Abstract 575

Sickle cell anemia (SCA) is characterized by polymerization of sickle hemoglobin (HbS), erythrocyte deformity, and hemolytic anemia. HbS induced red cell injury is believed to be critical for initiating acute vasoocclusive episodes, although the precise mechanism underlying this has not been elucidated. Our prior work has established a SCA sub-phenotype characterized by hyper-hemolysis, decreased nitric oxide (NO) bioavailability, increase tricuspid jet velocity (TRV), and early mortality. Surprisingly, it was also characterized by fewer acute pain episodes. Recently, a haplotype of GTP cyclohydrolase ( GCH1 ), the rate-limiting enzyme for tetrahydrobiopterin (BH4) synthesis, was associated with pain sensitivity in both animal and human experimental models. BH4 is a cofactor required for catecholamine, serotonin and NO production. Together, these findings led us to hypothesize that genetic variation resulting in uncoupled BH4 dependent enzymes might also modulate complications of SCA. We examined 7 markers of the GCH1 locus against interrelated traits, including hemolysis (LDH), NO bioavailability (arginine/ornithine ratios), TRV, painful episodes and survival among 188 contemporary SCA subjects followed at NIH. There was no association with LDH, arginine:ornithine ratios, TRV or survival at a median follow-up of 3.4 years. However, a GCH1 haplotype defined by 3 linked SNPs (rs8007267, rs2878172, rs7147286) was more prevalent in patients with more frequent pain compared to 73 SCA subjects with very infrequent painful episodes (odds ratio 2.13, 95% CI 1.21-3.78, P=0.007). Further evaluation in a replication study using the Cooperative Study of Sickle Cell Disease (CSSCD) database showed no association between pain and 2 of the GCH1 haplotype markers tested (rs8007267 P=0.59; rs2878172 P=0.35). However, analysis of 9 additional GCH1 SNPs in CSSCD cases indicated that an infrequent variant (rs17738966) is associated with pain (odds ratio 2.50, P=0.008). Further analysis for differences in population stratification, age, demographics and ascertainment bias is needed to better determine if GCH1 polymorphisms are associated with acute SCA pain. To study the possible functional significance of GCH1 polymorphisms, lymphoblastoid cell lines homozygous for these haplotype markers from the Yoruban Hapmap population were studied in vitro and had significantly lower GCH1 mRNA expression after stimulation to high levels of intracellular cAMP compared to homozygotes for the variant haplotype (P=0.004). In vivo , the GCH1 pain haplotype was also associated with diminished forearm blood vessel vasodilation in response to acetylcholine (ACh) infusion in 21 subjects with SCA (P=0.03). ACh induced vasodilation is an expected response to BH4 dependent endothelial NO synthesis and the variable SCA response suggests that those with a diminished vaso-relaxation have a relative BH4 deficiency. As a negative control, there was no association with nitroprusside induced vasodilation. Furthermore, examination of a congenic cross of Brown Norway chromosome 15 (site of rat Gch1 ) onto a Dahl SS background in rats demonstrated a chromosome dosage effect for ACh response (EC50, P#x003D;0.007). Taken together, we demonstrate an association between pain and a GCH1 haplotype in a contemporary SCA population, which also appears to involve a different haplotype effect than those previously described in non-SCA studies of pain. BH4 therapy has been studied in a Phase 2a clinical trial in SCD. The GCH1 association study with ACh dependent vasodilation in humans and animals suggests the need for additional studies to determine if polymorphisms in GCH1 and variability in BH4 synthesis modulates SCA pain, and if polymorphisms of this gene should be accounted for in clinical trials focused on pain prevention.

Disclosures: No relevant conflicts of interest to declare.


Fifteen F1 and F2 were used between five marked breeding lines with
open-bud parents and three upland parents to analyze high parent heterosis, mid-parent
heterosis and useful heterosis, and combining ability effects for 11 characters. The result
showed that the heterosis for yield and fiber properties were obvious for the prefrost lint cotton
yield, the range of high parent heterosis were -28.88%13.17% with average value -3.06%, 6
crosses have positive heterosis, the range of mid-parent heterosis were 18.14%80.12%, with
average value 53.08%. 15 crosses have positive heterosis,the range of useful heterosis were
-15.32%46.43% with average value 11.27%, and 10 crosses have positive heterosis. Of the
combining ability , CCRI 19 and Shi 321 of the females, 96-1, 96-67 and 96-33 of the males were
good perants for most of characters, A1B2, A2B2, and A4B1 were good crosses for most of SCA.


In this paper, a comparative study has been shown between the four meta-heuristics optimization techniques on the basis of loss minimization and voltage profile improvement. Reconfiguration of a network can be done by altering the status of sectionalizing and tie switches between the buses. But for effective reconfiguration, a network has to satisfy several constraints which have been discussed in this paper. After reconfiguration, results indicate the overall advantage of GWO compared with other meta-heuristics methods. Here four optimization methods GA, CA, PSO and GWO are used for optimal reconfiguration of distributed network.


In this work, we address Byzantine agreement in a message passing system with homonyms, i.e. a system with a number l of authenticated identities that is independent of the total number of processes n, in the presence of t < n Byzantine processes.
 We prove the following results: (i) agreement is possible if (and only if) l > 3t in a synchronous model; (ii) agreement is impossible, independently of the number of failures, in an eventually synchronous model; (iii) eventual agreement is possible, if (and only if) l > 3t, in an asynchronous model.


The segmentation of 3D point clouds is an important prerequisite step for many plant phenotype and data analysis. One of the main challenges is high resolution 3D plant model segmentation. In this paper, we present an iteration based approach for 3D segmentation directly from the dense point clouds that are reconstructed from multi-view images. We extend the existing euclidean distance and spectral clustering (SC) algorithms and using iteration approach to segment the 3D point clouds into elementary shape units that could represent the plant organs (stems, branches, leaves, etc.). Such approach only requires the 3D coordinate data information. Experimental results show our approach can effectively segmented the obtained point cloud for various plant species.


Some effects of microtopography on forest floor, organic matter dynamics, and tree species distribution were studied in a northern hardwood stand near Quebec. Forest floor thickness was 12.4 cm in ...


We reexamine the theoretical estimates of the decay {ital K}{r arrow}{pi}{ital H} and the experimental constraints on the existence of a light Higgs boson from this process. We find that (i) pole diagrams generated from the Higgs-boson--gluon coupling via a loop of heavy quarks do contribute to {ital K}{r arrow}{pi}{ital H}, (ii) there is an additional contribution to the {ital K}{r arrow}{pi}{ital H} amplitude coming from the effective {ital KHW} and {pi}{ital HW} couplings, (iii) even if {ital B}, the unknown parameter in the chiral-Lagrangian description of {ital K}{endash}{pi}{ital H} transitions, is nonzero and even if the real part of the {ital K}{r arrow}{pi}{ital H} amplitude is canceled accidentally, the imaginary contribution alone suffices to rule out a Higgs boson lighter than 2{ital m}{sub {pi}}, and (iv) whether Higgs bosons in the mass range 2{ital m}{sub {pi}}{lt}m{sub H}{lt}350 MeV are excluded by the imaginary part of the {ital K}{r arrow}{pi}{ital H} amplitude depends on the branching ratio of {ital H}{r arrow}{mu}{sup +}{mu}{sup {minus}} and the top-quark mass. Decay modes {ital K}{sub {ital L}}{r arrow}{pi}{sup +}{pi}{sup {minus}}H and {ital K}{sup +}{r arrow}l{sup +}{nu}H are briefly discussed.


Formal statements of the Eldredge-Gould model, which proposes that new species have originated almost wholly through evolution in small peripheral isolate populations, and the phyletic gradualism model, which proposes that new species have originated through phyletic evolution in large, widely distributed populations, clarify the relationship ofthese models as extremes in a spectrum ofpossibilities, and suggest alternative models incorporating elements ofboth. Eldredge and Gould (1) recently advanced the hypothesis that new species have arisen, in almost all cases, by speciation (splitting of lineages) through rapid evolution in small peripheral isolate populations (2). [I have added the qualifying phrase "in almost all cases"; it does not appear in the explicit statement of their hypothesis (1, p. 96), but it is clear from subsequent discussions that they do not rule out the possibility of occasional, albeit rare, origins through phyletic evolution in ancestor-descendant populations of established species.] Rapid evolution in small peripheral isolates is widely held by biologists to be the principal means of speciation (3), as Eldredge and Gould admit, and it has been utilized in interpretations of fossil populations in earlier works (4). Still, Eldredge and Gould deserve credit for introducing the hypothesis to the overwhelming majority of English-speaking paleontologists and calling attention to its paleontologic implications. Eldredge and Gould contrasted their hypothesis with an alternative that they termed phyletic gradualism (1, p. 89), which is contrary but not contradictory to it (so that while both hypotheses cannot be true, both can be false). Phyletic gradualism postulates that new species have arisen through slow evolution in ancestor-descendant sequences of populations (phyletic evolution); this involves large numbers, usually the entire population, over all, or a large part, of the ancestral species range. Speciation is allowed (1, p. 94), although the statement that the evolutionary change usually involves the entire population implies that it is rare; speciation in small peripheral isolate populations is ruled out. I doubt that this hypothesis is as widely held as Eldredge and Gould envisage; in particular, I think few paleontologists would completely rule out the possibility of rapid speciation in small peripheral isolates. The relationships of the two hypotheses 3 OCTOBER 1975 to one another and to alternatives are most easily seen if they are stated formally. For any two sets A and B, let A. B be the set of elements belonging to both A and B, AvB the set of elements belonging to A or B or both, and -A the set of all elements not belonging to A. Further, let P(A,B) be the probability of B given A, or the relative frequency of occurrence of members of set B within set A, using the notation of Reichenbach (5); S the set of all the species of sexually reproducing Metazoa which have existed in geologic time (6); Si the set of all species belonging to S which originated by speciation in small peripheral isolate populations; and S ,Si the set of all species belonging to S which did not originate by speciation in small peripheral isolate populations. The Eldredge-Gould hypothesis may then be stated