bluuebunny/crossref_metadata_2025_split huggingface dataset:
Climate‐induced forest dieback as an emergent global phenomenon
Authors: Allen Craig D. , Breshears David D. 
Published: December 2007

An organized oral session at the annual meeting of the Ecological Society of America in San Jose, Calif., posed this question: Is climate‐induced drought stress triggering increasing rates and unusual patterns of forest die‐off at a global scale? Twenty‐nine researchers representing five continents reported on patterns, mechanisms, and projections of forest mortality.Observations include widespread forest dieback or reductions in tree cover and biodiversity in response to drought and warmer temperatures in the African Sahel (Patrick Gonzalez, The Nature Conservancy), Mediterranean and alpine Europe (Jorge Castro, Universidad de Granada), and Argentinean Patagonia (Thomas Kitzberger, Universidad Nacional del Comahue). In contrast, although much Eucalyptus mortality has resulted from recent droughts in Australia, warming trends have been less pronounced in the Southern Hemisphere and it is unclear if contemporary climate‐induced tree mortality differs from previous historical drought impacts (Rod Fensham, Queensland Herbarium).
Large igneous provinces
Authors: Coffin Millard F. , Neal Clive 
Published: December 2007

Catastrophic massive volcanism and contemporaneous environmental change have punctuated Earth history for at least the past 3.5 billion years. Geodynamic and magmatic processes associated with large igneous province (LIP) formation interact with crustal structure and tectonic setting to produce various expressions of LIPs, the most common of which are oceanic plateaus, magma‐dominated divergent continental margins, and continental flood basalts. Environmental and biotic perturbations simultaneous with LIP formation include climate changes, mass extinctions, accelerated evolutionary rates, oceanic anoxic events (OAEs), and variations in ocean chemistry. Exploring these relationships promises exciting science.The LIP workshop, hosted by the Integrated Ocean Drilling Program (IODP) and Joint Oceanographic Institutions, was held at the University of Ulster in Coleraine, U.K. Eighty scientists from 16 nations discussed strategies for advancing understanding of LIPs and associated environmental changes using the three new IODP platforms and related technologies. Over 4 days of plenary and breakout sessions, including examination of the UNESCO World Heritage Giant's Causeway exposure of the North Atlantic LIP, scientists who approach LIPs through field, laboratory, and modeling studies shared their understanding of the world's LIPs; discussed outstanding problems related to LIP origin, emplacement, and environmental consequences; and outlined a global mission to address these problems via drilling in conjunction with complementary geoscientific studies.
Effects of zileuton and montelukast in mouse experimental spinal cord injury
Authors: Genovese T , Rossi A , Mazzon E , Di Paola R , Muià C , Caminiti R , Bramanti P , Sautebin L , Cuzzocrea S 
Published: December 2007

Background and purpose:5‐lipoxygenase (5‐LO) is the key enzyme in leukotriene (LT) biosynthesis from arachidonic acid (AA). Here, we examined the role of the 5‐LO‐product, cysteinyl‐LT (Cys‐LT), with a 5‐LO inhibitor (zileuton) and a Cys‐LT, receptor antagonist (montelukast), in the inflammatory response and tissue injury associated with spinal cord injury (SCI).Experimental approach:SCI was induced in mice by the application of vascular clips to the dura via a two‐level T6 to T7 laminectomy for 1 min. Cord inflammation was assessed histologically and by measuring inflammatory mediators (ELISA) and apoptosis by annexin V, TUNEL, Fas ligand staining and Bax and Bcl‐2 expression (immunohistochemistry and western blots). Motor function in hindlimbs was assessed by a locomotor rating scale, for 10 days after cord injury.Key results:SCI in mice resulted in tissue damage, oedema, neutrophil infiltration, apoptosis, tumour necrosis‐α (TNF‐α) and cyclooxygenase‐2 (COX‐2) expression, prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) production, and extracellular signal‐regulated kinase 1/2 (ERK1/2) phosphorylation in injured tissue. Treatment of the mice with zileuton or montelukast reduced the spinal cord inflammation and tissue injury, neutrophil infiltration, TNF‐α, COX‐2 and pERK1/2 expression, PGE2 and LTB4 production, and apoptosis. In separate experiments, zileuton or montelukast significantly improved the recovery of limb function over 10 days.Conclusions and implications:Zileuton and montelukast produced a substantial reduction of inflammatory events associated with experimental SCI. Our data underline the important role of 5‐LO and Cys‐LT in neurotrauma.British Journal of Pharmacology (2008) 153, 568–582; doi:10.1038/sj.bjp.0707577; published online 3 December 2007
Pharmacological approaches to acute ischaemic stroke: reperfusion certainly, neuroprotection possibly
Authors: Green A R 
Published: December 2007

Stroke is a major cause of both death and disability. However, there are no pharmacological treatments used in most countries other than recombinant tissue plasminogen activator, a thrombolytic, and this is only used in about 4% of patients presenting after an acute ischaemic stroke. One novel thrombolytic (desmoteplase) has just been reported to have failed in a Phase IIb/III trial, but other thrombolytics and reperfusion agents remain in development. The picture with neuroprotectant agents, that is compounds that act to preserve neurones following an acute cerebral ischaemic insult, is even more bleak. Despite the development of over 1000 compounds, many proving effective in animal models of stroke, none has demonstrated efficacy in patients in the over 100 clinical trials conducted. This includes NXY‐059, which was developed in accordance with the guidelines proposed by an academic‐industry roundtable group (STAIR). This review examines the available data on compounds currently in development. It also proposes that the failure of translation between efficacy in preclinical models and patients is likely to terminate most current neuroprotective drug development. It is suggested that animal models must be made more representative of the patient condition (with other co‐morbid conditions) and suggests that since stroke is primarily a cardiovascular disease with a neurological outcome, more research on the neurovascular unit would be valuable. New approaches on neuroinflammation, neurorestoration and neurorepair are also likely to gain prominence in the search for new drugs to treat this major clinical problem.British Journal of Pharmacology (2008) 153, S325–S338; doi:10.1038/sj.bjp.0707594; published online 3 December 2007
Cigarette smoke inhibits macrophage sensing of Gram‐negative bacteria and lipopolysaccharide: relative roles of nicotine and oxidant stress
Authors: McMaster S K , Paul‐Clark M J , Walters M , Fleet M , Anandarajah J , Sriskandan S , Mitchell J A 
Published: December 2007

Background and purpose:Smoking cigarettes is a major risk factor for the development of cardiovascular and respiratory disease. Moreover, smokers are more prone to infections. This has been associated with a suppression of the immune system by smoke. However, it is not clear how cigarette smoke affects the ability of immune cells to sense pathogens. Cigarette smoke contains a large number of molecules which may mediate responses on immune cells and of these, nicotine and oxidants have both been identified as inhibitory for the sensing of bacterial lipopolysaccharide (LPS). Nitric oxide synthase (NOS) and tumour necrosis factor (TNF)‐α are both induced in macrophages on stimulation with Gram negative bacteria or LPS.Experimental approach:We used murine macrophages stimulated with whole heat‐killed bacteria or LPS. We measured output of NO (as nitrite) and TNFα, NOS protein by Western blotting and cellular oxidant stress.Key results:Cigarette smoke extract suppressed the ability of murine macrophages to release NO, but not TNFα in response to whole bacteria. Cigarette smoke extract also inhibited nitric oxide synthase II protein expression in response to LPS. The effects of cigarette smoke extract on nitrite formation stimulated by LPS were unaffected by inhibition of nicotinic receptors with α‐bungarotoxin (100 units ml−1). However, the effects of cigarette smoke extract on LPS‐induced nitrite formation were mimicked by hydrogen peroxide and reversed by the anti‐oxidants N‐acetyl cysteine and glutathione.Conclusions and implications:We suggest that cigarette smoke exerts its immunosuppressive effects through an oxidant‐dependent and not a nicotine‐dependent mechanism.British Journal of Pharmacology (2008) 153, 536–543; doi:10.1038/sj.bjp.0707595; published online 3 December 2007
Activities of mixed NOP and μ‐opioid receptor ligands
Authors: Spagnolo B , Calo G , Polgar W E , Jiang F , Olsen C M , Berzetei‐Gurske I , Khroyan T V , Husbands S M , Lewis J W , Toll L , Zaveri N T 
Published: December 2007

Background and purpose:Compounds that activate both NOP and μ‐opioid receptors might be useful as analgesics and drug abuse medications. Studies were carried out to better understand the biological activity of such compounds.Experimental approach:Binding affinities were determined on membranes from cells transfected with NOP and opioid receptors. Functional activity was determined by [35S]GTPγS binding on cell membranes and using the mouse vas deferens preparationin vitroand the tail flick antinociception assayin vivo.Key results:Compounds ranged in affinity from SR14150, 20‐fold selective for NOP receptors, to buprenorphine, 50‐fold selective for μ‐opioid receptors. In the [35S]GTPγS assay, SR compounds ranged from full agonist to antagonist at NOP receptors and most were partial agonists at μ‐opioid receptors. Buprenorphine was a low efficacy partial agonist at μ‐opioid receptors, but did not stimulate [35S]GTPγS binding through NOP. In the mouse vas deferens, each compound, except for SR16430, inhibited electrically induced contractions. In each case, except for N/OFQ itself, the inhibition was due to μ‐opioid receptor activation, as determined by equivalent results in NOP receptor knockout tissues. SR14150 showed antinociceptive activity in the tail flick test, which was reversed by the opioid antagonist naloxone.Conclusions and implications:Compounds that bind to both μ‐opioid and NOP receptors have antinociceptive activity but the relative contribution of each receptor is unclear. These experiments help characterize compounds that bind to both receptors, to better understand the mechanism behind their biological activities, and identify new pharmacological tools to characterize NOP and opioid receptors.British Journal of Pharmacology(2008)153, 609–619; doi:10.1038/sj.bjp.0707598; published online 3 December 2007
Interleukin‐1‐induced interleukin‐6 synthesis is mediated by the neutral sphingomyelinase/Src kinase pathway in neurones
Authors: Tsakiri N , Kimber I , Rothwell N J , Pinteaux E 
Published: December 2007

Background and purpose:Interleukin (IL)‐1 is a key mediator of inflammatory and host defence responses and its effects in the brain are mediated primarily via effects on glia. IL‐1 induces release of inflammatory mediators such as IL‐6 from glia via the type‐1 receptor (IL‐1R1) and established signalling mechanisms including mitogen‐activated protein kinases and nuclear factor kappa‐B. IL‐1 also modifies physiological functions via actions on neurones, through activation of the neutral sphingomyelinase (nSMase)/Src kinase signalling pathway, although the mechanism of IL‐1‐induced IL‐6 synthesis in neurones remains unknown.Experimental approach:Primary mouse neuronal cell cultures, ELISA, Western blot and immunocytochemistry techniques were used.Key results:We show here that IL‐1β induces the synthesis of IL‐6 in primary mouse neuronal cultures, and this is dependent on the activation of IL‐1R1, nSMase and Src kinase. We demonstrate that IL‐1β‐induced Src kinase activation triggers the phosphorylation of the NMDA receptor NR2B subunit, leading to activation of Ca2+/calmodulin‐dependent protein kinase II (CamKII) and the nuclear transcription factor CREB. We also show that NR2B, CamKII and CREB are essential signalling elements involved in IL‐1β‐induced IL‐6 synthesis in neurones.Conclusions and implications:These results demonstrate that IL‐1 interacts with the same receptors on neurones and glia to elicit IL‐6 release, but does so via distinct signalling pathways. The mechanism by which IL‐1β induces IL‐6 synthesis in neurones could be critical in both physiological and pathophysiological actions of IL‐1β, and may provide a new therapeutic target for the treatment of acute CNS injury. British Journal of Pharmacology (2008) 153, 775–783; doi:10.1038/sj.bjp.0707610; published online 3 December 2007
Conformational changes in G‐protein‐coupled receptors—the quest for functionally selective conformations is open
Authors: Hoffmann C , Zürn A , Bünemann M , Lohse M J 
Published: December 2007

The G‐protein‐coupled receptors (GPCRs) represent one the largest families of drug targets. Upon agonist binding a receptor undergoes conformational rearrangements that lead to a novel protein conformation which in turn can interact with effector proteins. During the last decade significant progress has been made to prove that different conformational changes occur. Today it is mostly accepted that individual ligands can induce different receptor conformations. However, the nature or molecular identity of the different conformations is still ill‐known. Knowledge of the potential functionally selective conformations will help to develop drugs that select specific conformations of a given GPCR which couple to specific signalling pathways and may, ultimately, lead to reduced side effects. In this review we will summarize recent progress in biophysical approaches that have led to the current understanding of conformational changes that occur during GPCR activation.British Journal of Pharmacology (2008) 153, S358–S366; doi:10.1038/sj.bjp.0707615; published online 3 December 2007
Probing the role of AMPAR endocytosis and long‐term depression in behavioural sensitization: relevance to treatment of brain disorders, including drug addiction
Authors: Wang Y T 
Published: December 2007

Modifying the function of postsynaptic α‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionic acid subtype glutamate receptors (AMPARs) is one of the most important mechanisms by which the efficacy of synaptic transmission at excitatory glutamatergic synapses in the mammalian brain is regulated. Traditionally these types of modifications have been thought to be achieved mainly by altering the channel gating properties or conductance of the receptors. A large body of evidence accumulated from recent studies strongly suggests that AMPARs, like most integral plasma membrane proteins, are continuously recycled between the plasma membrane and the intracellular compartments via vesicle‐mediated plasma membrane insertion and clathrin‐dependent endocytosis. Regulation of either receptor insertion or endocytosis results in a rapid change in the number of these receptors expressed on the plasma membrane surface and in the receptor‐mediated responses, thereby playing an important role in mediating certain forms of synaptic plasticity, such as long‐term potentiation (LTP) and depression (LTD). These studies have significantly advanced our understanding of the molecular mechanisms underlying LTP and LTD, and their potential contributions to learning and memory‐related behaviours. Here I provide a brief summary of the current state of knowledge concerning clathrin‐mediated AMPAR endocytosis and its relationship to the expression of certain forms of LTD in several brain areas. The potential impact of recent advancements on our efforts to probe the roles of synaptic plasticity in learning and memory‐related behaviours, and their relevance to some brain disorders, particularly drug addiction, are also discussed.British Journal of Pharmacology (2008) 153, S389–S395; doi:10.1038/sj.bjp.0707616; published online 3 December 2007
Drugs and trafficking of ion channels: a new pro‐arrhythmic threat on the horizon?
Authors: van der Heyden M A G , Smits M E , Vos M A 
Published: December 2007

Tuning of functional expression levels of the ion channels that make up the cardiac action potential (AP) is crucial for preserving correct AP duration (APD) and QTc times. Many compounds inhibit human ether‐à‐go‐go related gene (hERG)‐mediated delayed rectifier currents and thus prolong cardiac repolarization that may cause life‐threatening arrhythmias like Torsades de Pointes. An increasing number of drugs are found to inhibit hERG function by a dual mechanism of short‐term channel block and long‐term trafficking defects that operate over different time and concentration scales. In safety screens at present used by pharmaceutical companies, the short‐term effect of channel block is covered. In contrast, specific screening for long‐term trafficking defects is not common, with the consequent risk of drugs that disturb trafficking entering the market. Whether that poses another pro‐arrhythmic threat for the patients treated has to be determined, but is not unlikely.British Journal of Pharmacology(2008)153, 406–409; doi:10.1038/sj.bjp.0707618; published online 3 December 2007
Generating Imaginal Disc Clones in Drosophila
Authors: Blair Seth S. 
Published: December 2007

INTRODUCTIONImaginal disc primordia appear in Drosophila embryos as clusters of cells that invaginate from the embryonic epithelium. During metamorphosis, the imaginal discs form much of the outer covering of the developing adult. Generation of genetic mosaics is useful for removing or adding gene function to imaginal cells. Mitotic recombinants can be generated in a small percentage of disc cells at any stage; each cell then divides normally, forming a clone of genetically altered tissue. Mitotic recombination is induced between homologous chromosomes to generate homozygotic cells in heterozygotic flies. This is done either by irradiating heterozygotic larvae, or by using heat-shock-induced expression of flippase recombinase (FLPase) to induce recombination between FLPase recombination targets (FRTs) inserted into selected chromosome arms. In the FLPout technique, heat-shock-induced expression of FLPase joins a ubiquitous promoter to a selected coding sequence by removing blocking DNA flanked by FRTs. This technique can be used with an upstream activation sequence (UAS)-GAL4. A GAL4 FLPout clone expresses GAL4, which in turn drives the expression of any gene coupled to the UAS promoter. This protocol describes methods for generating such mosaics, by which genetic changes can be limited to small groups of imaginal cells.
Dissection of Imaginal Discs in Drosophila: Figure 1.
Authors: Blair Seth S. 
Published: December 2007

INTRODUCTIONImaginal disc primordia appear in embryos as clusters of 20-40 cells that invaginate from the embryonic epithelium. Each disc is a single-layered epithelial sheet or sac that stays connected to the embryonic and larval epithelium by a thin stalk. Eventually, each sac flattens and the two sides of the sac take on different characteristics, forming on one side the thicker, highly folded disc epithelium and on the other side, the thinner, unfolded peripodial membrane. The imaginal discs are set aside during embryonic development and do not participate appreciably in larval life. However, the discs undergo extensive proliferation during the three larval instars, and by late in the third instar, just before metamorphosis, each disc contains tens of thousands of cells. During metamorphosis, the larval epidermis is converted into the pupal case, and the imaginal discs (along with the histoblast nests) form the outer covering of the developing adult. Most of the ectodermal adult structures are derived from the disc epithelium. This protocol describes methods for dissecting imaginal discs from Drosophila larvae.
Fixation of Imaginal Discs in Drosophila
Authors: Blair Seth S. 
Published: December 2007

INTRODUCTIONImaginal disc primordia appear in Drosophila embryos as clusters of cells that invaginate from the embryonic epithelium. During metamorphosis, the imaginal discs form much of the outer covering of the developing adult. Generation of genetic mosaics is useful for removing or adding gene function to imaginal cells. This protocol describes the methods for fixing such tissues in preparation for immunohistological techniques to monitor gene expression.
Triple-Label Fluorescent Antibody Staining of Imaginal Discs in Drosophila
Authors: Blair Seth S. 
Published: December 2007

INTRODUCTIONThis protocol describes a triple-label, fluorescent-antibody staining procedure that uses three different primary antisera generated in three different species. Biotin and rhodamine-streptavidin are used for the most critical of these antibodies, as they have the best signal-to-noise ratio. Fluorescein is used to visualize the second antibody, while Cy5 is used for the third. Cy5 is only poorly visible using a standard fluorescence microscope, but is used by the third channel on many laser-scanning confocal microscopes. Obviously, other fluorescent tags, as well as double and single fluorescent stains, are possible. Although these methods are useful for visualizing genetic mosaic clones in wandering larval stage imaginal discs and pupal tissues from Drosophila, the immunohistological techniques are generally applicable to the description of protein expression.
Analysis of siRNA Knockdown of Cell-Cycle Control Genes in G1/S and G2/M Cell-Cycle Phase Marker Cell Lines Using Multiplexed High-Content Analysis: Figure 1.
Authors: Roquemore Elizabeth P. 
Published: December 2007

INTRODUCTIONRNA interference using siRNA libraries is a powerful technology for elucidating gene function by downregulating gene expression at the post-transcriptional level. Phenotypic changes associated with siRNA knockdown can be monitored using cell lines expressing fluorescent reporter proteins. Test siRNAs are transiently transfected into the reporter cell line and behavior of the fluorescent reporter probe is monitored using a high-content imaging system. A range of cell features and additional fluorescent probes can be monitored to assess the effects of knockdown. This article provides a method of screening an siRNA cell-cycle array using cell lines that report cell-cycle phase. The subcellular distribution and intensity of the fluorescent phase reporter changes in a cell-cycle-dependent manner. The phase marker assay is multiplexed with an assay for bromodeoxyuridine (BrdU) incorporation, which identifies cells that have undergone DNA replication. When a G2/M cell-cycle phase reporter cell line is multiplexed with BrdU incorporation, information from both assays enables assignment of each cell to one of five distinct phases of the cell cycle (G1, S, G2, prophase, or mitosis).