthesia did not shift the clock. Taken together, our results suggest that general anesthesia during the day causes a persistent and marked shift of the clock effectively inducing “jet lag” and causing impaired time perception. Managing this effect in humans is likely to help expedite postoperative recovery.
ATP-independent substrate reduction by nitrogenase P-cluster variant
Authors: Lee Chi Chung , Hu Yilin , Ribbe Markus W.
Published: April 2012

The P-cluster of nitrogenase is largely known for its function to mediate electron transfer to the active cofactor site during catalysis. Here, we show that a P-cluster variant (designated P*-cluster), which consists of paired [Fe
4
S
4
]-like clusters, can catalyze ATP-independent substrate reduction in the presence of a strong reductant, europium(II) diethylenetriaminepentaacetate [Eu(II)-DTPA]. The observation of a decrease of activity in the rank Δ
nifH
, Δ
nifB
Δ
nifZ
, and Δ
nifB
MoFe protein, which corresponds to a decrease of the amount of P*-clusters in these cofactor-deficient proteins, firmly establishes P*-cluster as a catalytically active metal center in Eu(II)-DTPA–driven reactions. More excitingly, the fact that P*-cluster is not only capable of catalyzing the two-electron reduction of proton, acetylene, ethylene, and hydrazine, but also capable of reducing cyanide, carbon monoxide, and carbon dioxide to alkanes and alkenes, points to a possibility of developing biomimetic catalysts for hydrocarbon production under ambient conditions.
Chronic restraint stress attenuates p53 function and promotes tumorigenesis
Authors: Feng Zhaohui , Liu Lianxin , Zhang Cen , Zheng Tongsen , Wang Jiabei , Lin Meihua , Zhao Yuhan , Wang Xiaowen , Levine Arnold J. , Hu Wenwei
Published: April 2012

Epidemiological studies strongly suggest that chronic psychological stress promotes tumorigenesis. However, its direct link in vivo and the underlying mechanisms that cause this remain unclear. This study provides direct evidence that chronic stress promotes tumorigenesis in vivo; chronic restraint, a well-established mouse model to induce chronic stress, greatly promotes ionizing radiation (IR)-induced tumorigenesis in
p53
+/−
mice. The tumor suppressor protein p53 plays a central role in tumor prevention. Loss or attenuation of p53 function contriubutes greatly to tumorigenesis. We found that chronic restraint decreases the levels and function of p53 in mice, and furthermore, promotes the growth of human xenograft tumors in a largely p53-dependent manner. Our results show that glucocorticoids elevated during chronic restraint mediate the effect of chronic restraint on p53 through the induction of serum- and glucocorticoid-induced protein kinase (SGK1), which in turn increases MDM2 activity and decreases p53 function. Taken together, this study demonstrates that chronic stress promotes tumorigenesis in mice, and the attenuation of p53 function is an important part of the underlying mechanism, which can be mediated by glucocortcoids elevated during chronic restraint.
Immunotoxin resistance via reversible methylation of the DPH4 promoter is a unique survival strategy
Authors: Wei Hui , Xiang Laiman , Wayne Alan S. , Chertov Oleg , FitzGerald David J. , Bera Tapan K. , Pastan Ira
Published: April 2012

HA22 is a recombinant immunotoxin composed of an anti-CD22 Fv fused to a portion of
Pseudomonas
exotoxin A. HA22 produced a high rate of complete remissions in drug-resistant hairy cell leukemia and has a lower response rate in pediatric acute lymphoblastic leukemia (ALL). To understand why patients with ALL have poorer responses, we isolated an ALL cell line that is resistant to killing by HA22. The resistance is unstable; without HA22 the cells revert to HA22 sensitivity in 4 mo. We showed that in the resistant cell line, HA22 is unable to ADP ribosylate and inactivate elongation factor-2 (EF2), owing to a low level of DPH4 mRNA and protein, which prevents diphthamide biosynthesis and renders EF2 refractory to HA22. Analysis of the promoter region of the
DPH4
gene shows that the CpG island was hypomethylated in the HA22-sensitive cells, heavily methylated in the resistant cells, and reverted to low methylation in the revertant cells. Our data show that immunotoxin resistance is associated with reversible CpG island methylation and silencing of
DPH4
gene transcription. Incubation of sensitive cells with the methylation inhibitor 5-azacytidine prevented the emergence of resistant cells, suggesting that this agent in combination with HA22 may be useful in the treatment of some cases of ALL.
Population Structure and Run Timing of Steelhead in the Skeena River, British Columbia
Authors: Beacham Terry D. , Wallace Colin G. , Le Khai D. , Beere Mark
Published: April 2012

Identification of population-specific run timing is an important component of salmonid fisheries management and was a major focus of our study. Population structure of steelhead Oncorhynchus mykiss was examined in the Skeena River of northern British Columbia. Variation at 14 microsatellites was surveyed in 3,062 steelhead sampled from 17 populations in the drainage. During 1998–2010, 6,691 individuals were sampled in a lower river test fishery to obtain information on relative abundance and time of arrival of specific populations near the river mouth. The genetic differentiation index F  ST calculated over all populations and loci was 0.021; individual locus values ranged from 0.017 to 0.045. Differentiation in steelhead allele frequencies among populations was approximately 14 times the differentiation observed among years within populations. A regional structuring of populations was the general pattern observed, with steelhead populations from the upper portion of the drainage clustering together in 87% of dendrograms evaluated and those in the lower portion of the drainage clustering together in 100% of dendrograms. The 17 populations sampled were arranged in nine reporting groups for genetic stock identification applications. The estimated stock composition of a simulated known-origin mixture was within 2% of the correct estimate for seven of the nine reporting groups present in the mixture. The stock composition of an actual known-origin sample was estimated within 2% of the correct estimate for eight of the nine reporting groups present. Application to actual samples from the test fishery indicated that upper drainage populations generally migrated through the lower river earlier than other populations, whereas lower river populations typically migrated later. Genetic mixed-stock analysis can assist managers in regulating fisheries to maintain productivity of Skeena River steelhead.

Received July 25, 2011; accepted December 15, 2011
Chikungunya virus–induced autophagy delays caspase-dependent cell death
Authors: Joubert Pierre-Emmanuel , Werneke Scott W. , de la Calle Claire , Guivel-Benhassine Florence , Giodini Alessandra , Peduto Lucie , Levine Beth , Schwartz Olivier , Lenschow Deborah J. , Albert Matthew L.
Published: April 2012

Autophagy is an important survival pathway and can participate in the host response to infection. Studying Chikungunya virus (CHIKV), the causative agent of a major epidemic in India, Southeast Asia, and southern Europe, we reveal a novel mechanism by which autophagy limits cell death and mortality after infection. We use biochemical studies and single cell multispectral assays to demonstrate that direct infection triggers both apoptosis and autophagy. CHIKV-induced autophagy is mediated by the independent induction of endoplasmic reticulum and oxidative stress pathways. These cellular responses delay apoptotic cell death by inducing the IRE1α–XBP-1 pathway in conjunction with ROS-mediated mTOR inhibition. Silencing of autophagy genes resulted in enhanced intrinsic and extrinsic apoptosis, favoring viral propagation in cultured cells. Providing in vivo evidence for the relevance of our findings, Atg16LHM mice, which display reduced levels of autophagy, exhibited increased lethality and showed a higher sensitivity to CHIKV-induced apoptosis. Based on kinetic studies and the observation that features of apoptosis and autophagy were mutually exclusive, we conclude that autophagy inhibits caspase-dependent cell death but is ultimately overwhelmed by viral replication. Our study suggests that inducers of autophagy may limit the pathogenesis of acute Chikungunya disease.
Identification of a novel post-hydrolytic state in CFTR gating
Authors: Jih Kang-Yang , Sohma Yoshiro , Li Min , Hwang Tzyh-Chang
Published: April 2012

Adenosine triphosphate (ATP)-binding cassette (ABC) transporters, ubiquitous proteins found in all kingdoms of life, catalyze substrates translocation across biological membranes using the free energy of ATP hydrolysis. Cystic fibrosis transmembrane conductance regulator (CFTR) is a unique member of this superfamily in that it functions as an ATP-gated chloride channel. Despite difference in function, recent studies suggest that the CFTR chloride channel and the exporter members of the ABC protein family may share an evolutionary origin. Although ABC exporters harness the free energy of ATP hydrolysis to fuel a transport cycle, for CFTR, ATP-induced dimerization of its nucleotide-binding domains (NBDs) and subsequent hydrolysis-triggered dimer separation are proposed to be coupled, respectively, to the opening and closing of the gate in its transmembrane domains. In this study, by using nonhydrolyzable ATP analogues, such as pyrophosphate or adenylyl-imidodiphosphate as baits, we captured a short-lived state (state X), which distinguishes itself from the previously identified long-lived C2 closed state by its fast response to these nonhydrolyzable ligands. As state X is caught during the decay phase of channel closing upon washout of the ligand ATP but before the channel sojourns to the C2 closed state, it likely emerges after the bound ATP in the catalysis-competent site has been hydrolyzed and the hydrolytic products have been released. Thus, this newly identified post-hydrolytic state may share a similar conformation of NBDs as the C2 closed state (i.e., a partially separated NBD and a vacated ATP-binding pocket). The significance of this novel state in understanding the structural basis of CFTR gating is discussed.
A new approach to foam-lined indirect-drive NIF ignition targets
Authors: Biener J. , Dawedeit C. , Kim S.H. , Braun T. , Worsley M.A. , Chernov A.A. , Walton C.C. , Willey T.M. , Kucheyev S.O. , Shin S.J. , Wang Y.M. , Biener M.M. , Lee J.R.I. , Kozioziemski B.J. , van Buuren T. , Wu K.J.J. , Satcher J.H. , Hamza A.V.
Published: April 2012

Taking full advantage of the unique laboratory environment created by the National Ignition Facility (NIF) will require the availability of foam-lined indirect-drive inertial confinement fusion targets. Here, we report on a new approach that enables fabrication of target structures that consist of a thin-walled (<30 µm) ultra-low-density (<30 mg cm−3) hydrocarbon foam film inside a thick-walled, ∼2 mm diameter ablator shell. In contrast to previous work on direct-drive targets that started with the fabrication of foam shells, we use a prefabricated ablator as a mold to cast the foam liner within the shell. This work summarizes crucial components of this new approach, including the aerogel chemistry, filling of the ablator shell with the aerogel precursor solution with nanolitre precision, creating uniform polymer gel coatings inside the ablator capsule, supercritical drying and doping.
Demonstration of sawtooth period locking with power modulation in TCV plasmas
Authors: Lauret M. , Felici F. , Witvoet G. , Goodman T.P. , Vandersteen G. , Sauter O. , de Baar M.R.
Published: April 2012

Corroborating evidence is presented that the sawtooth period can follow the modulation frequency of an externally applied high power electron cyclotron wave source. Precise, fast and robust open loop control of the sawtooth period with a continuously changing reference period has been achieved. This period locking is not associated with the crash, but with the phase evolution of the inter-crash dynamics. This opens new possibilities of open loop control for physics studies and maybe for reactor performance control.
Kinetic damping of resistive wall mode in reversed field pinch
Authors: Wang Z.R. , Guo S.C. , Liu Y.Q. , Chu M.S.
Published: April 2012

The kinetic effects of thermal particles on the resistive wall mode (RWM) are studied in reversed field pinch (RFP) by adopting the toroidal hybrid stability code MARS-K (Liu et al 2008 Phys. Plasmas
15 112503) where the drift kinetic effects are included self-consistently. It is found that the transit ion resonance can provide ion acoustic Landau damping to stabilize the RWMs in high-beta plasmas. The trapped particles do not play a significant role in kinetic stabilization. The required critical flow rotation frequency is in the ion acoustic range which is much smaller than that predicted previously by fluid theory (Guo et al 1999 Phys. Plasmas

6 3868). The most unstable mode, having its rational surface closest to the plasma, can be stabilized for the wall near the plasma (e.g. n = 6 mode in RFX-mod) with the flow rotation in a few per cent of the Alfvén frequency. For other RWMs with different toroidal wave numbers n the stabilization conditions depend on the wall position and plasma βp. An analysis based on the potential energy components is carried out for physical understanding. The preliminary study on the effects of collisionality is also presented.
Quantitative comparison of experimental impurity transport with nonlinear gyrokinetic simulation in an Alcator C-Mod L-mode plasma
Authors: Howard N.T. , Greenwald M. , Mikkelsen D.R. , Reinke M.L. , White A.E. , Ernst D. , Podpaly Y. , Candy J.
Published: April 2012

Nonlinear gyrokinetic simulations of impurity transport are compared to experimental impurity transport for the first time. The GYRO code (Candy and Waltz 2003 J. Comput. Phys.
186 545) was used to perform global, nonlinear gyrokinetic simulations of impurity transport for a standard Alcator C-Mod, L-mode discharge. The laser blow-off technique was combined with soft x-ray measurements of a single charge state of calcium to provide time-evolving profiles of this non-intrinsic, non-recycling impurity over a radial range of 0.0 ⩽ r/a ⩽ 0.6. Experimental transport coefficient profiles and their uncertainties were extracted from the measurements using the impurity transport code STRAHL and rigorous Monte Carlo error analysis. To best assess the agreement of gyrokinetic simulations with the experimental profiles, the sensitivity of the GYRO predicted impurity transport to a wide range of turbulence-relevant plasma parameters was investigated. A direct comparison of nonlinear gyrokinetic simulation and experiment is presented with an in depth discussion of error sources and a new data analysis methodology.
Long-distance correlations in TCABR biasing experiments
Authors: Kuznetsov Yu.K. , Nascimento I.C. , Silva C. , Figueiredo H. , Guimarães-Filho Z.O. , Caldas I.L. , Galvão R.M.O. , Severo J.H.F. , Toufen D.L. , Ruchko L.F. , Elfimov A.G. , Elizondo J.I. , de Sá W.P. , Usuriaga O.C. , Sanada E. , Melnikov A.V. , Gryaznevich M.P. , Peres Alonso M. , Reis A.P. , Machida M. , Trembach D.J. , Germano T.M. , Narayanan R. , Ghoranneviss M. , Arvin R. , Mohammadi S. , Tekieh S.R.S. , Borges F.O. , Bellintani V. , Canal G.P. , Duarte P. , de Castro R.M. , Vorobyov G. , Mizintseva M. , Moiseenko V.E. , do Nascimento F. , Ronchi G. , Schmutzler L.M.F.
Published: April 2012

Long-distance correlations (LDCs) of plasma potential fluctuations in the plasma edge have been investigated in the TCABR tokamak in the regime of edge biasing H-mode using an array of multi-pin Langmuir probes. This activity was carried out as part of the scientific programme of the 4th IAEA Joint Experiment (2009). The experimental data confirm the effect of amplification of LDCs in potential fluctuations during biasing recently observed in stellarators and tokamaks. For long toroidal distances between probes, the cross-spectrum is concentrated at low frequencies f < 60 kHz with peaks at f < 5 kHz, f = 13–15 kHz and f ∼ 40 kHz and low wave numbers with a maximum at k = 0. The effects of MHD activity on the LDCs in potential fluctuation are investigated.
Syzygies of compact complex hyperbolic manifolds
Authors: Hwang Jun-Muk , To Wing-Keung
Published: April 2012

We give a sufficient condition for the pluri-canonical bundles of a compact complex hyperbolic manifold to satisfy the property

(

N
p

)

(N_p)

on linear syzygies in terms of the hyperbolic injectivity radius. In the process, we obtain sharp lower bounds for the volumes of one-dimensional complex analytic subvarieties in geodesic tubular neighborhoods of the Cartesian self-product of a compact complex hyperbolic manifold.
Renal artery stenosis: an innocent bystander or an independent predictor of worse outcome in patients with chronic heart failure? A magnetic resonance imaging study
Authors: Bourantas Christos V. , Loh Huan P. , Lukaschuk Elena I. , Nicholson Antony , Mirsadraee Saeed , Alamgir Farqad M. , Tweddel Ann C. , Ettles Duncan F. , Rigby Alan S. , Nikitin Nikolay P. , Clark Andrew L. , Cleland John G.F.
Published: April 2012

Aims

To investigate the prognostic impact of atherosclerotic renovascular disease in patients with chronic heart failure.

Methods and results

Patients with heart failure due to left ventricular systolic dysfunction underwent cardiac magnetic resonance imaging and contrast‐enhanced magnetic resonance angiography. Renal artery stenosis (RAS) was defined as a luminal narrowing >50%. Of the 366 patients investigated, 112 (31%) had RAS, of whom 41 had bilateral RAS. Patients with RAS were older (P < 0.001), had higher blood pressure (P < 0.001), and worse renal function (P = 0.001). In addition, these patients had more admissions and more prolonged hospital stays because of vascular events (0.09 ± 0.26 vs. 0.02 ± 0.16 admissions/per patient/year; P < 0.001; and 1.26 ± 5.79 vs. 0.31 ± 2.54 days/per patient/year; P < 0.001, respectively) and worse prognosis (hazard ratio 1.60, 95% confidence interval 1.10–2.34, P = 0.015). However, in multivariable analysis, a history of diabetes mellitus, decreasing haemoglobin, and increasing left ventricular end‐systolic volume index, but not age and RAS, were independently related to outcome.

Conclusions

RAS is a common finding in patients suffering from heart failure. Although it is associated with an increased vascular morbidity, it is not an independent predictor of mortality.
Fermented Wheat Bran as a Functional Ingredient in Baking
Authors: Katina Kati , Juvonen Riikka , Laitila Arja , Flander Laura , Nordlund Emilia , Kariluoto Susanna , Piironen Vieno , Poutanen Kaisa
Published: April 2012

The aim of the current study was to identify factors influencing the technological functionality of fermented bran. The influences of fermentation type and type of wheat bran on the microbial community, bioactivity, arabinoxylans (AX), and activity of xylanases were studied in the bran ferments. Furthermore, technological quality of ferments was established by using them to replace wheat in baking with a 20% substitution level. Solubilization of AX and endogenous xylanase activity of bran were influenced by the type of bran, fermentation type, and conditions. Peeled bran had a clearly reduced microbial load and different microbial community in comparison to native bran. Bran from peeled kernels contained 10‐fold lower activities of endogenous xylanases in comparison to native bran. Yeast fermentation of bran from peeled kernels increased the level of folates (+40%), free phenolic acids (+500%), and soluble AX (+60%). Bread containing yeast‐fermented peeled bran had improved volume (+10–15%) and crumb softness (25–35% softer) in comparison to unfermented counterparts. Solubilization of AX during the 20 hr fermentation and decreased endogenous xylanase activity are proposed as the main reasons for the improved technological functionality of fermented bran.
Comparison of Magnetic Resonance Enterography With Endoscopy, Histopathology, and Laboratory Evaluation in Pediatric Crohn Disease
Authors: Sauer Cary G. , Middleton Jeremy P. , Alazraki Adina , Udayasankar Unni K. , Kalb Bobby , Applegate Kimberly E. , Martin Diego R. , Kugathasan Subra
Published: April 2012

Background and Objective:

Children with Crohn disease (CD) often undergo cross‐sectional imaging during clinical evaluation. Magnetic resonance enterography (MRE) is becoming the preferred radiologic assessment due to the lack of radiation exposure; however, there are few data in children with CD comparing MRE with objective disease measures. The aim of the present study was to compare MRE with endoscopy, histopathology, and laboratory evaluation in children with CD.

Methods:

We performed an institutional review board–approved query of our prospective CD MRE database, which includes data in children with CD undergoing MRE since 2008.

Results:

A total of 147 MRE studies were performed in 119 different children with symptomatic CD. Of those, 53 (39.6%) MRE studies were performed at diagnosis to evaluate small bowel disease burden. A total of 117 (79.6%) MRE studies displayed active and/or chronic disease, whereas 30 (20.4%) MRE studies were normal. When compared with normal MRE studies, active inflammation on MRE was associated with a higher mean C‐reactive protein (3.6 vs 1.1, P < 0.001), higher erythrocyte sedimentation rate (36 vs 22, P = 0.0.31), higher platelet value (439 vs 352, P = 0.033), and lower albumin (3.4 vs 3.7, P = 0.049). Comparison between MRE and endoscopy demonstrated excellent agreement when ulcers were present, and moderate agreement with histopathology.

Conclusions:

Active inflammation on MRE is associated with higher C‐reactive protein, erythrocyte sedimentation rate, platelets, and lower albumin in children with CD. MRE displays excellent agreement with endoscopic disease described by ulcers but poor agreement with mild mucosal disease described by erythema and friability. The present study adds to a growing body of evidence that MRE provides excellent assessment of inflammation and measures disease activity in CD.
Genome-wide phosphoacetylation of histone H3 at Drosophila enhancers and promoters
Authors: Kellner Wendy A. , Ramos Edward , Van Bortle Kevin , Takenaka Naomi , Corces Victor G.
Published: April 2012

Transcription regulation is mediated by enhancers that bind sequence-specific transcription factors, which in turn interact with the promoters of the genes they control. Here, we show that the JIL-1 kinase is present at both enhancers and promoters of ecdysone-induced Drosophila genes, where it phosphorylates the Ser10 and Ser28 residues of histone H3. JIL-1 is also required for CREB binding protein (CBP)-mediated acetylation of Lys27, a well-characterized mark of active enhancers. The presence of these proteins at enhancers and promoters of ecdysone-induced genes results in the establishment of the H3K9acS10ph and H3K27acS28ph marks at both regulatory sequences. These modifications are necessary for the recruitment of 14-3-3, a scaffolding protein capable of facilitating interactions between two simultaneously bound proteins. Chromatin conformation capture assays indicate that interaction between the enhancer and the promoter is dependent on the presence of JIL-1, 14-3-3, and CBP. Genome-wide analyses extend these conclusions to most Drosophila genes, showing that the presence of JIL-1, H3K9acS10ph, and H3K27acS28ph is a general feature of enhancers and promoters in this organism.
Uncovering Small RNA-Mediated Responses to Cold Stress in a Wheat Thermosensitive Genic Male-Sterile Line by Deep Sequencing
Authors: Tang Zhonghui , Zhang Liping , Xu Chenguang , Yuan Shaohua , Zhang Fengting , Zheng Yonglian , Zhao Changping
Published: April 2012

The male sterility of thermosensitive genic male sterile (TGMS) lines of wheat (Triticum aestivum) is strictly controlled by temperature. The early phase of anther development is especially susceptible to cold stress. MicroRNAs (miRNAs) play an important role in plant development and in responses to environmental stress. In this study, deep sequencing of small RNA (smRNA) libraries obtained from spike tissues of the TGMS line under cold and control conditions identified a total of 78 unique miRNA sequences from 30 families and trans-acting small interfering RNAs (tasiRNAs) derived from two TAS3 genes. To identify smRNA targets in the wheat TGMS line, we applied the degradome sequencing method, which globally and directly identifies the remnants of smRNA-directed target cleavage. We identified 26 targets of 16 miRNA families and three targets of tasiRNAs. Comparing smRNA sequencing data sets and TaqMan quantitative polymerase chain reaction results, we identified six miRNAs and one tasiRNA (tasiRNA-ARF [for Auxin-Responsive Factor]) as cold stress-responsive smRNAs in spike tissues of the TGMS line. We also determined the expression profiles of target genes that encode transcription factors in response to cold stress. Interestingly, the expression of cold stress-responsive smRNAs integrated in the auxin-signaling pathway and their target genes was largely noncorrelated. We investigated the tissue-specific expression of smRNAs using a tissue microarray approach. Our data indicated that miR167 and tasiRNA-ARF play roles in regulating the auxin-signaling pathway and possibly in the developmental response to cold stress. These data provide evidence that smRNA regulatory pathways are linked with male sterility in the TGMS line during cold stress.
Supramolecular framework incatena-poly[[(nitrato-κO)silver(I)]-μ-(R,S)-2-(pyridin-4-ylsulfinyl)pyrimidine-κ3N,O:N′]
Authors: Wan Chong-Qing , Wang Zi-Jia , Qiao Peng , Wang Zhi-Wei , Li Ai-Min
Published: April 2012

In the title complex, [Ag(NO3)(C9H7N3OS)]n, η1:η1:η1:μ2-bridging 2-(pyridin-4-ylsulfinyl)pyrimidine (pypmSO) ligands with opposite chiralities are alternately arranged to link the AgIcations through two N atoms and one sulfinyl O atom of each ligand, leading to an extended zigzag coordination chain structure along the [\overline{2}01] direction. An FT–IR spectroscopic study shows a decreased stretching frequency for the η1-O-bonded S=O group compared with that of the free ligand. The parallel chains are arranged and interconnectedviaO(S=O)...π(pyridine/pyrimidine) and C—H(pyridine)...O(NO3−) interactions to furnish a layer almost parallel to theacplane. Along thebaxis, the layers are stacked and stabilized through anion(NO3−)...π(pyrimidine) interactions to form a three-dimensional supramolecular framework. The ligand behaviour of the new diheterocyclic sulfoxide and the unconventional O(S=O)...π(pyridine/pyrimidine) and anion(NO3−)...π(pyrimidine) interactions in the supramolecular assembly of the title complex are presented.
Pigmentation above the constitutive level: An indicator of excimer laser radiation‐induced erythema in Koreans
Authors: CHOI Jee‐Woong , NA Se‐Young , CHUNG Mi‐Young , NA Jung‐Im , HUH Chang‐Hun , YOUN Sang‐Woong , KANG Hee‐Young , PARK Kyoung‐Chan
Published: April 2012

Ultraviolet (UV) irradiation induces skin erythema, but it is not clear which factors have the greatest effects on UV sensitivity. Six healthy Korean adult men were enrolled and their melanin index (MI) and increment of erythema index (ΔEI) were measured. In each individual, 12 different sites were selected and 36 spots were irradiated with a single shot of monochromatic excimer laser with a dose of 350 mJ/cm2. The sites were categorized into three groups based on the cumulative sun exposure: UZ, unexposed zones; FEZ, frequently exposed zones; and IEZ, intermittently exposed zones. The sun exposure indexes (SEI) were also calculated based on previously described methods. ΔEI, MI and SEI were measured and calculated. The ΔEI of UZ was significantly higher than that of FEZ, but lower than that of IEZ. In general, there was a significant relationship between ΔEI and MI (R2 = 0.135). However, IEZ did not show significant results. In contrast, there was a stronger relationship between ΔEI and SEI (R2 = 0.344). Overall, the values were significantly higher for the SEI (0.541 [UZ], 0.281 [IEZ] and 0.228 [FEZ]) than for MI (0.311 [UZ], 0.011 [IEZ] and 0.073 [FEZ]). There were significant site variations in UV sensitivity along with skin pigmentation. In addition, significant differences were observed according to the exposure frequency. The SEI was found to be strongly correlated with UV sensitivity. These results suggest that the induced level of pigmentation above the constitutive level will be a better indicator for UV sensitivity than baseline MI.
Unilateral bullous pemphigoid without erythema and eosinophil infiltration in a hemiplegic patient
Authors: TSURUTA Daisuke , NISHIKAWA Takeji , YAMAGAMI Jun , HASHIMOTO Takashi
Published: April 2012

In this report, we describe an 88‐year‐old male stroke patient with unilateral bullous pemphigoid limited to the hemiplegic side. Physical examinations revealed multiple tense bullae with clear and/or bloody contents without apparent erythema on the right thigh and lower leg, accompanied by erosions on the right chest. Histopathologically, no eosinophils were infiltrated into and around the subepidermal bullae. Immunofluorescence revealed deposited and circulating immunoglobulin (Ig)G anti‐basement membrane zone antibodies. Immunoblot assays using various antigen sources and enzyme‐linked immunosorbent assay revealed that IgG antibodies in this case reacted with unique epitopes between NC16a and C‐terminal domains on the 120‐kDa LAD‐1, the extracellular truncated form of BP180. Three observations were unique in our case. First, the distribution of bullae in our patient was limited to the hemiplegic side. Second, there was no apparent erythema clinically and no eosinophilic infiltration histopathologically. Third, the patient achieved remission without the use of oral corticosteroids. The unusual epitopes in this case may contribute to these phenomena.
Direct‐to‐consumer genetic testing for addiction susceptibility: a premature commercialisation of doubtful validity and value
Authors: Mathews Rebecca , Hall Wayne , Carter Adrian
Published: April 2012

Genetic research on addiction liability and pharmacogenetic research on treatments for addiction have identified some genetic variants associated with disease risk and treatment. Genetic testing for addiction liability and treatment response has not been used widely in clinical practice because most of the genes identified only modestly predict addiction risk or treatment response. However, many of these genetic tests have been commercialized prematurely and are available direct to the consumer (DTC). The easy availability of DTC tests for addiction liability and lack of regulation over their use raises a number of ethical concerns. Of paramount concern is the limited predictive power and clinical utility of these tests. Many DTC testing companies do not provide the consumer with the necessary genetic counselling to assist them in interpreting and acting on their test results. They may also engage in misleading marketing to entice consumers to purchase their products. Consumers' genetic information may be vulnerable to misuse by third parties, as there are limited standards to protect the privacy of the genetic information. Non‐consensual testing and inappropriate testing of minors may also occur. The United States Food and Drug Administration plans to regulate DTC genetic tests. Based on the ethical concerns we discuss below, we believe there is a strong case for regulation of DTC genetic tests for addiction liability and treatment response. We argue that until this occurs, these tests have more potential to cause harm than to contribute to improved prevention and treatment of addiction.
Systematic review: acute liver failure – one disease, more than 40 definitions
Authors: Wlodzimirow K. A. , Eslami S. , Abu‐Hanna A. , Nieuwoudt M. , Chamuleau R. A. F. M.
Published: April 2012

Background

Acute liver failure (ALF) is a clinical syndrome with very high mortality estimates ranging between 60% and 80%.

Aim

To investigate the explicitness and extent of variability in the used ALF definitions in the ALF prognostic literature.

Methods

All studies that pertain to the prognosis of patients with ALF were electronically searched in MEDLINE (1950–2012) and EMBASE (1950–2012). Identified titles and abstracts were independently screened by three reviewers to determine eligibility for additional review. We included English articles that reported original data from clinical trials or observational studies on ALF patients.

Results

A total of 103 studies were included. Of these studies 87 used 41 different ALF definitions and the remaining 16 studies did not report any explicit ALF definition. Four components underlying ALF definitions accounted for the differences: presence and/or grading of hepatic encephalopathy (HE); the interval between onset of disease and occurrence of HE; presence of coagulopathy and pre‐existing liver disease.

Conclusions

The diversity in acute liver failure definitions hinders comparability and quantitative analysis among studies. There is room for improvement in the reporting of acute liver failure definitions in prognostic studies. The result of this review may be useful as a starting point to create a uniform acute liver failure definition.
Undetectable HBV DNA at month 12 of entecavir treatment predicts maintained viral suppression and HBeAg‐seroconversion in chronic hepatitis B patients at 3 years
Authors: Wong G. L.‐H. , Wong V. W.‐S. , Chan H.‐Y. , Tse P. C.‐H. , Wong J. , Chim A. M.‐L. , Yiu K. K.‐L. , Chu S. H.‐T. , Chan H. L.‐Y.
Published: April 2012

Background

On‐treatment monitoring of serum hepatitis B virus (HBV) DNA to guide treatment strategy for patients on entecavir has received little attention.

Aim

To investigate the predictive value of on‐treatment HBV DNA levels for responses to entecavir.

Methods

This was a retrospective cohort study among nucleos(t)ide analogue‐naïve HBV‐infected patients on entecavir with a minimum follow‐up of 2 years. Maintained virological suppression was defined as undetectable HBV DNA (<20 IU/mL) until the last visit. Genotypic drug resistance was screened by using the INNO‐LiPA DR assay.

Results

A total of 440 chronic hepatitis B patients (160 HBeAg‐positive) followed for 34 ± 9 months were included. The cumulative probability of maintained virological suppression at year 1, 2 and 3 were 76.5%, 83.0% and 88.3% respectively. On multivariate analysis, lower baseline HBV DNA, undetectable HBV DNA at month 12 and negative HBeAg were the independent predictors of maintained virological suppression. M12 responders (who had undetectable HBV DNA at month 12) had higher probability of maintained virological suppression at 3 years (99.1%) as compared to non responders (57.5%; P < 0.001). The cumulative probability of HBeAg‐seroconversion at year 1, 2 and 3 were 19.0%, 27.2% and 33.5% respectively. M12 responders had higher probability of HBeAg‐seroconversion at 3 years (43.2%) than the non responders (19.0%; P = 0.003). M12 responders had lower probability of drug resistance at 3 years (0%) than the non responders (2.6%; P = 0.004).

Conclusion

Month 12 HBV DNA responses could predict the probability of maintained virological suppression, HBeAg‐seroconversion and risk of drug resistance among patients on entecavir treatment at 3 years.
Pre‐operative use of anti‐TNF‐α agents and the risk of post‐operative complications in patients with ulcerative colitis – a nationwide cohort study
Authors: Nørgård B. M. , Nielsen J. , Qvist N. , Gradel K. O. , de Muckadell O. B. S. , Kjeldsen J.
Published: April 2012

Background

It is still controversial whether pre‐operative anti‐tumour necrosis factor‐alpha (anti‐TNF‐α) agents increase post‐operative complications in patients with ulcerative colitis (UC).

Aim

In a nationwide Danish cohort of patients with UC, we aimed to examine the impact of pre‐operative use of anti‐TNF‐α agents on post‐operative adverse outcomes after colectomy for UC. Outcomes (within 30 and 60 days after surgery) were reoperation, anastomosis leakage, intra‐abdominal abscess, bacteremia and death.

Methods

Based on the Danish National Patient Registry we identified all UC patients, aged ≥15 years, having their first surgery for UC in the period of 1 January 2003–31 December 2010 (n = 1226). Patients were classified according to use of anti‐TNF‐α agents within 12 weeks before surgery or not. Outcome data were obtained from Danish registries. Logistic regression analyses were used to estimate adjusted risks [with 95% confidence intervals (CI)] of post‐operative outcomes among patients treated with anti‐TNF‐α agents, relative to those not treated.

Results

A total of 199 UC patients were exposed to anti‐TNF‐α agents within 12 weeks before colectomy, and 1027 were not. Among exposed, the adjusted odds ratio of reoperation and anastomosis leakage within 30 days after colectomy was 1.07 (95% CI: 0.71–1.59) and 0.52 (95% CI: 0.06–4.11) respectively. No deaths, cases of abscess drainage or bacteremia occurred among exposed within 30 days. Furthermore, no increased relative risks were found within 60 days after colectomy.

Conclusions

Based on nationwide data on UC patients having colectomies, pre‐operative use of anti‐TNF‐α agents did not increase the risk of post‐operative complications.
Miocene shelf‐edge deltas and their impact on deepwater slope progradation and morphology, Northwest Shelf of Australia
Authors: Sanchez Carla M. , Fulthorpe Craig S. , Steel Ronald J.
Published: April 2012

Late‐middle Miocene to Pliocene siliciclastics in the Northern Carnarvon Basin, Northwest Shelf of Australia, are interpreted as having been deposited by deltas. Some delta lobes deposited sediments near and at the shelf break (shelf‐edge deltas), whereas other lobes did not reach the coeval shelf break before retreating landward or being abandoned. Shelf‐margin mapview morphology changes from linear to convex‐outward in the northern part of the study area where shelf‐edge deltas were focused. Location and character of shelf‐edge deltas also had significant impact on along‐strike variability of margin progradation and shelf‐edge trajectory. Total late‐middle and late Miocene margin progradation is ca. 13 km in the south, where there were no shelf‐edge deltas, vs. ca. 34 km in the north where shelf‐edge deltas were concentrated. In the central area, the deltas were arrested and accumulated a few kilometres landward of the shelf break, resulting in an aggradational shelf‐edge trajectory, in contrast to the more progradational trajectory farther north. This illustrates a potential limitation of shelf‐edge trajectory analysis: only where shelf‐edge deltas occur, there is sufficient sediment available for the shelf‐edge trajectory to record relative sea‐level fluctuations reliably. Small‐scale (ca. 400 m wide) incisions were already conspicuous on the coeval slope even before deltas reached the shelf break. However, slope gullies immediately downdip from active shelf‐edge deltas display greater erosion of underlying strata and are wider and deeper (>1 km wide, ca. 100 m deep) than coeval incisions that are laterally offset from the deltaic depocenter (ca. 0.7 km wide, ca. 25 m deep). We interpret this change in slope‐gully dimensions as the result of greater erosion by sediment gravity flows sourced from the immediately adjacent shelf‐edge deltas. Similarly, gullies also incised further (up to 6 km) into the outer shelf in the region of active shelf‐edge deltas.
Middle Miocene–Pliocene siliciclastic influx across a carbonate shelf and influence of deltaic sedimentation on shelf construction, Northern Carnarvon Basin, Northwest Shelf of Australia
Authors: Sanchez Carla M. , Fulthorpe Craig S. , Steel Ronald J.
Published: April 2012

Middle Miocene to Pliocene siliciclastics of the Bare Formation represent a long‐lived (ca. 11 Myr) break in the otherwise carbonate‐dominated shelf of the Northern Carnarvon Basin, Northwest Shelf of Australia. The quartz‐sandstone interval is correlated with the appearance of spectacular clinoform sets mapped on 3D and dense 2D seismic data. Twenty‐seven clinoform sets are interpreted as delta lobes primarily based on their plan‐view morphology (strike‐elongate to lobate features) and their 40–100‐m‐high clinoform amplitudes. The delta lobes were deposited on outer‐shelf to shelf‐edge positions, and the older deltas show evidence of a higher degree wave reworking than the younger deltas. Measurements of the along‐strike (migration) and down‐dip (progradation) movement of these deltas are compared with relative sea‐level behaviour inferred from shelf‐edge trajectory analysis. Delta lobes exhibit greater lateral shifting during relative sea‐level rise, whereas delta lobes are more restricted to dip‐oriented fairways during sea‐level fall, although no major incised valleys have been identified. Long‐term (cumulative) progradation of this delta system and subsequent backstepping correlates with long‐term sea‐level fall and rise during the late middle and late Miocene. In addition, a long‐term northeastward migration trend for these delta lobes was likely a result of localized uplift of an inversion anticline in the Rosemary–Legendre Trend; the growth of this anticline probably steered the fluvial source for the delta system towards the northeast. The Bare Formation siliciclastic influx correlates with other middle Miocene increases in siliciclastic sediment supply worldwide. Global cooling and a shift to more arid conditions, negatively influencing vegetation cover, may have combined with more seasonally variable rainfall to generate the high sediment supply that built the deltas. Retreat of the siliciclastics could correlate with ice‐sheet growth in the Northern Hemisphere and/or increase in the Indonesian Throughflow and Leeuwin Current (ca. 1.6 Ma), which might have modified climate regionally.
How biologics targeting the IL‐1 system are being considered for the treatment of type 2 diabetes
Authors: Böni‐Schnetzler Marianne , Donath Marc Y.
Published: April 2012

Metabolic diseases are associated with activation of the innate immune system in various tissues and characterized by elevated inflammatory factors and the presence of immune cells. Type 2 diabetes develops when islet beta cells are deficient in producing sufficient insulin to overcome peripheral insulin resistance. Intra‐islet IL‐1β activity diminishes beta cell function and survival and governs islet inflammation. Targeting the IL‐1 system with the IL‐1 receptor antagonist IL1Ra improved insulin secretion, glycaemia and reduced systemic inflammation in a proof of concept study with patients with type 2 diabetes. Currently, long lasting and specific IL‐1β blocking antibodies are being evaluated in clinical trials and this may lead to a novel cytokine‐based treatment for type 2 diabetes.
Increased freshwater discharge shifts the trophic balance in the coastal zone of the northern Baltic Sea
Authors: Wikner Johan , Andersson Agneta
Published: April 2012

Increased precipitation is one projected outcome of climate change that may enhance the discharge of freshwater to the coastal zone. The resulting lower salinity, and associated discharge of both nutrients and dissolved organic carbon, may influence food web functioning. The scope of this study was to determine the net outcome of increased freshwater discharge on the balance between auto‐ and heterotrophic processes in the coastal zone. By using long‐term ecological time series data covering 13 years, we show that increased river discharge suppresses phytoplankton biomass production and shifts the carbon flow towards microbial heterotrophy. A 76% increase in freshwater discharge resulted in a 2.2 times higher ratio of bacterio‐ to phytoplankton production (Pb:Pp). The level of Pb:Pp is a function of riverine total organic carbon supply to the coastal zone. This is mainly due to the negative effect of freshwater and total organic carbon discharge on phytoplankton growth, despite a concomitant increase in discharge of nitrogen and phosphorus. With a time lag of 2 years the bacterial production recovered after an initial decline, further synergistically elevating the microbial heterotrophy. Current climate change projections suggesting increased precipitation may therefore lead to increased microbial heterotrophy, thereby decreasing the transfer efficiency of biomass to higher trophic levels. This prognosis would suggest reduced fish production and lower sedimentation rates of phytoplankton, a factor of detriment to benthic fauna. Our findings show that discharge of freshwater and total organic carbon significantly contributes to the balance of coastal processes at large spatial and temporal scales, and that model's would be greatly augmented by the inclusion of these environmental drivers as regulators of coastal productivity.