FKBPL and Peptide Derivatives: Novel Biological Agents That Inhibit Angiogenesis by a CD44-Dependent Mechanism

Purpose: Antiangiogenic therapies can be an important adjunct to the management of many malignancies. Here we investigated a novel protein, FKBPL, and peptide derivative for their antiangiogenic activity and mechanism of action.

Experimental Design: Recombinant FKBPL (rFKBPL) and its peptide derivative were assessed in a range of human microvascular endothelial cell (HMEC-1) assays in vitro. Their ability to inhibit proliferation, migration, and Matrigel-dependent tubule formation was determined. They were further evaluated in an ex vivo rat model of neovascularization and in two in vivo mouse models of angiogenesis, that is, the sponge implantation and the intravital microscopy models. Antitumor efficacy was determined in two human tumor xenograft models grown in severe compromised immunodeficient (SCID) mice. Finally, the dependence of peptide on CD44 was determined using a CD44-targeted siRNA approach or in cell lines of differing CD44 status.

Results: rFKBPL inhibited endothelial cell migration, tubule formation, and microvessel formation in vitro and in vivo. The region responsible for FKBPL's antiangiogenic activity was identified, and a 24-amino acid peptide (AD-01) spanning this sequence was synthesized. It was potently antiangiogenic and inhibited growth in two human tumor xenograft models (DU145 and MDA-231) when administered systemically, either on its own or in combination with docetaxel. The antiangiogenic activity of FKBPL and AD-01 was dependent on the cell-surface receptor CD44, and signaling downstream of this receptor promoted an antimigratory phenotype.

Conclusion: FKBPL and its peptide derivative AD-01 have potent antiangiogenic activity. Thus, these agents offer the potential of an attractive new approach to antiangiogenic therapy.

Association of Genetic Variants at 3q22 with Nephropathy in Patients with Type 1 Diabetes Mellitus

Diabetic nephropathy (DN) is the primary cause of morbidity and mortality in patients with type 1 diabetes mellitus (T1DM) and affects about 30% of these patients. We have previously localized a DN locus on chromosome 3q with suggestive linkage in Finnish individuals. Linkage to this region has also been reported earlier by several other groups. To fine map this locus, we conducted a multistage case-control association study in T1DM patients, comprising 1822 cases with nephropathy and 1874 T1DM patients free of nephropathy, from Finland, Iceland, and the British Isles. At the screening stage, we genotyped 3072 tag SNPs, spanning a 28 Mb region, in 234 patients and 215 controls from Finland. SNPs that met the significance threshold of p

AKT1 Is Associated with Schizophrenia Across Multiple Symptom Dimensions in the Irish Study of High Density Schizophrenia Families

Background: The phosphatidylinositol 3-kinase (PI3K)-AKT signal transduction pathway is critical to cell growth and survival. In vitro functional studies indicate that the candidate schizophrenia susceptibility gene DTNBP1 influences AKT signaling to promote neuronal viability. The AKT1 gene has also been implicated in schizophrenia by association studies and decreased protein expression in the brains of schizophrenic patients. 
 Methods: The association of DTNBP1 in the Irish Study of High Density Schizophrenia Families (ISHDSF) prompted our investigation of AKT1 for association with disease in this sample. Eight single nucleotide polymorphisms spanning AKT1 were analyzed for association with schizophrenia across four definitions of affection and according to Operational Criteria Checklist of Psychotic Illness (OPCRIT) symptom scales. We examined expression of AKT1 messenger RNA from postmortem brain tissue of schizophrenic, bipolar, and control individuals. 
 Results: No single marker showed significant association, but the risk haplotype previously found over-transmitted to Caucasian schizophrenic patients was significantly under-transmitted in the ISHDSF (.01 < p < .05), across all OPCRIT symptom dimensions. Exploratory haplotype analysis confirmed association with schizophrenia toward the 5’ end of AKT1 (.008 < p < .049, uncorrected). We found significantly decreased RNA levels in prefrontal cortex of schizophrenic individuals, consistent with reduced AKT1 protein levels reported in schizophrenic brain. 
 Conclusions: The replication of association of AKT1 gene variants in a further Caucasian family sample adds support for involvement of AKT signaling in schizophrenia, perhaps encompassing a broader clinical phenotype that includes mood dysregulation. We show that AKT signaling might be compromised in schizophrenic and bipolar patients via reduced RNA expression of specific AKT isoforms.

Phylogeographic analysis of North American populations of the parasitic herbaceous plant Monotropa hypopitys reveals a complex history of range expansion from multiple late glacial refugia

Aim We carried out a phylogeographic study across the range of the herbaceous plant species Monotropa hypopitys L. in North America to determine whether its current disjunct distribution is due to recolonization from separate eastern and western refugia after the Last Glacial Maximum (LGM). Location North America: Pacific Northwest and north-eastern USA/south-eastern Canada. Methods Palaeodistribution modelling was carried out to determine suitable climatic regions for M. hypopitys at the LGM. We analysed between 155 and 176 individuals from 39 locations spanning the species' entire range in North America. Sequence data were obtained for the chloroplast rps2 gene (n=168) and for the nuclear ITS region (n=158). Individuals were also genotyped for eight microsatellite loci (n=176). Interpolation of diversity values was used to visualize the range-wide distribution of genetic diversity for each of the three marker classes. Minimum spanning networks were constructed showing the relationships between the rps2 and ITS haplotypes, and the geographical distributions of these haplotypes were plotted. The numbers of genetic clusters based on the microsatellite data were estimated using Bayesian clustering approaches. Results The palaeodistribution modelling indicated suitable climate envelopes for M. hypopitys at the LGM in both the Pacific Northwest and south-eastern USA. High levels of genetic diversity and endemic haplotypes were found in Oregon, the Alexander Archipelago, Wisconsin, and in the south-eastern part of the species' distribution range. Main conclusions Our results suggest a complex recolonization history for M. hypopitys in North America, involving persistence in separate eastern and western refugia. A generally high degree of congruence between the different marker classes analysed indicated the presence of multiple refugia, with at least two refugia in each area. In the west, putative refugia were identified in Oregon and the Alexander Archipelago, whereas eastern refugia may have been located in the southern part of the species' current distribution, as well as in the 'Driftless Area'. These findings are in contrast to a previous study on the related species Orthilia secunda, which has a similar disjunct distribution to M. hypopitys, but which appears to have recolonized solely from western refugia. © 2011 Blackwell Publishing Ltd.

A 7000 yr perspective on volcanic ash clouds affecting northern Europe

The ash cloud resulting from the 2010 eruption of Eyjafjöll caused severe disruption to air travel across Europe but as a geological event, it is not unprecedented. Analysis of peat and lake sediments from northern Europe has revealed the presence of microscopic layers of Icelandic volcanic ash (tephra). These sedimentary records, together with historical records of Holocene ash falls, demonstrate that Icelandic volcanoes have generated substantial ash clouds that reached northern Europe many times. Here we present the first comprehensive compilation of sedimentary and historical records of ash-fall events in northern Europe, spanning the last 7000 years. Within this period ten tephra layers have been identified in the Faroe Islands, 14 in Great Britain, 11 in Germany, 38 in Scandinavia and 33 in Ireland. Seven ash fall events have been historically documented prior to the Eyjafjöll 2010 event. Ash fall events appear to be more frequent in the last 1500 years, but it is unclear whether this reflects a true increase in eruption frequency or dispersal, or is an artefact of the records themselves or the way they have been generated. In the last 1,000 years, volcanic ash clouds reached Northern Europe with a mean return interval of 53 ± 8 years (the range of return intervals is between 6 and 112 years). Modelling using the ash records for the last millennium indicates that for any 10 year period there is a 17% probability of tephra fallout event in Northern Europe. These values must be considered as conservative estimates due to the nature of tephra capture and preservation in the sedimentary record.

ESC observations of SN 2005cf - I. Photometric evolution of a normal Type Ia supernova

We present early-time optical and near-infrared photometry of supernova (SN) 2005cf. The observations, spanning a period from about 12 d before to 3 months after maximum, have been obtained through the coordination of observational efforts of various nodes of the European Supernova Collaboration and including data obtained at the 2-m Himalayan Chandra Telescope. From the observed light curve we deduce that SN 2005cf is a fairly typical SN Ia with a post-maximum decline [Delta m(15)(B)(true) = 1.12] close to the average value and a normal luminosity of M-B,M-max = -19.39 +/- 0.33. Models of the bolometric light curve suggest a synthesized Ni-56 mass of about 0.7 M-circle dot. The negligible host galaxy interstellar extinction and its proximity make SN 2005cf a good Type Ia SN template.

SN 2009jf: a slow-evolving stripped-envelope core-collapse supernova

We present an extensive set of photometric and spectroscopic data for SN 2009jf, a nearby Type Ib supernova (SN), spanning from ˜20 d before B-band maximum to 1 yr after maximum. We show that SN 2009jf is a slowly evolving and energetic stripped-envelope SN and is likely from a massive progenitor (25-30 Msun). The large progenitor's mass allows us to explain the complete hydrogen plus helium stripping without invoking the presence of a binary companion. The SN occurred close to a young cluster, in a crowded environment with ongoing star formation. The spectroscopic similarity with the He-poor Type Ic SN 2007gr suggests a common progenitor for some SNe Ib and Ic. The nebular spectra of SN 2009jf are consistent with an asymmetric explosion, with an off-centre dense core. We also find evidence that He-rich Ib SNe have a rise time longer than other stripped-envelope SNe, however confirmation of this result and further observations are needed. This paper is based on observations with several telescopes, including NTT(184.D-1151), VLT-UT1(085.D-0750,386.D-0126), NOT, WHT, TNG, PROMPT, Ekar, Calar Alto and Liverpool Telescope.

Structural and kinetic studies of spin crossover in an Iron(II) complex with a novel tripodal ligand

Configurational and ligand conformational influences on the kinetics of (1)A(1) reversible arrow T-5(2) spin crossover in the Fe(II) complex with the novel tripodal ligand, 1,1,1-tris((N-(2-pyridylmethyl)-N-methylamino)methyl)ethane (tptMetame), have been explored. Despite having six chelate rings and three chiral nitrogen atoms, only one enantiomeric pair of isomers, Delta, SSS, and Lambda, RRR, of the complex ion is observed. The conformation of the three rings forming the upper ''cap'' of the complex structure can be assigned delta or lambda with respect to the 3-fold molecular axis. X-ray data at 300 and 153 K, above and below the critical temperature for the spin transition, show that the conformation of the ligand ''cap'' is the same as the absolute configuration of the complex, with the same Lambda lambda(CAP)(or Delta delta(CAP)) combination prevailing for both the LS ((1)A(1)) and HS (T-5(2)) isomers. Molecular mechanics calculations further show that the ligand energy remains lowest for this Lambda lambda(CAP) (or Delta delta(CAP)) combination at all Fe-N distances over the range spanning the LS and HS isomers. Measurements of the spin crossover relaxation time have been carried out in solution over the temperature range 293-170 K. The observed monophasic relaxation traces are also consistent with the absolute configuration of the complex remaining unaltered during the spin crossover.

PHOTOPERTURBATION OF THE (1)A-][-(5)T SPIN EQUILIBRIUM IN AN IRON(II) COMPLEX IN SOLUTION VIA LIGAND-FIELD EXCITATION

Variable-temperature magnetic susceptibility measurements in the solid state of the bis complex of tris(1-pyrazolyl)-methane with Fe(II), [Fe(tpm)2](ClO4)2, suggest the existence of singlet-quintet spin crossover with the singlet isomer largely favored at room temperature. In acetonitrile solution, measurement of the absorption spectrum as a function of temperature reveals a spin equilibrium with the quintet population varying from ca. 6% at 233 K to ca. 30% at 295 K. When the complex in solution is irradiated with a laser pulse at wavelengths within the ligand field absorption band of the singlet isomer, ground-state depletion occurs within the pulse duration followed by fast recovery to the original absorbance level with a time constant of 25 +/- 5ns. The recovery time is virtually independent of temperature over the range +23 to -43-degrees-C, but the signal:noise ratio of the transient signals increases with decreasing temperature. The effect was observable at several monitoring wavelengths spanning the LF and MLCT absorption regions of the complex but only when the irradiation wavelength fell within the LF absorption region. Irradiation within the MLCT band produced no effect other than that of laser pulse scatter. The observations are interpreted in terms of photoperturbation of the singlet-quintet spin state equilibrium, which in this case occurs solely through excitation in the ligand field absorption region of the complex and is the first reported instance of this type for a spin-crossover complex in solution.

QCA Systolic array design

Quantum-dot Cellular Automata (QCA) technology is a promising potential alternative to CMOS technology. To explore the characteristics of QCA and suitable design methodologies, digital circuit design approaches have been investigated. Due to the inherent wire delay in QCA, pipelined architectures appear to be a particularly suitable design technique. Also, because of the pipeline nature of QCA technology, it is not suitable for complicated control system design. Systolic arrays take advantage of pipelining, parallelism and simple local control. Therefore, an investigation into these architectures in QCA technology is provided in this paper. Two case studies, (a matrix multiplier and a Galois Field multiplier) are designed and analyzed based on both multilayer and coplanar crossings. The performance of these two types of interconnections are compared and it is found that even though coplanar crossings are currently more practical, they tend to occupy a larger design area and incur slightly more delay. A general semi-conductor QCA systolic array design methodology is also proposed. It is found that by applying a systolic array structure in QCA design, significant benefits can be achieved particularly with large systolic arrays, even more so than when applied in CMOS-based technology.

A 50,000-year record of Late Pleistocene tropical vegetation and human impact in lowland Borneo.

There has been considerable uncertainty about the nature of Pleistocene environments colonised by the first modern humans in Island SE Asia, and about the vegetation of the Last Glacial Maximum (LGM) in the region. Here, the palynology from a series of exposures in the Great Cave of Niah, Sarawak, Malaysian Borneo, spanning a period from ca. 52,000 to 5000 BP is described. Vegetation during this period was climate-driven and often highly unstable. Interstadials are marked by lowland forest, sometimes rather dry and at times by mangroves. Stadials are indicated by taxa characteristic of open environments or, as at the LGM, by highly disturbed rather open forest. Stadials are also characterised by taxa now restricted to 1000-1600 m above sea level, suggesting temperature declines of ca 7-9 C relative to present, by comparison with modern lapse rates. The practice of biomass burning appears associated with the earliest human activity in the cave.

Classical novae from the POINT-AGAPE microlensing survey of M31 - I. The nova catalogue

The POINT-AGAPE (Pixel-lensing Observations with the Isaac Newton Telescope-Andromeda Galaxy Amplified Pixels Experiment) survey is an optical search for gravitational microlensing events towards the Andromeda galaxy (M31). As well as microlensing, the survey is sensitive to many different classes of variable stars and transients. Here we describe the automated detection and selection pipeline used to identify M31 classical novae (CNe) and we present the resulting catalogue of 20 CN candidates observed over three seasons. CNe are observed both in the bulge region as well as over a wide area of the M31 disc. Nine of the CNe are caught during the final rise phase and all are well sampled in at least two colours. The excellent light-curve coverage has allowed us to detect and classify CNe over a wide range of speed class, from very fast to very slow. Among the light curves is a moderately fast CN exhibiting entry into a deep transition minimum, followed by its final decline. We have also observed in detail a very slow CN which faded by only 0.01 mag d(-1) over a 150-d period. We detect other interesting variable objects, including one of the longest period and most luminous Mira variables. The CN catalogue constitutes a uniquely well-sampled and objectively-selected data set with which to study the statistical properties of CNe in M31, such as the global nova rate, the reliability of novae as standard-candle distance indicators and the dependence of the nova population on stellar environment. The findings of this statistical study will be reported in a follow-up paper.

Sequence analysis of the 3' hypoxia-responsive element of the human erythropoietin gene in patients with erythrocytosis

Erythrocytosis arises from a variety of pathogenic mechanisms. We sequenced a 256-bp region 3' to the erythropoietin (Epo) gene which included a 24- to 50-bp minimal hypoxia-responsive element spanning HIF-1- and HNF-4-binding sites in 12 patients with erythrocytosis and 4 normal subjects. Four polymorphisms were found, none of which affected the HIF-1-binding site, although one polymorphism was present in the HNF-4 consensus region. The data indicate that none of these polymorphisms cause erythrocytosis.

The Paralax Infrastructure: Automatic Parallelization With a Helping Hand

Speeding up sequential programs on multicores is a challenging problem that is in urgent need of a solution. Automatic parallelization of irregular pointer-intensive codes, exempli?ed by the SPECint codes, is a very hard problem. This paper shows that, with a helping hand, such auto-parallelization is possible and fruitful. This paper makes the following contributions: (i) A compiler framework for extracting pipeline-like parallelism from outer program loops is presented. (ii) Using a light-weight programming model based on annotations, the programmer helps the compiler to ?nd thread-level parallelism. Each of the annotations speci?es only a small piece of semantic information that compiler analysis misses, e.g. stating that a variable is dead at a certain program point. The annotations are designed such that correctness is easily veri?ed. Furthermore, we present a tool for suggesting annotations to the programmer. (iii) The methodology is applied to autoparallelize several SPECint benchmarks. For the benchmark with most parallelism (hmmer), we obtain a scalable 7-fold speedup on an AMD quad-core dual processor. The annotations constitute a parallel programming model that relies extensively on a sequential program representation. Hereby, the complexity of debugging is not increased and it does not obscure the source code. These properties could prove valuable to increase the ef?ciency of parallel programming.

Phylogenetic analysis of porcine circovirus type 2 (PCV2) pre- and post-epizootic postweaning multisystemic wasting syndrome (PMWS)

The porcine circovirus type 2 (PCV2) genome encodes three major open reading frames (ORFs) encoding the replicase proteins (ORF1), the viral capsid protein (ORF2), and a protein with suggested apoptotic activity (ORF3). Previous phylogenetic analyses of complete genome sequences of PCV2 from GenBank have demonstrated 95-100% intra-group nucleotide sequence identity. However, although these isolates were readily grouped into clusters and clades, there was no correlation between the occurrence of specific PCV2 genotypes and the geographic origin or health status of the pig. In the present study, a unique dataset from a field study spanning the years pre and post the recognition of postweaning multisystemic wasting syndrome (PMWS) in Sweden was utilized. Using this dataset it was possible to discriminate three Swedish genogroups (SG1-3) of PCV2, of which SG1 was recovered from a pig on a healthy farm ten years before the first diagnosis of PMWS in Sweden. The SG1 PCV2/ORF2 gene sequence has been demonstrated to exhibit a high genetic stability over time and has subsequently only been demonstrated in samples from pigs on nondiseased farms. In contrast, SG2 was almost exclusively found on farms that had only recently broken down with PMWS whereas the SG3 genogroup predominated in pigs from PMWS-affected farms. These results further support the results obtained from earlier in vitro and in vivo experimental models and suggest the association of specific PCV2 genogroups with diseased and nondiseased pigs in the field.