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Salum, Rafaela B., Sharon A. Robinson, and Kerrylee Rogers. "A Validated and Accurate Method for Quantifying and Extrapolating Mangrove Above-Ground Biomass Using LiDAR Data." Remote Sensing 13, no. 14 (July 14, 2021): 2763. http://dx.doi.org/10.3390/rs13142763.
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LiDAR data and derived canopy height models can provide useful information about mangrove tree heights that assist with quantifying mangrove above-ground biomass. This study presents a validated method for quantifying mangrove heights using LiDAR data and calibrating this against plot-based estimates of above-ground biomass. This approach was initially validated for the mangroves of Darwin Harbour, in Northern Australia, which are structurally complex and have high species diversity. Established relationships were then extrapolated to the nearby West Alligator River, which provided the opportunity to quantify biomass at a remote location where intensive fieldwork was limited. Relationships between LiDAR-derived mangrove heights and mean tree height per plot were highly robust for Ceriops tagal, Rhizophora stylosa and Sonneratia alba (r2 = 0.84–0.94, RMSE = 0.03–0.91 m; RMSE% = 0.07%–11.27%), and validated well against an independent dataset. Additionally, relationships between the derived canopy height model and field-based estimates of above-ground biomass were also robust and validated (r2 = 0.73–0.90, RMSE = 141.4 kg–1098.58 kg, RMSE% of 22.94–39.31%). Species-specific estimates of tree density per plot were applied in order to align biomass of individual trees with the resolution of the canopy height model. The total above-ground biomass at Darwin Harbour was estimated at 120 t ha−1 and comparisons with prior estimates of mangrove above-ground biomass confirmed the accuracy of this assessment. To establish whether accurate and validated relationships could be extrapolated elsewhere, the established relationships were applied to a LiDAR-derived canopy height model at nearby West Alligator River. Above-ground biomass derived from extrapolated relationships was estimated at 206 t ha−1, which compared well with prior biomass estimates, confirming that this approach can be extrapolated to remote locations, providing the mangrove forests are biogeographically similar. The validated method presented in this study can be used for reporting mangrove carbon storage under national obligations, and is useful for quantifying carbon within various markets.
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Moravec, F., B. Diggles, L. Barnes, and W. Macbeth. "Buckleyella ornata n. sp. (Nematoda: Philometridae) from the abdominal cavity of the talang queenfish Scomberoides commersonnianus (Perciformes: Carangidae) off the northern coast of Australia." Helminthologia 51, no. 3 (September 1, 2014): 230–35. http://dx.doi.org/10.2478/s11687-014-0234-7.
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AbstractA new nematode species, Buckleyella ornata n. sp. (Philometridae), is described from female specimens found in the abdominal cavity (mesenteries) of the talang queenfish Scomberoides commersonnianus Lacepède (Carangidae, Perciformes) caught in Darwin Harbour, northern Australia. Based on light and scanning electron microscopical examination, the new species mainly differs from the only other congeneric species B. buckleyi Rasheed, 1963 in having a markedly shorter oesophagus (2.04–2.75 mm long), by the absence of a cephalic mound around the mouth aperture, by the presence of four submedian cephalic papillae of the inner circle, and by a somewhat different arrangement of cuticular ornamentations on the body surface. Three protruding oesophageal teeth and large, dome-shaped cephalic papillae of the external circle present in the smallest gravid female of B. ornata are atrophied in larger conspecific gravid females. Buckleyella ornata is the first known nominal species of a philometrid parasitizing carangid fishes in Australian waters.
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Stone, I. R., and R. J. Crampton. "‘A disastrous affair’; the Franco-British attack on Petropavlovsk, 1854." Polar Record 22, no. 141 (September 1985): 629–41. http://dx.doi.org/10.1017/s003224740000632x.
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AbstractThe battle of Petropavlovsk in August/September 1854 was a significant though little known victory for the Russians during the Crimean War. Petropavlovsk, i n Kamchatka, was attacked by a Franco-British naval force intending to destroy Russian ships within the harbour and to render the port unusable as a naval base. Allied plans were disrupted by the death ofthe commander in chief, the British Admiral Price, just before the action was joined. A bombardment on 31 August badly damaged the harbour defences and, if followed up, would probably have resulted in success. After a gap of three days, the allies mounted a landing in the rear of the town which was, after severefighting, repelled by the Russians. After this defeat, the squadron dispersed t o ports on the other side of the Pacific.
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RODRIGUES, CLARA F., P. GRAHAM OLIVER, and MARINA R. CUNHA. "Thyasiroidea (Mollusca: Bivalvia) from the mud volcanoes of the Gulf of Cadiz (NE Atlantic)." Zootaxa 1752, no. 1 (April 18, 2008): 41. http://dx.doi.org/10.11646/zootaxa.1752.1.2.
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The Thyasiroidea collected from the mud volcanoes of the Gulf of Cadiz are reviewed. Of the seven species identified only one, Thyasira vulcolutre n. sp., is closely associated with a chemosynthetic setting. This species has anatomical features typical of chemosymbiotic taxa and is compared with T. sarsi (Philippi, 1845), T. southwardae Oliver & Holmes, 2006, T. oleophila Clarke, 1989 and T. methanophila Oliver & Sellanes, 2005. The other six, Thyasira (Parathyasira) granulosa (Monterosato, 1874), Thyasira tortuosa (Jeffreys, 1881), Thyasira obsoleta (Verrill & Bush, 1898), Axinulus croulinensis (Jeffreys, 1847), Mendicula ferruginosa (Forbes, 1844) and Leptaxinus minutus Verrill & Bush 1898, are previously known from typical deep-water benthic settings. Of these only A. croulinensis is known to harbour chemosymbionts although the gill anatomy of T. tortuosa suggests that it might also be chemosymbiotic. Thyasira vulcolutre is restricted to active seeps but there is no pattern in the distribution of the other species.
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Cui, Yonggang, Wei Haur Lam, Tianming Zhang, Chong Sun, Desmond Robinson, and Gerard Hamill. "Temporal Model for Ship Twin-Propeller Jet Induced Sandbed Scour." Journal of Marine Science and Engineering 7, no. 10 (September 27, 2019): 339. http://dx.doi.org/10.3390/jmse7100339.
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This research paper proposes the use of empirical equations to estimate the temporal maximum scour that is induced by twin-propeller ( ε t w i n = Ω t [ l n ( t ) ] Γ t ) when acting over non-cohesive bed materials. A purpose built experimental apparatus is used to obtain the measurement data required for the calculation of the empirical constants. The output from rigorous experimental investigations demonstrates that the maximum scour depth produced from the operation of twin-propeller ( ε t w i n ), within the confines of a harbour basin, varies as a logarithmic function of time. A dimensional analysis of the standard single propeller configuration is used as the foundation upon which the scour equation is postulated. This is extended to include the influence of the operating distance between the twin-propeller configurations for the first time. The division of scours by twin-propeller and single-propeller ( ε twin / ε m ) enables the establishment of mathematical relation to calculate C1, C2, A, and B. The constants are C 1 = 366.11, C 2 = 0.3376, A = 0.859, and B = 0.1571. The proposed scour equation is more reliable within the time zone up to two hours based on the experimental data.
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Mwamuye, Micky M., David Odongo, Yvette Kazungu, Fatuma Kindoro, Paul Gwakisa, Richard P. Bishop, Ard M. Nijhof, and Isaiah Obara. "Variant analysis of the sporozoite surface antigen gene reveals that asymptomatic cattle from wildlife-livestock interface areas in northern Tanzania harbour buffalo-derived T. parva." Parasitology Research 119, no. 11 (October 3, 2020): 3817–28. http://dx.doi.org/10.1007/s00436-020-06902-1.
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Abstract Buffalo-derived Theileria parva can ‘break through’ the immunity induced by the infection and treatment vaccination method (ITM) in cattle. However, no such ‘breakthroughs’ have been reported in northern Tanzania where there has been long and widespread ITM use in pastoralist cattle, and the Cape buffalo (Syncerus caffer) is also present. We studied the exposure of vaccinated and unvaccinated cattle in northern Tanzania to buffalo-derived T. parva using p67 gene polymorphisms and compared this to its distribution in vaccinated cattle exposed to buffalo-derived T. parva in central Kenya, where vaccine ‘breakthroughs’ have been reported. Additionally, we analysed the CD8+ T cell target antigen Tp2 for positive selection. Our results showed that 10% of the p67 sequences from Tanzanian cattle (n = 39) had a buffalo type p67 (allele 4), an allele that is rare among East African isolates studied so far. The percentage of buffalo-derived p67 alleles observed in Kenyan cattle comprised 19% of the parasites (n = 36), with two different p67 alleles (2 and 3) of presumptive buffalo origin. The Tp2 protein was generally conserved with only three Tp2 variants from Tanzania (n = 33) and five from Kenya (n = 40). Two Tanzanian Tp2 variants and two Kenyan Tp2 variants were identical to variants present in the trivalent Muguga vaccine. Tp2 evolutionary analysis did not show evidence for positive selection within previously mapped epitope coding sites. The p67 data indicates that some ITM-vaccinated cattle are protected against disease induced by a buffalo-derived T. parva challenge in northern Tanzania and suggests that the parasite genotype may represent one factor explaining this.
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Keever, Gary J., and William J. Foster. "Chemically Induced Branching of Woody Landscape Plants." Journal of Environmental Horticulture 8, no. 2 (June 1, 1990): 78–82. http://dx.doi.org/10.24266/0738-2898-8.2.78.
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Abstract Axillary budbreak of Ilex Crenata Thunb. ‘Helleri’ and ‘Ilex vomitoria’ Ait. ‘Stoke's Dwarf’ hollies was promoted by a single BA (N-(phenylmethyl)-1H-purin-6-amine) application of 125–1000 ppm compared to an unpruned control. Budbreak of Photinia × Fraseri Dress was stimulated by 500–2500 ppm BA and 2000–5000 ppm Promalin (BA + GA4+7). Budbreak in Nandina domestica Thunb. ‘Harbour Dwarf’ increased with 1000–2500 ppm BA and 2000–5000 ppm Promalin application. Budbreak of Rhododendron × ‘Formosa’ azalea was promoted by 2000 and 2500 ppm BA and 2000–5000 ppm Promalin. Axillary budbreak of Ternstroemia gymnanthera (Wight & Arn.) T. Sprague) and Raphiolepis indica (L.) Lindl. was not affected by BA or Promalin application.
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Koschinski, Sven, Ansgar Diederichs, and Mats Amundin. "Click train patterns of free-ranging harbour porpoises acquired using T-PODs may be useful as indicators of their behaviour." J. Cetacean Res. Manage. 10, no. 2 (February 15, 2023): 147–55. http://dx.doi.org/10.47536/jcrm.v10i2.649.
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Harbour porpoise signals consist of directional, high frequency stereotypic clicks which can be logged using T-PODs. Variation in interclick intervals (ICIs) can be used to distinguish different acoustic behaviours. So far, studies on ICI variation are mostly descriptive and the behavioural context in which certain click train patterns are emitted is poorly understood. In this study, the behaviour of free-ranging porpoises was quantified by using typical ICI patterns known from the literature. These were recorded using two T-PODs deployed at a wind farm site (Nysted, Denmark) between 14 June and 12 July 2005 and during the entanglement of a porpoise calf in a gillnet (Clayoquot Sound Canada). It was possible to distinguish between feeding, approach behaviour and communication and known ICI patterns associated with these behaviours were used to categorise acoustic data. During feeding typical click trains start with long ICIs (30-70ms) and end with ICIs down to about 2ms. In a transition phase ICIs rapidly decrease. Click trains attributed to feeding were found in the wind farm data at a rate of 6.3d–1 (n=174) with a patchy distribution. We found 20 to 74s long click train sequences with ICIs gradually decreasing from a median of 72ms (range 34 to 143ms) down to 5ms at a rate of 1.6day–1 (n=45). This was interpreted as approach behaviour, in which the animal was acoustically ‘locked on’ to a reflective structure. Communication signals are built up of click trains with very short ICIs (<7.7ms). During the entanglement of a porpoise calf, three different call types were determined at a rate of 8.9min–1 (n=89). One call with variable duration (100 to 890ms) and relatively stable ICIs as low as 3.6ms resembled ‘distress calls’ described by Amundin (1991b). Another call type with durations from 780 to 830ms and ICIs ranging from 3.0 to 10 ms and thus different with respect to ICI curve progression was found only three times. These had a U-shaped ICI curve, similar to an ‘alarm’ or ‘fright’ call described by Busnel and Dziedzic (1966). A third and previously unreported call is characterised by a long call duration (up to 1,270ms) and sometimes oscillating ICIs with an initial decrease from about 9ms to around 7ms and an increase towards the end. The data presented suggest that the T-POD is a promising tool for behavioural studies. It is possible to recognise certain acoustic behavioural categories described in the literature, but it is important to look at the temporal context with other vocalisations in T-POD data, such as ICIs of preceding click trains.
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Tabrizi, Sepehr N., Barbara A. Paterson, Christopher K. Fairley, Francis J. Bowden, and Suzanne M. Garland. "Comparison of tampon and urine as self-administered methods of specimen collection in the detection of Chlamydia trachomatis , Neisseria gonorrhoeae and Trichomonas vaginalis in women." International Journal of STD & AIDS 9, no. 6 (June 1, 1998): 347–49. http://dx.doi.org/10.1258/0956462981922386.
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1 Department of Microbiology, The Royal Women's Hospital, Victoria, 2 Menzies School of Health Research, Rocklands Drive, Tiwi, 3 Department of Epidemiology and Preventive Medicine, Alfred Hospital, Monash University, Prahran, Victoria and 4 AIDS/STD Unit, Centre for Disease Control, Territory Health Services, Darwin, Australia Summary: Self-administered sampling techniques for the detection of sexually transmitted diseases (STDs) are particularly useful due to their ease of collection and better patient compliance. Urine specimens, and recently tampons, have been described as methods of specimen collection for the detection of some STDs in women. In this study, 660 women had both first-void urine (FVU) and tampon specimens analysed by polymerase chain reaction (PCR) for the detection of Chlamydia trachomatis , Neisseria gonorrhoeae and Trichomonas vaginalis . Overall 6.5%, 10.1% and 17.9% of urine samples were positive whereas 7%, 21.2% and 22% of tampon specimens were positive for C. trachomatis , N. gonorrhoeae and T. vaginalis respectively. Tampon-collected specimens tested by PCR were more sensitive than urine specimens for the detection of N. gonorrhoeae and T. vaginalis ( P 0.001) and equally sensitive for the detection of C. trachomatis ( P =0.45). <
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Margalit, Ben, and Tsvi Piran. "Shock within a shock: revisiting the radio flares of NS merger ejecta and gamma-ray burst-supernovae." Monthly Notices of the Royal Astronomical Society 495, no. 4 (May 30, 2020): 4981–93. http://dx.doi.org/10.1093/mnras/staa1486.
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ABSTRACT Fast ejecta expelled in binary neutron star (NS) mergers or energetic supernovae (SNe) should produce late-time synchrotron radio emission as the ejecta shocks into the surrounding ambient medium. Models for such radio flares typically assume the ejecta expands into an unperturbed interstellar medium (ISM). However, it is also well known that binary NS mergers and broad-lined Ic SNe Ic can harbour relativistic jetted outflows. In this work, we show that such jets shock the ambient ISM ahead of the ejecta, thus evacuating the medium into which the ejecta subsequently collides. Using an idealized spherically symmetric model, we illustrate that this inhibits the ejecta radio flare at early times $t \lt t_{\rm col} \approx 12 \, {\rm yr} \, (E_{\rm j}/10^{49} \, {\rm erg})^{1/3} (n/1 \, {\rm cm}^{-3})^{-1/3} (\upsilon _{\rm ej}/0.1c)^{-5/3}$, where Ej is the jet energy, n the ISM density, and $\upsilon$ej the ejecta velocity. We also show that this can produce a sharply peaked enhancement in the light curve at t = tcol. This has implications for radio observations of GW170817 and future binary NS mergers, gamma-ray burst (GRB) SNe, decade-long radio transients such as FIRST J1419, and possibly other events where a relativistic outflow precedes a slower moving ejecta. Future numerical work will extend these analytic estimates and treat the multidimensional nature of the problem.
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KANE, R. P. "Comparison of quasi-biennial oscillations of stratospheric winds and atmospheric temperatures at different altitudes." MAUSAM 49, no. 2 (December 16, 2021): 223–28. http://dx.doi.org/10.54302/mausam.v49i2.3622.
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During 1959-89, the 12-month running means of 50 hPa zonal winds, the average atmospheric temperatures in the northern and southern hemisphere at four altitude slabs (950 hPa, 850- 300 hPa, 300-100 hPa and 100-50 hPa), Pacific and Atlantic sea surface temperature (SST) and-30hPa temperatures at North Pole and average for (10°-90° N), all showed quasi-biennial oscillations (QBO). However, whereas the wind QBO had an average spacing of 29 months, only temperatures at 300-100 hPa and Atlantic SST had similar average spacing. Other temperatures as also SO index (represented by Tahiti minus Darwin atmospheric pressure) had larger average spacing. Spectral analysis showed that whereas wind QBO had only one prominent peak at T=2.33 years, other parameters had weak QBOs near T=2.5-2.6 years except Pacific SST and 30 hPa North Pole temperature which had small peaks near T=2.3 years. All the temperatures had prominent peaks in the 3-6 year region which matched with similar peaks in the SO index. There is some indication that stratospheric wind QBO had some relation with parameters at all altitudes in tropics and with North Pole, while ENSO had considerable influence at other latitudes/altitudes.
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Todd, Victoria L. G., William D. Pearse, Nick C. Tregenza, Paul A. Lepper, and Ian B. Todd. "Diel echolocation activity of harbour porpoises (Phocoena phocoena) around North Sea offshore gas installations." ICES Journal of Marine Science 66, no. 4 (March 4, 2009): 734–45. http://dx.doi.org/10.1093/icesjms/fsp035.
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Abstract Todd, V. L. G., Pearse, W. D., Tregenza, N. C., Lepper, P. A., and Todd, I. B. 2009. Diel echolocation activity of harbour porpoises (Phocoena phocoena) around North Sea offshore gas installations. – ICES Journal of Marine Science, 66: 734–745. Echolocation clicks of harbour porpoises (Phocoena phocoena) were detected with T-PODs, autonomous, passive, acoustic-monitoring devices, deployed from an offshore-exploration-drilling-rig and gas-production-platform complex in the Dogger Bank region of the North Sea from 2005 to 2006. Echolocation-click trains were categorized into four phases of the diel cycle: morning, day, evening, and night. Porpoises were present near (<200 m) the platform, and there was a pronounced diel pattern in echolocation activity; the number of porpoise encounters (visits) was greater by night than by day. The number of click trains with a minimum inter-click interval of <10 ms also increased at night. This was confirmed by a comparison of the ratios of feeding buzzes to search-phase clicks (feeding buzz ratios) and an analysis of the changes in pulse-repetition frequencies within each train. A reasonable interpretation of this pattern was that porpoises were feeding below or around the platform at night. The evidence for changes in activity during the morning and evening was less clear, so these may be transitional phases. The pattern of porpoise-echolocation behaviour around this platform is related most probably to the diel activity of their prey. If porpoises cluster regularly around such installations within 500-m shipping exclusion zones, they may be omitted from population surveys. We conclude that offshore installations may play an important role as nocturnal porpoise-feeding stations in an overfished environment, but that further replicated and controlled studies are required. These findings should be taken into consideration during offshore-installation-decommissioning decisions in the North Sea.
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Zhang, Mengjuan, Yuefeng Cai, Nanjing Ji, Benny Kwok Kan Chan, and Xin Shen. "The Mitochondrial Genome of the Globally Invasive Barnacle Megabalanus coccopoma Darwin 1854 (Crustacea: Balanomorpha): Rearrangement and Phylogenetic Consideration within Balanomorpha." Diversity 15, no. 1 (January 14, 2023): 117. http://dx.doi.org/10.3390/d15010117.
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Megabalanus coccopoma (Darwin, 1854) is a globally invasive species in Balanomorpha (Crustacea). This species is a model organism for studying marine pollution and ecology. However, its mitogenome remains unknown. The mitogenome sequencing of M. coccopoma is completed in the present study. It has a 15,098 bp in length, including 13 protein-coding genes (PCGs), 2 ribosomal RNAs (rRNAs), 22 transfer RNAs (tRNAs), along with a putative regulatory area. A substantial A+T bias was observed in the genome composition (68.2%), along with a negative AT (0.82) and GC (−0.136) skew. Compared to the gene sequence of the ground model of pan-crustacea, 13 gene clusters (or genes), such as 10 tRNAs and 3 PCGs, were observed in a different order. This was in line with the previously observed large-scale gene rearrangements of Balanomorpha. Among the 37 genes, the gene cluster (M-nad2-W-cox1-L2-cox2-D-atp8-atp6-cox3-G- nad3-R-N-A-E-S1) Balanomorpha was conserved. Furthermore, phylogeny analysis indicated that the existing Balanomorpha species family was divided into nine rearrangement patterns, supporting the polyphyly of Balanoidea.
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Lubis, Yovi Namara, Hendryan Winata, and Sobirin Sobirin. "Data Mining Untuk Memprediksi Data Pengunjung dengan Menggunakan Algoritma Simple Moving Average." Jurnal SAINTIKOM (Jurnal Sains Manajemen Informatika dan Komputer) 21, no. 2 (August 30, 2022): 50. http://dx.doi.org/10.53513/jis.v21i2.5958.
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Goemans, Bianca F., Christian M. Zwaan, Gertjan J. L. Kaspers, Karel Hählen, Dirk Reinhardt, Ursula Creutzig, and Michael C. Heinrich. "In-Vitro Cytotoxicity of Tipifarnib (Zarnestra TM) in Pediatric AML and ALL Samples Is Independent of RAS Mutations." Blood 104, no. 11 (November 16, 2004): 1172. http://dx.doi.org/10.1182/blood.v104.11.1172.1172.
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Abstract The farnesyltransferase inhibitor tipifarnib (Zarnestra™) was originally developed to target malignancies harbouring RAS mutations. In the first clinical studies with tipifarnib, in adults with leukemia, it was found that patients who responded did not harbour any RAS mutations, suggesting a different mechanism of response. In a previous study we showed that 18% of 150 untreated pediatric AML patients harbour mutations in RAS, of which 30% were CBF-AML. We now studied 44 untreated and 13 relapsed pediatric AML, as well as 22 untreated ALL samples for mutations in RAS, using D-HPLC and direct sequencing. In vitro tipifarnib resistance was determined by a 4-day MTT assay (concentration 0.016-51μM, kindly provided by Janssen Research). The LC50 value, the concentration at which 50% of cells are killed by tipifarnib, was used as a measure of resistance. Patient characteristics were; for untreated AML: 64% boys; median age 9.3 years; median WBC 74.8x109/L; FAB 2xM0, 2xM1, 8xM2, 3xM3, 16xM4, 8xM5, 5x unclassified; for relapsed AML: 77% boys; median age 4.0 years; median WBC 41.6x109/L; FAB 2xM0, 2xM2, 3xM4, 2xM5, 2xM7, 2x unclassified; for untreated ALL: 73%boys; median age 6.0 years; median WBC 10.2x109/L; 15 B-cell precursor (BCP) ALL and 7 T-ALL. We found RAS mutations in 14 (32%) untreated AML samples (N-RAS : 8 samples exon 1, 1 sample exon 2; K-RAS: 5 samples exon 1 mutations). In relapsed AML 2 samples showed an N-RAS exon 1 mutation (15.4%). In ALL 18.2% had a RAS mutation: an N-RAS exon 1 mutation was found in 2 patients (9.1%) and a K-RAS exon 1 mutation in another 2 patients (9.1%). The distribution of tipifarnib sensitivity was similar in RAS mutated- and non-mutated untreated AML patients [median LC50 RAS mutated 7.1μM (P25-P75: 6.0-9.6μM) vs. non-mutated 4.9μM (P25-P75 2.3-8.2μM); p=0.199]. When we compared N-RAS mutated samples with K-RAS mutated samples there was no statistically significant difference in sensitivity to tipifarnib (median LC50 [p25-p75] 3.2μM [2.9-3.9μM] and 4.9μM [3.7-23.1μM], p=0.20), and comparing them separately with non-mutated AML did not show differences in sensitivity to tipifarnib (p=0.172 and p=0.463 respectively). One out of 9 (11%) N-RAS mutated and 3 out of 5 (60%) K-RAS mutated samples had an LC50 value above the 75th percentile for non-mutated AML and were considered resistant. Within relapsed AML the 2 RAS mutated samples had LC50 values of 0.83 and 6.3μM, versus a median value of 6.9μM for non-mutated relapsed AML. In ALL, we found similar results [median LC50 RAS mutated 7.8μM (P25-75: 4.1-12.8μM) vs. non-mutated 17.4μM (P25-75: 4.5-22.9μM), p=0.3], but the groups were very small. In conclusion, primary pediatric AML and ALL samples withRAS mutations show similar distributions of tipifarnib sensitivity as samples withoutRAS mutations. Hence, some RAS mutated samples may be relatively in-vitro resistant to tipifarnib, and some non-mutated samples may be relatively sensitive. Therefore, clinical studies with these compounds should not be restricted to RAS-mutated leukemia. Further studies are necessary to determine the molecular targets of farnesyltransferase inhibitors.
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Duffy, Josh, Bhargavi Patham, and Kojo Mensa-Wilmot. "Discovery of functional motifs in h-regions of trypanosome signal sequences." Biochemical Journal 426, no. 2 (February 9, 2010): 135–45. http://dx.doi.org/10.1042/bj20091277.
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N-terminal signal peptides direct secretory proteins into the ER (endoplasmic reticulum) of eukaryotes or the periplasmic space of prokaryotes. A hydrophobic core (h-region) is important for signal sequence function; however, the mechanism of h-region action is not resolved. To gain new insight into signal sequences, bioinformatic analysis of h-regions from humans, Saccharomyces cerevisiae, Trypanosoma brucei and Escherichia coli was performed. Each species contains a unique set of peptide motifs (h-motifs) characterized by identity components (i.e. sequence of conserved amino acids) joined by spacers. Human h-motifs have four identity components, whereas those from the other species utilize three identity components. Example of h-motifs are human Hs3 {L-x(2)-[AGILPV]-L-x(0,2)-L}, S. cerevisiae Sc1 [L-x(0,2)-S-x(0,3)-A], T. brucei Tb2 {L-x(1,2)-L-[AILV]} and E. coli Ec1 [A-x(0,2)-L-x(0,3)-A]. The physiological relevance of h-motifs was tested with a T. brucei microsomal system for translocation of a VSG (variant surface glycoprotein)-117 signal peptide. Disruption of h-motifs by scrambling of sequences in h-regions produced defective signal peptides, although the hydrophobicity of the peptide was not altered. We conclude that: (i) h-regions harbour h-motifs, and are not random hydrophobic amino acids; (ii) h-regions from different species contain unique sets of h-motifs; and (iii) h-motifs contribute to the biological activity of ER signal peptides. h-Regions are ‘scaffolds’ in which functional h-motifs are embedded. A hypothetical model for h-motif interactions with a Sec61p protein translocon is presented.
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Stengel, Anna, Wolfgang Kern, Torsten Haferlach, Susanne Schnittger, Melanie Zenger, and Claudia Haferlach. "Comparison of TP53 Alterations in Hematological Malignancies." Blood 126, no. 23 (December 3, 2015): 4819. http://dx.doi.org/10.1182/blood.v126.23.4819.4819.
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Abstract Background: TP53 is altered in ~50% of human cancers. Alterations include mutations and deletions. Both frequently occur together, supporting the classical "two-hit" hypothesis for tumor-suppressor genes. Aim: Comparison of TP53 mutation/deletion patterns in different hematological malignancies, including AML, MDS, ALL, Burkitt lymphoma, CLL and T-PLL. We analyzed (i) the frequencies of TP53 mutations and deletions, (ii) the types of mutation, (iii) the mutation load, (iv) the correlations to cytogenetic aberrations, (v) the age dependency, and (vi) impact on survival. Patient cohort and methods: A total of 3383 cases (AML: n=858, MDS: n=943, ALL: n=358, Burkitt lymphoma: n=25, CLL: n=1148 and T-PLL: n=51) were analyzed for TP53 deletions by interphase FISH determining the copy number state and for TP53 mutations by next-generation amplicon deep sequencing. Karyotype data was available for all cases. Results: Overall, alterations in TP53 were detected in 361/3383 cases (11%; 186 cases with mutation only (mut only), 51 cases with deletion only (del only), 124 cases with mutation and deletion (mut+del)). Regarding the respective entities, the highest frequency of TP53 alterations was observed in patients with Burkitt lymphoma (total alteration frequency: 56%, mut+del: 12%, mut only: 44%, no case del only). Alterations in TP53 also occured with a high incidence in patients with T-PLL (total: 30%; mut+del: 10%; mut only: 4%; del only: 16%) followed by cases with ALL (total: 19%; mut+del: 6%; mut only: 8%; del only: 5%) and AML (total: 13%; mut+del: 5%; mut only: 7%; del only: 1%). By contrast, TP53 alterations occurred less frequently in patients with CLL (total: 8%; mut+del: 4%; mut only: 3%; del only: 1%) and MDS (total: 7%; mut+del: 1%; mut only: 5%; del only: 1%). Missense mutations were found to be the most abundant mutation type in all entities analyzed with a frequency ranging from 71% - 88%. In all entities mainly one mutation per case was detected; however, MDS cases were found to harbour a statistically increased proportion of cases with two mutations compared to the other entities (p = 0.003). High TP53 mutation loads were detected in T-PLL (median: 88%) and AML (47%), whereas the lower ones were found in ALL (28%), Burkitt lymphoma (39%), MDS (39%), and CLL (36%). A strong correlation of TP53 alterations with a complex karyotype was observed in AML (of patients with TP53 alteration: 5% with normal karyotype, 67% with complex karyotype, 28% with other aberrations), ALL (16% normal, 45% complex, 39% other), MDS (14% normal, 53% complex, 33% other), and T-PLL (20% normal, 47% complex, 33% other). By contrast, in CLL and Burkitt lymphoma, TP53 alterations were mainly correlated with other aberrations (CLL: 10% normal, 30% complex, 60% other; Burkitt: 29% normal, 0% complex, 71% other). TP53 mut and TP53 mut+del were significantly more frequent in patients ≥ 60 vs < 60 years in AML (9% vs. 2% for mut only, p < 0.001; 7% vs. 2% for mut+del, p = 0.001) and ALL (12% vs. 6% for mut only, p < 0.001; 13% vs. 3% for mut+del, p = 0.001). By contrast, no such differences were observed for patients with CLL, MDS, T-PLL and Burkitt lymphoma. Moreover, TP53 alterations (especially of TP53 mut+del) had a significant negative impact on OS in all entities except for T-PLL and Burkitt lymphoma, most probably due to their overall short OS or due the lower number of cases. Conclusion: The frequency of TP53 mutations and/or deletions as well as the mutation load clearly varied between different hematological malignancies with the highest incidence of TP53 mut in patients with Burkitt lymphoma (56%) and a rather low frequency in CLL (7%) and MDS (6%). TP53 del were frequent in patients with T-PLL (26%) and Burkitt lymphoma (12%) and are hardly found in MDS cases (2%). TP53 alterations are correlated to higher age in AML and ALL. Moreover, alterations in TP53 are correlated to a short OS and to a complex karyotype, with the exception of Burkitt lymphoma and CLL, were they were found to be associated to other cytogenetic aberrations. Thus, TP53 mutations and deletions need further investigation in the future, especially regarding their clinical impact in different hematologic entities. Disclosures Stengel: MLL Munich Leukemia Laboratory: Employment. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Zenger:MLL Munich Leukemia Laboratory: Employment. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.
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Vinogradova, O. A., and A. V. Ugleva (Yastrebtseva). "The Birth of the Idea of Perfectibility: From the Enlightenment to Transhumanism." Russian Journal of Philosophical Sciences 62, no. 4 (July 6, 2019): 113–31. http://dx.doi.org/10.30727/0235-1188-2019-62-4-113-131.
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Starting from the Age of Enlightenment, a person’s ability of self-improvement, or perfectibility, is usually seen as a fundamental human feature. However, this term, introduced into the philosophical vocabulary by J.-J. Rousseau, gradually acquired additional meaning – largely due to the works of N. de Condorcet, T. Malthus and C. Darwin. Owing to perfectibility, human beings are not only able to work on themselves: by improving their abilities, they are also able to change their environment (both social and natural) and create favorable conditions for their existence. It is no coincidence that perfectibility became the key concept of the idea of social progress proposed by French thinkers in the Age of Enlightenment, despite the fact that later it was criticized, above all, by English authors, who justified its organic and biological nature and gave a different evolutionary interpretation to this concept, without excluding perfectibility from the philosophical vocabulary. In this article, we address the opposition and mutual counterarguments of these two positions. Beyond that, we draw a parallel with some of the ideas of S. Kapitsa, who proved to be not only a critic of Malthusianism but also a direct disciple of Condorcet. In the modern age, the ideas of human self-improvement caused the development of transhumanist movement. Condorcet is more relevant than ever, and today his theory of the progress of the human mind, which influenced the genesis of modern historical science, needs a re-thinking in the newest perspective of improving the mental and physical human nature with the help of modern technologies.
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Yakimov, Michail M., Laura Giuliano, Renata Denaro, Ermanno Crisafi, Tatiana N. Chernikova, Wolf-Rainer Abraham, Heinrich Luensdorf, Kenneth N. Timmis, and Peter N. Golyshin. "Thalassolituus oleivorans gen. nov., sp. nov., a novel marine bacterium that obligately utilizes hydrocarbons." International Journal of Systematic and Evolutionary Microbiology 54, no. 1 (January 1, 2004): 141–48. http://dx.doi.org/10.1099/ijs.0.02424-0.
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An aerobic, heterotrophic, Gram-negative, curved bacterial strain, designated MIL-1T, was isolated by extinction dilution from an n-tetradecane enrichment culture that was established from sea water/sediment samples collected in the harbour of Milazzo, Italy. In the primary enrichment, the isolate formed creamy-white, medium-sized colonies on the surface of the agar. The isolate did not grow in the absence of NaCl; growth was optimal at 2·7 % NaCl. Only a narrow spectrum of organic compounds, including aliphatic hydrocarbons (C7–C20), their oxidized derivatives and acetate, were used as growth substrates. The isolate was not able to grow under denitrifying conditions. The DNA G+C content and genome size of strain MIL-1T were estimated to be 53·2 mol% and 2·2 Mbp, respectively. The major cellular and phospholipid fatty acids were palmitoleic, palmitic and oleic acids (33·5, 29·5 and 11·0 % and 18, 32 and 31 %, respectively). 3-Hydroxy lauric acid was the only hydroxy fatty acid detected. Thirteen different compounds that belonged to two types of phospholipid (phosphatidylethylamine and phosphatidylglycerol) were identified. 16S rRNA gene sequence analysis revealed that this isolate represents a distinct phyletic lineage within the γ-Proteobacteria and has about 94·4 % sequence similarity to Oceanobacter kriegii (the closest bacterial species with a validly published name). The deduced protein sequence of the putative alkane hydrolase, AlkB, of strain MIL-1T is related to the corresponding enzymes of Alcanivorax borkumensis and Pseudomonas oleovorans (81 and 80 % similarity, respectively). On the basis of the analyses performed, Thalassolituus oleivorans gen. nov., sp. nov. is described. Strain MIL-1T (=DSM 14913T=LMG 21420T) is the type and only strain of T. oleivorans.
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BOZKURTOĞLU ÖZCAN, Özge. "M. WALSH, T. KISS - N. COUREAS (Eds.), The Harbour of All This Sea and Realm: Crusader to Venetian Famagusta. Budapest 2014. Central European University Press, 272 sayfa (1 harita ve 81 resim ile birlikte). ISBN: 9786155225963." LIBRI Kitap Tanitimi, Elestiri ve Ceviri Dergisi, no. 2 (December 20, 2016): 447. http://dx.doi.org/10.20480/lbr.2016036.
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Schnittger, Susanne, Torsten Haferlach, Petro E. Petrides, Wolfgang Kern, and Claudia Schoch. "JAK2 Mutation Screening and Chromosome Analysis Are Necessary for a Comprehensive Diagnostic Work up in CMPD: A Study on 469 Cases." Blood 106, no. 11 (November 16, 2005): 4963. http://dx.doi.org/10.1182/blood.v106.11.4963.4963.
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Abstract The diagnosis of BCR-ABL negative chronic myeloproliferative disorders (CMPD) is still a challenge for the morphologist and clinician, mainly because of overlapping phenotypes of essential thrombocythemia (ET), polycythemia vera (PV), idiopathic myelofibrosis (IMF) and non-malignant reactive phenotypes. Recently, a new mutation in JAK2 leading to V617F exchange in exon 12 was described in these entities. Therefore, we developed a rapid and easy LightCycler based melting curve assay and screened 469 patients with various malignancies for the respective JAK2 mutation using cDNA prepared from mononucleated cells. All cases tested positive were confirmed by sequencing and without any exception all mutations were G to T exchanges at nucleotide 1849. In total, 61 cases with PV were analysed. 56 (91.8%) were mutated (see table). A karyotype was available in 36 cases. Of the JAK2- cases 4 had normal karyotypes and one 20q-. Of the JAK2+ cases 21 had normal karyotype; four (7.1%) had +9, one +8, one +22, one 20q-, and three showed a complex aberrant karyotype. Of the 47 analyzed ET 26 (55%) were mutated. Cytogenetics was available in 20 cases (9 JAK2-, 11 JAK2+). All JAK2- cases all had normal karyotypes. Of the JAK2+ 10 had a normal karyotype and one a t(9;13)(p24;q22) involving the JAK2 locus. Of the 25 IMF cases 14 (56%) were mutated. Karyotype was available in 17 cases (7 JAK2-, 10 JAK2+). All 7 JAK2- had normal karyotype. Of the 10 JAK2+ 6 had normal karyotype and four were aberrant (+9:n=2; 20q-: n=2). In addition, 2/7 cases (28.6%) with CMML were JAK2+. Furthermore, we analysed 89 BCR-ABL negative MPS that were not further specified. V617F was detectable in 43 patients (48.3%). At next 128 AML were analyzed (84 novo AML, 11 t-AML after a previous malignancy, 15 secondary to MDS, and 16 secondary to MPS (PV:n=7, ET:n=5, OMF:n=2). No V617F was detected in all cases with t-AML and s-AML after MDS. In contrast, in de novo AML 6/84 (7.1%) were JAK2+, of which 4 were proven homozygous. Surprisingly, 4 of these six cases had a +9. In AML secondary to a previous CMPD 11/16 (68.8 %) were JAK2+. Of these 2 had +9, one a normal karyotype and 12 a complex aberrant karyotype. These data suggest that acquisition of +9 may lead to progress or blast crisis in JAK2 mutated MPS and supports the gain of function mechanism of the mutation. In conclusion, more than half of all BCR-ABL-negative MPS harbour a V617F mutation. This helps in the differential diagnosis of MPS versus reactive disorders. V617F is more frequently associated with aberrant karyotype than wildtype JAK2. In addition, there is an increasing level of aberrant cytogenetics and mutation rate with respect to incidence and status from ET<IMF<PV indicating that these diseases might be overlapping or even a continuum. It demonstrates that the present classification is artificial and a new classification of “JAK2” positive diseases may be more adequate. In addition, the same mutation was observed in most cases of AML secondary to CMPD. It was also found in few cases with de novo AML and correlated with +9. JAK2V617F is a new and promising target for therapy as well as for molecular monitoring of therapy response in CMPD. Distribution of JAK2 mutation in various malignancies ET IMF PV MPS* CMML de novo AML AML after MPS *not further specified total 47 25 61 89 7 84 16 mutated (n=) 26 14 56 43 2 6 11 mutated (% of all) 55.0 % 56.0 % 91.8 % 48.3 % 28.6 % 7.1 % 68.8 % homozygous (n=) 3 9 33 19 1 4 7 homozygous (% of all) 6.4 % 36.0 % 54.1 % 21.3 % 14.3 % 4.8 % 43.8 %
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Schnittger, Susanne, Sabrina Kuznia, Manja Meggendorfer, Niroshan Nadarajah, Sabine Jeromin, Tamara Alpermann, Andreas Roller, et al. "Tyrosine Kinase Inhibitor Treated CML Patients Harboring Philadelphia-Negative Cytogenetically Aberrant Clones Show Molecular Mutations In 31% Of Cases Not Present At Diagnosis: A High-Throughput Amplicon Sequencing Study Of 29 Genes." Blood 122, no. 21 (November 15, 2013): 611. http://dx.doi.org/10.1182/blood.v122.21.611.611.
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Abstract Background In chronic myeloid leukemia (CML), clonal chromosome aberrations in metaphases not carrying a t(9;22)(q34;q11) have been described during treatment with tyrosine kinase inhibitors (TKIs), so-called Philadelphia-negative (Ph-) clones. The most frequent abnormalities in these Ph- clones reported are -7, +8 and -Y. This pattern of cytogenetic aberrations is comparable to alterations found in MDS. In the majority of patients no clear evidence of a secondary hematologic malignancy is observed. However, few cases especially with -7 were reported to evolve to MDS or even AML. Aim 1) Analyze whether TKI-treated CML patients who developed Ph- clones also harbour molecular mutations. 2) Evaluate whether these mutations were already present at diagnosis of CML. Patients and Methods We selected 42 patients (pts) treated with TKIs (Imatinib: n=27, Nilotinib: n=2, and 13 pts who were treated with 2 or 3 different TKIs) who developed Ph- clones. Median time from start of therapy to analysis was 3.2 years (range 8.9 months-13.5 years). 23 cases were male and 19 female; median age was 63.3 years (range: 34.1-83.9 years). Cytogenetics in pts with Ph- clones were as follows: +8 sole (n=18), -Y (n=7), -7 sole (n=2), +9 (n=2), an 10 cases with various abnormalities. Additional three cases had two different clones: 1) -7 and +8; 2) +8 and +Y, 3) -Y and +Y. Median clone size was 37.5% (range 10-100%) of all metaphases. BCR-ABL1 levels at the time point of analysis were between 0 and 4.5 (median: 0.019) according to international scale. All cases were analyzed with a pan-myeloid gene panel of 29 genes: ASXL1, BCOR, BRAF, CBL, DNMT3A, ETV6, EZH2, FLT3 (TKD), IDH1, IDH2, JAK2, KIT, KRAS, MLL-PTD, NOTCH1, NPM1, NRAS, PRPF40B, PTPN11, RUNX1, SF1, SF3A1, SF3B1, SRSF2, TET2, TP53, U2AF1, U2AF2 and ZRSR2. Either complete coding genes or hotspots were first amplified by a microdroplet-based assay (RainDance, Lexington, MA) and subsequently sequenced with a MiSeq instrument (Illumina, San Diego, CA). RUNX1 was sequenced on the 454 Life Sciences NGS platform and the MLL-PTD was analyzed by quantitative real time PCR. Median coverage per amplicon was 2215 reads (range 100-24,716). The lower limit of detection was set at a cut-off of 1.5%. Results In total, in 13/42 pts (31.0%) one (n=9) or two (n=4) of the analyzed genes were mutated. Median mutation load was 15% (range: 3-50%). In detail, mutations in the following genes were detected: ASXL1 (n=5), DNMT3A (n=4), NRAS (n=2) and each one in BCOR, CBL, MLL-PTD, RUNX1, TET2 and ZRSR2. 4 pts had combinations of: 2 ASXL1mut, 2 NRASmut, BCORmut and RUNX1mut, or ASXL1mut with MLL-PTD, respectively. Subsequently, the mutations were tracked as far as serially collected samples were available (12 pts with a total of 125 samples, range: 3-20 samples/pt) from earlier or later time points. In 6 cases it clearly could be shown that the mutations were not present at diagnosis and arose 5 months, 7 months, 14 months, 15 months, 5 years, and 7 years after start of TKI therapy, respectively. In all these cases the mutation loads increased in parallel to decreasing BCR-ABL1 levels. In one of these cases one mutation was found 3 years and a second 11 years after start of therapy. Importantly, in three of these cases the molecular mutations were detectable before the cytogenetic aberration in the Ph- clone. In six further cases mutations were present with similar levels in several samples but due to lack of samples from initial diagnosis no estimation of the time to their occurrence was possible. In one of these cases the BCR-ABL1 load increased again during therapy and the DNMT3A mutation decreased showing that the BCR-ABL+ clone and the DNMT3Amut clone were competitive clones. Conclusions 1) For the first time we show that more than 30% of CML patients treated with TKI who develop Ph- clones as defined by cytogenetic abnormalities, also harbour molecular mutations. 2) For most of the cases it was shown that these mutations arose during treatment. 3) In some cases the molecular mutations were detectable before the cytogenetic aberrations. This may be regarded as further proof of the malignant character of these Ph- clones. However, none of the analyzed cases, so far, developed a secondary disease, i.e. MDS or AML, thus the relevance of these findings is still unclear and needs further attention. Disclosures: Schnittger: MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Kuznia:MLL Munich Leukemia Laboratory: Employment. Meggendorfer:MLL Munich Leukemia Laboratory: Employment. Nadarajah:MLL Munich Leukemia Laboratory: Employment. Jeromin:MLL Munich Leukemia Laboratory: Employment. Alpermann:MLL Munich Leukemia Laboratory: Employment. Roller:MLL Munich Leukemia Laboratory: Employment. Albuquerque:MLL Munich Leukemia Laboratory: Employment. Weissmann:MLL Munich Leukemia Laboratory: Employment. Eder:MLL Munich Leukemia Laboratory: Employment. Dicker:MLL Munich Leukemia Laboratory: Employment. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Kohlmann:MLL Munich Leukemia Laboratory: Employment. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership; Novartis: Research Funding. Hochhaus:Novartis: Research Funding. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.
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Stewart, Peter, Jana Gazdova, Nikos Darzentas, Dorte Wren, Paula Proszek, Grazia Fazio, Simona Songia, et al. "Euroclonality-NGS DNA Capture Panel for Integrated Analysis of IG/TR Rearrangements, Translocations, Copy Number and Sequence Variation in Lymphoproliferative Disorders." Blood 134, Supplement_1 (November 13, 2019): 888. http://dx.doi.org/10.1182/blood-2019-127822.
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Introduction: Current diagnostic standards for lymphoproliferative disorders include detection of clonal immunoglobulin (IG) and/or T cell receptor (TR) rearrangements, translocations, copy number alterations (CNA) and somatic mutations. These analyses frequently require a series of separate tests such as clonality PCR, fluorescence in situ hybridisation and/or immunohistochemistry, MLPA or SNParrays and sequencing. The EuroClonality-NGS DNA capture (EuroClonality-NDC) panel, developed by the EuroClonality-NGS Working Group, was designed to characterise all these alterations by capturing variable, diversity and joining IG and TR genes along with additional clinically relevant genes for CNA and mutation analysis. Methods: Well characterised B and T cell lines (n=14) representing a diverse repertoire of IG/TR rearrangements were used as a proficiency assessment to ensure 7 testing EuroClonality centres achieved optimal sequencing performance using the EuroClonality-NDC optimised and standardised protocol. A set of 56 IG/TR rearrangements across the 14 cell lines were compiled based on detection by Sanger, amplicon-NGS and capture-NGS sequencing technologies. For clinical validation of the NGS panel, clinical samples representing both B and T cell malignancies (n=280), with ≥ 5% tumour infiltration were collected from 10 European laboratories, with 88 (31%) being formalin fixed paraffin-embedded samples. Samples were distributed to the 7 centres for library preparation, hybridisation with the EuroClonality-NDC panel and sequencing on a NextSeq 500, using the EuroClonality-NDC standard protocol. Sequencing data were analysed using a customised version of ARResT/Interrogate, with independent review of the results by 2 centres. All cases exhibiting discordance between the benchmark and capture NGS results were submitted to an internal review committee comprising members of all participating centres. Results: All 7 testing centres detected all 56 rearrangements of the proficiency assessment and continued through to the validation phase. A total of 10/280 (3.5%) samples were removed from the validation analysis due to NGS failures (n=1), tumour infiltration < 5% (n=7), and sample misidentification (n=2). The EuroClonality-NDC panel detected B cell clonality (i.e. detection of at least one clonal rearrangement at IGH, IGK or IGL loci) in 189/197 (96%) B cell malignancies. Seven of the 8 discordant cases were post-germinal centre malignancies exhibiting Ig somatic hypermutation. The EuroClonality-NDC panel detected T cell clonality (i.e. detection of at least one clonal rearrangement at TRA, TRB, TRD or TRG loci) in 70/73 (96%) T cell malignancies. In all 3 discordant cases analysis of benchmark PCR data was not able to detect clonality at any TR loci. Next, we examined whether the EuroClonality-NDC panel could detect clonality at each of the individual loci, resulting in sensitivity values of 95% or higher for all IG/TR loci, with the exception of those where limited benchmark data were available, i.e. IGL (n=3) and TRA (n=7). The specificity of the panel was assessed on benign reactive lesions (n=21) that did not contain clonal IG/TR rearrangements based on BIOMED-2/EuroClonality PCR results; no clonality was observed by EuroClonality-NDC in any of the 21 cases. Limit of detection (LOD) assessment to detect IG/TR rearrangements was performed using cell line blends with each of the 7 centres receiving blended cell lines diluted to 10%, 5.0%, 2.5% and 1.25%. Across all 7 centres the overall detection rate was 100%, 94.1%, 76.5% and 32.4% respectively, giving an overall LOD of 5%. Sufficient data were available in 239 samples for the analysis of translocations. The correct translocation was detected in 137 out of 145 cases, resulting in a sensitivity of 95%. Table 1 shows how translocations identified by the EuroClonality-NDC protocol were restricted to disease subtypes known to harbour those types of translocations. Analysis of CNA and somatic mutations in all samples is underway and will be presented at the meeting. Conclusions: The EuroClonality-NDC panel, with an optimised laboratory protocol and bioinformatics pipeline, detects IG and TR rearrangements and translocations with high sensitivity and specificity with a LOD ≤ 5% and provides a single end-to-end workflow for the simultaneous detection of IG/TR rearrangements, translocations, CNA and sequence variants. Table. Disclosures Stamatopoulos: Janssen: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding. Klapper:Roche, Takeda, Amgen, Regeneron: Honoraria, Research Funding. Ferrero:Gilead: Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSA Pharma: Membership on an entity's Board of Directors or advisory committees; Servier: Speakers Bureau. van den Brand:Gilead: Speakers Bureau. Groenen:Gilead: Speakers Bureau. Brüggemann:Incyte: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy. Langerak:Gilead: Research Funding, Speakers Bureau; F. Hoffmann-La Roche Ltd: Research Funding; Genentech, Inc.: Research Funding; Janssen: Speakers Bureau. Gonzalez:Roche: Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau.
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Jiang, Jie, Austin G. Kulasekararaj, Alexander E. Smith, Azim M. Mohamedali, Shreyans A. Gandhi, Barbara Czepulkowski, Judith Marsh, and Ghulam J. Mufti. "Somatic Mutations Implicated In Myeloid Malignancies Are Frequent In Idiopathic Aplastic Anaemia and Its Relevance To Disease Classification and Treatment- a Comprehensive Analysis Of 150 Patients." Blood 122, no. 21 (November 15, 2013): 803. http://dx.doi.org/10.1182/blood.v122.21.803.803.
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Abstract Background Acquired aplastic anemia (AA) is an immune mediated disease, characterized by severe quantitative defects in stem cell number leading to a hypocellular marrow and peripheral blood cytopenias. A major complication of AA following immunosuppressive therapy (IST) is the emergence of clonal hemopoiesis, manifesting as paroxysmal nocturnal hemoglobinuria (PNH), myelodysplastic syndrome (MDS) and acute myeloid leukaemia. The nature of genetic defects in such cases evolving to clonal hemopoiesis has not been addressed hitherto. It is likely that the hematopoietic stress leads to telomere attrition, chromosomal instability and susceptibility to acquire mutations in genes several years after the initial diagnosis. We postulated the existence of mutations leading to clonal haemopoiesis in a subset of AA and thereby helping in early prediction. Methods We undertook a massively parallel targeted sequencing of 832 genes implicated in regulating hematopoiesis initially in a cohort of 57 patients with acquired AA. We also performed single nucleotide polymorphism-array karyotyping, telomere measurement, PNH flow cytometry and correlated it with clinical characteristics. A second cohort of 93 patients was sequenced at a greater depth for ASXL1 and DNMT3A. Results The median age of AA patients was 44 years (range 17-87 years). The diagnosis was non severe AA (NSAA) 64, severe AA (SAA) 52, very severe AA (VSAA) 27 and pure red cell aplasia (PRCA)/amegakaryocytic thrombocytopenia 7. PNH-type cells and cytogenetic aberrations were seen in 52% and 9% of patients respectively. IST was administered in 72% of patients with 55% receiving ATG containing regimens. Allogeneic hematopoietic stem cell transplant was performed in 25% (n=37). Clonal evolution to MDS/AML was observed in 12% of patients. Somatic mutations in genes usually implicated in myeloid malignancies were detected in 15% (22/150) of AA. No particular sub-group of AA patients had a predilection to harbour somatic mutations, although a slightly higher incidence was noted in SAA and NSAA, compared to VSAA (22% vs. 14%, p=0.1).Thirty-five (23%) AA patients had either morphological (n=18) and/or molecular (n=22) evidence of evolution to MDS. Of the 18 patients with morphological evolution to MDS, ASXL1 and TET2 mutations were observed in 5 patients. ASXL1 (n=11) mutations were the most common somatic variation and correlated with older age, evolution to MDS and the presence of monosomy 7. Although there was no predilection for a particular ‘hot spot’, all mutations occurred in exon 12 and were uniformly heterozygous. DNMT3A (n=7) and BCOR(n=2) were the other frequent mutations. The median allele burden of somatic mutations was 30%. AA with somatic mutations were older (51 vs. 38 years, p<0.07), had a longer disease duration (44 vs. 9 months, p< 0.06), shorter telomere lengths (median T/S length, 1.3 vs. 0.8, p<0.008) and were less likely to achieve complete remission to IST (10% vs. 34%) compared to those without mutations. Conclusion Up to 25% of AA patients have morphological or molecular evidence of clonal evolution with a fifth of AA patients harboring mutations in genes implicated in myeloid malignancies, with both diagnostic and therapeutic implications. Disclosures: No relevant conflicts of interest to declare.
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Lee, Joan. "Reviewer Acknowledgements for Sustainable Agriculture Research, Vol. 9, No. 2." Sustainable Agriculture Research 9, no. 2 (April 26, 2020): 129. http://dx.doi.org/10.5539/sar.v9n2p129.
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Sustainable Agriculture Research wishes to acknowledge the following individuals for their assistance with peer review of manuscripts for this issue. Their help and contributions in maintaining the quality of the journal are greatly appreciated.
Sustainable Agriculture Research is recruiting reviewers for the journal. If you are interested in becoming a reviewer, we welcome you to join us. Please contact us for the application form at: sar@ccsenet.org
Reviewers for Volume 9, Number 2
Adel Khashaveh, Islamic Azad University, Iran
Darwin Pangaribuan, Lampung University, Indonesia
Dietrich Darr, Hochschule Rhein-Waal, Germany
Entessar Mohammad Al JBawi, General Commission for Scientific Agricultural Research, Syria
Francesco Sunseri, Università Mediterranea di Reggio Calabria, Italy
Gema Parra, Universidad de Jaén, Spain
Giuseppina Migliore, University of Palermo, Italy
Gunnar Bengtsson, Sweden
Inder Pal Singh, Guru Angad Dev Veterinary and Animal Science University (GADVASU), India
Isaac Danso, Council for Scientific and Industrial Research-Oil Palm Research Institute, Ghana
Kassim Adekunle Akanni, Olabisi Onabanjo University, Nigeria
Katarzyna Panasiewicz, Poznan University of Life Sciences, Poland
Manuel Teles Oliveira, University Tras os Montes Alto Douro (UTAD), Portugal
Maren Langhof, Julius Kühn-Institut, Germany
Murtazain Raza, Subsidiary of Habib Bank AG Zurich, Pakistan
Nehemie T. Donfagsiteli, Institute of Medical Research and Medicinal Plants Studies, Cameroon
Nicusor-Flavius Sima, University of Agricultural Studies and Veterinary Medicine Cluj-Napoca, Romania
Sait Engindeniz, Ege University Faculty of Agriculture, Turkey
Stefano Marino, University of Molise, Italy
Subhash Chand, Central Agricultural Research Institute CARI Port Blair, India
Suheb Mohammed, University of Virginia, United States
Tenaw Workayehu, Hawassa Research Center, Southern Agricultural Research Institute, Ethiopia
26
Alkhatabi, Heba A., Azim M. Mohamedali, Austin G. Kulasekararaj, Sneha Shinde, Joop Gaken, Syed A. Mian, Alexander E. Smith, and Ghulam J. Mufti. "Utility of Peripheral Blood for Cytogenetic and Mutation Analysis in Myelodysplastic Syndrome." Blood 120, no. 21 (November 16, 2012): 1707. http://dx.doi.org/10.1182/blood.v120.21.1707.1707.
Full textAbstract:
Abstract Abstract 1707 With the advent of high throughput and high resolution techniques, >80% of myelodysplastic syndrome (MDS) patients harbour somatic mutations and/or genomic aberrations, which provide diagnostic and prognostic utility; however, frequent bone marrow (BM) aspirates are required. In a significant minority, the BM is hypocellular and fibrotic with suboptimal in vitro growth and, additionally, the procedure causes discomfort particularly in the elderly. This led us to investigate the use of peripheral blood (PB) and serum to identify and monitor BM derived genetic markers using high resolution single nucleotide polymorphism array (SNP-A) karyotyping and 454 parallel sequencing (454-PS) of a 22 gene myeloid panel comprising of all the exons of DNMT3a, RUNX1, CEBPα, TP53, EZH2, TET2 and ZRSR2 and mutations ‘hotposts’ for NPM1, FLT3, ASXL1, IDH1, IDH2, MPL, JAK2, BRAF, cCBL, NRAS, KRAS, C-KIT, SF3B1, SRSF2, and U2AF1. We selected 23 MDS patients with concurrent BM and PB samples and detected 45 mutations in TET2, SF3B1, ASXL1, TP53, DNMT3a, FLT3, U2AF1, NRAS, cCBL, JAK2 and IDH2 in BM and subsequently analysed their PB using 454-PS with independent validation performed by Sanger sequencing (SS). All the mutations identified in BM were detected in PB with the exception of a single NRAS (BM-11%). Nine patients had a single mutation in SF3B1, ASXL1, TP53, TET2, DNMT3a and U2AF1 with the remaining patients having multiple coexisting mutations. Overall there was no significant difference in the mutation burden between the PB (median 25%(1.5%-50%)) and the BM (median 33%(5%-68%)). Concurrent analysis of unamplified and whole genome amplified PB DNA from 3 patients with mutations in TET2, U2AF1, ASXL1 and NRAS showed no difference in their mutation profile. As expected, in three patients post therapy the mutation burden in the PB was lower than in the pre-treatment BM sample. The lower mutation burden and sequence context in the PB contributed significantly to the quality of SS analysis. Prior knowledge of the mutation site resulted in 98% concordance (smallest clone size - 1.5%) between BM and PB, however, a blind approach decreased this to 84% (smallest clone size - 15%). In addition, serum was available from 14 patients (22 known mutations in BM) and SS of serum DNA identified 12 mutations correctly (U2AF1, FLT3, SF3B1, TET2, TP53, ASXL1, DNMT3a and IDH2, 4 as wildtype (TET2, cCBL, ASXL1 and SF3B1) and 6 failed to amplify (ASXL1, TP53 and TET2) without any preference for specific genes and the failure attributed to the quantity of serum DNA. Karyotype aberrations in PB were assessed using Affymetrix SNP 6.0 arrays on 31 MDS patients; normal karyotype (n=11), del5q (n=9), del7q/-7 (n=5), trisomy 8 (n=2), complex (n=2), isodiXq13 (n=1) and t(2:4)(q33;q27). An overall karyotype concordance of 94% was observed in PB with the 2 discordant cases showing normal karyotype in PB and BM by SNP-A but having monosomy 7 (partial cytogenetic remission after 5-azacitidine) and t(2:4)(q33;q27) respectively in their BM by MC. The mean copy number (CN) in the PB was lower than BM (PB vs BM); deletions (CN of 1.8 vs 1.6) and gains(CN of 2.2 vs 2.4), implying a smaller abnormal clone in the PB. Concurrent SNP-A karyotype from BM from 9 patients was concordant with SNP-A karyotype from PB, although a patient with complex karyotype determined by SNP-A in the BM and having 30 aberrations had only 15 aberrations detected in the PB. To determine if the 5q deletion was lineage restricted, we enriched PB for CD3+, CD19+ and CD3-CD19- populations from 4 patients. FISH and SNP-A karyotyping showed the presence of the 5q deletion using both techniques in all three fractions, however at a lower level in PB lymphocytes indicating the presence of a smaller clone. In conclusion, our study showed an excellent concordance between BM and PB, both for karyotype and mutational analyses using high resolution SNP-A karyotyping and 454-PS suggesting its clinical utility as a surrogate for BM, thereby, avoiding the discomfort of repeated BM aspirates and help in monitoring response to therapy more frequently. Disclosures: No relevant conflicts of interest to declare.
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Thol, Felicitas, Larissa Köhler, Sabrina Klesse, Razif Gabdoulline, Arnold Kloos, Alessandro Liebich, Martin Wichmann, et al. "Characteristics and Prognosis of AML Patients with or without a History of Clonal Hematopoiesis." Blood 126, no. 23 (December 3, 2015): 224. http://dx.doi.org/10.1182/blood.v126.23.224.224.
Full textAbstract:
Abstract Background: Clonal hematopoiesis of indeterminate potential (CHIP) is defined by the detection of mutations in genes like DNA methyltransferase 3A (DNMT3A) and has recently been described to occur in healthy people and to predispose them to myeloid malignancies. DNMT3A is frequently mutated in acute myeloid leukemia (AML) and mutations have been detected in CD3 positive T-cells of some AML patients. In these patients DNMT3A mutations are early events that are likely to arise from CHIP. It is unknown how a history (hx) of CHIP influences the characteristics of AML patients and their response to therapy. We studied this question on the basis of a large cohort of DNMT3A mutated AML patients. Patients and Methods: 171 DNMT3A mutated AML patients (aged 18-87 years) were included in our study. 127 patients were treated intensively in trials of the AMLSHG and AMLSG. 34 patients received non-intensive therapy and for 10 patients the therapy is unknown. 148 patients carried a mutation at arginine R882. At the time of diagnosis and relapse samples were further sequenced for 54 genes involved in leukemia with next generation sequencing (NGS) on the Illumina platform. Library preparation of diagnostic samples was performed with the TruSight Myeloid sequencing panel (Illumina). T-cells (CD3+ CD11b- CD14- CD33-) were purified by flow cytometry from AML samples at the time of diagnosis. DNMT3A mutational analysis of T-cell samples and of mononuclear cells during remission or at relapse was performed also with ultra-deep sequencing using customized DNMT3A NGS primers. Presence of a DNMT3A mutation in sorted T cell populations was used as an indicator of a hx of CHIP. Results: A total of 40 patients (23%) were found to have the DNMT3A mutation in mononuclear cells and T-cells (hx of CHIP), while 131 patients (77%) had a DNMT3A mutation in mononuclear cells, but not T-cells (control cohort). Comparing these two patient cohorts revealed that significantly more patients in the hx of CHIP cohort had secondary AML (p=0.009), were older (p=0.005) and less likely to receive intensive treatment (p=0.047) while other clinical parameters did not significantly differ. Analysing the mutational profile of 54 genes revealed that the number of mutations per patient between these 2 groups was similar (median 5 vs 4 mutations, p=0.39). Patients with a hx of CHIP were significantly more likely to harbour mutations in TET2 (p=0.006), RUNX1 (p=0.004), SF3B1 (p=0.049), U2AF1 (p=0.015) but less likely to be NPM1 mutated (p=0.005). There was no significant difference in the allelic burden of DNMT3A in the CHIP hx (mean 43.6) vs control group (mean 44.5). The mean variant allele frequencies of DNMT3A, RUNX1 and NPM1 were highest (44, 45 and 43 respectively) as compared to other mutated genes like IDH1, IDH2 and FLT3 (32, 37 and 34). In relapse samples (n=11), the identical DNMT3A mutation could always be identified. However, patients with a hx of CHIP (n=2) had comparable allelic frequencies compared to diagnosis of mutated DNMT3A (<10% difference), but not NPM1 (> 10% difference), while 7 out of 9 patients in the control group had a change in the allelic frequency at the time of relapse (mostly reduction). In all remission samples DNMT3A mutations could be identified with ultra-deep NGS but with variable allelic frequencies (0.13-50.01% in the control group, 0.25-70.14% in the hx of CHIP group). In the cohort of patients with intensive therapy there was no difference in CR rates between hx of CHIP and control groups (82 vs 90%, p=0.31). Overall survival (OS) was not influenced by a hx of CHIP (whole cohort: HR 1.09; 95%CI 0.67-1.79; P=.73; intensively treated cohort: HR 0.72; 95%CI 0.34-1.51; P=.38). Relapse-free survival (RFS) was also not different in the hx of CHIP vs the control group (HR 1.06; 95%CI 0.58-1.93; P=.85; intensively treated cohort only HR 0.91; 95%CI 0.46-1.78; P=.78). However, when looking at the influence of allogeneic stem cell transplantations (HSCT) on outcome in intensively treated patients, patients with a hx of CHIP showed abenefit from HSCT (HR 0.082; 95%CI 0.009-0.75; P= 0.027 Figure 1A) as compared to the control group (HR 0.68; 95%CI 0.39-1.21; P= 0.19, Figure 1B). Conclusion: AML patients with a hx of CHIP, as defined by mutated DNMT3A in T-cells, show a distinct clinical and molecular profile and may benefit from HSCT. Figure 1A. Figure 1A. Figure 1B. Figure 1B. Disclosures Bug: TEVA Oncology, Astellas: Other: Travel Grant; NordMedica, Boehringer Ingelheim, Gilead: Membership on an entity's Board of Directors or advisory committees; Celgene, Novartis: Research Funding. Fiedler:Pfizer, Amgen, Kolltan: Research Funding; Teva, Amgen, Astellas: Other: Travel Grant; Karyopharm: Research Funding. Schlenk:Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Research Funding; Arog: Honoraria, Research Funding; Teva: Honoraria, Research Funding; Boehringer-Ingelheim: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Research Funding.
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Wellbrock, Jasmin, Sara Sheikhzadeh, Veronika Bonk, Leticia Oliveira-Ferrer, Kristin Klaetschke, Thomas Streichert, Carsten Bokemeyer, Yskert von Kodolitsch, and Walter Fiedler. "Gremlin-1 Is Overexpressed in Endothelial Cells of Patients with Loeys-Dietz Syndrome Due to Dysregulation of TGF-β Signalling,." Blood 118, no. 21 (November 18, 2011): 3269. http://dx.doi.org/10.1182/blood.v118.21.3269.3269.
Full textAbstract:
Abstract Abstract 3269 The Loeys-Dietz syndrome (LDS) is an inherited connective tissue disorder with symptoms similar to those of Marfan syndrome and the vascular type of Ehlers-Danlos syndrome. Most patients with LDS develop severe aortic aneurysms resulting in early need of surgical intervention. Patients with LDS harbour a mutation in the transforming growth factor β (TGF-β) receptors TGFBR1 (also named ALK-5) or TGFBR2. Since the TGF-β pathway plays a crucial role in many cellular processes including angiogenesis, we focussed our analyses on endothelial cell dysfunction in patients with Loeys-Dietz syndrome. We isolated circulating outgrowth endothelial cells (OEC) from the peripheral blood of two LDS patients (one female, 54 years; one male, 26 years old) both harbouring a mutation in the TGFBR2 gene. Gene expression profiles of OEC clones were performed using Affymetrix Human Genome U133 Plus 2.0 Arrays and confirmed by quantitative PCR analysis for genes of interest. OEC clones isolated from age- and sex-matched healthy controls served as reference subjects. We demonstrate that several genes belonging to the TGF-β pathway had altered expression in OECs isolated from LDS patients compared to those from healthy controls. For example, mRNA levels of bone morphogenic proteins (BMP) 2 and 4 were decreased in both LDS OEC clones (mean decrease 4 and 6 fold, respectively) whereas gene expression of inhibitory downstream molecule SMAD-6 was increased 2-fold. In both analysed OEC clones from LDS patients, gene expression of BMP antagonist Gremlin-1 (also known as Drm) showed the most prominent dysregulation with a 1136-fold and 164-fold higher expression in LDS OECs compared to healthy controls, respectively. Interestingly, in OECs isolated from healthy donors, Gremlin-1 expression was significantly down-regulated after incubation with SB431542 (5 μM), a small molecule inhibitor of the TGF-β receptor complex (mean decrease 4 fold; t-test: p = 0.002; n = 6). In contrast, the stimulation of OEC clones with TGF-β1 (1 ng/ml) resulted in significant up-regulation of Gremlin-1 mRNA levels (mean increase 7 fold; t-test: p = 0.014; n = 6). Apparently, the up-regulation of Gremlin-1 in LDS OECs seems to mirror an activated TGF-β signalling cascade in outgrowth endothelial cells. These findings are in line with other studies published on LDS where hyperactivity of the TGF-β downstream signalling was demonstrated by higher phosphorylation levels of SMAD-2 in the aortic media of LDS patients (Loeys et al., Nat Genet. 2005 Mar;37(3):275–81). Gremlin-1 might represent a second gene supporting the concept of increased TGF-β signalling in Loeys-Dietz syndrome. Gremlin-1 itself displays opposing effects on angiogenesis. First, it is known as a pro-angiogenic factor and was recently shown to stimulate angiogenesis via direct binding to the VEGF receptor 2 (Mitola et al., Blood. 2010 Nov 4;116(18):3677–80). On the other hand, as antagonist of bone morphogenic proteins, Gremlin-1 possesses anti-angiogenic properties by suppressing pro-angiogenic effects of BMP-2 and BMP-4. In summary, we believe that due to its drastic up-regulation in OECs of LDS patients, Gremlin-1 represents a crucial effector of dysregulated TGF-β signalling in endothelial cells inducing vascular pathology in Loeys-Dietz syndrome. Disclosures: Fiedler: Pfizer: Research Funding.
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Creasey, Thomas, Emilio Barretta, Amy A. Kirkwood, Claire Schwab, Pip Patrick, Laura Clifton-Hadley, Bela Wrench, et al. "Genetic and Genomic Characterisation of Older Adults with Acute Lymphoblastic Leukemia Treated on the UKALL14 and UKALL60+ Clinical Trials." Blood 134, Supplement_1 (November 13, 2019): 2746. http://dx.doi.org/10.1182/blood-2019-124395.
Full textAbstract:
Acute lymphoblastic leukemia (ALL) is characterised by recurrent chromosomal abnormalities and genomic microdeletions. Although the incidence of adult ALL increases with age, very few studies have specifically examined the genetic aberrations in adults aged ≥60 years. The objectives of the study were to define the frequency of recurrent chromosomal abnormalities and characterise the copy number profile of ALL in older adults. All patients from UKALL14 and UKALL60+ clinical trials aged ≥60 years at diagnosis of ALL were considered in the study. Cytogenetic and fluorescence in situ hybridisation (FISH) results at diagnosis were used to classify patients in 1 of 5 genetic subgroups - BCR-ABL1, TCF3-PBX1, MLL/KMT2A rearranged (KMT2Ar), low hypodiploidy/near triploidy (HoTr) and high hyperdiploidy (HeH). T-ALL patients were considered separately. B-cell precursor (BCP) ALL patients lacking a primary chromosomal abnormality (B-other ALL - including normal, failed and complex karyotypes, and other non-recurrent chromosomal abnormalities), were selected for extended FISH screening to identify ABL-class fusions, JAK-STAT activating rearrangements and other primary translocations using dual colour break apart probes for ABL1, ABL2, PDGFRB/CSF1R, CRLF2, JAK2, IGH@, ZNF384 and MEF2D. Separately, single nucleotide polymorphism (SNP) arrays were performed to identify copy number abnormalities (CNAs). Multiplex ligation-dependent probe amplification (MLPA) was used to confirm CNAs in 9 specific genes/regions (EBF1, IKZF1, CDKN2A/B, JAK2, PAX5, ETV6, BTG1, RB1, and PAR1). 207 patients aged ≥60 years at diagnosis were identified from UKALL14 (n=91) and UKALL60+ (n=116). Median age was 64 years (range 60-83) and 50% were male. Cytogenetic data at diagnosis were available for 86% (n=178) of patients. Frequencies of individual genetic subgroups are shown in figure (A). Extended FISH screening of B-other ALL cases identified rearrangements in CRLF2 in 5% (8/146), ZNF384 in 2% (3/137) and MEF2D in <1% (1/136) of the cohort. IGH@ translocations were found in 9% (13/148, including 6 IGH-CRLF2). No variant ABL1 (0/168), ABL2 (0/148), PDGFRB/CSF1R (0/151) or JAK2 (0/149) rearrangements were detected. SNP arrays were performed on 83 patient samples using Illumina CytoSNP 850k (n=52) or Affymetrix Cytoscan HD (n=31) arrays. Recurrent whole chromosome and whole arm abnormalities seen in >3 cases are shown in figure (B) (HeH and HoTr cases (n=10) excluded). Recurrent deletions were identified affecting IKZF1 in 52% (n=43), CDKN2A/B in 45% (n=37), PAX5 in 39% (n=32), RB1 in 22% (n=18), ETV6 in 21% (n=17), EBF1 in 19% (n=16), BTG1 in 12% (n=10), CD200/BTLA in 16% (n=13) and ATP10A in 13% (n=11). The frequency of individual deletions varied by genetic subtypes (Figure (C)). Recurrent novel and less-well described intragenic microdeletions were also seen in COL11A1 (n=11, 13%), MEF2C (n=8, 10%), MBNL1 (n=7, 8%), PTEN (n=6, 7%), NF1 (n=4, 5%), LEMD3 (n=5, 6%), and KDM6A (n=4, 5%). These deletions will need to be validated by a second technique. In this large cohort of older adults with ALL, we confirm that over a quarter of patients harbour BCR-ABL1. HoTr ALL is rare in younger patients but was the second most common specific chromosomal abnormality and good risk genetic subgroups were very uncommon. Additionally, we confirm the rarity of T-cell ALL in older adults (<5% of all cases). Within B-other ALL, CRLF2 rearrangements were the most common kinase activating abnormality, present in 5% of all patients, with IGH@ the translocation partner in 6/8 cases. ABL-class fusions were completely absent in this cohort of older patients, differing from published studies (Roberts et. al. JCO 2017). IKZF1 and CDKN2A/B deletions were seen in 52% and 45% of patients respectively. Importantly, these are frequently included in high risk copy number profiles such as IKZF1 plus (Stanulla et. al. JCO 2018), albeit not validated in older patients. A number of novel intragenic microdeletions, including tumour suppressor genes unreported in BCP-ALL, were identified and will require validation in a larger cohort. Collectively, these data further confirm the high risk of ALL in older adults. These patients appear genetically distinct to younger adults and the primary genetic abnormality remains unidentified in significant numbers, underlying the need for further genomic studies to elucidate the mutational landscape of ALL in older adults. Disclosures Menne: Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Kite/Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Kyowa Kirin: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. McMillan:Sandoz: Honoraria; Gilead: Honoraria; F. Hoffmann-La Roche Ltd: Honoraria, Speakers Bureau; BMS: Honoraria; Pfizer: Honoraria, Research Funding; MSD: Honoraria; Novartis: Honoraria; Celgene: Honoraria, Speakers Bureau. Morley:Amgen: Membership on an entity's Board of Directors or advisory committees, Other: speaker fees, conference support ; TAKEDA: Other: conference support ; Janssen Pharmaceuticals: Other: speaker fees; ROCHE: Membership on an entity's Board of Directors or advisory committees, Other: conference support; ABBVIE: Other: speaker fees. Snowden:Kiadis: Membership on an entity's Board of Directors or advisory committees; Mallinckrodt: Honoraria; Janssen: Honoraria; IDMC: Honoraria; Jazz: Honoraria; Gilead: Honoraria. Papaemmanuil:Celgene: Research Funding. Rowntree:Novartis: Consultancy. Fielding:Amgen: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Incyte: Consultancy.
30
Ma, Yuxiang, Guohai Dong, and Xiaozhou Ma. "SEPARATION OF LOW-FREQUENCY WAVES BY AN ANALYTICAL METHOD." Coastal Engineering Proceedings 1, no. 32 (January 31, 2011): 64. http://dx.doi.org/10.9753/icce.v32.waves.64.
Full textAbstract:
A new method for separating low-frequency waves in time domain is proposed by constructing the analytical signals of the measured waves. Using three simultaneous wave records, the time series of incident bound, free and reflected low-frequency waves can be obtained by the present method. This method is only suitable for separating monochromatic low-frequency waves. The applicability of the method is examined by numerical tests. The results show that the present method can give accurate results over sloping beaches when water depth (kh) is larger than 0.2. Then, the present method is used to study an experiment of low-frequency waves over a mild slope beach.
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Schwab, Claire, Rebecca Andrews, Lucy Chilton, Alannah Elliott, Gerald Keil, Stacey Richardson, Sarra L. Ryan, et al. "EBF1-PDGFRΒ Fusion in Paediatric Acute Lymphoblastic Leukaemia (ALL): Genetic Profile and Clinical Implications." Blood 124, no. 21 (December 6, 2014): 1068. http://dx.doi.org/10.1182/blood.v124.21.1068.1068.
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Abstract Incorporating cytogenetics into risk stratification for the treatment of childhood ALL has contributed to increased survival rates. However 25% patients, the B-other subgroup, do not have any of the known major chromosomal abnormalities. Within this group, BCR-ABL1-like cases show a similar gene expression profile to those with BCR-ABL1 fusion and share the same high risk of relapse. BCR-ABL1-like cases are genetically heterogeneous and some harbour tyrosine kinase activating gene fusions e.g. EBF1-PDGFRB. Recent reports suggest patients with EBF1-PDGFRB ALL who are refractory to conventional therapy respond to the tyrosine kinase inhibitor (TKI), imatinib. Here we present 14 patients treated on ALL97 (n=3), UKALL2003 (n=10) or UKALL2011 (n=1) who were EBF1-PDGFRB positive including 1 patient treated with imatinib. Involvement of PDGFRB and EBF1 was confirmed using dual colour break-apart probes (normal signal pattern=0R0G2F). Eleven patients showed signal patterns (1R0G1F) consistent with a deletion of 5q33 having breakpoints within EBF1 and PDGFRB, as seen in previously reported cases of the fusion. The presence of the deletion was confirmed by single nucleotide polymorphism (SNP) array in 6 cases. Three cases showed signal patterns (1R1G1F) consistent with a balanced rearrangement resulting in the EBF1-PDGFRB fusion and a balanced t(5;5)(q33.1;q33.3) was seen in one of these cases. SNP array analysis for 2 of these cases showed no copy number abnormalities of chromosome 5. However, in the third case a series of deletions were seen along the long arm of chromosome 5, indicating that the EBF1-PDGFRB fusion was generated by a complex rearrangement such as chromothripsis. Multiplex Ligation-dependent Probe Amplification (MLPA) using the P335 IKZF1 kit (MRC Holland) was carried out in 11 cases. Deletions of the probe for exon 16 of EBF1 were seen in all cases with the 5q33 deletion. Loss of PAX5 was detected in 4 patients, while IKZF1 and CDKN2A/B were deleted in 3 cases each. Among the 14 patients there was a predominance of females (n=10). The median age was 12 years with 9 patients >10 years at diagnosis. The median white cell count (WCC) was 34.4 x109/L with 5 patients presenting with a WCC of >50×109/L. Two of 3 patients treated on ALL97 remain alive (one after relapse); both patients received regimen C and a transplant. The third patient, who was not treated as high risk, relapsed and died within 5 years. An unselected cohort of 276 B-other UKALL2003 patients revealed 8 (3%) cases of EBF1-PDGFRB (~0.6% of BCP-ALL). All 8 patients achieved CR but were MRD positive at day 29. Overall 4 patients relapsed, including 2/3 patients who received standard chemotherapy (regimen A/B) and 2/5 patients who received high risk chemotherapy (regimen C). Three relapsed patients were salvaged and remain in second CR 1-7 years post relapse. Targeted screening of 13 UKALL2003 patients who failed induction revealed 2 more patients with EBF1-PDGFRB; one subsequently died while the second remains in 1st CR 7 years later. None of the UKALL2003 or ALL97 EBF1-PDGFRB patients received TKI therapy. As a result of these findings, patients entered on UKALL2011 are screened for EBF1-PDGFRB fusion if they fail to achieve CR by day 29 or remain MRD positive (>0.5%) at week 14. A 5 year old girl who failed induction (50% blasts at day 35) tested positive for EBF1-PDGFRB. This prompted her withdrawal from UKALL2011 and she was treated according to EsPhALL with standard BFM consolidation plus imatinib (300mg/m2) followed by 3 intensive BFM HR blocks. After 4 weeks consolidation therapy her MRD levels had fallen to 6% and she was MRD negative by flow cytometry after 8 weeks. She continues in molecular remission 2 months after a transplant. In this largest cohort of EBF1-PDGFRB patients reported to date, we demonstrate the genetic mechanisms by which the fusion occurs and the spectrum of cooperating mutations. EBF1-PDGFRB fusion is associated with female sex, older age and a mixed outcome. Although these patients had high levels of MRD and a high relapse rate there was also evidence of durable remissions; especially with intensive chemotherapy. Evidence from this study and others suggest patients with this abnormality who fail standard chemotherapy may respond to imatinib. It is possible that treatment with imatinib might avoid the need for intensive chemotherapy to achieve a cure in these patients but that would need to be tested within a prospective trial. Disclosures No relevant conflicts of interest to declare.
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Ben Barouch, Sharon, Tracy Lackraj, Jessie Medeiros, Mehran Bakhtiari, Jesse Joynt, Kit Tong, Andrea Arruda, et al. "Clinical Significance of Clonal Hematopoiesis in the Setting of Autologous Stem Cell Transplantation for Lymphoma." Blood 138, Supplement 1 (November 5, 2021): 655. http://dx.doi.org/10.1182/blood-2021-150102.
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Abstract Introduction : Peripheral blood samples of healthy individuals may harbour detectable mutations in genes recurrently mutated in myeloid malignancies, a situation referred to as clonal hematopoiesis (CH). Risk factors for CH include increasing age as well as previous exposure to cytotoxic therapy. CH has been associated with an increased risk of overall mortality, including in the setting of autologous stem cell transplantation (ASCT) for non-Hodgkin lymphoma (Gibson et al, JCO, 2017). The excess mortality is largely driven by cardio-vascular disease, but may also be additionally attributable to an increased risk of myeloid malignancies that arise through the selection of CH subclones. Herein, we aimed to investigate the prognostic implications of CH after ASCT in an independent and diversified, large cohort of lymphoma patients using ultra-deep, highly sensitive error-correction sequencing. Methods : DNA was obtained from 420 residual apheresis products obtained from patients who had undergone autologous stem cell transplantation for lymphoma at the Princess Margaret Cancer Center between 2002 and 2018. Target DNA sequences corresponding to regions recurrently mutated in myeloid neoplasms (affecting n = 36 genes) were captured using single molecule molecular inversion probes (smMIPs) that incorporate molecular tagging. Single nucleotide variants and short insertions and deletions were identified using SmMIP-tools (Medeiros et al, bioRxiv, 2021), which implements a series of steps including probabilistic modeling of allele-specific error rates and generation of consensus sequences to suppress next-generation sequencing-associated errors. Given the high sensitivity and precision of our method, we did not prespecify a variant allele fraction cut-off. Results : All patients had relapsed/refractory lymphoma, except for 98 (23.3%) mantle cell lymphoma patients and one patient with extranodal NK/T-cell lymphoma where ASCT was part of frontline management. The most common conditioning regimens were high-dose melphalan and etoposide (77.5%) and high-dose melphalan and Ara-C (16.4%). We identified 275 high-confidence mutations in 181 out of 420 patients (43.1%), with 64 of these 181 patient samples (35.4%) having more than one mutation. The median age was higher in patients with CH than in patients without (55 years vs. 51, P = 0.002). The most frequently mutated gene were PPM1D (11.9%), followed by TET2 (11.4%), DNMT3A (8.8%), ASXL1 (5.2%) and TP53 (4.5%). The lymphoma subtype with the highest prevalence of CH was T-cell lymphoma (CH found in 72.2% of cases), followed by transformed indolent lymphoma (51.4%), mantle cell lymphoma (47.5%), diffuse large B-cell lymphoma (40.4%) and Hodgkin lymphoma (33.3%). While there was no difference in the number of CD34+ cells infused for patients with and without CH, the median time to neutrophil engraftment and the median time to platelet engraftment were significantly longer in patients with CH (11 days vs. 10 days, P = 0.025; and 14 days vs. 13 days, P < 0.001, respectively). The median follow-up of living patients was 4.2 years. Patients with CH had inferior 5-year OS from the time of first relapse (38.9% vs. 45.5%, P = 0.037) and from the time of ASCT (51.2% vs. 59.1%, P = 0.017, see figure). Five-year OS from ASCT was 47.5% vs. 53.7% in patients with 1 mutation and > 1 mutation, respectively, compared to 59.1% in patients without CH (P = 0.005). The presence of CH did not have an impact on the risk of post-ASCT relapse. In multivariate Cox regression analysis in which CH and age (as a continuous variable) were included, CH remained significantly associated with adverse OS post-ASCT (HR 1.39, 95% 1.02-1.91, P = 0.038). Only seven patients out of 420 (1.7%) developed a therapy-related myeloid neoplasm (TMN). The cumulative incidence of TMN was not significantly increased in patients with CH (10-year cumulative incidence 3.3% vs. 3.0% in those without CH, P = 0.433). Conclusions : Our results show that CH was associated with delayed neutrophil and platelet engraftment. Moreover, CH conferred an increased risk of death after ASCT that was not explained by lymphoma relapse. The risk of TMN was low in our cohort and CH was not a risk factor for TMN, an observation that is distinct from prior observations (e.g. Gibson et al, JCO, 2017 and Husby et al, Leukemia, 2020). Our results raise the possibility that the risk of TMN may be modulated by factors other than CH. Figure 1 Figure 1. Disclosures Minden: Astellas: Consultancy. Kuruvilla: Janssen: Honoraria, Research Funding; Antengene: Honoraria; AstraZeneca: Honoraria, Research Funding; Amgen: Honoraria; Incyte: Honoraria; Novartis: Honoraria; Karyopharm: Honoraria, Other: Data and Safety Monitoring Board; Pfizer: Honoraria; AbbVie: Honoraria; TG Therapeutics: Honoraria; Medison Ventures: Honoraria; Merck: Honoraria; Gilead: Honoraria; BMS: Honoraria; Roche: Honoraria, Research Funding; Seattle Genetics: Honoraria. Crump: Roche: Research Funding; Epizyme: Research Funding; Kyte/Gilead: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Prica: Kite Gilead: Honoraria; Astra-Zeneca: Honoraria. Chen: Beigene: Membership on an entity's Board of Directors or advisory committees; Astrazeneca: Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy. Kridel: Gilead Sciences: Research Funding.
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McGrath, Alister E. "Science and Religion: A New Introduction, 3rd ed." Perspectives on Science and Christian Faith 73, no. 1 (March 2021): 59–60. http://dx.doi.org/10.56315/pscf3-21mcgrath.
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SCIENCE AND RELIGION: A New Introduction, 3rd edition by Alister E. McGrath. Hoboken, NJ: John Wiley and Sons, 2020. 272 pages. Paperback; $28.99. ISBN: 9781119599876. *Alister McGrath is a major international scholar who is prolific in his output. He has produced many popular books and academic tomes, and as a theological educator his output also includes many textbooks for students. Science and Religion: A New Introduction is now into its third edition and is an excellent introduction to the whole field of science and religion. The restructuring and inclusion of new material is designed to be helpful to the student, and reflects comments on the previous editions. The book introduces most of the areas of interaction between these bodies of thought, and I myself have used earlier editions in my own teaching, giving students a chapter of McGrath to start with for an essay, followed by more detailed material from elsewhere. *McGrath notes that science and religion are wide categories and serious study entails narrowing them down. He describes Ian Barbour's four models for interaction followed by what he calls four ways of imagining the relationship between them. The conflict model is rightly dismissed as a late nineteenth-century myth, and areas where conflict has been perceived, notably with Galileo and Darwin, are given the more nuanced treatment they deserve, thus dispelling the myths surrounding them. McGrath also gives a broader historical overview, refuting the further myth that the scientific revolution owed nothing to the medieval period. He describes the development of the Newtonian mechanistic model of the universe and brings us to the twentieth century with the development of the Big Bang theory. Regarding this last, it would have been good to note the pioneering work of Roman Catholic priest Georges Lemaître, often dubbed the "Father of the Big Bang," who, in contrast to Alexander Friedman, regarded solutions of Einstein's equations as physically realistic and not just mathematical curiosities. *McGrath moves on to a helpful chapter on religion and the philosophy of science. Some form of realism seems predominant and, indeed, the most rational position to take. It is interesting to note the adoption of "critical realism," including not only by science-religion scholars such as John Polkinghorne and others, but also such as the biblical scholar N. T. Wright and James Dunn. McGrath moves on to the role of explanation in science, noting how in science there are different methods for different sciences, and thus different levels of explanation across the different subdisciplines. Theology too has its own methods appropriate to its own object but there are differing views on the role of explanation. He discusses an important case study, that of "non-reductive physicalism" associated with Nancey Murphy and others. He also gives criteria for drawing an "inference to the best explanation." Various perspectives on the philosophy of science--logical positivism and the criteria of verification, falsificationism, and Kuhn's paradigm shifts--are discussed. Worthy of mention here would have been Imre Lakatos whose "methodology of scientific research programmes" has been applied to theology by Philip Hefner and Nancey Murphy. *Complementing the above there follows a useful chapter on science and the philosophy of religion. McGrath describes arguments for the existence of God, beginning with Aquinas's five ways. A section on the Kalām cosmological argument notes how this has been given a new lease on life by the Big Bang theory's postulation of a temporal origin to the universe, although it would have been good to note that the existence of the universe would demand an explanation even if it were to lack a temporal origin. He gives a careful analysis of Paley's natural theology, noting neglected aspects of Paley's work such as his responses to arguments of David Hume. He examines ways in which God may act in the world given the laws of nature uncovered by science, including through miracles, where he notes Hume's critique. However, as McGrath rightly says, Hume's critique needs to be qualified, since, on the one hand, he defines miracles as violations of laws of nature and yet, on the other, has a problem with inductive generalizations from past experience--which is just what laws of nature are. McGrath rightly sees evolutionary arguments debunking religion as committing the genetic fallacy and self-defeating if human rationality is flawed, since that could equally well affect judgments in areas other than religion, notably science. There is a good section on natural theology and the role of explanation. *In the next chapter, McGrath turns to models and analogies: first, as found within the natural sciences and then, within religion. After considering what the terms mean more generally, he gives specific examples for the sciences, including the kinetic theory of gases, wave-particle duality, Galileo's analogical reasoning which led him to postulate mountains on the moon, and Darwin's metaphor of "natural selection." In the theological sphere, he considers Aquinas's notion of analogia entis whereby the creation bears a likeness to its creator, and Ian Ramsey's model of the "divine economy" utilizing the Greek concept of oikonomia. He looks at Arthur Peacocke's theological application of models as linked to "critical realism," and Sally McFague's metaphors in theology--though he could perhaps have allowed more than one sentence on Janet Soskice. He then examines specific theological examples: creation and theories of the atonement. He has a helpful section on the notion of "mystery" in science and religion before returning to Ian Barbour on models. *McGrath's final chapter considers a number of contemporary debates. Noting Hume's distinction between "ought" and "is" he critiques the idea that science, say, evolutionary biology or neuroscience, can determine ethics and moral values. That leads to a more general critique of the imperialist stance that science can answer all interesting questions or that the only reality is that disclosed by science. An interesting example is mathematics, which discovers truths that do not belong to the natural sciences. It is also utterly astonishing that mathematics is effective in describing nature and very hard to explain on an atheistic view. *An important area considered is theodicy, which is arguably made more difficult by the long process of evolution, preceding the existence of humans by hundreds of millions of years. McGrath provides an overview of the helpful contributions of Christopher Southgate and his former student Bethany Sollereder. For these scholars, there is "no other way" for God to create such a rich diversity of creatures, with whom God suffers, and for whom God will bring eschatological fulfilment. On transhumanism, McGrath describes the approaches of Philip Hefner and Ted Peters who, while recognizing the creativity of technological enhancement, are also aware that, given fallen human nature, this can also be abused. *McGrath returns to the anthropic principle and fine-tuning. He says that fine-tuning is strongly consistent with a theistic perspective, but the debate about a multiverse as a possible explanation continues. He also considers the legitimacy of teleological language and directionality in biology. Simon Conway Morris's notion of convergent evolution may be the "best explanation" of what is observed and is resonant with a religious perspective but, like cosmological fine-tuning, does not prove that God exists. *McGrath concludes with two sections on the psychology of religion, considering whether this field can "explain away" religion. Religion may be "natural," but it is debatable as to whether that has any implication at all about the existence of God. Moreover, it is a long way from primitive apprehension of some vague supernatural agent to the systematic theology of, say, Thomas Aquinas or Karl Barth. To my mind, this is not unlike the difference--to give a scientific analogy--between the discovery of fire by early humans and the modern scientific understanding of combustion. *This is an excellent introduction to the field and very well suited to its pedagogic purpose. There are a few typographical errors (e.g., "magisterial" for "magisteria"). I also noticed that British cosmologist Paul Davies is mistakenly described as American. But these and my earlier minor points should not detract from a volume that provides a vital resource to educators and their students. *Reviewed by Rodney Holder, Emeritus Course Director, The Faraday Institute for Science and Religion, Cambridge, UK CB3 0UB.
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Kim, Kicheol, Anne-Katrin Pröbstel, Ryan Baumann, Julia Dyckow, James Landefeld, Elva Kogl, Lohith Madireddy, et al. "Cell type-specific transcriptomics identifies neddylation as a novel therapeutic target in multiple sclerosis." Brain, December 29, 2020. http://dx.doi.org/10.1093/brain/awaa421.
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Abstract Multiple sclerosis is an autoimmune disease of the CNS in which both genetic and environmental factors are involved. Genome-wide association studies revealed more than 200 risk loci, most of which harbour genes primarily expressed in immune cells. However, whether genetic differences are translated into cell-specific gene expression profiles and to what extent these are altered in patients with multiple sclerosis are still open questions in the field. To assess cell type-specific gene expression in a large cohort of patients with multiple sclerosis, we sequenced the whole transcriptome of fluorescence-activated cell sorted T cells (CD4+ and CD8+) and CD14+ monocytes from treatment-naive patients with multiple sclerosis (n = 106) and healthy subjects (n = 22). We identified 479 differentially expressed genes in CD4+ T cells, 435 in monocytes, and 54 in CD8+ T cells. Importantly, in CD4+ T cells, we discovered upregulated transcripts from the NAE1 gene, a critical subunit of the NEDD8 activating enzyme, which activates the neddylation pathway, a post-translational modification analogous to ubiquitination. Finally, we demonstrated that inhibition of NEDD8 activating enzyme using the specific inhibitor pevonedistat (MLN4924) significantly ameliorated disease severity in murine experimental autoimmune encephalomyelitis. Our findings provide novel insights into multiple sclerosis-associated gene regulation unravelling neddylation as a crucial pathway in multiple sclerosis pathogenesis with implications for the development of tailored disease-modifying agents.
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Nkone, Paballo, Shayne Loubser, Thomas C. Quinn, Andrew D. Redd, Arshad Ismail, Caroline T. Tiemessen, and Simnikiwe H. Mayaphi. "Deep sequencing of the HIV-1 polymerase gene for characterisation of cytotoxic T-lymphocyte epitopes during early and chronic disease stages." Virology Journal 19, no. 1 (March 28, 2022). http://dx.doi.org/10.1186/s12985-022-01772-8.
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Abstract Background Despite multiple attempts, there is still no effective HIV-1 vaccine available. The HIV-1 polymerase (pol) gene is highly conserved and encodes cytotoxic T-lymphocyte (CTL) epitopes. The aim of the study was to characterise HIV-1 Pol CTL epitopes in mostly sample pairs obtained during early and chronic stages of infection. Methods Illumina deep sequencing was performed for all samples while Sanger sequencing was only performed on baseline samples. Codons under immune selection pressure were assessed by computing nonsynonymous to synonymous mutation ratios using MEGA. Minority CTL epitope variants occurring at $$\ge$$ ≥ 5% were detected using low-frequency variant tool in CLC Genomics. Los Alamos HIV database was used for mapping mutations to known HIV-1 CTL epitopes. Results Fifty-two participants were enrolled in the study. Their median age was 28 years (interquartile range: 24–32 years) and majority of participants (92.3%) were female. Illumina minority variant analysis identified a significantly higher number of CTL epitopes (n = 65) compared to epitopes (n = 8) identified through Sanger sequencing. Most of the identified epitopes mapped to reverse transcriptase (RT) and integrase (IN) regardless of sequencing method. There was a significantly higher proportion of minority variant epitopes in RT (n = 39, 60.0%) compared to IN (n = 17, 26.2%) and PR (n = 9, 13.8%), p = 0.002 and < 0.0001, respectively. However, no significant difference was observed between the proportion of minority variant epitopes in IN versus PR, p = 0.06. Some epitopes were detected in either early or chronic HIV-1 infection whereas others were detected in both stages. Different distribution patterns of minority variant epitopes were observed in sample pairs; with some increasing or decreasing over time, while others remained constant. Some of the identified epitopes have not been previously reported for HIV-1 subtype C. There were also variants that could not be mapped to reported CTL epitopes in the Los Alamos HIV database. Conclusion Deep sequencing revealed many Pol CTL epitopes, including some not previously reported for HIV-1 subtype C. The findings of this study support the inclusion of RT and IN epitopes in HIV-1 vaccine candidates as these proteins harbour many CTL epitopes.
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Fiorani, Valeria Piacentini. "RICERCHE STORICO-ARCHEOLOGICHE DELL’UNIVERSITÀ CATTOLICA DI MILANO SUL DELTA DELL’INDO (2010-2018)." Istituto Lombardo - Accademia di Scienze e Lettere - Rendiconti di Lettere, May 5, 2020. http://dx.doi.org/10.4081/let.2018.648.
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Historic-Archaeological Research of the Catholic University of the Sacred Heart of Milano on the Indus Delta (2010-2018). The following text is only an abridged note on the excavations at Banbhore and some significant extra-moenia surveys carried out by the Italian Team within the Institutional framework of a “Pak-French-Italian Historical and Archaeological Research at Banbhore” on the basis of a Licence issued by the competent Pakistani Authorities (2010-2015 - Coordinator of the Project Dr Kaleemullah Lashari), and, some later, within a new institutional asset: a “Memorandum of Understanding” (MoU) signed in the 2017 between the Director General of the Department of Antiquities of Sindh (Manzoor A. Kanasro) and the Magnifico Rettore of the Catholic University of the Sacred Heart of Milan (Prof. Franco Anelli). Aims of the said MoU are: (a) historical-archaeological research-work at Banbhore and Rani Kot; (b) training (theoretical and on the job) to selected students and officers of the DAS. The Italian group works under the sponsorship of the Italian Ministry for Foreign Affairs (now Ministry for Foreign Affairs and International Cooperation/MAECI). Scientific director for the Italian Team is Prof. Valeria Piacentini, member of the Board of Directors of the Research Centre CRiSSMA of the Catholic University.
In the following dissertation I won’t linger on the debated issue about the identification of the site of Banbhore with historic sites on the Indus delta (the historical Mihrān river) mentioned and described in the written sources of the past. Too many respected scholars and archaeologists have entered this debate since the end of the 19th Century, for which I refer to a well-known exhaustive literature. In the “50s of the previous century, Leslie Alckok – then official to the Department of Archaeology of Pakistan – carried out some preliminary excavations, followed by Dr Rafique Mughal and F.A. Khan. This latter carried out a systematic and extensive archaeological campaign of several years between the “50s and the “60s, well backed by one of the most authoritative Pakistani historians, N.A. Baloch. Khan brought to light extraordinary archaeological and architectural evidence, but, unfortunately, his excavation-notes have gone lost and little or nothing has been published. Thence, our research-work had to start from nothing.
First of all and most urgent was an updated planimetric and altimetric study of the site by kite-photos: a massive wall of c. 1,4 km with 55 towers, 7 posterns, and major and secondary accesses to the citadel (2010-2012 by Y. Ubelman, S. Reynard, A. Tilia), regularly updated with advanced technologies (A. Tilia).
Then, in collaboration with Dr M. Kervran, head of the French Team, we undertook an accurate study of the bastions and the shapes of its towers (squared, U-shaped, circular), which has brought to envisage three main occupational phases of the intra-moenia area: 1. Indo-Parthian/Indo-Kushan phase (c. III-II Century b.CE – III-IV Century CE); 2. Sasanian/Indo-Sasanian phase (c. III-IV Century – early VIII Century CE); 3. Islamic phase (VIII – XII/early XIII Century CE). Decay and/or abandonment and end of any settled life on the site can be dated around the XII-early XIII Century, due to attacks and pillaging by Turco-Mongol nomadic tribes, and/or the deviation of this branch of the Indus delta and consequent filling of the harbour, or both. Archaeological evidence come to light confirms the historical information.
Our third aim (2010-2015) was to arrive to a first chronological panorama of the site through levels in stratigraphy and the assemblage of pottery and other significant evidence with the individual levels (N. Manassero – A. Fusaro – A. Tilia). Deep trenches were excavated (T/7 and T/9 on the Italian side; T/1 on the French side near the western portion of the bastions skirting the Hindu Temple. These brought to the very early Sasanian period or late Indo-Parthian (c. II-III Century CE), then the water-table invaded the trenches preventing us to go deeper; however, drillings (T/9) have allowed to go deeper for c.1,8 mt of shards …thus reaching a much earlier occupational phase. The question about an Hellenistic occupation at the bottom of the site (Arrian’s harbour of Alexander) is still unanswered… a dream…but the importance of Banbhore has induced to take it seriously and include it within our priorities.
Ours and the French trenches have also produced significant information on the architectural panorama of the site for its earlier periods of life. A main N-S and E-W road axis was traced. The site was organised in insulae, each insula with its pits of organic and inorganic refusals, densely built along narrow roads by small mono-nuclear houses, roofed, bases in local stones and the elevation in unbacked bricks. Interesting the presence of refusals of some crafts, as if each building had at the same time the function of “home” and workshop. The refusals shew activities of ivory-working (T/1,T/4, T/9), and other crafts carried out “within the bastions of the citadel”, such as glass, shells and mother of pearl, alloys and various metallurgic activities, too, and so on. Significant the presence of a wealth of clay-moulds. T/5 has produced a clay-mould nearly intact in its shape. No less interesting, in the deeper layers, the presence of a well arranged organisation of the hydraulic resources (small canals, little domed cisterns in roughly cut local stones, wells..: T/9).
One element of the site attracted our attention: the so called “Partition Wall”. It has a North-South direction; then, it bends Eastwards, including the Mosque and the Eastern lagoon, but cutting out the majestic Southern Gate. So far, it had been interpreted as a Wall that had a “religious” or “social” function to separate – after the Islamic conquest – the Muslims from the non-Muslim inhabitants of the site. Manassero dedicated the 2014 Field-Season to investigate: T/7 and T/8 were the trenches that gave a new profile to this structure and to the general occupational organisation of the citadel during its last period of life. The round-shaped tower in mud-bricks and the walls on both sides show that they had been hurriedly erected in a late phase of the life of the citadel (around the end of the X – early XI Century CE). They had been built on the top of pre-existing buildings either abandoned and collapsed or hastily flatted-down, likely to defend this eastern portion of the site and its Mosque by some human ravage that had succeeded to open a breach in the lower western bastion leaving the higher north-eastern area exposed to attacks (the skeleton found by Dr Kervran on her portion of the wall, and Khan’s skeletons with arrow-heads in their skulls and chests). According to F.A. Khan’s excavations and what he left us in his little booklet that so far – printed and re-printed – is the guide for visitors to Banbhore, in the eastern portion of the site during the latest stage of its life still stood beautiful palaces, the Friday Mosque, markets, and an eastern gate where a staircase (still in situ in the 2015) brought to a lagoon at the foot of the eastern bastions and to the river.
At the end of this first stage of our historical and archaeological research-work, the identification of the site of Banbhore with the historic Sasanian/Indo-Sasanian fortified harbour-town seemed quite feasible. When we resumed our field-work in the 2017, we decided to go deeper in this direction. In the meantime, Dr Manassero had resigned due to personal choices of life. Dr Simone Mantellini bravely accepted to be our Field-Director for the archaeological sector. T/9 had unearthed an imposing Building (Building 1) running along the East-West road-axis, parallel to a second Building (Building 2). The road – wide about 5 meters – must have been a major road, that had played a central role within the general architectural urban asset of the site. Building 2 had the typical structure of the local houses: base in rough stones, elevation in mud-bricks. Excavations of Building 1 produced fillings well flatted and an endless chronological procession of floors in row mud, likely the re-occupation of an important palace during the last phase of the occupational life of Banbhore. The material (pottery and others) associated with the various levels in stratigraphy (Dr A. Fusaro) confirmed the dating of the dug portion from c. the early XIII to the XI Century CE. Historically speaking, it makes sense: chronicles of the time report about the invasion of Lower Sindh by the Seljuks (second half of the XI Century CE); they indulge on the assaults against the walls of its great harbour-town named Daybul, its long siege concluded with a peace-treaty that fixed the border with Makrān at Gwadar and gave to Daybul an autonomous status (nāḥiya) within the Seljuk dominion of Qāvurd-Khān ibn Chaghrī Beg. More interesting was the copious filling with ivory refusals. Along Building 2, were found semi-worked shells, glass, iron and brass rivets, iron instruments, alloys, coins and other. This induced to think to a late quarter of work-shops outside the Partition Wall, built on previous buildings. Lastly, some surveys extra-moenia and in the Lahiri Bandar and Mullah-ka Kot islands have revealed a close connection and interaction between these spaces and the citadel. Around the bastions: the remains of a densely settled area and a well organised regulation of the waters and the territory, rock quarries, urban quarters, dwellings, cairn-tombs (some of them re-used), an artificial lake of sweet water delimited to the south by a “barrage”, wells, and a vast so called “industrial area” to the north-northwest of the bastions, pottery kilns and others completed the image of a urban asset at least for a given span of time. Architectural and archaeological evidences have regularly been graphically, photographically and topographically documented (A. Tilia).
Archaeometric analyses on the job (pottery, metals, alloys, coins…) and in Italy (ivory, glass, clay-moulds, shards…) have provided precious support and new elements to the archaeological work.
We are now confronted with the plan of a positive shahristān. Banbhore is no longer only a fortified citadel. Written sources in Arabic and Persian confirm this feature. After the Jan.-Feb. 2018 field-season, the Islamic occupational phase of Banbhore and the “archaeological park” surrounding it enhanced this image: a positive fluvial and maritime system stemmed out, a well-fortified system and harbour-town, a centre of mercantile power, production and re-distribution of luxury goods, an international centre of pilgrimage and religious learning, too, outlet to the sea of the capital-city of the moment.
For the forthcoming field-seasons, it was decided to concentrate the attention on the sector where the North-South axis crosses the East-West one. In particular: to further investigate Building 1; to look for the ivory-workshops that must be there around – given the copious pieces so far brought to light and used as refilling (more than 9.000 fragments) and some fragments of rough ivory (specialist of the Italian Team G. Affanni); to organise a deep-trench in the Pakistani sector (T/11), in order to resume Manassero’s investigations on the urban and architectural features of the pre-Islamic phases...and (why not?) try to overcome the water-table problem with the technological support offered by the Bahrya University of Karachi…the much dreamed quest of Alexander the Macedonian’s port.
All in all and to conclude. Nowadays, at the end of this first stage of historical and archaeological research-work in collaboration with the DAS, the identification of the site of Banbhore and its surrounding area with the Sasanian/Indo-Sasanian and the Early-Islamic well-fortified harbour-town of Daybul/Debol can be confirmed. No other site with the characteristics described by the written sources of the time (chronicles, geographies, travelogues…plus Marco Polo and some significant Genoese archival documents) has so far come to light on the Indus deltaic region. Conversely, still un-answered are other queries: Banbhore can be identified also with the great harbour of Alexander the Macedonian? Or with the Barbaricum/Barbarikon/Barbariké, harbour-town of Parthian rulers or local lords of “Skuthia”, also mentioned in the Periplus Maris Erythraei? Or again with Dib/Deb, harbour mentioned in a Parthian-Manichaean text? Or again the Dibos of Greek sources? Or the Dêbuhl/Dêphul of an Arminian text à propos of the Prophet Mani? Wishful thinking; however, these queries represent some amongst the ambitious aims of our future research-work.
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Shariq, Omair. "Clinical Features, Genotype-Phenotype Correlations and Treatment Outcomes in Children and Adolescents with Multiple Endocrine Neoplasia Type 1: An International Cohort Study." Journal of the Nuffield Department of Surgical Sciences 2, no. 4 (October 12, 2021). http://dx.doi.org/10.37707/jnds.v2i4.206.
Full textAbstract:
Omair A. Shariq1,2, Kate E. Lines3, Katherine A. English3, Bahram Jafar-Mohammadi3, PhilippaPrentrice3, Ruth Casey5, Benjamin G. Challis5, Andreas Selberherr6, Fiona J. Ryan3, Ultan Healy3,Tom Kurzawinski7, Mehul T Dattani7, Irina Bancos8, Duncan Richards9, Benzon M. Dy2, Melanie L.Lyden2, William F. Young, Jr.8, Travis J. McKenzie2, Rajesh V. Thakker3
1Nuffield Department of Surgical Sciences, University of Oxford, UK2Department of Surgery, Mayo Clinic, Rochester, MN3Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, UK4Department of Paediatric Endocrinology, Great Ormond Street Hospital for Children, London, UK5Department of Endocrinology, Cambridge University Hospital NHS Foundation Trust, Cambridge, UK.6Department of Surgery, Medical University of Vienna, Vienna, Austria.7Centre for Endocrine Surgery, Great Ormond Street Hospital for Children, London, UK8Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, MN9Oxford Clinical Trials Research Unit, Botnar Research Centre, Oxford, UK
Background: Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterised by parathyroid, pituitary and duodenopancreatic neuroendocrine tumours (DP-NETs). Knowledge regarding manifestations and outcomes is largely derived from adult cohorts. Thus, we investigated the occurrence and treatment of MEN1 manifestations in children and adolescents, and also explored potential genotype-phenotype correlations.
Methods Eighty MEN1 patients who underwent childhood/adolescent tumour surveillance at 5 international referral centres were included. Fisher’s exact, Wilcoxon rank-sum and Kaplan-Meier tests were used to compare proportions, continuous variables and recurrence-free survival, respectively.
Results Fifty-six patients (70%) developed an MEN1 manifestation before 19 years, at a median age of 14 years (range: 6-18 years). Primary hyperparathyroidism occurred in 46/56 patients (82.1%), 33 (72%) of whom underwent parathyroidectomy. Less-than-subtotal (<3-gland) parathyroidectomy resulted in worse recurrence/persistence-free survival vs subtotal (3-3.5-gland) or total (4-gland) parathyroidectomy (median 27 months vs not reached; P=0.005). Twenty-one patients (37.5%) developed DP-NETs (non-functioning [n=15], insulinomas [n=8], and gastrinoma [n=1]), 12 (57.1%) underwent surgery and 3 (14.3%) had metastases (hepatic [n=2] and lymph node [n=1]). Compared to patients without DP-NETs, those with DP-NETs at <19 years were more likely to harbour MEN1 mutations disrupting the menin-JunD interaction domain (80% vs 51.9%; P=0.0459). Pituitary tumours developed in 18/56 patients (32%) and were mostly dopamine agonist-responsive prolactinomas.
Conclusions Morbidity from MEN1 manifestations occurs during childhood and adolescence in 70% of patients. Less-than-subtotal parathyroidectomy leads to high failure rates. DP-NETs are the second most common manifestation in this age group and may be more frequent in patients with mutations that disrupt menin-JunD binding.
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Smith, Hazel, and Roger T. Dean. "Posthuman Collaboration: Multimedia, Improvisation, and Computer Mediation." M/C Journal 9, no. 2 (May 1, 2006). http://dx.doi.org/10.5204/mcj.2619.
Full textAbstract:
Artistic collaboration involves a certain loss of self, because it arises out of the merging of participants. In this sense collaboration questions the notion of the creative individual and the myth of the isolated artistic genius. As such, artistic collaborations can be subversive interventions into the concept of authorship and the ideologies that surround it (Smith 189-194). Collaborations also often simultaneously superimpose many different approaches to the collaborative process. Collaboration is therefore a multiplicitous activity in which different kinds of interactivity are interlinked; this process may also be facilitated by improvisation which allows for continuous modification of the interactions (Smith and Dean, Improvisation). Even when we are writing individually, we are always collaborating with prior texts and employing ideas from others, advice and editing suggestions. This eclectic aspect of creative work has led some to argue that collaboration is the dominant mode, while individual creativity is an illusion (Stillinger; Bennett 94-107). One of the reasons why collaboration tends to be multiplicitous is that contemporary creative endeavour sometimes involves collaboration across different media and with computers. Artworks are created by an ‘assemblage’ of different expertises, media, and machines in which the computer may be a ‘participant’. In this respect contemporary collaboration is what Katherine Hayles calls posthuman: for Hayles ‘the posthuman subject is an amalgam, a collection of heterogeneous components, a material-informational entity whose boundaries undergo continuous construction and reconstruction (Hayles 3). Particularly important here is her argument about the conceptual shifts that information systems are creating. She suggests that the binary of presence and absence is being progressively replaced in cultural and literary thought by the binary of pattern and randomness created by information systems and computer mediation (Hayles 25-49). In other words, we used to be primarily concerned with human interactions, even if sometimes it was the lack of them, as in Roland Barthes concept of ‘the death of the author’. However, this has shifted to our concern with computer systems as methods of organisation. Nevertheless, Hayles argues, computers can never totally replace embodied human subjects, rather we need to continually negotiate between presence and pattern, absence and randomness (Hayles 25-49). This very negotiation is central to many computer-mediated collaborations. Our own collaborative practice—Roger is primarily a musician and Hazel primarily a writer but we both have interdisciplinary performance and technological expertise—spans 15 years and has resulted in approximately 18 collaborative works. They are all cross-media: initially these brought together word and sound; now they sometimes also include image. They all involve multiple forms of collaboration, improvised and unfixed elements, and computer interfaces. Here we want to outline some of the stages in the making of our recent collaboration, Time, the Magician, and its ‘posthuman’ engagement with computerised processes. Time, the Magician is a collaborative performance and sound-video piece. It combines words, sound and image, and involves composed and improvised elements as well as computer mediation. It was conceived largely by us, but the first performance, at the Sydney Conservatorium of Music in 2005 also involved collaboration with Greg White (sound processing) and Sandy Evans (saxophone). The piece begins with a poem by Hazel, initially performed solo, and then juxtaposed with live and improvised sound. This sound involves some real-time and pre-recorded sampling and processing of the voice: this—together with other sonic materials—creates a ‘voicescape’ in which the rhythm, pitch, and timbre of the voice are manipulated and the voice is also spatialised in the performance space (Smith and Dean, “Voicescapes”). The performance of the poem is followed (slightly overlapping) by screened text created in the real-time image-processing program Jitter, and this is also juxtaposed with sound and voice samples. One of the important aspects of the piece is its variability: the video-manipulated text and images change both in order and appearance each time, and the sampling and manipulation of the voice is different too. The example here shows short extracts from the longer performance of the work at the Sydney 2005 event. (This is a Quicktime 7 compressed video of excerpts from the first performance of Time, the Magician by Hazel Smith and Roger Dean. The performance was given by austraLYSIS (Roger Dean, computer sound and image; Sandy Evans, saxophone; Hazel Smith, speaker; Greg White, computer sound and sound projection) at the Sydney Conservatorium of Music, October 2005. The piece in its entirety lasts about 11 minutes, while these excerpts last about four minutes, and are not cross-faded, but simply juxtaposed. The piece itself will later be released elsewhere as a Web video/sound piece, made directly from the sound and the Jitter-processed images which accompany it. This Quicktime 7 performance video uses AAC audio compression (44kHz stereo), H.264 video compression (320x230), and has c. 15fps and 200kbits/sec.; it is prepared for HTTP fast-start streaming. It requires the Quicktime 7 plugin, and on Macintosh works best with Safari or Firefox Explorer is no longer supported for Macintosh. The total file size is c. 6MB. You can also access the file directly through this link.) All of our collaborations have involved different working processes. Sometimes we start with a particular topic or process in mind, but the process is always explorative and the eventual outcome unpredictable. Usually periods of working individually—often successively rather than simultaneously—alternate with discussion. We will now each describe our different roles in this particular collaboration, and the points of intersection between them. Hazel In creating Time, the Magician we made an initial decision that Roger—who would be responsible for the programming and sound component of the piece—would work with Jitter, which we had successfully used for a previous collaboration. I would write the words, and I decided early on that I would like our collaboration to circle around ideas—which interested both Roger and me—about evolution, movement, emergence, and time. We decided that I would first write some text that would then be used as the basis of the piece, but I had no idea at this stage what form the text would take, and whether I would produce one continuous text or a number of textual fragments. In the early stages I read and ‘collaborated with’ a number of different texts, particularly Elizabeth Grosz’s book The Nick of Time. I was interested in the way Grosz sees Darwin’s work as a treatise on difference—she argues that for Darwin there are no clear-cut distinctions between different species and no absolute origin of the species. I was also stimulated by her idea that political resistance is always potential, if latent, in the repressive regimes or social structures of the past. As I was reading and absorbing the material, I opened a file on my computer and—using a ‘bottom-up’ approach—started to write fragments, sometimes working with the Grosz text as direct trigger. A poem evolved which was a continuous whole but also discontinuous in essence: it consisted of many small fragments that, when glued together and transformed in relation to each other, reverberated though association. This was appropriate, because as the writing process developed I had decided that I would write a poem, but then also disassemble it for the screened version. This way Roger could turn each segment into a module in Jitter, and program the sequence so that the texts would appear in a different order each time. After I had written the poem we decided on a putative structure for the work: the poem would be performed first, the musical element would start about halfway through, and the screened version—with the fragmented texts—would follow. Roger said that he would video some background material to go behind the texts, but he also suggested that I design the texts as visual objects with coloured letters, different fonts, and free spatial arrangements, as I had in some previous multimedia pieces. So I turned the texts into visual designs: this often resulted in my pulling apart sentences, phrases and words and rearranging them. I then converted the texts files into jpg files and gave them to Roger to work on. Roger When Hazel gave me her 32 text images, I turned these into a QuickTime video with 10 seconds per image/frame. I also shot a 5 minute ‘background’ video of vegetation and ground, often moving the camera quickly over blurred objects or zooming in very close to them. The video was then edited as a continually moving sequence with an oscillation between clearly defined and abstracted objects, and between artificial and natural ones. The Jitter interface is constructed largely as a sequence of three processing modules. One of these involves continuously changing the way in which two layers (in this case text and background) are mixed; the second, rotation and feedback of segments from one or both layers; and the third a kind of dripping across the image, with feedback, of segments from one or both layers. The interface is performable, in that the timing and sequence can be altered as the piece progresses, and within any one module most of the parameters are available for performer control—this is the essence of what we call ‘hyperimprovisation’ (Dean). Both text and image layers are ‘granulated’: after a randomly variable length of time—between 2 and 20 seconds or so—there is a jump to a randomly chosen new position in the video, and these jumps occur independently for the two layers. Having established this approach to the image generation, and the overall shape of the piece (as defined above), the remaining aspects were left to the creative choices of the performers. In the Sydney performance both Greg White and I exploited real-time processing of the spoken text by means of the live feed and pre-recorded material. In addition we used long buffers (which contained the present performance of the text) to access the spoken text after Hazel had finished her performed opening segment. I worked on the sound and speech components with some granulation and feedback techniques, throughout, while Greg used a range of other techniques, as well as focusing on the spatial movement of the sound around four loudspeakers surrounding the performance and listening space. Sandy Evans (saxophone)—who was familiar with the overall timeline—improvised freely while viewing the video and listening to our soundscape. In this first performance, while I drove the sound, the computer ‘posthumanly’ (that is without intervention) drove the image. I worked largely with MSP (Max Signal Processing), a part of the MAX/MSP/Jitter suite of platforms for midi, sound and image, to complement sonically the Jitter-mediated video. So processes of granulation, feedback, spatial rotation (of image) or redistribution (of sound)—as well as re-emergence of objects which had been retained in the memory of the computer—were common to both the sound and image manipulation. There was therefore a degree of algorithmic synaesthesia—that is shared algorithms between image and sound (Dean, Whitelaw, Smith, and Worrall). The collaborative process involved a range of stimuli: not only with regard to those of process, as discussed, but also in relation to the ideas in the text Hazel provided. The concepts of evolution, movement, and emergence which were important to her writing also informed and influenced the choice of biological and artificial objects in the background video, and the nature and juxtaposition of the processing modules for both sound and image. Conclusion If we return to the issues raised at the beginning of this article, we can see how our collaboration does involve the merging of participants and the destabilising of the concept of authorship. The poem was not complete after Hazel had written it—or even after she had dislocated it—but is continually reassembled by the Jitter interface that Roger has constructed. The visual images were also produced first by Hazel, then fused with Roger’s video in continuously changing formations through the Jitter interface. The performance may involve collaboration by several people who were not involved in the original conception of the work, indicating how collaboration can become an extended and accumulative process. The collaboration also simultaneously superimposes several different kinds of collaborative process, including the intertextual encounter with the Grosz text; the intermedia fusion of text, image and sound; the participation of a number of different people with differentiated roles and varying degrees of input; and collaboration with the computer. It is an assemblage in the terms mentioned earlier: a continuously modulating conjunction of different expertises, media, and machines. Finally, the collaboration is simultaneously both human and posthuman. It negotiates—in the way Hayles suggests—between pattern, presence, randomness, and absence. On the one hand, it involves human intervention (the writing of the poem, the live music-making, the shooting of the video, the discussion between participants) though sometimes those interventions are hidden, merged, or subsumed. On the other hand, the Jitter interface allows for both tight programming and elements of variability and unpredictability. In this way the collaboration displaces the autonomous subject with what Hayles calls a ‘distributed system’ (Hayles 290). The consequence is that the collaborative process never reaches an endpoint: the computer interface will construct the piece differently each time, we may choose to interact with it in performance, and the sound performance will always contain many improvised and unpredictable elements. The collaborative process, like the work it produces, is ongoing, emergent, and mutating. References Bennett, Andrew. The Author. London: Routledge, 2005. Dean, Roger T. Hyperimprovisation: Computer Interactive Sound Improvisation; with CD-ROM. Madison, WI: A-R Editions, 2003. Dean, Roger, Mitchell Whitelaw, Hazel Smith, and David Worrall. “The Mirage of Real-Time Algorithmic Synaesthesia: Some Compositional Mechanisms and Research Agendas in Computer Music and Sonification.” Contemporary Music Review, in press. Grosz, Elizabeth. The Nick of Time: Politics, Evolution and the Untimely. Sydney: Allen and Unwin, 2004. Hayles, N. Katherine. How We Became Posthuman: Virtual Bodies in Cybernetics, Literature, and Informatics. Chicago: U of Chicago P, 1999. Smith, Hazel. Hyperscapes in the Poetry of Frank O’Hara: Difference, Homosexuality, Topography. Liverpool: Liverpool UP, 2000. Smith, Hazel, and Roger T. Dean. Improvisation, Hypermedia and the Arts since 1945. London: Harwood Academic, 1997. ———. “Voicescapes and Sonic Structures in the Creation of Sound Technodrama.” Performance Research 8.1 (2003): 112-23. Stillinger, Jack. Multiple Authorship and the Myth of Solitary Genius. Oxford: Oxford UP, 1991. Citation reference for this article MLA Style Smith, Hazel, and Roger T. Dean. "Posthuman Collaboration: Multimedia, Improvisation, and Computer Mediation." M/C Journal 9.2 (2006). echo date('d M. Y'); ?> <http://journal.media-culture.org.au/0605/14-smithdean.php>. APA Style Smith, H., and R. Dean. (May 2006) "Posthuman Collaboration: Multimedia, Improvisation, and Computer Mediation," M/C Journal, 9(2). Retrieved echo date('d M. Y'); ?> from <http://journal.media-culture.org.au/0605/14-smithdean.php>.
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