Interplay of initial deformation and Coulomb proximity on nuclear decay

Alpha particles emitted from an excited projectile-like fragment (PLF*) formed in a peripheral collision of two intermediate-energy heavy ions exhibit a strong preference for emission towards the target-like fragment (TLF). The interplay of the initial deformation of the PLF* caused by the reaction, Coulomb proximity, and the rotation of the PLF* results in the observed anisotropic angular distribution. Changes in the shape of the angular distribution with excitation energy are interpreted as being the result of forming more elongated initial geometries in the more peripheral collisions.Comment: 4 figure

SHQ1 regulation of RNA splicing is required for T-lymphoblastic leukemia cell survival

T-acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy with complicated heterogeneity. Although expression profiling reveals common elevated genes in distinct T-ALL subtypes, little is known about their functional role(s) and regulatory mechanism(s). We here show that SHQ1, an H/ACA snoRNP assembly factor involved in snRNA pseudouridylation, is highly expressed in T-ALL. Mechanistically, oncogenic NOTCH1 directly binds to the SHQ1 promoter and activates its transcription. SHQ1 depletion induces T-ALL cell death in vitro and prolongs animal survival in murine T-ALL models. RNA-Seq reveals that SHQ1 depletion impairs widespread RNA splicing, and MYC is one of the most prominently downregulated genes due to inefficient splicing. MYC overexpression significantly rescues T-ALL cell death resulted from SHQ1 inactivation. We herein report a mechanism of NOTCH1-SHQ1-MYC axis in T-cell leukemogenesis. These findings not only shed light on the role of SHQ1 in RNA splicing and tumorigenesis, but also provide additional insight into MYC regulation

Fragment Isospin as a Probe of Heavy-Ion Collisions

Isotope ratios of fragments produced at mid-rapidity in peripheral and central collisions of 114Cd ions with 92Mo and 98Mo target nuclei at E/A = 50 MeV are compared. Neutron-rich isotopes are preferentially produced in central collisions as compared to peripheral collisions. The influence of the size (A), density, N/Z, E*/A, and Eflow/A of the emitting source on the measured isotope ratios was explored by comparison with a statistical model (SMM). The mid-rapidity region associated with peripheral collisions does not appear to be neutron-enriched relative to central collisions.Comment: 12 pages including figure

Fragment Production in Non-central Collisions of Intermediate Energy Heavy Ions

The defining characteristics of fragment emission resulting from the non-central collision of 114Cd ions with 92Mo target nuclei at E/A = 50 MeV are presented. Charge correlations and average relative velocities for mid-velocity fragment emission exhibit significant differences when compared to standard statistical decay. These differences associated with similar velocity dissipation are indicative of the influence of the entrance channel dynamics on the fragment production process

Excitation and decay of projectile-like fragments formed in dissipative peripheral collisions at intermediate energies

Projectile-like fragments (PLF:15<=Z<=46) formed in peripheral and mid-peripheral collisions of 114Cd projectiles with 92Mo nuclei at E/A=50 MeV have been detected at very forward angles, 2.1 deg.<=theta_lab<=4.2 deg. Calorimetric analysis of the charged particles observed in coincidence with the PLF reveals that the excitation of the primary PLF is strongly related to its velocity damping. Furthermore, for a given V_PLF*, its excitation is not related to its size, Z_PLF*. For the largest velocity damping, the excitation energy attained is large, approximately commensurate with a system at the limiting temperatureComment: 5 pages, 6 figure

WEE1 inhibition induces glutamine addiction in T-cell acute lymphoblastic leukemia

T-cell acute lymphoblastic leukemias (T-ALLs) are aggressive and heterogeneous hematologic tumors resulting from the malignant transformation of T-cell progenitors. The major challenges in the treatments of T-ALL are dose-limiting toxicities of chemotherapeutics and drug resistance. Despite important progress in deciphering the genomic landscape of T-ALL, translation of these findings into effective targeted therapies remains largely unsuccessful. New targeted agents with significant antileukemic efficacy and less toxicity are in urgent need. We herein report that the expression of WEE1, a nuclear tyrosine kinase involved in cell cycle G2-M checkpoint signaling, is significantly elevated in T-ALL. Mechanistically, oncogenic MYC directly binds to the WEE1 promoter and activates its transcription. T-ALL cells particularly rely on the elevated WEE1 for cell viability. Pharmacological inhibition of WEE1 elicits global metabolic reprogramming which results in a marked suppression of aerobic glycolysis in T-ALL cells, leading to an increased dependency on glutaminolysis for cell survival. As such, dual targeting of WEE1 and glutaminase (GLS1) induces synergistic lethality in multiple T-ALL cell lines and shows great efficacy in T-ALL patient-derived xenografts. These findings provide mechanistic insights in the regulation of WEE1 kinase in T-ALL and suggest an additional vulnerability during WEE1 inhibitor treatments. In aggregate, we highlight a promising combination strategy of dual inhibition of cell cycle kinase and metabolic enzymes for T-ALL therapeutics

Genome-wide analyses identify KLF4 as an important negative regulator in T-cell acute lymphoblastic leukemia through directly inhibiting T-cell associated genes

é 2015 Li et al. Background: Kruppel-like factor 4 (KLF4) induces tumorigenesis or suppresses tumor growth in a tissue-dependent manner. However, the roles of KLF4 in hematological malignancies and the mechanisms of action are not fully understood. Methods: Inducible KLF4-overexpression Jurkat cell line combined with mouse models bearing cell-derived xenografts and primary T-cell acute lymphoblastic leukemia (T-ALL) cells from four patients were used to assess the functional role of KLF4 in T-ALL cells in vitro and in vivo. A genome-wide RNA-seq analysis was conducted to identify genes regulated by KLF4 in T-ALL cells. Chromatin immunoprecipitation (ChIP) PCR was used to determine direct binding sites of KLF4 in T-ALL cells. Results: Here we reveal that KLF4 induced apoptosis through the BCL2/BCLXL pathway in human T-ALL cell lines and primary T-ALL specimens. In consistence, mice engrafted with KLF4-overexpressing T-ALL cells exhibited prolonged survival. Interestingly, the KLF4-induced apoptosis in T-ALL cells was compromised in xenografts but the invasion capacity of KLF4-expressing T-ALL cells to hosts was dramatically dampened. We found that KLF4 overexpression inhibited T cell-associated genes including NOTCH1, BCL11B, GATA3, and TCF7. Further mechanistic studies revealed that KLF4 directly bound to the promoters of NOTCH1, BCL2, and CXCR4 and suppressed their expression. Additionally, KLF4 induced SUMOylation and degradation of BCL11B. Conclusions: These results suggest that KLF4 as a major transcription factor that suppresses the expression of T-cell associated genes, thus inhibiting T-ALL progression.Link_to_subscribed_fulltex

Scavenger Decapping Activity Facilitates 5′ to 3′ mRNA Decay

mRNA degradation occurs through distinct pathways, one primarily from the 5′ end of the mRNA and the second from the 3′ end. Decay from the 3′ end generates the m(7)GpppN cap dinucleotide, which is subsequently hydrolyzed to m(7)Gp and ppN in Saccharomyces cerevisiae by a scavenger decapping activity termed Dcs1p. Although Dcs1p functions in the last step of mRNA turnover, we demonstrate that its activity modulates earlier steps of mRNA decay. Disruption of the DCS1 gene manifests a threefold increase of the TIF51A mRNA half-life. Interestingly, the hydrolytic activity of Dcs1p was essential for the altered mRNA turnover, as Dcs1p, but not a catalytically inactive Dcs1p mutant, complemented the increased mRNA stability. Mechanistic analysis revealed that 5′ to 3′ exoribonucleolytic activity was impeded in the dcs1Δ strain, resulting in the accumulation of uncapped mRNA. These data define a new role for the Dcs1p scavenger decapping enzyme and demonstrate a novel mechanism whereby the final step in the 3′ mRNA decay pathway can influence 5′ to 3′ exoribonucleolytic activity