Structural properties of hard disks in a narrow tube

Positional ordering of a two-dimensional fluid of hard disks is examined in such narrow tubes where only the nearest-neighbor interactions take place. Using the exact transfer-matrix method the transverse and longitudinal pressure components and the correlation function are determined numerically. Fluid-solid phase transition does not occur even in the widest tube, where the method just loses its exactness, but the appearance of the dramatic change in the equation of state and the longitudinal correlation function shows that the system undergoes a structural change from a fluid to a solid-like order. The pressure components show that the collisions are dominantly longitudinal at low densities, while they are transverse in the vicinity of close packing density. The transverse correlation function shows that the size of solid-like domains grows exponentially with increasing pressure and the correlation length diverges at close packing. It is managed to find an analytically solvable model by expanding the contact distance up to first order. The approximate model, which corresponds to the system of hard parallel rhombuses, behaves very similarly to the system of hard disks.Comment: Acceped in Journal of Statistical Mechanics: Theory and Experimen

SOCS1 function in BCR-ABL mediated myeloproliferative disease is dependent on the cytokine environment

Treatment with tyrosine kinase inhibitors is the standard of care for Philadelphia chromosome positive leukemias. However the eradication of leukemia initiating cells remains a challenge. Circumstantial evidence suggests that the cytokine microenvironment may play a role in BCR-ABL mediated leukemogenesis and in imatinib resistance. Gene expression analyses of BCR-ABL positive ALL long-term cultured cells revealed strong reduction of SOCS mRNA expression after imatinib treatment, thereby demonstrating a strong inhibition of cytokine signaling. In this study we employed SOCS1—a strong inhibitor of cytokine signaling—as a tool to terminate external cytokine signals in BCR-ABL transformed cells in vitro and in vivo. In colony formation assays with primary bone marrow cells, expression of SOCS1 decreased colony numbers under pro-proliferative cytokines, while it conferred growth resistance to anti-proliferative cytokines. Importantly, co-expression of SOCS1 with BCR-ABL led to the development of a MPD phenotype with a prolonged disease latency compared to BCR-ABL alone in a murine bone marrow transplantation model. Interestingly, SOCS1 co-expression protected 20% of mice from MPD development. In summary, we conclude that under pro-proliferative cytokine stimulation at the onset of myeloproliferative diseases SOCS1 acts as a tumor suppressor, while under anti-proliferative conditions it exerts oncogenic function. Therefore SOCS1 can promote opposing functions depending on the cytokine environment

Mouse transplantation model.

<p>Transduction efficiency of Sca-1⁺ cells was normalized according to GFP expression and 2.5 x 10⁴ GFP-positive cells were transplanted into the tail vein of sub-lethally irradiated recipient mice. Moribund mice were sacrificed and analyzed. All data shown are from time of death. <b>A.</b> Disease free survival of transplanted animals is plotted in Kaplan-Meier curves. <b>B.</b> White blood counts and hemoglobin content in the peripheral blood. <b>C.</b> Spleen and liver weights of analyzed mice. <b>D.</b> Spleen samples were stained with H&E. Representative images are shown.</p

BCR-ABL induces gene expression levels of SOCS proteins.

<p><b>A.</b> Ba/F3 cells were transduced with BCR-ABL or an empty vector control. Prior to RNA extraction, cells were starved over night from IL-3. RT-PCR was performed for SOCS family members. Relative gene expression normalized to <i>RNA pol II</i> is depicted. The experiment was performed three times, the error bars are indicating the standard deviation. <b>B.</b> Sca-1+ cells were enriched from murine BM and transduced with BCR-ABL or an empty vector control. GFP-sorted cells were starved over night from cytokines prior to RNA extraction. Relative gene expression of SOCS family members is shown. Relative gene expression normalized to <i>RNA pol II</i> is depicted. The experiment was performed three times, the error bars are indicating the standard deviation. *P ≤ 0.05, **P ≤ 0.009, ***P ≤ 0.001.</p

Gene expression levels of SOCS proteins after BCR-ABL kinase inhibition.

<p><b>A-B.</b> Philadelphia chromosome positive (Ph+) or negative (Ph-) long term cultures of primary human acute lymphoblastic leukemia cells were treated with 1 μM imatinib for 16h. RNA was extracted and RT-PCR was performed for SOCS family members. Relative gene expression normalized to B2M is shown. The experiment was performed three times, the error bars are indicating the standard deviation. **P ≤ 0.009, ***P ≤ 0.001 <b>C.</b> K562 cells were treated with 2 μM imatinib for 16h. RNA was extracted and RT-PCR performed for SOCS family members. Gene expression relative to B2M is depicted. The experiment was performed three times, the error bars are indicating the standard deviation. *P ≤ 0.02, **P ≤ 0.009, ***P ≤ 0.001 <b>D.</b> K562 cells were washed with PBS and resuspended in RPMI medium containing 1% FCS. BCR-ABL was inhibited for 16h with 2 μM imatinib or 20 nM dasatinib. Total cell lysates were immunoblotted and probed with indicated antibodies. Tubulin is shown as loading control. Inhibition of BCR-ABL was assessed by its phosphorylation status. The experiment was performed three times.</p