bluuebunny/crossref_metadata_2025 huggingface dataset:
Monte Carlo model of electron energy degradation in a CO2 atmosphere
Authors: Bhardwaj Anil , Jain Sonal Kumar
Published: November 2009

A Monte Carlo model has been developed to study the degradation of ≤1000 eV electrons in an atmosphere of CO2, which is one of the most abundant species in Mars' and Venus's atmospheres. The e‐CO2 cross sections are presented in an assembled set along with their analytical representations. Monte Carlo simulations are carried out at several energies to calculate the “yield spectra,” which embodied all the information related to the electron degradation process and can be used to calculate “yield” (or population) for any inelastic process. The numerical yield spectra have been fitted analytically, resulting in an analytical yield spectra. We have calculated the mean energy per ion pair and efficiencies for various inelastic processes, including the double and dissociative double ionization of CO2 and negative ion formation. The energy distribution of the secondary electrons produced per incident electron is also presented at few incident energies. The mean energy per ion pair for CO2 is 37.5 (35.8) eV at 200 (1000) eV, compared to the experimental value 32.7 eV at high energies. Ionization is the dominant loss process at energies above 50 eV with a contribution of ∼50%. Among the excitation processes, 13.6 eV and 12.4 eV states are the dominant loss processes consuming ∼28% energy above 200 eV. Around and below ionization threshold, 13.6 eV, 12.4 eV, and 11.1 eV, followed by 8.6 eV and 9.3 eV, excitation states are important loss processes, while below 10 eV, vibrational excitation dominates.
Mineralogy of Juventae Chasma: Sulfates in the light‐toned mounds, mafic minerals in the bedrock, and hydrated silica and hydroxylated ferric sulfate on the plateau
Authors: Bishop Janice L. , Parente Mario , Weitz Catherine M. , Noe Dobrea Eldar Z. , Roach Leah H. , Murchie Scott L. , McGuire Patrick C. , McKeown Nancy K. , Rossi Christopher M. , Brown Adrian J. , Calvin Wendy M. , Milliken Ralph , Mustard John F.
Published: November 2009

Juventae Chasma contains four light‐toned sulfate‐bearing mounds (denoted here as A–D from west to east) inside the trough, mafic outcrops at the base of the mounds and in the wall rock, and light‐toned layered deposits of opal and ferric sulfates on the plateau. Hyperspectral visible/near‐infrared Compact Reconnaissance Imaging Spectrometer for Mars (CRISM) spectra were used to identify monohydrated and polyhydrated sulfate (PHS) outcrops of layered material on the bright mounds. Most of the monohydrated sulfate signatures closely resemble those of szomolnokite (FeSO4·H2O), characterized by a water band near 2.08 μm, while some areas exhibit spectral features more similar to those of kieserite (MgSO4·H2O), with a band centered closer to 2.13 μm. The largest PHS outcrops occur on the top of mound B, and their spectral features are most consistent with ferricopiapite, melanterite, and starkeyite, but a specific mineral cannot be uniquely identified at this time. Coordinated analyses of CRISM maps, Mars Orbiter Laser Altimeter elevations, and High Resolution Imaging Science Experiment images suggest that mounds A and B may have formed together and then eroded into separate mounds, while mounds C and D likely formed separately. Mafic minerals (low‐Ca pyroxene, high‐Ca pyroxene, and olivine) are observed in large ∼2–10 km wide outcrops in the wall rock and in smaller outcrops ∼50–500 m across at the floor of the canyon. Most of the wall rock is covered by at least a thin layer of dust and does not exhibit strong features characteristic of these minerals. The plateau region northwest of Juventae Chasma is characterized by an abundance of light‐toned layered deposits. One region contains two spectrally unique phases exhibiting a highly stratified, terraced pattern. CRISM spectra of one unit eroded into swirling patterns with arc‐like ridges exhibit a narrow 2.23‐μm band assigned to hydroxylated ferric sulfate. A thin layer of a fractured material bearing an opaline silica phase is observed at the contact between the older plateau unit and the younger hydroxylated ferric sulfate‐bearing light‐toned layered deposits. Hydrothermal processes may have produced an acidic environment that fostered formation of the hydrated silica and hydroxylated ferric sulfate units.
Geomorphic and geologic settings of the Phoenix Lander mission landing site
Authors: Heet T. L. , Arvidson R. E. , Cull S. C. , Mellon M. T. , Seelos K. D.
Published: November 2009

The Phoenix Lander touched down on the northern distal flank of the shield volcano Alba Patera in a ∼150 km wide valley underlain by the Scandia region unit. The geomorphology and geology of the landing site is dominated by the ∼0.6 Ga, 11.5 km wide, bowl‐shaped impact crater, Heimdal, and its areally extensive ejecta deposits. The Lander is located ∼20 km to the west of the crater and is sitting on a plains surface underlain by partially eroded Heimdal ejecta deposits. Heimdal was produced by a hypervelocity impact into fine‐grained, ice‐rich material and is inferred to have produced high velocity winds and a ground‐hugging ejecta emplacement mode that destroyed or buried preexisting surfaces and rock fields out to ∼10 crater radii. Patterned ground is ubiquitous, with complex polygon patterns and rock rubble piles located on older plains (∼3.3 Ga) to the west of the ejecta deposits. Crater size frequency distributions are complex and represent equilibria between crater production and destruction processes (e.g., aeolian infill, cryoturbation, relaxation of icy substrate). Rock abundances increase near craters for the older plains and rocks with their dark shadows explain the reason for the few percent lower albedo for these plains as opposed to the Heimdal ejecta deposits. Many rocks at the landing site have been reworked by cryoturbation and moved to polygon troughs. The evidence for cryoturbation and the lack of aeolian features imply that the soils sampled by Phoenix are locally derived and mixed with a subordinate amount of windblown dust.
Effect of lower sea level on geostrophic transport through the Florida Straits during the Last Glacial Maximum
Authors: Ionita Dana A. , Di Lorenzo Emanuele , Lynch‐Stieglitz Jean
Published: November 2009

We investigate the effect of a 120 m sea level drop on transport through the Caribbean Sea and the Florida Straits during the Last Glacial Maximum (LGM) relative to the present, using the Regional Ocean Modeling System (ROMS). A geostrophic transport estimate for the Florida Straits suggests the LGM Florida Current was weaker than today by one third assuming that the velocity at the bottom of the channel was as small as it is today. This is consistent with a decrease in the North Atlantic overturning circulation, but there are other possible reasons for a flow decrease. It is possible that a shallower LGM Florida Straits sill depth could cause the diversion of some flow from the Florida Current. Our model results show that the volume transport through the Florida Straits is slightly reduced in a lower sea level model simulation when compared to a control sea level simulation (34.8 ± 2.0 Sv versus 39.8 ± 2.3 Sv). The difference in transport is of the order of 5 Sv, likely representing a maximum limit to the LGM flow reduction due to sea level change. Therefore, the change in sill depth between the LGM and the present is unlikely to have been a cause of the entire observed flow reduction. We also use the model output to demonstrate that transport through the Florida Straits can be accurately calculated from ocean margin density data at the core locations in the work of Lund et al. (2006) and Lynch‐Stieglitz et al. (2009), provided that a sufficiently deep reference level is chosen.
A model of surface heat fluxes based on the theory of maximum entropy production
Authors: Wang J. , Bras Rafael L.
Published: November 2009

A model of heat fluxes over a dry land surface is proposed based on the theory of maximum entropy production (MEP) as a special case of the maximum entropy principle (MaxEnt). When the turbulent heat transfer in the atmospheric boundary layer is parameterized using a Monin‐Obukhov similarity model, a dissipation function or entropy production function may be expressed in terms of the heat fluxes following the MEP formalism. A solution of the heat fluxes can be obtained by finding the extreme of the dissipation function under the constraint of conservation of energy for a given energy input (i.e., net radiation) at the surface. The MEP solution of the surface heat fluxes is tested using observations from fields experiments.
New asymptotic and preasymptotic results on rainfall maxima from multifractal theory
Authors: Veneziano Daniele , Langousis Andreas , Lepore Chiara
Published: November 2009

Contrary to common belief, Fisher‐Tippett's extreme value (EV) theory does not typically apply to annual rainfall maxima. Similarly, Pickands' extreme excess (EE) theory does not typically apply to rainfall excesses above thresholds on the order of the annual maximum. This is true not just for long‐averaging durationsdbut also for shortdand in the high‐resolution limit asd→ 0. We reach these conclusions by applying large‐deviation theory to multiplicative rainfall models with scale‐invariant structure. We derive several asymptotic results. One is that, asd→ 0, the annual maximum rainfall intensity ind,Iyr,d, has generalized extreme value (GEV) distribution with a shape parameterkthat is significantly higher than that predicted by EV theory and is always in the EV2 range. The value ofkdepends not on the upper tail of the marginal distribution but on regions closer to the body. Under the same conditions, the excesses above levels close to the annual maximum have generalized Pareto distribution with parameterkthat is always higher than that predicted by Pickands' EE theory. For finited, the distribution ofIyr,dis not GEV, but in accordance with empirical evidence is well approximated by a GEV distribution with shape parameterkthat increases asddecreases. We propose a way to estimatekunder preasymptotic conditions from the scaling properties of rainfall and suggest a near‐universalk(d) relationship. The new estimator promises to be more accurate and robust than conventional estimators. These developments represent a significant conceptual change in the way rainfall extremes are viewed and evaluated.
Functioningin situ: gene expression inMethylotenera mobilisin its native environment as assessed through transcriptomics
Authors: Kalyuzhnaya Marina G , Beck David A C , Suciu Dominic , Pozhitkov Alexander , Lidstrom Mary E , Chistoserdova Ludmila
Published: November 2009

Methylotrophs, organisms able to gain energy and carbon from compounds containing no carbon–carbon bonds, such as methane, methanol and methylated amines, are widespread in nature. However, knowledge of their nutrient preference and their metabolism is mostly based on experiments with cultures grown in defined laboratory conditions. Here, we use transcriptomics to explore the activity of one methylotroph, Methyotenera mobilis in its natural environment, lake sediment from which it has been previously isolated. Cells encapsulated in incubation cassettes were exposed to sediment conditions, with or without supplementation with a carbon/energy source (methylamine), and gene-expression patterns were compared for those cells to patterns for cells incubated in a defined medium supplemented with methylamine. A few specific trends in gene expression were observed at in situ conditions that may be of environmental significance, as follows. Expression of genes for the linear formaldehyde oxidation pathway linked to tetrahydromethanopterin increased, suggesting an important role for this pathway in situ, in contrast to laboratory condition culture, in which the cyclic ribulose monophosphate pathway seemed to be the major route for formaldehyde oxidation. Along with the ribulose monophosphate cycle that is also a major pathway for assimilating C1 units, the methylcitric acid cycle seemd to be important in situ, suggesting that multicarbon compounds may be the natural carbon and/or energy substrates for M. mobilis, challenging the notion of an obligately methylotrophic lifestyle for this bacterium. We also detected a major switch in expression of genes responsible for the mode of motility between different conditions: from flagellum-enabled motility in defined medium to in situ expression of pili known to be involved in twitching motility and adherence. Overall, this study offers a novel approach for gaining insights into the lifestyle of individual microbes in their native environments.
Relationships of BMI to Cardiovascular Risk Factors Differ by Ethnicity
Authors: Taylor Herman A. , Coady Sean A. , Levy Daniel , Walker Evelyn R. , Vasan Ramachandran S. , Liu Jiankang , Akylbekova Ermeg L. , Garrison Robert J. , Fox Caroline
Published: November 2009

The burden of cardiovascular risk associated with obesity disproportionately affects African Americans and little is known about ethnic/racial differences in the relationship of obesity to cardiometabolic risk. This report assesses whether obesity is similarly associated with cardiometabolic risk factors in African Americans and whites of European ancestry. Cross‐sectional observational data from the Jackson Heart Study (JHS) and the Framingham Heart Study (FHS) were compared. This analysis uses participants aged 35–74 years with BMI >18.5 kg/m2, and free of prevalent cardiovascular disease (CVD), from the initial JHS clinical examination (2000–2004) and the FHS Offspring (1998–2001) and Third Generation (2002–2005) cohorts. Participants were evaluated for the presence of lipid abnormalities, hypertension, and diabetes. Overall, 4,030 JHS (mean age 54 years, 64% women) and 5,245 FHS (mean age 51 years, 54% women) participants were available for analysis. The prevalence of all risk factors except high triglycerides and low high‐density lipoprotein (HDL) was substantially higher in JHS (all P < 0.001) and BMI was associated with increasing prevalence of most CVD risk factors within each race. For diabetes mellitus, hypertension, and low HDL, steeper relationships to BMI were observed in FHS than in JHS (P values <0.001–0.016). There were larger proportional increases in risk factor prevalence with increasing BMI in whites than in African Americans. The higher prevalence rates of cardiometabolic risk factors at nearly all levels of BMI in African Americans, however, suggest that additional factors contribute to the burden of CVD risk in African Americans.
Environmental Endocrine Disruptors Promote Adipogenesis in the 3T3‐L1 Cell Line through Glucocorticoid Receptor Activation
Authors: Sargis Robert M. , Johnson Daniel N. , Choudhury Rashikh A. , Brady Matthew J.
Published: November 2009

The burgeoning obesity and diabetes epidemics threaten health worldwide, yet the molecular mechanisms underlying these phenomena are incompletely understood. Recently, attention has focused on the potential contributions of environmental pollutants that act as endocrine disrupting chemicals (EDCs) in the pathogenesis of metabolic diseases. Because glucocorticoid signaling is central to adipocyte differentiation, the ability of EDCs to stimulate the glucocorticoid receptor (GR) and drive adipogenesis was assessed in the 3T3‐L1 cell line. Various EDCs were screened for glucocorticoid‐like activity using a luciferase reporter construct, and four (bisphenol A (BPA), dicyclohexyl phthalate (DCHP), endrin, and tolylfluanid (TF)) were shown to significantly stimulate GR without significant activation of the peroxisome proliferator‐activated receptor‐γ. 3T3‐L1 preadipocytes were then treated with EDCs and a weak differentiation cocktail containing dehydrocorticosterone (DHC) in place of the synthetic dexamethasone. The capacity of these compounds to promote adipogenesis was assessed by quantitative oil red O staining and immunoblotting for adipocyte‐specific proteins. The four EDCs increased lipid accumulation in the differentiating adipocytes and also upregulated the expression of adipocytic proteins. Interestingly, proadipogenic effects were observed at picomolar concentrations for several of the EDCs. Because there was no detectable adipogenesis when the preadipocytes were treated with compounds alone, the EDCs are likely promoting adipocyte differentiation by synergizing with agents present in the differentiation cocktail. Thus, EDCs are able to promote adipogenesis through the activation of the GR, further implicating these compounds in the rising rates of obesity and diabetes.
MSK1 regulates the transcription of IL-1ra in response to TLR activation in macrophages
Authors: Darragh Joanne , Ananieva Olga , Courtney Alan , Elcombe Suzanne , Arthur J. Simon C.
Published: November 2009

The activity of the pro-inflammatory cytokine IL (interleukin)-1 is closely regulated in vivo via a variety of mechanisms, including both the control of IL-1 production and secretion as well as naturally occurring inhibitors of IL-1 function, such as IL-1ra (IL-1 receptor antagonist). IL-1ra is homologous with IL-1, and is able to bind but not activate the IL-1 receptor. IL-1ra can be produced by a variety of cell types, and its production is stimulated by inflammatory signals. In the present study, we show that in macrophages the TLR (Toll-like receptor)-mediated induction of IL-1ra from both its proximal and distal promoters involves the p38 and ERK1/2 (extracellular-signal-regulated kinase 1/2) MAPK (mitogen-activated protein kinase) cascades. In addition, we show that MSK1 and 2 (mitogen- and stress-activated kinase 1 and 2), kinases activated by either ERK1/2 or p38 in vivo, are required for the induction of both IL-1ra mRNA and protein. MSKs regulate IL-1ra transcription via both IL-10-dependent and -independent mechanisms in cells. Consistent with this, knockout of MSK in mice was found to result in a decrease in IL-1ra production following LPS (lipopolysaccharide) injection. MSKs therefore act as important negative regulators of inflammation following TLR activation.
Intermolecular cross-linking of monomers in Helicobacter pylori Na+/H+ antiporter NhaA at the dimer interface inhibits antiporter activity
Authors: Karasawa Akira , Mitsui Keiji , Matsushita Masafumi , Kanazawa Hiroshi
Published: November 2009

We have previously shown that HPNhaA (Helicobacter pylori Na+/H+ antiporter) forms an oligomer in a native membrane of Escherichia coli, and conformational changes of oligomer occur between monomers of the oligomer during ion transport. In the present study, we use Blue-native PAGE to show that HPNhaA forms a dimer. Cysteine-scanning mutagenesis of residues 55–61 in a putative β-sheet region of loop1 and subsequent functional analyses revealed that the Q58C mutation resulted in an intermolecular disulfide bond. G56C, I59C and G60C were found to be cross-linked by bifunctional cross-linkers. Furthermore, the Q58E mutant did not form a dimer, possibly due to electrostatic repulsion between monomers. These results imply that Gln-58 and the flanking sequence in the putative β-sheet of the monomer are located close to the identical residues in the dimer. The Q58C mutant of NhaA was almost inactive under non-reducing conditions, and activity was restored under reducing conditions. This result showed that cross-linking at the dimer interface reduces transporter activity by interfering with the flexible association between the monomers. A mutant HPNhaA protein with three amino acid substitutions at residues 57–59 did not form a dimer, and yet was active, indicating that the monomer is functional.
Phosphatome profiling reveals PTPN2, PTPRJ and PTEN as potent negative regulators of PKB/Akt activation in Ras-mutated cancer cells
Authors: Omerovic Jasminka , Clague Michael J. , Prior Ian A.
Published: November 2009

Oncogenic Ras mutations render the protein constitutively active and promote tumorigenesis via chronic stimulation of effector pathways. In A549 lung adenocarcinoma approx. 50% of the total Ras population is constitutively active, yet these cells display only weak activation of the effectors: ERK1/2 (extracellular-signal-regulated kinase 1/2) and Akt. In order to identify key negative regulators of oncogenic Ras signalling we performed a phosphatome RNAi (RNA interference) screen in A549 cells and ranked their effects on phosphorylation of Ser473 of Akt. As expected, the tumour suppressor PTEN (phosphatase and tensin homologue deleted on chromosome 10) emerged as a leading hit: knockdown elevated Akt activation to 70% of maximal generated by acute EGF (epidermal growth factor) stimulation. Importantly, we identified other phosphatases with similar potencies including PTPN2 (T-cell protein tyrosine phosphatase; also known as TC-PTP) and PTPRJ (protein tyrosine phosphatase receptor type J; also known as DEP-1/CD148). Potentiation of Akt phosphorylation by knockdown of PTEN or PTPRJ was contingent on the presence of oncogenic K-Ras. Our data reveal a synergy between oncogene function and the loss of a tumour suppressor within the same pathway that was necessary for full effector activation since each alone failed to elicit significant Akt phosphorylation. Taken together, these data reveal potent regulators of Akt signalling which contribute to ameliorating the consequences of oncogenic K-Ras activity.
Coupling of the NMDA receptor to neuroprotective and neurodestructive events
Authors: Hardingham Giles E.
Published: November 2009

NMDA (N-methyl-D-aspartate) receptors are a subtype of ionotropic glutamate receptor with an important role in the physiology and pathophysiology of central neurons. Inappropriate levels of Ca2+ influx through the NMDA receptor can contribute to neuronal loss in acute trauma such as ischaemia and traumatic brain injury, as well as certain neurodegenerative diseases such as Huntington's disease. However, normal physiological patterns of NMDA receptor activity can promote neuroprotection against both apoptotic and excitotoxic insults. As a result, NMDA receptor blockade can promote neuronal death outright or render neurons vulnerable to secondary trauma. Thus responses to NMDA receptor activity follow a classical hormetic dose–response curve: both too much and too little can be harmful. There is a growing knowledge of the molecular mechanisms underlying both the neuroprotective and neurodestructive effects of NMDA receptor activity, as well as the factors that determine whether an episode of NMDA receptor activity is harmful or beneficial. It is becoming apparent that oxidative stress plays a role in promoting neuronal death in response to both hyper- and hypo-activity of the NMDA receptor. Increased understanding in this field is leading to the discovery of new therapeutic targets and strategies for excitotoxic disorders, as well as a growing appreciation of the harmful consequences of NMDA receptor blockade.
Unique signal transduction of the VEGF family members VEGF-A and VEGF-E
Authors: Shibuya Masabumi
Published: November 2009

Both VEGF (vascular endothelial growth factor)-A and Orf-virus-encoded VEGF-E bind and activate VEGFR (VEGF receptor)-2; however, only VEGF-A binds VEGFR-1. To understand the biological differences between VEGF-A and VEGF-E in vivo, we established transgenic mouse models. K14 (keratin-14)-promoter-driven VEGF-E transgenic mice showed a significant increase in mature blood vessels. However, K14–VEGF-A transgenic mice exhibited severe inflammation and oedema with increased angiogenesis, as well as lymphangiogenesis and lymph vessel dilatation. K14–VEGF-A transgenic mice deficient in VEGFR-1 signalling (K14–VEGF-A-tg/VEGFR-1 TK−/− mice) showed decreases in oedema and inflammation with less recruitment of macrophage-lineage cells, suggesting an involvement of VEGFR-1 in these adverse effects. VEGFE might be more useful than VEGFA for pro-angiogenic therapy.
VEGF resistance as a molecular basis to explain the angiogenesis paradox in diabetes mellitus
Authors: Waltenberger Johannes
Published: November 2009

The action of VEGF (vascular endothelial growth factor) is essential to maintain proper endothelial and vascular function. VEGF stimulates virtually all aspects of endothelial function, namely proliferation, migration, permeability and nitric oxide production and release. In addition, the action of VEGF makes the endothelium anti-apoptotic. In turn, the inhibition of VEGF action is associated with endothelial dysfunction. Likewise, endothelial dysfunction can be found in the presence of several cardiovascular risk factors, including diabetes mellitus, hypercholesterolaemia and smoking. As circulating monocytes express functionally active VEGFR-1 (VEGF receptor 1) on their surface, monocytes and the related VEGFR-1-mediated signal transduction cascades have come into focus. The function of monocytes is negatively affected by diabetes mellitus, resulting in monocyte dysfunction. More specifically, a VEGF-related signal transduction defect can be detected in monocytes isolated from diabetic individuals. This reduced monocyte response to VEGF, demonstrated by a reduced chemotactic response, can be regarded as VEGF resistance. It is based on the pre-activation of certain intracellular pathways secondary to the diabetes mellitus-related RAGE (receptor for advanced glycation end-products) activation, ROS (reactive oxygen species) activation and inhibition of PTPs (protein tyrosine phosphatases). This unspecific pre-activation of intracellular pathways represents the molecular basis of VEGF resistance in diabetes mellitus.
VEGF receptor trafficking in angiogenesis
Authors: Scott Alice , Mellor Harry
Published: November 2009

The intracellular trafficking of receptors provides a way to control the overall sensitivity of a cell to receptor stimulation. These sorting pathways are also used to shape the balance of signals that are generated in response to receptor activation. The major pro-angiogenic growth factor receptor is VEGFR2 (vascular endothelial growth factor 2). VEGFR2 activates a very similar set of signalling pathways to other RTKs (receptor tyrosine kinases); however, its intracellular trafficking is very different. Furthermore, VEGFR2 can form a complex with a range of different angiogenic regulators that in turn regulate the trafficking of VEGFR2 through the endosomal pathway. This regulated trafficking of VEGFR2 has important consequences for angiogenic signalling and is a clear demonstration of how the endosomal pathway plays a critical role in connecting receptor signalling pathways to cellular events.
A role for protein ubiquitination in VEGFR-2 signalling and angiogenesis
Authors: Rahimi Nader
Published: November 2009

Regulation of angiogenesis is often viewed as a balance between pro-angiogenic and anti-angiogenic factors, and when the balance shifts in favour of angiogenesis stimulators, an angiogenic switch turns on the normally inactive endothelial cells to grow new blood vessels. Recent studies have shown that PLCγ1 (phospholipase Cγ1), a major signalling substrate of VEGFR-2 (vascular endothelial growth factor receptor 2), undergoes c-Cbl-mediated ubiquitination. c-Cbl suppresses tyrosine phosphorylation of PLCγ1 and with it VEGF (vascular endothelial growth factor)-induced endothelial cell proliferation and angiogenesis. Loss of c-Cbl in mice results in enhanced retinal neovascularization, VEGF- and tumour-induced angiogenesis. Notably, this observation suggests that c-Cbl-mediated ubiquitination pathway plays a central role in the ‘angiogenic switch’ employed by the VEGF system. The present article highlights the recent findings demonstrating a novel role for protein ubiquitination in angiogenesis and its potential in angiogenesis-based therapy.
The anti-angiogenic isoforms of VEGF in health and disease
Authors: Qiu Yan , Hoareau-Aveilla Coralie , Oltean Sebastian , Harper Steven J. , Bates David O.
Published: November 2009

Anti-angiogenic VEGF (vascular endothelial growth factor) isoforms, generated from differential splicing of exon 8, are widely expressed in normal human tissues but down-regulated in cancers and other pathologies associated with abnormal angiogenesis (cancer, diabetic retinopathy, retinal vein occlusion, the Denys–Drash syndrome and pre-eclampsia). Administration of recombinant VEGF165b inhibits ocular angiogenesis in mouse models of retinopathy and age-related macular degeneration, and colorectal carcinoma and metastatic melanoma. Splicing factors and their regulatory molecules alter splice site selection, such that cells can switch from the anti-angiogenic VEGFxxxb isoforms to the pro-angiogenic VEGFxxx isoforms, including SRp55 (serine/arginine protein 55), ASF/SF2 (alternative splicing factor/splicing factor 2) and SRPK (serine arginine domain protein kinase), and inhibitors of these molecules can inhibit angiogenesis in the eye, and splice site selection in cancer cells, opening up the possibility of using splicing factor inhibitors as novel anti-angiogenic therapeutics. Endogenous anti-angiogenic VEGFxxxb isoforms are cytoprotective for endothelial, epithelial and neuronal cells in vitro and in vivo, suggesting both an improved safety profile and an explanation for unpredicted anti-VEGF side effects. In summary, C-terminal distal splicing is a key component of VEGF biology, overlooked by the vast majority of publications in the field, and these findings require a radical revision of our understanding of VEGF biology in normal human physiology.
Notch signalling in ischaemia-induced angiogenesis
Authors: Zen Ayman Al Haj , Madeddu Paolo
Published: November 2009

Notch signalling represents a key pathway essential for normal vascular development. Recently, great attention has been focused on the implication of Notch pathway components in postnatal angiogenesis and regenerative medicine. This paper critically reviews the most recent findings supporting the role of Notch in ischaemia-induced neovascularization. Notch signalling reportedly regulates several steps of the reparative process occurring in ischaemic tissues, including sprouting angiogenesis, vessel maturation, interaction of vascular cells with recruited leucocytes and skeletal myocyte regeneration. Further characterization of Notch interaction with other signalling pathways might help identify novel targets for therapeutic angiogenesis.
The DDAH/ADMA pathway in the control of endothelial cell migration and angiogenesis
Authors: Fiedler Lorna R. , Wojciak-Stothard Beata
Published: November 2009

ADMA (asymmetric dimethylarginine) is a cardiovascular risk factor and an endogenous inhibitor of NOS (nitric oxide synthase). ADMA is metabolized by DDAHs (dimethylarginine dimethylaminohydrolases). ADMA levels are increased in cardiovascular disorders associated with abnormal angiogenesis but the mechanisms are poorly understood. Recent studies show that altering ADMA metabolism in vivo and in vitro modulates the activity of Rho GTPases, key regulators of actin dynamics, endothelial cell motility and angiogenesis. In the present review, we consider this and other NO-dependent and -independent molecular mechanisms by which the DDAH/ADMA pathway regulates angiogenesis.
ERK5 and the regulation of endothelial cell function
Authors: Roberts Owain Llŷr , Holmes Katherine , Müller Jürgen , Cross Darren A.E. , Cross Michael J.
Published: November 2009

ERK5 (extracellular-signal-regulated kinase 5), also termed BMK1 [big MAPK1 (mitogen-activated protein kinase 1)], is the most recently discovered member of the MAPK family. It is expressed in a variety of tissues and is activated by a range of growth factors, cytokines and cellular stresses. Targeted deletion of Erk5 in mice has revealed that the ERK5 signalling cascade is critical for normal cardiovascular development and vascular integrity. In vitro studies have revealed that in endothelial cells, ERK5 is required for preventing apoptosis, mediating shear-stress signalling, regulating hypoxia, tumour angiogenesis and cell migration. This review focuses on our current understanding of the role of ERK5 in regulating endothelial cell function.
Gene Expression in Neuronal Disease
Authors: Wood Ian C. , Gray Nicola K. , Jones Lesley
Published: November 2009

The brain is the most complex organ of the body and it contains the greatest diversity of cell types. Collectively, the cells within the brain express the greatest number of genes encoded within our genome. Inappropriate gene expression within these cells plays a fundamental role in many neuronal diseases. Illuminating the mechanisms responsible for gene expression is key to understanding these diseases. Because of the complexity, however, there is still much to understand about the mechanisms responsible for gene expression in the brain. There are many steps required for a protein to be generated from a gene, and groups who focus on gene expression normally study a single step such as regulation of transcription, mechanisms of RNA processing or control of translation. To address this, experts were brought together at the Gene Expression in Neuronal Disease meeting in Cardiff. This forum provided the latest insights into specific stages of gene expression in the brain and encompassed the complete pathway from DNA to protein. The present article summarizes the meeting talks and related papers in this issue of Biochemical Society Transactions.
Unravelling neurogenetic networks implicated in developmental language disorders
Authors: Vernes Sonja C. , Fisher Simon E.
Published: November 2009

Childhood syndromes disturbing language development are common and display high degrees of heritability. In most cases, the underlying genetic architecture is likely to be complex, involving multiple chromosomal loci and substantial heterogeneity, which makes it difficult to track down the crucial genomic risk factors. Investigation of rare Mendelian phenotypes offers a complementary route for unravelling key neurogenetic pathways. The value of this approach is illustrated by the discovery that heterozygous FOXP2 (where FOX is forkhead box) mutations cause an unusual monogenic disorder, characterized by problems with articulating speech along with deficits in expressive and receptive language. FOXP2 encodes a regulatory protein, belonging to the forkhead box family of transcription factors, known to play important roles in modulating gene expression in development and disease. Functional genetics using human neuronal models suggest that the different FOXP2 isoforms generated by alternative splicing have distinct properties and may act to regulate each other's activity. Such investigations have also analysed the missense and nonsense mutations found in cases of speech and language disorder, showing that they alter intracellular localization, DNA binding and transactivation capacity of the mutated proteins. Moreover, in the brains of mutant mice, aetiological mutations have been found to disrupt the synaptic plasticity of Foxp2-expressing circuitry. Finally, although mutations of FOXP2 itself are rare, the downstream networks which it regulates in the brain appear to be broadly implicated in typical forms of language impairment. Thus, through ongoing identification of regulated targets and interacting co-factors, this gene is providing the first molecular entry points into neural mechanisms that go awry in language-related disorders.
Whole genome expression as a quantitative trait
Authors: Hardy John , Trabzuni Danyah , Ryten Mina
Published: November 2009

Surprisingly, whole genome analyses of complex human neurological and psychiatric disorders have revealed that many genetic risk factors are likely to influence gene expression rather than alter protein sequences. Previous analyses of neurological diseases have shown that genetic variability in gene expression levels of deposited proteins influence disease risk. With this background, we have embarked on a comprehensive project to determine the effects of common genetic variability on whole genome gene expression.
High-throughput sequencing methods to study neuronal RNA–protein interactions
Authors: Ule Jernej
Published: November 2009

UV-cross-linking and RNase protection, combined with high-throughput sequencing, have provided global maps of RNA sites bound by individual proteins or ribosomes. Using a stringent purification protocol, UV-CLIP (UV-cross-linking and immunoprecipitation) was able to identify intronic and exonic sites bound by splicing regulators in mouse brain tissue. Ribosome profiling has been used to quantify ribosome density on budding yeast mRNAs under different environmental conditions. Post-transcriptional regulation in neurons requires high spatial and temporal precision, as is evident from the role of localized translational control in synaptic plasticity. It remains to be seen if the high-throughput methods can be applied quantitatively to study the dynamics of RNP (ribonucleoprotein) remodelling in specific neuronal populations during the neurodegenerative process. It is certain, however, that applications of new biochemical techniques followed by high-throughput sequencing will continue to provide important insights into the mechanisms of neuronal post-transcriptional regulation.
Pathogenic mechanisms of myotonic dystrophy
Authors: Lee Johanna E. , Cooper Thomas A.
Published: November 2009

DM (myotonic dystrophy) is a dominantly inherited genetic disorder that is the most common cause of muscular dystrophy in adults affecting 1 in 8500 individuals worldwide. Different microsatellite expansions in two loci cause different forms of the disease that share similar features: DM1 (DM type 1) is caused by a tri- (CTG) nucleotide expansion within the DMPK (dystrophia myotonica protein kinase) 3′-untranslated region and DM2 (DM type 2) is caused by a tetra- (CCTG) nucleotide expansion within intron 1 of the ZNF9 (zinc finger 9) gene. The pathogenic mechanism of this disease involves the RNA transcribed from the expanded allele containing long tracts of (CUG)n or (CCUG)n. The RNA results in a toxic effect through two RNA-binding proteins: MBNL1 (muscleblind-like 1) and CUGBP1 (CUG-binding protein 1). In DM1, MBNL1 is sequestered on CUG repeat-containing RNA resulting in its loss-of-function, while CUGBP1 is up-regulated through a signalling pathway. The downstream effects include disrupted regulation of alternative splicing, mRNA translation and mRNA stability, which contribute to the multiple features of DM1. This review will focus on the RNA gain-of-function disease mechanism, the important roles of MBNL1 and CUGBP1 in DM1, and the relevance to other RNA dominant disorders.
Gene expression networks: competing mRNA decay pathways in mammalian cells
Authors: Maquat Lynne E. , Gong Chenguang
Published: November 2009

Nonsense-mediated mRNA decay and Staufen1-mediated mRNA decay are mechanistically related pathways that serve distinct purposes. In the present article, we give an overview of each pathway. We describe how a factor that is common to both pathways results in their competition. We also explain how competition between the two pathways contributes to the differentiation of C2C12 myoblasts to multinucleated myotubes.
eEF1A2 and neuronal degeneration
Authors: Abbott Catherine M. , Newbery Helen J. , Squires Charlotte E. , Brownstein David , Griffiths Lowri A. , Soares Dinesh C.
Published: November 2009

Translation elongation factor eEF1A (eukaryotic elongation factor 1A) exists as two individually encoded variants in mammals, which are 98% similar and 92% identical at the amino acid level. One variant, eEF1A1, is almost ubiquitously expressed, the other variant, eEF1A2, shows a very restricted pattern of expression. A spontaneous mutation was described in 1972, which gives rise to the wasted phenotype: homozygous wst/wst mice develop normally until shortly after weaning, but then lose muscle bulk, acquire tremors and gait abnormalities and die by 4 weeks. This mutation has been shown to be a deletion of 15 kb that removes the promoter and first exon of the gene encoding eEF1A2. The reciprocal pattern of expression of eEF1A1 and eEF1A2 in muscle fits well with the timing of onset of the phenotype of wasted mice: eEF1A1 declines after birth until it is undetectable by 3 weeks, whereas eEF1A2 expression increases over this time. No other gene is present in the wasted deletion, and transgenic studies have shown that the phenotype is due to loss of eEF1A2. We have shown that eEF1A2, but not eEF1A1, is also expressed at high levels in motor neurons in the spinal cord. Wasted mice develop many pathological features of motor neuron degeneration and may represent a good model for early onset of motor neuron disease. Molecular modelling of the eEF1A1 and eEF1A2 protein structures highlights differences between the two variants that may be critical for functional differences. Interactions between eEF1A2 and ZPR1 (zinc-finger protein 1), which interacts with the SMN (survival motor neuron) protein, may be important in motor neuron biology.
Protein synthesis and its control in neuronal cells with a focus on vanishing white matter disease
Authors: Pavitt Graham D. , Proud Christopher G.
Published: November 2009

Protein synthesis (also termed mRNA translation) is a key step in the expression of a cell's genetic information, in which the information contained within the coding region of the mRNA is used to direct the synthesis of the new protein, a process that is catalysed by the ribosome. Protein synthesis must be tightly controlled, to ensure the right proteins are made in the right amounts at the right time, and must be accurate, to avoid errors that could lead to the production of defective and potentially damaging proteins. In addition to the ribosome, protein synthesis also requires proteins termed translation factors, which mediate specific steps of the process. The first major stage of mRNA translation is termed ‘initiation’ and involves the recruitment of the ribosome to the mRNA and the identification of the correct start codon to commence translation. In eukaryotic cells, this process requires a set of eIFs (eukaryotic initiation factors). During the second main stage of translation, ‘elongation’, the ribosome traverses the coding region of the mRNA, assembling the new polypeptide: this process requires eEFs (eukaryotic elongation factors). Control of eEF2 is important in certain neurological processes. It is now clear that defects in eIFs or in their control can give rise to a number of diseases. This paper provides an overview of translation initiation and its control mechanisms, particularly those examined in neuronal cells. A major focus concerns an inherited neurological condition termed VHM (vanishing white matter) or CACH (childhood ataxia with central nervous system hypomyelination). VWM/CACH is caused by mutations in the translation initiation factor, eIF2B, a component of the basal translational machinery in all cells.
Neuronal Glutamate and GABAA Receptor Function in Health and Disease
Authors: Moult Peter R.
Published: November 2009

Glutamate and GABA (γ-aminobutyric acid) are the predominant excitatory and inhibitory neurotransmitters in the mammalian CNS (central nervous system) respectively, and as such have undergone intense investigation. Given their predominance, it is no wonder that the reciprocal receptors for these neurotransmitters have attracted so much attention as potential targets for the promotion of health and the treatment of disease. Indeed, dysfunction of these receptors underlies a number of well-characterized neuropathological conditions such as anxiety, epilepsy and neurodegenerative diseases. Although intrinsically linked, the glutamatergic and GABAergic systems have, by and large, been investigated independently, with researchers falling into the ‘excitatory’ or ‘inhibitory’ camps. Around 70 delegates gathered at the University of St Andrews for this Biochemical Society Focused Meeting aimed at bringing excitation and inhibition together. With sessions on behaviour, receptor structure and function, receptor trafficking, activity-dependent changes in gene expression and excitation/inhibition in disease, the meeting was the ideal occasion for delegates from both backgrounds to interact. This issue of Biochemical Society Transactions contains papers written by those who gave oral presentations at the meeting. In this brief introductory review, I put into context and give a brief overview of these contributions.
Fractionating spatial memory with glutamate receptor subunit-knockout mice
Authors: Bannerman David M.
Published: November 2009

In recent years, the contribution that different glutamate receptor subtypes and subunits make to spatial learning and memory has been studied extensively using genetically modified mice in which key proteins are knocked out. This has revealed dissociations between different aspects of spatial memory that were not previously apparent from lesion studies. For example, studies with GluA1 AMPAR [AMPA (α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) receptor] subunit-knockout mice have revealed the presence of a GluA1-dependent, non-associative short-term memory mechanism that is important for performance on spatial working memory tasks, and a GluA1-independent, long-term associative memory mechanism which underlies performance on spatial reference memory tasks. Within this framework we have also studied the contributions of different GluN2-containing NMDARs [NMDA (N-methyl-D-aspartate) receptors] to spatial memory. Studies with GluN2 NMDAR mutants have revealed different contributions from GluN2A- and GluN2B-containing NMDARs to spatial learning. Furthermore, comparison of forebrain- and hippocampus-specific GluN2B-knockout mice has demonstrated that both hippocampal and extra-hippocampal NMDARs make important contributions to spatial memory performance.
Role of GABAA receptors in cognition
Authors: Möhler Hanns
Published: November 2009

Complex brains have developed specialized mechanisms for the grouping of principal cells into temporal coalitions of local or distant networks: the inhibitory interneuron ‘clocking’ networks. They consist of GABAergic (where GABA is γ-aminobutyric acid) interneurons of a rich diversity. In cortical circuits, these neurons control spike timing of the principal cells, sculpt neuronal rhythms, select cell assemblies and implement brain states. On the basis of these considerations, the deficits in cognition, emotion and perception in psychiatric disorders such as anxiety, depression or schizophrenia are considered to manifest themselves through a dysregulation of the inhibitory interneuron ‘clocking’ network as a final common denominator, irrespective of the diverse underlying disease pathologies. The diversity of GABAergic interneurons is paralleled by a corresponding diversity of GABAA receptors in network regulation. The region-, cell- and domain-specific location of these receptor subtypes offers the possibility to gain functional insights into the role of behaviourally relevant neuronal circuits. Using genetic manipulation, the regulation of anxiety behaviour was attributed to neuronal circuits characterized by the expression of α2-GABAA receptors. Neurons expressing α3-GABAA receptors, located mainly in aminergic and basal forebrain cholinergic neurons, were related to a hyperdopaminergic phenotype, typical of schizophrenic symptoms. Temporal and spatial memory were selectively modulated by extrasynaptic α5-GABAA receptors. Chronic pathological pain was under the regulation of spinal and cortical α2- (and α3-) GABAA receptors. Thus the relevance of the diversity of inhibitory GABAA receptor subtypes for the regulation of cognition, emotion and memory is increasingly being recognized. The clinical proof-of-concept of a subtype-specific pharmacology is most advanced for the alleviation of cognitive dysfunctions in schizophrenia, based on the treatment of patients with an α2/α3-GABAA receptor ligand.