bluuebunny/crossref_metadata_2025 huggingface dataset:
2-Hydroxyoleate, a nontoxic membrane binding anticancer drug, induces glioma cell differentiation and autophagy
Authors: Terés Silvia , Lladó Victoria , Higuera Mónica , Barceló-Coblijn Gwendolyn , Martin Maria Laura , Noguera-Salvà Maria Antònia , Marcilla-Etxenike Amaia , García-Verdugo José Manuel , Soriano-Navarro Mario , Saus Carlos , Gómez-Pinedo Ulises , Busquets Xavier , Escribá Pablo V.
Published: May 2012

Despite recent advances in the development of new cancer therapies, the treatment options for glioma remain limited, and the survival rate of patients has changed little over the past three decades. Here, we show that 2-hydroxyoleic acid (2OHOA) induces differentiation and autophagy of human glioma cells. Compared to the current reference drug for this condition, temozolomide (TMZ), 2OHOA combated glioma more efficiently and, unlike TMZ, tumor relapse was not observed following 2OHOA treatment. The novel mechanism of action of 2OHOA is associated with important changes in membrane-lipid composition, primarily a recovery of sphingomyelin (SM) levels, which is markedly low in glioma cells before treatment. Parallel to membrane-lipid regulation, treatment with 2OHOA induced a dramatic translocation of Ras from the membrane to the cytoplasm, which inhibited the MAP kinase pathway, reduced activity of the PI3K/Akt pathway, and downregulated Cyclin D-CDK4/6 proteins followed by hypophosphorylation of the retinoblastoma protein (RB). These regulatory effects were associated with induction of glioma cell differentiation into mature glial cells followed by autophagic cell death. Given its high efficacy, low toxicity, ease of oral administration, and good distribution to the brain, 2OHOA constitutes a new and potentially valuable therapeutic tool for glioma patients.
Photoperiodic regulation of the seasonal pattern of photosynthetic capacity and the implications for carbon cycling
Authors: Bauerle William L. , Oren Ram , Way Danielle A. , Qian Song S. , Stoy Paul C. , Thornton Peter E. , Bowden Joseph D. , Hoffman Forrest M. , Reynolds Robert F.
Published: May 2012

Although temperature is an important driver of seasonal changes in photosynthetic physiology, photoperiod also regulates leaf activity. Climate change will extend growing seasons if temperature cues predominate, but photoperiod-controlled species will show limited responsiveness to warming. We show that photoperiod explains more seasonal variation in photosynthetic activity across 23 tree species than temperature. Although leaves remain green, photosynthetic capacity peaks just after summer solstice and declines with decreasing photoperiod, before air temperatures peak. In support of these findings, saplings grown at constant temperature but exposed to an extended photoperiod maintained high photosynthetic capacity, but photosynthetic activity declined in saplings experiencing a naturally shortening photoperiod; leaves remained equally green in both treatments. Incorporating a photoperiodic correction of photosynthetic physiology into a global-scale terrestrial carbon-cycle model significantly improves predictions of seasonal atmospheric CO2cycling, demonstrating the benefit of such a function in coupled climate system models. Accounting for photoperiod-induced seasonality in photosynthetic parameters reduces modeled global gross primary production 2.5% (∼4 PgC y−1), resulting in a >3% (∼2 PgC y−1) decrease of net primary production. Such a correction is also needed in models estimating current carbon uptake based on remotely sensed greenness. Photoperiod-associated declines in photosynthetic capacity could limit autumn carbon gain in forests, even if warming delays leaf senescence.
Allosteric pathways in imidazole glycerol phosphate synthase
Authors: Rivalta Ivan , Sultan Mohammad M. , Lee Ning-Shiuan , Manley Gregory A. , Loria J. Patrick , Batista Victor S.
Published: May 2012

Protein allosteric pathways are investigated in the imidazole glycerol phosphate synthase heterodimer in an effort to elucidate how the effector (PRFAR, N′-[(5′-phosphoribulosyl)formimino]-5-aminoimidazole-4-carboxamide ribonucleotide) activates glutaminase catalysis at a distance of 25 Å from the glutamine-binding site. We apply solution NMR techniques and community analysis of dynamical networks, based on mutual information of correlated protein motions in the active and inactive enzymes. We find evidence that the allosteric pathways in the PRFAR bound enzyme involve conserved residues that correlate motion of the PRFAR binding loop to motion at the protein-protein interface, and ultimately at the glutaminase active site. The imidazole glycerol phosphate synthase bienzyme is an important branch point for the histidine and nucleotide biosynthetic pathways and represents a potential therapeutic target against microbes. The proposed allosteric mechanism and the underlying allosteric pathways provide fundamental insights for the design of new allosteric drugs and/or alternative herbicides.
Quorum-sensing
agr
mediates bacterial oxidation response via an intramolecular disulfide redox switch in the response regulator AgrA
Authors: Sun Fei , Liang Haihua , Kong Xiangqian , Xie Sherrie , Cho Hoonsik , Deng Xin , Ji Quanjiang , Zhang Haiyan , Alvarez Sophie , Hicks Leslie M. , Bae Taeok , Luo Cheng , Jiang Hualiang , He Chuan
Published: May 2012

Oxidation sensing and quorum sensing significantly affect bacterial physiology and host–pathogen interactions. However, little attention has been paid to the cross-talk between these two seemingly orthogonal signaling pathways. Here we show that the quorum-sensing
agr
system has a built-in oxidation-sensing mechanism through an intramolecular disulfide switch possessed by the DNA-binding domain of the response regulator AgrA. Biochemical and mass spectrometric analysis revealed that oxidation induces the intracellular disulfide bond formation between Cys-199 and Cys-228, thus leading to dissociation of AgrA from DNA. Molecular dynamics (MD) simulations suggest that the disulfide bond formation generates a steric clash responsible for the abolished DNA binding of the oxidized AgrA. Mutagenesis studies further established that Cys-199 is crucial for oxidation sensing. The oxidation-sensing role of Cys-199 is further supported by the observation that the mutant
Staphylococcus aureus
strain expressing AgrAC199S is more susceptible to H
2
O
2
owing to repression of the antioxidant
bsaA
gene under oxidative stress. Together, our results show that oxidation sensing is a component of the quorum-sensing
agr
signaling system, which serves as an intrinsic checkpoint to ameliorate the oxidation burden caused by intense metabolic activity and potential host immune response.
Dermatophytic defensin with antiinfective potential
Authors: Zhu Shunyi , Gao Bin , Harvey Peta J. , Craik David J.
Published: May 2012

Fungi are a newly emerging source of peptide antibiotics with therapeutic potential. Here, we report 17 new fungal defensin-like peptide (fDLP) genes and the detailed characterization of a corresponding synthetic fDLP (micasin) from a dermatophyte in terms of its structure, activity and therapeutic potential. NMR analysis showed that synthetic micasin adopts a “hallmark” cysteine-stablized α-helical and β-sheet fold. It was active on both Gram-positive and Gram-negtive bacteria, and importantly it killed two clinical isolates of methicillin-resistant
Staphylococcus aureus
and the opportunistic pathogen
Pseudomonas aeruginosa
at low micromolar concentrations. Micasin killed approximately 100% of treated bacteria within 3 h through a membrane nondisruptive mechanism of action, and showed extremely low hemolysis and high serum stability. Consistent with these functional properties, micasin increases survival in mice infected by the pathogenic bacteria in a peritonitis model. Our work represents a valuable approach to explore novel peptide antibiotics from a large resource of fungal genomes.
Yno1p/Aim14p, a NADPH-oxidase ortholog, controls extramitochondrial reactive oxygen species generation, apoptosis, and actin cable formation in yeast
Authors: Rinnerthaler Mark , Büttner Sabrina , Laun Peter , Heeren Gino , Felder Thomas K. , Klinger Harald , Weinberger Martin , Stolze Klaus , Grousl Tomas , Hasek Jiri , Benada Oldrich , Frydlova Ivana , Klocker Andrea , Simon-Nobbe Birgit , Jansko Bettina , Breitenbach-Koller Hannelore , Eisenberg Tobias , Gourlay Campbell W. , Madeo Frank , Burhans William C. , Breitenbach Michael
Published: May 2012

The large protein superfamily of NADPH oxidases (NOX enzymes) is found in members of all eukaryotic kingdoms: animals, plants, fungi, and protists. The physiological functions of these NOX enzymes range from defense to specialized oxidative biosynthesis and to signaling. In filamentous fungi, NOX enzymes are involved in signaling cell differentiation, in particular in the formation of fruiting bodies. On the basis of bioinformatics analysis, until now it was believed that the genomes of unicellular fungi like
Saccharomyces cerevisiae
and
Schizosaccharomyces pombe
do not harbor genes coding for NOX enzymes. Nevertheless, the genome of
S. cerevisiae
contains nine ORFs showing sequence similarity to the catalytic subunits of mammalian NOX enzymes, only some of which have been functionally assigned as ferric reductases involved in iron ion transport. Here we show that one of the nine ORFs (YGL160W, AIM14) encodes a genuine NADPH oxidase, which is located in the endoplasmic reticulum (ER) and produces superoxide in a NADPH-dependent fashion. We renamed this ORF
YNO1
(yeast NADPH oxidase 1). Overexpression of
YNO1
causes YCA1-dependent apoptosis, whereas deletion of the gene makes cells less sensitive to apoptotic stimuli. Several independent lines of evidence point to regulation of the actin cytoskeleton by reactive oxygen species (ROS) produced by Yno1p.
Higher-order motion sensitivity in fly visual circuits
Authors: Lee Yu-Jen , Nordström Karin
Published: May 2012

In higher-order motion stimuli, the direction of object motion does not follow the direction of luminance change. Such stimuli could be generated by the wing movements of a flying butterfly and further complicated by its motion in and out of shadows. Human subjects readily perceive the direction of higher-order motion, although this stands in stark contrast to prevailing motion vision models. Flies and humans compute motion in similar ways, and because flies behaviorally track bars containing higher-order motion cues, they become an attractive model system for investigating the neurophysiology underlying higher-order motion sensitivity. We here use intracellular electrophysiology of motion-vision–sensitive neurons in the hoverfly lobula plate to quantify responses to stimuli containing higher-order motion. We show that motion sensitivity can be broken down into two separate streams, directionally coding for elementary motion and figure motion, respectively, and that responses to Fourier and theta motion can be predicted from these. The sensitivity is affected both by the stimulus’ time course and by the neuron’s underlying receptive field. Responses to preferred-direction theta motion are sexually dimorphic and particularly robust along the visual midline.
Macaque studies of vaccine and microbicide combinations for preventing HIV-1 sexual transmission
Authors: Barouch Dan H. , Klasse Per Johan , Dufour Jason , Veazey Ronald S. , Moore John P.
Published: May 2012

Vaccination and the application of a vaginal microbicide have traditionally been considered independent methods to prevent the sexual transmission of HIV-1 to women. Both techniques can be effective in macaque models, and limited efficacy has been observed in clinical trials for each. Here, we have addressed whether vaccines and microbicides can be used together to provide reinforced protection against virus challenge of rhesus macaques. In two separate experiments, four groups of animals were vaccinated with a T-cell–based adenovirus (Ad) vectored vaccine aimed at reducing postinfection viral loads and/or a partially effective dose of a vaginal microbicide aimed at blocking infection of a high-dose vaginal challenge with SIVmac251 or SHIV-162P3. In the first study, the only two protected animals were in the group that received Ad26/Ad5HVR48 vaccine vectors combined with the fusion inhibitor T-1249 as the vaginal microbicide before SIVmac251 challenge. In the second study, vaccination with Ad35/Ad26 vectors combined with the CCR5 inhibitor maraviroc as the vaginal microbicide led to significant reductions of both acquisition of infection and postinfection viral loads following SHIV-SF162P3 challenge. As expected, the vaccine by itself reduced viral loads but had no acquisition effect, whereas the microbicide had a partial acquisition effect but minimal impact on viral loads. For both measures of protective efficacy, the vaccine–microbicide combination differed more from controls than did either separate intervention. Overall, the data suggest that vaccines and microbicides are complementary techniques that may protect better when used together than separately.
Peptidomics approach to elucidate the proteolytic regulation of bioactive peptides
Authors: Kim Yun-Gon , Lone Anna Mari , Nolte Whitney M. , Saghatelian Alan
Published: May 2012

Peptide hormones and neuropeptides have important roles in physiology and therefore the regulation of these bioactive peptides is of great interest. In some cases proteolysis controls the concentrations and signaling of bioactive peptides, and the peptidases that mediate this biochemistry have proven to be extremely successful drug targets. Due to the lack of any general method to identify these peptidases, however, the role of proteolysis in the regulation of most neuropeptides and peptide hormones is unknown. This limitation prompted us to develop an advanced peptidomics-based strategy to identify the peptidases responsible for the proteolysis of significant bioactive peptides. The application of this approach to calcitonin gene-related peptide (CGRP), a neuropeptide associated with blood pressure and migraine, revealed the endogenous CGRP cleavage sites. This information was then used to biochemically purify the peptidase capable of proteolysis of CGRP at those cleavage sites, which led to the identification of insulin-degrading enzyme (IDE) as a candidate CGRP-degrading enzyme. CGRP had not been identified as an IDE substrate before and we tested the physiological relevance of this interaction by quantitative measurements of CGRP using IDE null (IDE
−/−
) mice. In the absence of IDE, full-length CGRP levels are elevated in vivo, confirming IDE as an endogenous CGRP-degrading enzyme. By linking CGRP and IDE, this strategy uncovers a previously unknown pathway for CGRP regulation and characterizes an additional role for IDE. More generally, this work suggests that this may be an effective general strategy for characterizing these pathways and peptidases moving forward.
China’s life satisfaction, 1990–2010
Authors: Easterlin Richard A. , Morgan Robson , Switek Malgorzata , Wang Fei
Published: May 2012

Despite its unprecedented growth in output per capita in the last two decades, China has essentially followed the life satisfaction trajectory of the central and eastern European transition countries—a U-shaped swing and a nil or declining trend. There is no evidence of an increase in life satisfaction of the magnitude that might have been expected to result from the fourfold improvement in the level of per capita consumption that has occurred. As in the European countries, in China the trend and U-shaped pattern appear to be related to a pronounced rise in unemployment followed by a mild decline, and an accompanying dissolution of the social safety net along with growing income inequality. The burden of worsening life satisfaction in China has fallen chiefly on the lowest socioeconomic groups. An initially highly egalitarian distribution of life satisfaction has been replaced by an increasingly unequal one, with decreasing life satisfaction in persons in the bottom third of the income distribution and increasing life satisfaction in those in the top third.
Glutathione/thioredoxin systems modulate mitochondrial H2O2 emission: An experimental-computational study
Authors: Aon Miguel Antonio , Stanley Brian Alan , Sivakumaran Vidhya , Kembro Jackelyn Melissa , O'Rourke Brian , Paolocci Nazareno , Cortassa Sonia
Published: May 2012

The net emission of hydrogen peroxide (H2O2) from mitochondria results from the balance between reactive oxygen species (ROS) continuously generated in the respiratory chain and ROS scavenging. The relative contribution of the two major antioxidant systems in the mitochondrial matrix, glutathione (GSH) and thioredoxin (Trx), has not been assessed. In this paper, we examine this key question via combined experimental and theoretical approaches, using isolated heart mitochondria from mouse, rat, and guinea pig.

As compared with untreated control mitochondria, selective inhibition of Trx reductase with auranofin along with depletion of GSH with 2,4-dinitrochlorobenzene led to a species-dependent increase in H2O2 emission flux of 17, 11, and 6 fold in state 4 and 15, 7, and 8 fold in state 3 for mouse, rat, and guinea pig mitochondria, respectively. The maximal H2O2 emission as a percentage of the total O2 consumption flux was 11%/2.3% for mouse in states 4 and 3 followed by 2%/0.25% and 0.74%/0.29% in the rat and guinea pig, respectively.

A minimal computational model accounting for the kinetics of GSH/Trx systems was developed and was able to simulate increase in H2O2 emission fluxes when both scavenging systems were inhibited separately or together. Model simulations suggest that GSH/Trx systems act in concert. When the scavenging capacity of either one of them saturates during H2O2 overload, they relieve each other until complete saturation, when maximal ROS emission occurs.

Quantitatively, these results converge on the idea that GSH/Trx scavenging systems in mitochondria are both essential for keeping minimal levels of H2O2 emission, especially during state 3 respiration, when the energetic output is maximal. This suggests that the very low levels of H2O2 emission observed during forward electron transport in the respiratory chain are a result of the well-orchestrated actions of the two antioxidant systems working continuously to offset ROS production.
Abiotic drivers of coastal fish community change during four decades in the Baltic Sea
Authors: Olsson Jens , Bergström Lena , Gårdmark Anna
Published: May 2012

Olsson, J., Bergström, L., and Gårdmark, A. 2012. Abiotic drivers of coastal fish community change during four decades in the Baltic Sea – ICES Journal of Marine Science, 69: 961–970. Evidence for long-term change of marine ecosystems is increasing worldwide. Coastal areas harbour the socio-economically and ecologically most vital aquatic ecosystems, but are under increasing anthropogenic pressure. Little is known, however, about how environmental perturbations affect the development of coastal systems. In this paper, datasets of coastal fish communities covering almost four decades (early/mid 1970s to 2008) in three different basins of the Baltic Sea were analysed. There were clear changes in species composition over time in all but one dataset and coherence among basins in the timing of change. Changes were mainly associated with variables related to climate (water temperature, salinity, and North Atlantic Oscillation index), but less so with those reflecting nutrient status (nutrient concentrations and loading). Despite the importance of local water temperature, regional climatic variables were more important for the temporal development of communities. The results indicate that Baltic coastal fish communities have undergone large structural changes governed by processes acting on both local and regional scales. The findings suggest that ecological targets should be set accounting for long-term changes in community structure and that a common management of coastal and offshore ecosystems would be beneficial.
Transient Receptor Potential Ankyrin 1 Ion Channel Contributes to Guarding Pain and Mechanical Hypersensitivity in a Rat Model of Postoperative Pain
Authors: Wei Hong , Karimaa Mari , Korjamo Timo , Koivisto Ari , Pertovaara Antti
Published: May 2012

Background

The transient receptor potential ankyrin 1 (TRPA1) ion channel is expressed on nociceptive primary afferent nerve fibers. On the distal ending, it is involved in transduction of noxious stimuli, and on the proximal ending (within the spinal dorsal horn), it regulates transmission of nociceptive signals. Here we studied whether the cutaneous or spinal TRPA1 ion channel contributes to mechanical hypersensitivity or guarding, an index of spontaneous pain, in an experimental model of postoperative pain in the rat.

Methods

A skin plus deep-tissue incision was performed under general anesthesia in the plantar skin of one hind paw, after which the incised skin was closed with sutures. Postoperative pain and hypersensitivity were assessed 24-48 h after the operation. Guarding pain was assessed by scoring the hind-paw position. Mechanical hypersensitivity was assessed with a calibrated series of monofilaments applied to the wound area in the operated paw or the contralateral control paw. Chembridge-5861528, a TRPA1 channel antagonist, was administered intaperitoneally (10-30 mg/kg), intraplantarly (10-30 μg), or intrathecally (10 μg) in attempts to suppress guarding and hypersensitivity.

Results

Intraperitoneal or ipsi- but not contralateral intraplantar treatment with Chembridge-5861528 reduced mechanical hypersensitivity and guarding in the operated limb. Intrathecal treatment attenuated hypersensitivity but not guarding. Intraplantar Chembridge-5861528 suppressed preferentially mechanical hyperalgesia and intrathecal Chembridge-5861528 tactile allodynia.

Conclusions

The TRPA1 channel in the skin contributes to sustained as well noxious mechanical stimulus-evoked postoperative pain, whereas the spinal TRPA1 channel contributes predominantly to innocuous mechanical stimulus-evoked postoperative pain.
Orchestrating transcriptional control of adult neurogenesis
Authors: Hsieh Jenny
Published: May 2012

Stem cells have captured our imagination and generated hope, representing a source of replacement cells to treat a host of medical conditions. Tucked away in specialized niches, stem cells maintain tissue function and rejuvenate organs. Balancing the equation between cellular supply and demand is especially important in the adult brain, as neural stem cells (NSCs) in two discrete regions, the subgranular zone (SGZ) of the dentate gyrus and the subventricular zone (SVZ) next to the lateral ventricles, continuously self-renew and differentiate into neurons in a process called adult neurogenesis. Through the interplay of intrinsic and extrinsic factors, adult neurogenic niches ensure neuronal turnover throughout life, contributing to plasticity and homeostatic processes in the brain. This review summarizes recent progress on the molecular control of adult neurogenesis in the SGZ and SVZ, focusing on the role of specific transcription factors that mediate the progression from NSCs to lineage-committed progenitors and, ultimately, the generation of mature neurons and glia.
Suprainduction of p53 by disruption of 40S and 60S ribosome biogenesis leads to the activation of a novel G2/M checkpoint
Authors: Fumagalli Stefano , Ivanenkov Vasily V. , Teng Teng , Thomas George
Published: May 2012

Impairment of ribosome biogenesis leads to p53 induction and cell cycle arrest, a checkpoint involved in human disease. Induction of p53 is attributed to the binding and inhibition of human double minute 2 (Hdm2) by a subset of ribosomal proteins (RPs): RPS7, RPL5, RPL11, and RPL23. However, we found that only RPL11 or RPL5, in a mutually dependent manner, elicit this response. We show that depletion of RPS7 or RPL23, like depletion of other RPs, except for RPL11 and RPL5, induces a p53 response and that the effects of RPS7 and RPL23 on p53 induction reported earlier may be ascribed to inhibition of global translation. Moreover, we made the surprising observation that codepletion of two essential RPs, one from each subunit, but not the same subunit, leads to suprainduction of p53. This led to the discovery that the previously proposed RPL11-dependent mechanism of p53 induction, thought to be caused by abrogation of 40S biogenesis and continued 60S biogenesis, is still operating, despite abrogation of 60S biogenesis. This response leads to both a G1 block and a novel G2/M block not observed when disrupting either subunit alone. Thus, induction of p53 is mediated by distinct mechanisms, with the data pointing to an essential role for ribosomal subunits beyond translation.
Widespread recognition of 5′ splice sites by noncanonical base-pairing to U1 snRNA involving bulged nucleotides
Authors: Roca Xavier , Akerman Martin , Gaus Hans , Berdeja Andrés , Bennett C. Frank , Krainer Adrian R.
Published: May 2012

An established paradigm in pre-mRNA splicing is the recognition of the 5′ splice site (5′ss) by canonical base-pairing to the 5′ end of U1 small nuclear RNA (snRNA). We recently reported that a small subset of 5′ss base-pair to U1 in an alternate register that is shifted by 1 nucleotide. Using genetic suppression experiments in human cells, we now demonstrate that many other 5′ss are recognized via noncanonical base-pairing registers involving bulged nucleotides on either the 5′ss or U1 RNA strand, which we term “bulge registers.” By combining experimental evidence with transcriptome-wide free-energy calculations of 5′ss/U1 base-pairing, we estimate that 10,248 5′ss (∼5% of human 5′ss) in 6577 genes use bulge registers. Several of these 5′ss occur in genes with mutations causing genetic diseases and are often associated with alternative splicing. These results call for a redefinition of an essential element for gene expression that incorporates these registers, with important implications for the molecular classification of splicing mutations and for alternative splicing.
Copy number variation detection and genotyping from exome sequence data
Authors: Krumm Niklas , Sudmant Peter H. , Ko Arthur , O'Roak Brian J. , Malig Maika , Coe Bradley P. ,   NHLBI Exome Sequencing Project, Quinlan Aaron R. , Nickerson Deborah A. , Eichler Evan E.
Published: May 2012

While exome sequencing is readily amenable to single-nucleotide variant discovery, the sparse and nonuniform nature of the exome capture reaction has hindered exome-based detection and characterization of genic copy number variation. We developed a novel method using singular value decomposition (SVD) normalization to discover rare genic copy number variants (CNVs) as well as genotype copy number polymorphic (CNP) loci with high sensitivity and specificity from exome sequencing data. We estimate the precision of our algorithm using 122 trios (366 exomes) and show that this method can be used to reliably predict (94% overall precision) both de novo and inherited rare CNVs involving three or more consecutive exons. We demonstrate that exome-based genotyping of CNPs strongly correlates with whole-genome data (median r2 = 0.91), especially for loci with fewer than eight copies, and can estimate the absolute copy number of multi-allelic genes with high accuracy (78% call level). The resulting user-friendly computational pipeline, CoNIFER (copy number inference from exome reads), can reliably be used to discover disruptive genic CNVs missed by standard approaches and should have broad application in human genetic studies of disease.
TheSmall Angle Scattering ToolBox(SASTBX): an open-source software for biomolecular small-angle scattering
Authors: Liu Haiguang , Hexemer Alexander , Zwart Peter H.
Published: May 2012

Small-angle X-ray and neutron scattering experiments are broadly applied to study biomolecular structure and dynamics. This article presents theSmall Angle Scattering ToolBox(SASTBX), which provides a wide-ranging functionality for the analysis of biological small-angle scattering data, from data reduction to model reconstruction and refinement. TheSASTBXis an open-source package, which is freely available at http://sastbx.als.lbl.gov.
Lanthanum tetrazinc, LaZn4
Authors: Oshchapovsky Igor , Pavlyuk Volodymyr , Dmytriv Grygoriy , Griffin Alexandra
Published: May 2012

The structure of lanthanum tetrazinc, LaZn4, has been determined from single-crystal X-ray diffraction data for the first time, approximately 70 years after its discovery. The compound exhibits a new structure type in the space groupCmcm, with one La atom and two Zn atoms occupying sites withm2msymmetry, and one Zn atom occupying a site with 2.. symmetry. The structure is closely related to the BaAl4, La3Al11, BaNi2Si2and CaCu5structure types, which can be presented as close-packed arrangements of 18-vertex clusters, in this case LaZn18. The kindred structure types contain related 18-vertex clusters around atoms of the rare earth or alkaline earth metal.
Two androsterone derivatives as inhibitors of androgen biosynthesis
Authors: Djigoue Guy-Bertrand , Simard Michel , Kenmogne Lucie-Carolle , Poirier Donald
Published: May 2012

The title compounds, (3R,5S,5′R,8R,9S,10S,13S,14S)-10,13-dimethyl-5′-(2-methylpropyl)tetradecahydro-6′H-spiro[cyclopenta[a]phenanthrene-3,2′-[1,4]oxazinane]-6′,17(2H)-dione, C26H41NO3, (I), and methyl (2R)-2-[(3R,5S,8R,9S,10S,13S,14S)-10,13-dimethyl-2′,17-dioxohexadecahydro-3′H-spiro[cyclopenta[a]phenanthrene-3,5′-[1,3]oxazolidin-3′-yl]]-4-methylpentanoate, C28H43NO5, (II), possess the typical steroid shape (A–Drings), but they differ in their extraEring. The azalactoneEring in (I) shows a half-chair conformation, while the carbamateEring of (II) is planar. The orientation of theE-ring substituent is clearly established and allows a rationalization of the biological results obtained with such androsterone derivatives.
3-(2-Methyl-2-nitropropyl)-1H-indole
Authors: Fang Zheng , Zhang Feng , Zou Bao-hua , Guo Kai
Published: May 2012

In the title compound, C12H14N2O2, the indole ring is essentially planar, with an r.m.s. deviation of 0.0136 Å. In the crystal, pairs of N—H...O hydrogen bonds link the molecules into inversion dimers..
2-Aminoethanaminium iodide
Authors: Kennedy Alan R. , Okoth Maurice O.
Published: May 2012

The title salt, [NH3CH2CH2NH2]+·I−, has an array structure based on strong intermolecular N—H...N hydrogen bonding formed between the ammonium and amine groups of adjacent cations. This interaction gives a helical chain of cations that runs parallel to the b axis. The four remaining NH group H atoms all form hydrogen bonds to the iodide anion, and these iodide anions lie in channels parallel to the cation–cation chains.
2,4-Dioxa-λ6-thiatetracyclo[5.3.1.15,9.01,5]dodecane-3,3-dione
Authors: Ioannou Savvas , Moushi Eleni
Published: May 2012

The crystal structure of the title compound, C9H12O4S, was determined in order to investigate the effect of the eclipsed O atoms on the bond length of the vicinal quaternary C atoms. The two quaternary C atoms of the noradamantane skeleton and the two O atoms to which they are connected all located essentially in the same plane (maximum deviation = 0.01 Å), resulting in an eclipsed conformation of the C—O bonds. The C—C bond of the quaternary C atoms is 1.581 (3) Å, considerably longer than the other C—C bonds of the molecule due to the stretch of the cage structure.
catena-Poly[cadmium-μ-[1,3-bis(imidazol-1-yl)propane]-di-μ-chlorido]
Authors: Shen Qiao-Lian , Lin Hong
Published: May 2012

The title complex, [CdCl2(C9H12N4)]
n
, is characterized by the formation of a zigzag chain structure parallel to [001]. In the chain, the Cd2+ cation is coordinated by four bridging Cl− ligands in equatorial positions and two N atoms from symmetry-related and likewise bridging 1,3-bis(imidazol-1-yl)propane ligands in axial positions, forming a distorted CdCl4N2 octahedron.
Bis(3-methylanilinium) naphthalene-1,5-disulfonate
Authors: Liu Ming-Liang , Chen Zi-Qi
Published: May 2012

In the crystal of the title molecular salt, 2C7H10N+·C10H6O6S2
2−, the naphthalene-1,5-disulfonate anion is located on an inversion center and accepts N—H...O hydrogen bonds from the 3-methylanilinium cations, forming supramolecular layers parallel to the ac plane.
2-Bromo-2-methyl-1-[4-(methylsulfanyl)phenyl]propan-1-one
Authors: Liu Fei , Ren Shi-Ying , Yang Wei-Ji
Published: May 2012

In the title compound, C11H13BrOS, the thioether unit and the phenyl ring adopt an essentially planar conformation, with a maximum deviation of 0.063 Å. In the crystal, molecules are linked by C—H...O hydrogen bonds, extending in zigzag chains along the b axis. A weak intramolecular C—H...Br hydrogen bond is also observed, which forms an S(6) ring motif.
Lipopolysaccharide biosynthesis genes discriminate between Rubus‐ and Spiraeoideae‐infective genotypes of Erwinia amylovora
Authors: REZZONICO FABIO , BRAUN‐KIEWNICK ANDREA , MANN RACHEL A. , RODONI BRENDAN , GOESMANN ALEXANDER , DUFFY BRION , SMITS THEO H. M.
Published: May 2012

Comparative genomic analysis revealed differences in the lipopolysaccharide (LPS) biosynthesis gene cluster between the Rubus‐infecting strain ATCC BAA‐2158 and the Spiraeoideae‐infecting strain CFBP 1430 of Erwinia amylovora. These differences corroborate rpoB‐based phylogenetic clustering of E. amylovora into four different groups and enable the discrimination of Spiraeoideae‐ and Rubus‐infecting strains. The structure of the differences between the two groups supports the hypothesis that adaptation to Rubus spp. took place after species separation of E. amylovora and E. pyrifoliae that contrasts with a recently proposed scenario, based on CRISPR data, in which the shift to domesticated apple would have caused an evolutionary bottleneck in the Spiraeoideae‐infecting strains of E. amylovora which would be a much earlier event. In the core region of the LPS biosynthetic gene cluster, Spiraeoideae‐infecting strains encode three glycosyltransferases and an LPS ligase (Spiraeoideae‐type waaL), whereas Rubus‐infecting strains encode two glycosyltransferases and a different LPS ligase (Rubus‐type waaL). These coding domains share little to no homology at the amino acid level between Rubus‐ and Spiraeoideae‐infecting strains, and this genotypic difference was confirmed by polymerase chain reaction analysis of the associated DNA region in 31 Rubus‐ and Spiraeoideae‐infecting strains. The LPS biosynthesis gene cluster may thus be used as a molecular marker to distinguish between Rubus‐ and Spiraeoideae‐infecting strains of E. amylovora using primers designed in this study.
Macrophages and mesenchymal stromal cells support survival and proliferation of multiple myeloma cells
Authors: Kim Jaehyup , Denu Ryan A. , Dollar Bridget A. , Escalante Leah E. , Kuether Justin P. , Callander Natalie S. , Asimakopoulos Fotis , Hematti Peiman
Published: May 2012

Multiple myeloma (MM) is characterized by almost exclusive tropism of malignant cells for the bone marrow (BM) milieu. The survival and proliferation of malignant plasma cells have been shown to rely on interactions with nonmalignant stromal cells, in particular mesenchymal stromal cells (MSCs), in the BM microenvironment. However, the BM microenvironment is composed of a diverse array of cell types. This study examined the role of macrophages, an abundant component of BM stroma, as a potential niche component that supports malignant plasma cells. We investigated the proliferation of MM tumour cell lines when cultured alone or together with MSCs, macrophages, or a combination of MSCs and macrophages, using the carboxyfluorescein succinimidyl ester assay. Consistently, we observed increased proliferation of MM cell lines in the presence of either MSCs or macrophages compared to cell line‐only control. Furthermore, the combined co‐culture of MSCs plus macrophages induced the greatest degree of proliferation of myeloma cells. In addition to increased proliferation, MSCs and macrophages decreased the rate of apoptosis of myeloma cells. Our in vitro studies provide evidence that highlights the role of macrophages as a key component of the BM microenvironment facilitating the growth of malignant plasma cells in MM.
Can we predict nutrient limitation in streams and rivers?
Authors: KECK FRANÇOIS , LEPORI FABIO
Published: May 2012

1. Anthropogenic impacts on the biogeochemical cycles of nitrogen (N) and phosphorus (P) affect natural ecosystems worldwide. Modelling is required to predict where and when these key nutrients limit primary production in freshwaters.

2. We reviewed 382 nutrient‐enrichment experiments to examine which factors promote limitation of microphytobenthos biomass by N or P in streams and rivers. Using regression models, we examined whether the response of microphytobenthos biomass to N and P additions could be predicted by the absolute N and P concentrations in the water, the water N:P ratio or a combination of the two.

3. The absolute N concentration in the water was the best predictor of the magnitude of the response of microphytobenthos biomass to N additions. In comparison, the N:P ratio was the best predictor of whether or not N was limiting. However, predictions were uncertain except at extreme N:P ratios <1 : 1 and >100 : 1.

4. The absolute P concentration in the water was the best predictor of the magnitude of the response of microphytobenthos biomass to P additions. Neither the absolute nor the relative N and P concentrations predicted whether or not P was limiting.

5. The absolute and the relative N and P water concentrations contribute significant and complementary insights into the responses of microphytobenthos biomass to nutrient enrichment in running waters. However, ability to predict nutrient limitation from these concentrations is constrained by substantial error in the models. In the future, the prediction ability of models of nutrient limitation might be improved by focussing on regional scales and accounting for additional factors such as light and disturbance.
Constrained 1D joint inversion of seismic surface waves and P‐refraction traveltimes
Authors: Piatti C. , Socco L.V. , Boiero D. , Foti S.
Published: May 2012

We present a joint inversion scheme that couples P‐wave refraction and seismic surface‐wave data for a layered subsurface. An algorithm is implemented with a damped least‐squares approach. The estimated parameters are S‐ and P‐wave velocities and layer thicknesses, while densities are assumed constant during inversion. The coupling is both geometric and physical: layer thicknesses are the same for S‐ and P‐wave velocity profiles and P‐wave velocities enter in both forward algorithms. Sensitivity analysis, performed on synthetic data, reveals that surface‐wave dispersion curves can be sensitive also to P‐wave velocity of some layers (especially for Poisson's ratio values smaller than about 0.35), allowing synergic resolution of this parameter. Applications on both synthetic and field data show that the proposed approach mitigates the hidden layer problem of seismic refraction and leads to more accurate results than individual inversions also for surface waves. Additional constraints on the objective function on a priori Poisson's ratio values allow unrealistic and not admissible VP and VS values to be avoided; such constraints were applied in one field case considering the a priori information available about water‐table depth. It is also shown that estimation of porosity can help the selection of the proper constraint on a priori Poisson's ratio.
China's crop productivity and soil carbon storage as influenced by multifactor global change
Authors: Ren Wei , Tian Hanqin , Tao Bo , Huang Yao , Pan Shufen
Published: May 2012

Much concern has been raised about how multifactor global change has affected food security and carbon sequestration capacity in China. By using a process‐based ecosystem model, the Dynamic Land Ecosystem Model (DLEM), in conjunction with the newly developed driving information on multiple environmental factors (climate, atmospheric CO2, tropospheric ozone, nitrogen deposition, and land cover/land use change), we quantified spatial and temporal patterns of net primary production (NPP) and soil organic carbon storage (SOC) across China's croplands during 1980–2005 and investigated the underlying mechanisms. Simulated results showed that both crop NPP and SOC increased from 1980 to 2005, and the highest annual NPP occurred in the Southeast (SE) region (0.32 Pg C yr−1, 35.4% of the total NPP) whereas the largest annual SOC (2.29 Pg C yr−1, 35.4% of the total SOC) was found in the Northeast (NE) region. Land management practices, particularly nitrogen fertilizer application, appear to be the most important factor in stimulating increase in NPP and SOC. However, tropospheric ozone pollution and climate change led to NPP reduction and SOC loss. Our results suggest that China's crop productivity and soil carbon storage could be enhanced through minimizing tropospheric ozone pollution and improving nitrogen fertilizer use efficiency.
Oxidation of ortho‐diphenols in red clover with and without polyphenol oxidase (PPO) activity and their role in PPO activation and inactivation
Authors: Lee M. R. F. , Tweed J. K. S. , Sullivan M. L.
Published: May 2012

Oxidation of phenol to quinone with its subsequent binding and complexing with protein in red clover (Trifolium pratense L.) when fed to ruminant livestock has been shown to improve nitrogen‐use efficiency and the deposition of polyunsaturated fats into animal products. This oxidation has, almost exclusively, been attributed to the activity of the enzyme group polyphenol oxidases (PPOs) and, specifically, catecholase during conservation. However, during conservation, temporal inactivation of PPO occurs and oxidation of phenolic substrate may occur through other mechanisms not associated with PPO. T1 progeny of a cross between a red clover clone having normal levels of foliar PPO activity and a transgenic PPO‐silenced red clover plant with undetectable levels of PPO activity were divided into two populations based on the presence of the silencing transgene and lack of measurable PPO activity (PPO−) or the absence of the silencing transgene and normal levels of PPO activity (PPO+). This material was subsequently used to determine the relevant extent of phenolic oxidation in the presence and absence of PPO activity under two damage regimes (heavy and light). PPO+ and PPO− material was passed through a garden shredder as the light‐damaged regime, or frozen at −20°C as the heavy damaged regime. Material was left at room temperature and sampled at regular intervals for the determination of PPO enzyme activity (active and total), PPO activation (conversion from latent to active forms) and formation of protein‐bound phenol (PBP) as a measure of oxidation. Experiments with red clover leaf extracts were carried out to determine the mechanism for the temporal activation and inactivation (loss of enzymatic activity) of PPO during wilting. PBP formation was evident in both PPO− and PPO+ treatments with the response further catalysed during the first 2 h by extent of damage that increased the activation of PPO, but which also resulted in a more rapid temporal inactivation of PPO. PBP formation, PPO activation and PPO inactivation were all shown to be mediated predominantly by quinone binding. A role of non‐PPO oxidation in PBP formation in wilted red clover is reported, showing the importance of o‐diphenolic substrate concentration and not just PPO activity to increase nitrogen use efficiency and the deposition of polyunsaturated fats into animal products.
Different morphology, stage and treatment affect immune cell infiltration and long‐term outcome in patients with non‐small‐cell lung carcinoma
Authors: da Costa Souza Paola , Parra Edwin Roger , Atanazio Marcelo Junqueira , da Silva Osmar Bianchi , Noleto Gustavo Sousa , Ab’Saber Alexandre Muxfeldt , de Morais Fernezlian Sandra , Takagaki Tereza , Capelozzi Vera Luiza
Published: May 2012

da Costa Souza P, Parra E R, Atanazio M J, da Silva O B, Noleto G S, Ab’Saber A M, de Morais Fernezlian S, Takagaki T & Capelozzi V L  (2012) Histopathology 61, 587–596

Different morphology, stage and treatment affect immune cell infiltration and long‐term outcome in patients with non‐small‐cell lung carcinoma

Aims:  Development of effective immune‐based therapies for patients with non‐small‐cell lung carcinoma (NSCLC) depends on an accurate characterization of complex interactions that occur between immune cells and the tumour environment.

Methods and results:  Innate and adaptive immune responses were evaluated in relation to prognosis in 65 patients with surgically excised NSCLC. Immunohistochemistry and morphometry were used to determine the abundance and distribution of immune cells. We found low numbers of immune cells and levels of cytokines in the tumour environment when compared with surrounding parenchyma. Smoking was associated inversely with the adaptive immune response and directly with innate immunity. We observed a prominent adaptive immune response in squamous cell carcinomas (SCC) but greater innate immune responses in adenocarcinomas and large cell carcinomas. Cox model analysis showed a low risk of death for smoking <41 packs/year, N0 tambour stage, squamous carcinoma, CD4+ > 16.81% and macrophages/monocytes >4.5%. Collectively, the data indicate that in NSCLC there is not a substantive local immune cell infiltrate within the tumour.

Conclusion:  Although immune cell infiltration is limited in NSCLC it appears to have an impact on prognosis and this may be of relevance for new immunotherapeutic approaches.
Research evidence uptake in a developing country: a survey of attitudes, education and self‐efficacy, engagement, and barriers among physical therapists in the Philippines
Authors: Gorgon Edward James R. , Barrozo Hazel Gaile T. , Mariano Laarni G. , Rivera Emmalou F.
Published: May 2012

Rationale and objective  Use of evidence from systematic research is critical in evidence‐based physical therapy, yet this has not been described well in developing countries where its purported benefits are most needed. This study explored research evidence uptake among physical therapists in the Philippines.

Method  A probability survey of practitioners in tertiary hospitals in the Philippines' National Capital Region was conducted.

Results  Of the 188 questionnaires distributed, 152 were returned for an 81% response rate. Positive attitudes were consistently reported (78–93%), although education and self‐efficacy related to key dimensions such as searching, appraising and integrating evidence were varied (53–82%). Less than 50% reported using research evidence routinely in five of six dimensions of clinical practice, except in selecting treatments (53%). Textbooks, own observations and expert opinion were consistently relied upon (74–96%) while average‐month approximations of engagement in relevant activities such as searching, reading, appraising and applying research literature were low (10–18%). Participants faced a number of barriers such as lack of time, resources, skills, access to research literature, supporting administrative policies, in‐service training and authority in decision making.

Conclusions  The low research evidence uptake and heavy reliance on potentially biased evidence sources strongly indicate the need for effective professional education for practitioners to address current barriers as well as early intensive undergraduate education for students to ensure adequate preparation on being effective research evidence consumers. Given the profile of Filipino physical therapists, alternatives to ‘from scratch’ evidence searching and appraisal are required if widespread uptake is envisaged.