bluuebunny/crossref_metadata_2025 huggingface dataset:
Novel RuII Complexes with Bispidine‐Based Bridging Ligands: Luminescence Sensing and Photocatalytic Properties
Authors: Busche Christoph , Comba Peter , Mayboroda Andrey , Wadepohl Hubert
Published: February 2010

New ligands with a bidentate bipyridyl (bpy) and a tetradentate bispidine (bisp) subunit (bipyridyl = 2,2′‐bipyridine derivative, bispidine = 3,7‐diazabicyclo[3.3.1]nonane derivative) and their heterodinuclear {[Ru(bpy)3]2+‐[M(bisp)]2+} complexes (M = Cu2+, Fe2+) were prepared and characterized. The luminescence of the mononuclear RuII complexes (metal‐free bisp subunit) is efficiently quenched in presence of CuII. An EPR spectroscopic study reveals thatvisible light irradiation does not alter the oxidation states of the two metal ions in {[Ru(bpy)3]2+‐[Cu(bisp)]2+}, i.e. there is energy rather than electron transfer. The heterodinuclear {[Ru(bpy)3]2+‐[Cu(bisp)]2+} complex shows a significantphotocatalytic activity in the aziridination of styrene.
Double‐Shelled Mn2O3 Hollow Spheres and Their Application in Water Treatment
Authors: Cao Jie , Zhu Yongchun , Shi Liang , Zhu Lingling , Bao Keyan , Liu Shuzhen , Qian Yitai
Published: February 2010

Double‐shelled Mn2O3 hollow spheres have been successfully prepared on a large scale by using core‐shell‐structured MnCO3 microspheres as sacrificial templates. This new method is based on an inward oxidation/etching treatment and sequential heat treatment in air. The as‐prepared double‐shelled Mn2O3 hollow spheres consist of small nanoparticles with a size of ca. 50 nm, and there are many nanopores among the particles. As the double‐shelled Mn2O3 hollow spheres were employed in water treatment, they could remove about 86 % of phenol without any other additives.
Biaryl Peptides from 4‐Iodophenylalanine by Solid‐Phase Borylation and Suzuki–Miyaura Cross‐Coupling
Authors: Afonso Ana , Rosés Cristina , Planas Marta , Feliu Lidia
Published: February 2010

Resin‐bound phenylalanine boronates were prepared by solid‐phase Miyaura borylation of 4‐iodophenylalanine peptides. Subsequent arylation through a Suzuki–Miyaura cross‐coupling was carried out using a variety of aryl halides under conventional heating and under microwave irradiation. Microwaves greatly enhanced the arylation, shortening thereaction time and providing the biaryl peptides in higherpurities.
General Multicomponent Strategy for the Synthesis of 2‐Amino‐1,4‐diazaheterocycles: Scope, Limitations, and Utility
Authors: Kysil Volodymyr , Khvat Alexander , Tsirulnikov Sergey , Tkachenko Sergey , Williams Caroline , Churakova Marina , Ivachtchenko Alexandre
Published: February 2010

Multicomponent reactions of primary 1,2‐ and 1,3‐diamines with carbonyl compounds and isocyanides resulting in the formation of diverse 2‐amino‐1,4‐diazaheterocycles are described. Lewis acids (LAs) promote the reactions effectively, and chlorotrimethylsilane (TMSCl) has been found to be a promoter of choice. The scope and limitations of the reactions with regard to each of the components are evaluated and discussed. Post‐IMCR modifications of the synthesized heterocycles have been elaborated.
β,meso‐Acetylenyl‐Bridged, Asymmetrical, Porphyrin Dyads – Synthesis, Spectral, Electrochemical and Computational Studies
Authors: Yedukondalu Meesala , Maity Dilip K. , Ravikanth Mangalampalli
Published: February 2010

The first examples of β,meso‐acetylenyl‐bridged, asymmetrical, covalently linked, porphyrin dyads, containing two different subunits, such as ZnN4P‐N3OP (1), ZnN4P‐N3SP (2), ZnN4P‐N2SOP (4) and ZnN4P‐N2S2P (6), were synthesized by the coupling of a β‐acetylenyl, ZnN4 porphyrin with a meso‐bromoheteroporphyrin under mild, Pd0‐catalyzed, coupling conditions. The dyads containing different types of metal‐free subunits, such as N4P‐N3SP (3), N4P‐N2SOP (5) and N4P‐N2S2P (7), were synthesized by the demetallation of the corresponding dyads. The seven β,meso‐acetylenyl dyads 1–7 were characterized by NMR, MS, absorption, fluorescence and electrochemical techniques. The NMR, absorption and electrochemical studies support an electronic interaction between the subunits in all seven dyads. The steady‐statefluorescence studies on dyads 1–7 support an efficient energy transfer from the donor (ZnN4 or N4) subunit to the acceptor heteroporphyrin subunit upon excitation of the ZnN4/N4 subunit. First‐principle‐based, quantum‐chemical studies carried out on dyads 1, 2, 4 and 6 further support an electronic interaction between the donor and acceptor subunits. The computational studies also predict significant tuning of the electronic energy levels in these dyads with the modification of the porphyrin core of the acceptor groups. The calculations support the experimental results of efficient donor→acceptor energy transfer in these dyads.
Tidal estuary width convergence: Theory and form in North Australian estuaries
Authors: Davies Gareth , Woodroffe Colin D.
Published: February 2010

In order to better understand the relations between tidal estuary shape and geomorphic processes, the width profiles of 79 tidal channels from within 30 estuaries in northern Australia have been extracted from LANDSAT 5 imagery using GIS. Statistics describing the shape and width convergence of individual channels and entire estuaries (which can contain several channels) are analysed along with proxies for the tidal range and fluvial inputs of the estuaries in question. The width profiles of most individual channels can be reasonably approximated with an exponential curve, and this is also true of the width profiles of estuaries. However, the shape of this exponential width profile is strongly related to the mouth width of the system. Channels and estuaries with larger mouths generally exhibit a more pronounced ‘funnel shape’ than those with narrower mouths, reflecting the hydrodynamic importance of the distance over which the channel or estuarine width converges. At the estuarine scale, this ‘convergence length’ also tends to be higher in estuaries which have larger catchments relative to their size. No clear relation between the estuarine width convergence length and tidal range could be discerned within the Northern Australian estuaries although, when these data are combined with data from other studies, a weak relationship emerges. Copyright © 2010 John Wiley & Sons, Ltd.
Critical notch depths for failure of coastal limestone cliffs: case study at Kuro‐shima Island, Okinawa, Japan
Authors: Kogure Tetsuya , Matsukura Yukinori
Published: February 2010

Development of a notch at the base of a cliff reduces cliff stability and often induces a collapse. Pleistocene limestone coastal cliffs of elevation 5?m in Kuro‐shima, Ryukyu Islands, have a prominent notch with a depth of 3–4?m at their bases. Around these coastal cliffs, collapses different from previous studies of cliff collapses in the Ryukyu Islands were found; collapses in Kuro‐shima have a horizontal failure surface. The horizontal failure surface, situated at the height of the failure surface corresponding to the retreat point of the notch, is bounded by vertical joints cutting the whole cliff and the reef flat in front of the cliff. Two types of horizontal failure surface were found, triangular and quadrangular; the distinction appears to depend on the angle between the vertical joints and the front face of the cliff. Prior to collapse, these cliffs appear to have been separated from the adjacent cliffs by the development of vertical joints. Consequently, a cliff that will collapse can be identified in advance; cliff instability is strongly dependent on the development of a notch. To study the effect of notch development on cliff collapse, the notch depth at which collapse occurs was calculated using stability analysis. Instability of a cliff increases with notch depth; collapse occurs at the horizontal failure surface when the ratio of the notch depth to the seaward length of the cliff is approximately 0·5–0·7 for a triangular failure surface, and 0·7–0·9 for a quadrangular failure surface. Copyright © 2010 John Wiley & Sons, Ltd.
Causes, consequences and chronology of large‐magnitude palaeoflows in Middle and Late Pleistocene river systems of northwest Europe
Authors: Westaway Rob , Bridgland David R.
Published: February 2010

This study examines the record of high‐palaeoflow phases in river systems in northwest Europe, investigating their causes (whether due to ‘unique’ events, such as the formation of the Dover Strait, or as ‘characteristic’ consequences of climate change), examining their consequences with regard to landscape evolution and possible effects on climate, and determining the chronology of key events. Large‐magnitude palaeoflows, more than an order‐of‐magnitude larger than present‐day flood peaks, are shown to be characteristic of rivers in this region at particular times within the Pleistocene. These events, the most recent of which were during Heinrich events 2 and 1 at ∼25 and ∼17 ka, were evidently caused by the combined effects of glacial outwash, rainfall, snowmelt and melting of permafrost in some proportion. They released such large volumes of water that the thermohaline circulation of the Atlantic Ocean, and thus the climate, may well have been affected. These large‐magnitude palaeoflows are thus a significant aspect of the Pleistocene Earth system that has hitherto gone unquantified. Copyright © 2010 John Wiley & Sons, Ltd.
Rock glacier dynamics in marginal periglacial environments
Authors: Serrano Enrique , de Sanjosé José Juan , González‐Trueba Juan José
Published: February 2010

Vertical electric sounding, bottom temperature of winter snowcover (BTS) and ground thermal measurement, debris surface analysis and a differential global positioning system (DGPS) survey were performed on the Posets rock glacier (Pyrenees) between 2001 and 2008. High precision records of horizontal and vertical movements of the rock glacier were measured using a DGPS on ten steel rods. Total and annual average displacements and thickness changes for each control point were derived from the field survey. Horizontal and vertical displacement rates in different sectors of the rock glacier were compared, and these compared with thermal, structural and morphological maps. The inferred surface deformation was characterized by extensional and compressive flows in which two dynamic types were found. The first type of movement is defined by the slide and flows related to the existence of an ice body over the frost body. The second dynamic type involved the displacement generated by deformation of the frozen body. The study attempts to understand the surface movement and dynamics of rock glaciers in marginal cold environments and their usefulness as environmental geoindicators. Copyright © 2010 John Wiley & Sons, Ltd.
The antimicrobial triclocarban stimulates embryo production in the freshwater mudsnailPotamopyrgus antipodarum
Authors: Giudice Ben D. , Young Thomas M.
Published: February 2010

Recent research has indicated that the antimicrobial chemical triclocarban (TCC) represents a new type of endocrine disruptor, amplifying the transcriptional activity of steroid hormones and their receptors while itself exhibiting little affinity for these receptors. The effects of TCC were studied in the freshwater mudsnail Potamopyrgus antipodarum. Specimens were exposed to concentrations ranging from 0.05 to 10.5 µg/L dissolved TCC and were removed and dissected, and embryos contained within the brood pouch were counted and classified as shelled or unshelled after two and four weeks of exposure. After four weeks, environmentally relevant TCC concentrations of 1.6 to 10.5 µg/L resulted in statistically significant increases in the number of unshelled embryos, whereas 0.2, 1.6, and 10.5 µg/L exposures significantly increased numbers of shelled embryos. The lowest observed effect concentration (LOEC) was 0.2 µg/L, the no observed effect concentration (NOEC) was 0.05 µg/L; the 10% effective concentration (EC10) and the median effective concentration (EC50) for unshelled effects were 0.5 µg/L and 2.5 µg/L, respectively. Given the widespread occurrence of TCC in the environment and the effects shown at environmentally relevant concentrations, these results indicate that TCC may be causing reproductive effects in the environment. Furthermore, the present study indicates that environmental risk from a new class of endocrine-disrupting chemicals (EDCs) is both qualitatively and quantitatively similar to risk from existing classes of EDCs. Environ. Toxicol. Chem. 2010;29:966–970. © 2009 SETAC
Incidence and prognostic impact of secondary cytogenetic aberrations in a series of 145 patients with mantle cell lymphoma
Authors: Espinet Blanca , Salaverria Itziar , Beà Sílvia , Ruiz‐Xivillé Neus , Balagué Olga , Salido Marta , Costa Dolors , Carreras Joaquim , Rodríguez‐Vicente Ana Eugenia , Luís García Juan , Hernández‐Rivas Jesús María , Calasanz María José , Siebert Reiner , Ferrer Ana , Salar Antonio , Carrió Ana , Polo Natividad , García‐Marco José Antonio , Domingo Alicia , González‐Barca Eva , Romagosa Vicenç , Marugán Isabel , López‐Guillermo Armando , Millá Fuensanta , Luís Mate José , Luño Elisa , Sanzo Carmen , Collado Rosa , Oliver Isabel , Monzó Sebastià , Palacín Antonio , González Teresa , Sant Francesc , Salinas Ramon , Ardanaz María Teresa , Font Llorenç , Escoda Lourdes , Florensa Lourdes , Serrano Sergi , Campo Elias , Solé Francesc
Published: February 2010

Mantle cell lymphoma (MCL) is a mature B‐cell neoplasm with an aggressive behavior, characterized by the t(11;14)(q13;q32). Several secondary genetic abnormalities with a potential role in the oncogenic process have been described. Studies of large MCL series using conventional cytogenetics, and correlating with proliferation and survival, are scarce. We selected 145 MCL cases at diagnosis, displaying an aberrant karyotype, from centers belonging to the Spanish Cooperative Group for Hematological Cytogenetics. Histological subtype, proliferative index and survival data were ascertained. Combined cytogenetic and molecular analyses detected CCND1 translocations in all cases, mostly t(11;14)(q13;q32). Secondary aberrations were present in 58% of patients, the most frequent being deletions of 1p, 13q and 17p, 10p alterations and 3q gains. The most recurrent breakpoints were identified at 1p31‐32, 1p21‐22, 17p13, and 1p36. Aggressive blastoid/pleomorphic variants displayed a higher karyotypic complexity, a higher frequency of 1p and 17p deletions and 10p alterations, a higher proliferation index and poor survival. Gains of 3q and 13q and 17p13 losses were associated with reduced survival times. Interestingly, gains of 3q and 17p losses added prognostic significance to the morphology in a multivariate analysis. Our findings confirm previous observations indicating that proliferation index, morphology and several secondary genetic alterations (3q gains and 13q and 17p losses) have prognostic value in patients with MCL. Additionally, we observed that 3q gains and 17p losses detected by conventional cytogenetics are proliferation‐independent prognostic markers indicating poor outcome. © 2010 Wiley‐Liss, Inc.
Glutamine synthetase deficiency in murine astrocytes results in neonatal death
Authors: He Youji , Hakvoort Theodorus B. M. , Vermeulen Jacqueline L. M. , Labruyère Wilhelmina T. , De Waart D. Rudi , Van Der Hel W. Saskia , Ruijter Jan M. , Uylings Harry B. M. , Lamers Wouter H.
Published: February 2010

Glutamine synthetase (GS) is a key enzyme in the “glutamine‐glutamate cycle” between astrocytes and neurons, but its function in vivo was thus far tested only pharmacologically. Crossing GSfl/lacZ or GSfl/fl mice with hGFAP‐Cre mice resulted in prenatal excision of the GSfl allele in astrocytes. “GS‐KO/A” mice were born without malformations, did not suffer from seizures, had a suckling reflex, and did drink immediately after birth, but then gradually failed to feed and died on postnatal day 3. Artificial feeding relieved hypoglycemia and prolonged life, identifying starvation as the immediate cause of death. Neuronal morphology and brain energy levels did not differ from controls. Within control brains, amino acid concentrations varied in a coordinate way by postnatal day 2, implying an integrated metabolic network had developed. GS deficiency caused a 14‐fold decline in cortical glutamine and a sevenfold decline in cortical alanine concentration, but the rising glutamate levels were unaffected and glycine was twofold increased. Only these amino acids were uncoupled from the metabolic network. Cortical ammonia levels increased only 1.6‐fold, probably reflecting reduced glutaminolysis in neurons and detoxification of ammonia to glycine. These findings identify the dramatic decrease in (cortical) glutamine concentration as the primary cause of brain dysfunction in GS‐KO/A mice. The temporal dissociation between GSfl elimination and death, and the reciprocal changes in the cortical concentration of glutamine and alanine in GS‐deficient and control neonates indicate that the phenotype of GS deficiency in the brain emerges coincidentally with the neonatal activation of the glutamine‐glutamate and the associated alanine‐lactate cycles. © 2010 Wiley‐Liss, Inc.
3D comparison of low, intermediate, and advanced hippocampal atrophy in MCI
Authors: Apostolova Liana G. , Thompson Paul M. , Green Amity E. , Hwang Kristy S. , Zoumalan Charleen , Jack Clifford R. , Harvey Danielle J. , Petersen Ronald C. , Thal Leon J. , Aisen Paul S. , Toga Arthur W. , Cummings Jeffrey L. , DeCarli Charles S.
Published: February 2010

We applied the hippocampal radial atrophy mapping technique to the baseline and follow‐up magnetic resonance image data of 169 amnestic mild cognitive impairment (MCI) participants in the imaging arm of the Alzheimer's Disease Cooperative Study MCI Donepezil/Vitamin E trial. Sixty percent of the subjects with none to mild hippocampal atrophy rated with the visual medial temporal atrophy rating scale (MTA score < 2) and 33.8% of the subjects with moderate to severe (MTA ≥ 2) hippocampal atrophy converted to Alzheimer's disease (AD) during 3‐year follow‐up. MTA ≥ 2 showed a trend for greater left sided hippocampal atrophy versus MTA < 2 groups at baseline (Pcorrected = 0.08). Higher MTA scores were associated with progressive atrophy of the subiculum and the CA1‐3 subregions. The MTA < 2 group demonstrated significant bilateral atrophy progression at follow‐up (left Pcorrected = 0.008; right Pcorrected = 0.05). Relative to MTA < 2 nonconverters, MTA < 2 converters showed further involvement of the subiculum and CA1 and additional involvement of CA2‐3 at follow‐up. Right CA1 atrophy was significantly associated with conversion to dementia (for 1 mm greater right CA1 radial distance subjects had 50% reduced hazard for conversion). Greater CA1 and subicular atrophy can be demonstrated early and is predictive of future conversion to AD, whereas CA2‐3 involvement becomes more evident as the disease progresses. Hum Brain Mapp, 2010. © 2010 Wiley‐Liss, Inc.
Left cytoarchitectonic BA 44 processes syntactic gender violations in determiner phrases
Authors: Heim Stefan , van Ermingen Muna , Huber Walter , Amunts Katrin
Published: February 2010

Recent neuroimaging studies make contradictory predictions about the involvement of left Brodmann's area (BA) 44 in processing local syntactic violations in determiner phrases (DPs). Some studies suggest a role for BA 44 in detecting local syntactic violations, whereas others attribute this function to the left premotor cortex. Therefore, the present event‐related functional magnetic resonance imaging (fMRI) study investigated whether left‐cytoarchitectonic BA 44 was activated when German DPs involving syntactic gender violations were compared with correct DPs (correct: ‘der Baum’—the[masculine] tree[masculine]; violated: ‘das Baum’—the[neuter] tree[masculine]). Grammaticality judgements were made for both visual and auditory DPs to be able to generalize the results across modalities. Grammaticality judgements involved, among others, left BA 44 and left BA 6 in the premotor cortex for visual and auditory stimuli. Most importantly, activation in left BA 44 was consistently higher for violated than for correct DPs. This finding was behaviourally corroborated by longer reaction times for violated versus correct DPs. Additional brain regions, showing the same effect, included left premotor cortex, supplementary motor area, right middle and superior frontal cortex, and left cerebellum. Based on earlier findings from the literature, the results indicate the involvement of left BA 44 in processing local syntactic violations when these include morphological features, whereas left premotor cortex seems crucial for the detection of local word category violations. Hum Brain Mapp, 2010. © 2010 Wiley‐Liss, Inc.
Cortical responses to consciousness of schematic emotional facial expressions: A high‐resolution EEG study
Authors: Babiloni Claudio , Vecchio Fabrizio , Buffo Paola , Buttiglione Maura , Cibelli Giuseppe , Rossini Paolo Maria
Published: February 2010

Is conscious perception of emotional face expression related to enhanced cortical responses? Electroencephalographic data (112 channels) were recorded in 15 normal adults during the presentation of cue stimuli with neutral, happy or sad schematic faces (duration: “threshold time” inducing about 50% of correct recognitions), masking stimuli (2 s), and go stimuli with happy or sad schematic faces (0.5 s). The subjects clicked left (right) mouse button in response to go stimuli with happy (sad) faces. After the response, they said “seen” or “not seen” with reference to previous cue stimulus. Electroencephalographic data formed visual event‐related potentials (ERPs). Cortical sources of ERPs were estimated by LORETA software. Reaction time to go stimuli was generally shorter during “seen” than “not seen” trials, possibly due to covert attention and awareness. The cue stimuli evoked four ERP components (posterior N100, N170, P200, and P300), which had similar peak latency in the “not seen” and “seen” ERPs. Only N170 amplitude showed differences in amplitude in the “seen” versus “not seen” ERPs. Compared to the “not seen” ERPs, the “seen” ones showed prefrontal, premotor, and posterior parietal sources of N170 higher in amplitude with the sad cue stimuli and lower in amplitude with the neutral and happy cue stimuli. These results suggest that nonconscious and conscious processing of schematic emotional facial expressions shares a similar temporal evolution of cortical activity, and conscious processing induces an early enhancement of bilateral cortical activity for the schematic sad facial expressions (N170). Hum Brain Mapp, 2010. © 2010 Wiley‐Liss, Inc.
Music interferes with learning from television during infancy
Authors: Barr Rachel , Shuck Lauren , Salerno Katherine , Atkinson Emily , Linebarger Deborah L.
Published: February 2010

Infants are frequently exposed to music during daily activities, including free play, and while viewing infant‐directed videotapes that contain instrumental music soundtracks. In Experiment 1, an instrumental music soundtrack was played during a live or televised demonstration to examine its effects on deferred imitation by 6‐, 12‐, and 18‐month‐old infants. Transfer of information was indexed via deferred imitation of the target actions following a 24‐h delay. For half the infants, the music context was also reinstated at the time of test. Performance by experimental groups was compared to that of a baseline control group that participated in the test session without prior exposure to the demonstration. Imitation performance was above baseline for the live groups but not for the video groups regardless of age or the music context at test. In Experiment 2, we added matched sound effects to the video demonstration and infants performed above baseline. We conclude that the music track creates additional cognitive load, disrupts selective attention to the target actions and inhibits transfer of learning from television of the imitation task. Music may impair an infant's ability to translate information from a two‐dimensional to three‐dimensional world even if the auditory context remains the same. Copyright © 2010 John Wiley & Sons, Ltd.
In vivo tumor suppression activity by T cell‐specific T‐bet restoration
Authors: Lee Kihyun , Min Hyun Jung , Jang Eun Jung , Hong Jeong‐Ho , Hwang Eun Sook
Published: February 2010

T‐box‐containing protein expressed in T cells (T‐bet) is a master transcription factor for the development of interferon (IFN) γ‐producing T helper 1 (Th1) cells and also functions in other immune cells including natural killer (NK), cytotoxic T lymphocytes and dendritic cells. T‐bet‐deficient mice increased susceptibility to viral infection and tumor development due to the defective functions of immune cells. T‐bet is known to play a key role in NK‐mediated antimetastatic response; however, it remains to be characterized whether T‐bet is essential for in vivo tumor suppression mediated by T cells. Here, we have investigated in vivo tumor suppression effect of T‐bet‐restored T cells using T cell‐specific and inducible T‐bet transgenic mice generated in a T‐bet‐deficient background. T‐bet‐null mice increased susceptibility to tumor development, whereas induction of T cell‐specific T‐bet expression upon melanoma cell injection substantially suppressed tumor development by inducing IFNγ production in T cells and tumor cell apoptosis. Late induction of T‐bet expression in tumor‐bearing mice produced comparable amounts of IFNγ with control and significantly decreased tumor volume. In addition, increased melanoma lung metastasis in T‐bet‐deficient mice was strikingly inhibited by T‐bet restoration in T cells. Intravenous injection of activated Th1 cells, not T‐bet‐null Th1 cells, attenuated metastatic melanoma progression, in addition, restoration of T‐bet in T‐bet‐null Th1 cells certainly retrieved antimetastatic activity. These results suggest that T‐bet expression in T cells is crucial for the control of tumor development and antimetastatic activity.
The marine compound spongistatin 1 targets pancreatic tumor progression and metastasis
Authors: Rothmeier Andrea S. , Schneiders Uta M. , Wiedmann Romina M. , Ischenko Ivan , Bruns Christiane J. , Rudy Anita , Zahler Stefan , Vollmar Angelika M.
Published: February 2010

Treatment of pancreatic cancer remains a major challenge and new anticancer drugs are urgently required. Our study presents the marine natural compound spongistatin 1 as a promising experimental drug. Spongistatin 1 was applied in an orthotopicin vivomodel of human pancreatic cancer. Spongistatin 1 significantly reduced tumor growth, which correlates with a strong apoptosis induction (DNA‐fragmentation) and long‐term effects on clonogenic survival of pancreatic tumor cells (L3.6pl)in vitro. In addition, the formation of metastasis was reduced in spongistatin 1‐treated mice, which is in line with a diminished MMP‐9 activity in tumor tissue determined by zymography. Based on the pronounced efficacy of spongistatin 1, the underlying mechanisms were studied in more detail.In vitroadhesion, as well as migration, and invasion assays showed spongistatin 1 to influence these critical steps in the metastatic cascade. Furthermore, spongistatin 1 induced anoikis in L3.6pl cells. Exposure to spongistatin 1 leads to phosphorylation, and thus inactivation of the antiapoptotic protein Bcl‐2 in pancreatic tumor cells. siRNA experiments silencing Bcl‐2 suggest a role of Bcl‐2 in anoikis and cell migration. Taken together, spongistatin 1 not only proved to be a potent experimental drug but also served as a chemical tool to examine the role of the antiapoptotic protein Bcl‐2 in pancreas carcinoma, thereby supporting the hypothesis of a link between apoptosis signaling and metastasis.
Estimating the attributable fraction for melanoma: A meta‐analysis of pigmentary characteristics and freckling
Authors: Olsen Catherine M. , Carroll Heidi J. , Whiteman David C.
Published: February 2010

Epidemiologic research has demonstrated convincingly that certain pigmentary characteristics are associated with increased relative risks of melanoma; however there has been no comprehensive review to rank these characteristics in order of their importance on a population level. We conducted a systematic review of the literature and meta‐analysis to quantify the contribution of pigmentary characteristics to melanoma, estimated by the population‐attributable fraction (PAF). Eligible studies were those that permitted quantitative assessment of the association between histologically confirmed melanoma and hair colour, eye colour, skin phototype and presence of freckling; we identified 66 such studies using citation databases, followed by manual review of retrieved references. We calculated summary relative risks using weighted averages of the log RR, taking into account random effects, and used these to estimate the PAF. The pooled RRs for pigmentary characteristics were: 2.64 for red/red‐blond, 2.0 for blond and 1.46 for light brown hair colour (vs. dark); 1.57 for blue/blue‐grey and 1.51 for green/grey/hazel eye colour (vs. dark); 2.27, 1.99 and 1.35 for skin phototypes I, II and III respectively (vs. IV); and 1.99 for presence of freckling. The highest PAFs were observed for skin phototypes 1/II (0.27), presence of freckling (0.23), and blond hair colour (0.23). For eye colour, the PAF for blue/blue‐grey eye colour was higher than for green/grey/hazel eye colour (0.18 vs. 0.13). The PAF of melanoma associated with red hair colour was 0.10. These estimates of melanoma burden attributable to pigmentary characteristics provide a basis for designing prevention strategies for melanoma.
TNF-α mediates diabetes-enhanced chondrocyte apoptosis during fracture healing and stimulates chondrocyte apoptosis Through FOXO1
Authors: Kayal Rayyan A , Siqueira Michelle , Alblowi Jazia , McLean Jody , Krothapalli Nanarao , Faibish Dan , Einhorn Thomas A , Gerstenfeld Louis C , Graves Dana T
Published: February 2010

To gain insight into the effect of diabetes on fracture healing, experiments were carried out focusing on chondrocyte apoptosis during the transition from cartilage to bone. Type 1 diabetes was induced in mice by multiple low-dose streptozotocin injections, and simple transverse fractures of the tibia or femur was carried out. Large-scale transcriptional profiling and gene set enrichment analysis were performed to examine apoptotic pathways on total RNA isolated from fracture calluses on days 12, 16, and 22, a period of endochondral bone formation when cartilage is resorbed and chondrocyte numbers decrease. Tumor necrosis factor α (TNF-α) protein levels were assessed by ELISA and caspase-3 by bioactivity assay. The role of TNF was examined by treating mice with the TNF-specific inhibitor pegsunercept. In vitro studies investigated the proapoptotic transcription factor FOXO1 in regulating TNF-induced apoptosis of chondrogenic ATDC5 and C3H10T1/2 cells as representative of differentiated chondrocytes, which are important during endochondral ossification. mRNA profiling revealed an upregulation of gene sets related to apoptosis in the diabetic group on day 16 when cartilage resorption is active but not day 12 or day 22. This coincided with elevated TNF-α protein levels, chondrocyte apoptosis, enhanced caspase-3 activity, and increased FOXO1 nuclear translocation (p < .05). Inhibition of TNF significantly reduced these parameters in the diabetic mice but not in normoglycemic control mice (p < .05). Silencing FOXO1 using siRNA in vitro significantly reduced TNF-induced apoptosis and caspase activity in differentiated chondrocytes. The mRNA levels of the proapoptotic genes caspase-3, caspase-8, caspase-9, and TRAIL were significantly reduced with silencing of FOXO1 in chondrocytic cells. Inhibiting caspase-8 and caspase-9 significantly reduced TNF-induced apoptosis in chondrogenic cells. These results suggest that diabetes causes an upregulation of proapoptotic genes during the transition from cartilage to bone in fracture healing. Diabetes increased chondrocyte apoptosis through a mechanism that involved enhanced production of TNF-α, which stimulates chondrocyte apoptosis and upregulates mRNA levels of apoptotic genes through FOXO1 activation. © 2010 American Society for Bone and Mineral Research
Critical role for Y1 receptors in mesenchymal progenitor cell differentiation and osteoblast activity
Authors: Lee Nicola J , Doyle Kharen L , Sainsbury Amanda , Enriquez Ronaldo F , Hort Yvonne J , Riepler Sabrina J , Baldock Paul A , Herzog Herbert
Published: February 2010

The neuropeptide Y (NPY) system has been implicated in the regulation of bone homeostasis and osteoblast activity, but the mechanism behind this is unclear. Here we show that Y1 receptor signaling is directly involved in the differentiation of mesenchymal progenitor cells isolated from bone tissue, as well as the activity of mature osteoblasts. Importantly, the mRNA levels of two key osteogenic transcription factors, runx2 and osterix, as well as the adipogenic transcription factor PPAR-γ, were increased in long bones of Y1−/− mice compared with wild-type mice. In vitro, bone marrow stromal cells (BMSCs) isolated from Y1−/− mice formed a greater number of mineralized nodules under osteogenic conditions and a greater number of adipocytes under adipogenic conditions than controls. In addition, both the number and size of fibroblast colony-forming units formed in vitro by purified osteoprogenitor cells were increased in the absence of the Y1 receptors, suggestive of enhanced proliferation and osteogenesis. Furthermore, the ability of two specific populations of mesenchymal progenitor cells isolated from bone tissue, an immature mesenchymal stem cell population and a more committed osteoprogenitor cell population, to differentiate into osteoblasts and adipocytes in vitro was enhanced in the absence of Y1 receptor signaling. Finally, Y1 receptor deletion also enhanced the mineral-producing ability of mature osteoblasts, as shown by increased in vitro mineralization by BMSCs isolated from osteoblast-specific Y1−/− mice. Together these data demonstrate that the NPY system, via the Y1 receptor, directly inhibits the differentiation of mesenchymal progenitor cells as well as the activity of mature osteoblasts, constituting a likely mechanism for the high-bone-mass phenotype evident in Y1−/− mice. © 2010 American Society for Bone and Mineral Research
Replication of previous genome-wide association studies of bone mineral density in premenopausal American women
Authors: Ichikawa Shoji , Koller Daniel L , Padgett Leah R , Lai Dongbing , Hui Siu L , Peacock Munro , Foroud Tatiana , Econs Michael J
Published: February 2010

Bone mineral density (BMD) achieved during young adulthood (peak BMD) is one of the major determinants of osteoporotic fracture in later life. Genetic variants associated with BMD have been identified by three recent genome-wide association studies. The most significant single-nucleotide polymorphisms (SNPs) from these studies were genotyped to test whether they were associated with peak BMD in premenopausal American women. Femoral neck and lumbar spine BMD were determined by dual-energy X-ray absorptiometry in two groups of premenopausal women: 1524 white women and 512 black women. In premenopausal white women, two SNPs in the C6orf97/ESR1 region were significantly associated with BMD (p < 4.8 × 10−4), with suggestive evidence for CTNNBL1 and LRP5 (p < .01). Evidence of association with one of the two SNPs in the C6orf97/ESR1 region also was observed in premenopausal black women. Furthermore, SNPs in SP7 and a chromosome 4 intergenic region showed suggestive association with BMD in black women. Detailed analyses of additional SNPs in the C6orf97/ESR1 region revealed multiple genomic blocks independently associated with femoral neck and lumbar spine BMD. Findings in the three published genome-wide association studies were replicated in independent samples of premenopausal American women, suggesting that genetic variants in these genes or regions contribute to peak BMD in healthy women in various populations. © 2010 American Society for Bone and Mineral Research
Cross-sectional evidence of suppressed bone mineral accrual among female adolescent runners
Authors: Barrack Michelle T , Rauh Mitchell J , Nichols Jeanne F
Published: February 2010

We aimed to evaluate patterns of bone mineral accrual among a cross-sectional sample of female adolescent runners and girls participating in a nonendurance running sport. One-hundred and eighty-three interscholastic competitive female athletes (age 16.0 ± 0.1 years), 93 endurance runners and 90 nonrunners, completed a menstrual and sports history questionnaire, had their height and weight measured, and underwent a dual-energy X-ray absorptiometry scan for the measurements of body composition and bone mass. For the majority of analyses, the girls were separated into four groups according to their age (13 to 14 years, 15 years, 16 years, and 17 to 18 years). Runners' height, weight, body mass index (BMI), percent body fat, lean tissue mass, number of menstrual cycles in the past year, and months of participation in a non-lean-build/variable-impact-loading sport were significantly lower than mean values for nonrunners. Although bone mass rose at all sites in the nonrunners between the ages of 13 to 14 years and 17 to 18 years, no such increase was noted in the runners. Runners compared with nonrunners exhibited significantly lower body weight and height-adjusted total body and lumbar spine bone mineral content (BMC) values and lower bone mineral density (BMD) Z-score values among the older (16 years and/or 17 to 18 years) but not younger (13 to 14 years and/or 15 years) age groups. These findings suggest that the runners, in contrast to the nonrunners, exhibited a suppressed bone mineral accrual pattern, which supports the notion that female adolescent endurance runners may be at risk for inadequate bone mass gains and thus a low peak BMD. © 2010 American Society for Bone and Mineral Research
Archaeological skeletons support a northwest European origin for Paget's disease of bone
Authors: Mays Simon
Published: February 2010

The strong genetic component in the etiology of Paget's disease of bone (PDB), together with marked geographic variation in its prevalence, with high frequencies in British populations, has led some to suggest that the disease originated in Britain and spread around the world in recent times by the migration and admixture of British populations. This study aims to investigate this hypothesis by studying the world geographic distribution of PDB cases identified in ancient skeletons excavated from archaeological sites. The methodology is a review of PDB cases described in the literature. There were 109 cases that met modern diagnostic criteria. All came from Western Europe, 94% from England. These data support the hypothesis that PDB originated in this geographic region. © 2010 American Society for Bone and Mineral Research
Evaluation of comparative effect of pre‐ and posttreatment of selenium on mercury‐induced oxidative stress, histological alterations, and metallothionein mRNA expression in rats
Authors: Agarwal Rakhi , Raisuddin S. , Tewari Shikha , Goel Sudhir K. , Raizada R. B. , Behari Jai Raj
Published: February 2010

To evaluate the effect of pre‐ or posttreatment of selenium (6 μmol/kg b.w., single intraperitoneal injection) in mercury intoxication, rats were exposed to mercury (12 μmol/kg b.w., single intraperitoneal injection). Exposure to mercury resulted in induced oxidative stress in liver, kidney, and brain tissues. Marked changes in serum biochemical parameters together with alterations in histopathology and an induction in metallothionein‐I and metallothionein‐II mRNA expression in the liver and kidney were observed. Pretreatment with selenium to mercury‐exposed animals had protective effect on the liver, whereas posttreatment had partial protection on restoration of altered oxidative stress parameters. In the kidney, pretreatment with selenium showed partial protection on restoration of altered biochemical parameters, whereas no protection was observed in posttreatment. The pretreatment with selenium resulted in restoration of mercury‐induced metallothionein‐I and metallothionein‐II mRNA expression, which was completely restored in the liver whereas partial restoration was observed in the kidney. Posttreatment with selenium resulted in further induction in metallothionein‐I and metallothionein‐II mRNA expression in the liver and kidney. In the brain, selenium showed partial protection on alerted biochemical parameters. Results indicate that pretreatment with selenium is beneficial in comparison to posttreatment in mercury intoxication. Thus, dietary intake of selenium within safe limit may, therefore, enable us in combating any foreseen effects due to mercury exposure. © 2010 Wiley Periodicals, Inc. J Biochem Mol Toxicol 24:123–135, 2010; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.20320
Sulfur mustard induced cytokine production and cell death: Investigating the potential roles of the p38, p53, and NF‐κB signaling pathways with RNA interference
Authors: Ruff Albert L. , Dillman James F.
Published: February 2010

Cutaneous and ocular injuries caused by sulfur mustard (SM; bis‐(2‐chloroethyl) sulfide) are characterized by severe inflammation and death of exposed cells. Given the known roles of p38MAPK and NF‐κB in inflammatory cytokine production, and the known roles of NF‐κB and p53 in cell fate, these pathways are of particular interest in the study of SM injury. In this study, we utilized inhibitory RNA (RNAi) targeted against p38α, the p50 subunit of NF‐κB, or p53 to characterize their role in SM‐induced inflammation and cell death in normal human epidermal keratinocytes (NHEK). Analysis of culture supernatant from 200 μM SM‐exposed cells showed that inflammatory cytokine production was inhibited by p38α RNAi but not by NF‐κB p50 RNAi. These findings further support a critical role for p38 in SM‐induced inflammatory cytokine production in NHEK and suggest that NF‐κB may not play a role in the SM‐induced inflammatory response of this cell type. Inhibition of NF‐κB by p50 RNAi did, however, partially inhibit SM‐induced cell death, suggesting a role for NF‐κB in SM‐induced apoptosis or necrosis. Interestingly, inhibition of p53 by RNAi potentiated SM‐induced cell death, suggesting that the role of p53 in SM injury, may be complex and not simply prodeath. © 2010 Wiley Periodicals, Inc. J Biochem Mol Toxicol 24:155–164, 2010; Published online inWiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.20321
Small noncoding RNAs: Biogenesis, function, and emerging significance in toxicology
Authors: Choudhuri Supratim
Published: February 2010

In recent years, the discovery of small ncRNAs (noncoding RNAs) has unveiled a slew of powerful riboregulators of gene expression. So far, many different types of small ncRNAs have been described. Of these, miRNAs (microRNAs), siRNAs (small interfering RNAs), and piRNAs (Piwi‐interacting RNAs) have been studied in more detail. A significant fraction of genes in most organisms and tissues is targets of these small ncRNAs. Because these tiny RNAs are turning out to be important regulators of gene and genome expression, their aberrant expression profiles are expected to be associated with cellular dysfunction and disease. In fact, an ever‐increasing number of studies have implicated miRNAs and siRNAs in human health and disease ranging from metabolic disorders to diseases of various organ systems as well as various forms of cancer. Nevertheless, despite the flurry of research on these small ncRNAs, many aspects of their biology still remain to be understood. The following discussion focuses on some aspects of the biogenesis and function of small ncRNAs with major emphasis on miRNAs since these are the most widespread endogenous small ncRNAs that have been called “micromanagers” of gene expression. Their emerging significance in toxicology is also discussed. © 2010 Wiley Periodicals, Inc. J Biochem Mol Toxicol 24:195–216, 2010; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.20325
Inhibition by Cu2+ and Cd2+ of a mu‐class glutathione S‐transferase from shrimp Litopenaeus vannamei
Authors: Salazar‐Medina Alex J. , García‐Rico Leticia , García‐Orozco Karina D. , Valenzuela‐Soto Elisa , Contreras‐Vergara Carmen A. , Arreola Rodrigo , Arvizu‐Flores Aldo , Sotelo‐Mundo Rogerio R.
Published: February 2010

Glutathione S‐transferases (GSTs) are a family of detoxifying enzymes that catalyze the conjugation of glutathione (GSH) to electrophiles, thereby increasing the solubility of xenobiotics and aiding its excretion from the cell. The present work presents the inhibition of a mu‐class GST of the marine shrimp Litopenaeus vannamei by copper (Cu2+) and cadmium (Cd2+). The protein was overexpressed in bacteria and its enzymatic activity measured using 1‐chloro‐2,4‐dinitrobenzene. The mean inhibitory concentration (IC50) for shrimp GST against Cu2+ was 4.77 μM and for Cd2+ was 0.39 μM. A molecular model of the protein based on the crystal structure of a maize GST bound to cadmium showed that the metal binds in the GSH‐binding site by coordination with Asp and Gln residues. These results are consistent with the experimental data and suggest that sublethal concentration of metals may affect the capacity of the organism to detoxify pesticides or xenobiotics. © 2010 Wiley Periodicals, Inc. J Biochem Mol Toxicol 24:218–222, 2010; View this article online at wileyonlinelibrary.com. DOI 10.1002/jbt.20326
Effects of zinc and cadmium on erythrocyte antioxidant systems of a freshwater fish Oreochromis niloticus
Authors: Fırat Özgür , Kargın Ferit
Published: February 2010

In this work to determine the effects of metals exposure of Oreochromis niloticus on erythrocyte antioxidant systems, fish were exposed to 5.0 mg/L Zn, 1.0 mg/L Cd, and 5.0 mg/L Zn + 1.0 mg/L Cd mixtures for 7 and 14 days and reduced glutathione (GSH) level, catalase (CAT), and glucose‐6‐phosphate dehydrogenase (G6PD) activities were investigated. In addition, Zn or Cd levels in whole blood were studied. Erythrocyte GSH level and CAT and G6PD enzyme activities increased in response to single and combined Zn and Cd exposure. The elevation observed in the CAT activity was higher in the Cd alone, and in combination with Zn, than in Zn alone. Time‐dependent alteration was not observed in all antioxidant parameters. Exposure to metals (alone and in mixture) resulted in elevatation of Zn and Cd levels in the blood. Concentration of metals in the blood of fish exposed to the Zn + Cd combination was lower than in fish exposed to the single metal. This study demonstrates that metals caused oxidative stress in fish erythrocytes, and an adaptation with an increase in CAT and G6PD activities and GSH level, which were important in the protection against metal damage, was observed. © 2010 Wiley Periodicals, Inc. J Biochem Mol Toxicol 24:223–229, 2010; View this article online at wileyonlinelibrary.com. DOI 10.1002/jbt.20327
Compartmentalization of EGFR in cellular membranes: Role of membrane rafts
Authors: Balbis Alejandro , Posner Barry I.
Published: February 2010

There is now abundant evidence that the intracellular concentration of the EGFR and many other receptors for peptide hormones and growth factors is important for the temporal and spatial regulation of cell signaling. Spatial control is achieved by the selective compartmentalization of signaling components into endosomes. However further control may be effected by sequestration into sub‐domains within a given organelle such as membrane rafts which are dynamic, nano scale structures rich in cholesterol and sphingolipids. Current data suggest the presence of EGFRs in non‐caveolae membrane rafts. High doses of EGF seem to promote the sorting of EGFR to late endosomes through a raft/cholesterol dependant mechanism, implicating them in EGFR degradation. However our work and that of others has led us to propose a model in which membrane rafts in late endosomes sequester highly active EGFR leading to the recruitment and activation of MAPK in this compartment. J. Cell. Biochem. 109: 1103–1108, 2010. © 2010 Wiley‐Liss, Inc.