In patients with beta-hemoglobinopathies butyrate, a natural fatty acid, can significantly and rapidly increase fetal-globin production to levels that can ameliorate beta-globin disorders. Further trials of this class of compounds are warranted to determine long-term tolerance and efficacy in patients with sickle cell anemia or beta-thalassemia.

Adhesive interactions between circulating sickle red blood cells (RBCs), leukocytes, and endothelial cells are major pathophysiologic events in sickle cell disease (SCD). To develop new therapeutics that efficiently inhibit adhesive interactions, we generated an anti-P-selectin aptamer and examined its effects on cell adhesion using knockout-transgenic SCD model mice. Aptamers, single-stranded oligonucleotides that bind molecular targets with high affinity and specificity, are emerging as new therapeutics for cardiovascular and hematologic disorders. In vitro studies found that the anti-P-selectin aptamer exhibits high specificity to mouse P-selectin but not other selectins. SCD mice were injected with the anti-P-selectin aptamer, and cell adhesion was observed under hypoxia. The anti-P-selectin aptamer inhibited the adhesion of sickle RBCs and leukocytes to endothelial cells by 90% and 80%, respectively. The anti-Pselectin aptamer also increased microvascular flow velocities and reduced the leukocyte rolling flux. SCD mice treated with the anti-P-selectin aptamer demonstrated a reduced mortality rate associated with the experimental procedures compared with control mice. These results demonstrate that anti-P-selectin aptamer efficiently inhibits the adhesion of both sickle RBCs and leukocytes to endothelial cells in SCD model mice, suggesting a critical role for P-selectin in cell adhesion. Anti-Pselectin aptamer may be useful as a novel therapeutic agent for SCD. (Blood. 2011; 117(2):727-735) IntroductionSickle cell disease (SCD) is caused by a point mutation of the ␤-globin chain, but its pathophysiology is extremely complex and heterogeneous. A salient clinical feature of this disorder is vasoocclusive crisis, which is a major cause of morbidity and mortality in SCD patients; repetitive crises could eventually lead to multiorgan damage in the long term. 1 Adhesive interactions between circulating sickle red blood cells (RBCs), leukocytes, and endothelial cells have been implicated as critical pathologic events for the development of vaso-occlusion. Much attention has been directed to identifying adhesion molecules involved in cell-cell interactions.Endothelial cell P-selectin, a member of the selectin family of cell adhesion molecules, 2 plays a key role in leukocyte recruitment as well as the adhesion of sickle RBCs to the endothelium. 3,4 Presynthesized P-selectin is stored in the Weibel-Palade bodies in endothelial cells and rapidly translocated to the cell surface in response to extracellular stimuli such as hypoxia. 5 Expression levels of P-selectin are elevated in patients with SCD. 6,7 The interactions between P-selectin and its ligands are likely to contribute to cell adhesion between multiple types of cells, which results in the impairment of microvascular circulation presumably involved in the development of painful vaso-occlusive episodes. 4,8 Several antiadhesion compounds have been tested for their ability to inhibit sickle RBC adhesion to endothelial cells, however, no agents are currently used...

Computers based on physical systems are increasingly anticipated to overcome the impending limitations on digital computer performance. One such computer is a coherent Ising machine (CIM) for solving combinatorial optimization problems. Here, we report a CIM with 100,512 degenerate optical parametric oscillator pulses working as the Ising spins. We show that the CIM delivers fine solutions to maximum cut problems of 100,000-node graphs drastically faster than standard simulated annealing. Moreover, the CIM, when operated near the phase transition point, provides some extremely good solutions and a very broad distribution. This characteristic will be useful for applications that require fast random sampling such as machine learning.

We have investigated in vivo protein-DNA interactions in the R3-globin gene locus by dimethyl sulfate (DMS) footprinting in K562 cells, which express E-and -y-globin but not I3-globin. In the locus control region, hypersensitive site 2 (HS-2) exhibited footprints in several putative protein binding motifs. HS-3 was not footprinted. We examined the regions of HS-2 and HS-3 that account for the major activity of the complete LCR (5, 6, 11), the promoter regions of /3-and y-globin genes (3,4), and the A y (12) and , / 3' enhancer (13). We compared the footprints ofthe