Transcriptional activation by the Myb proteins requires a specific local promoter structure

AbstractThe biological effects of the cellular c-Myb and the viral v-Myb proteins are strikingly different. While c-Myb is indispensable for normal hematopoiesis, v-Myb induces acute leukemia. The v-Myb DNA-binding domain (DBD) differs from that of c-Myb mainly by deletion of the first of three repeats which correlates with efficient oncogenic transformation and a decrease in DNA-binding activity. To investigate the difference in DNA-binding and transcriptional activation, oligonucleotide selection and electrophoretic mobility shift assays were employed. The v-Myb DBD (R2R3) shows an intrinsic DNA-binding specificity for an AT-rich downstream extension of the Myb recognition element (MRE) PyAACT/GG for efficient binding to this site, whereas R1 within the c-Myb DBD allows for more flexibility for this downstream extension. Therefore, due to the presence of repeat R1, c-Myb can bind to a greater number of target sites. The intrinsic DNA-binding specificity of R2R3 is further supported with the results from in vivo transcriptional activation experiments which demonstrated that both the v-Myb and c-Myb DBDs require an extension of the MRE (motif #1) by a downstream T-stretch (motif #2) for full activity. Surprisingly, the T-stretch improves binding when present on either strand, but is required on a specific strand for transcriptional activation

Breaking Tolerance to Double Stranded DNA, Nucleosome, and Other Nuclear Antigens Is Not Required for the Pathogenesis of Lupus Glomerulonephritis

In lupus-prone NZM2328 mice, a locus Cgnz1 on chromosome 1 was linked to chronic glomerulonephritis, severe proteinuria, and early mortality in females. A locus Adnz1 on chromosome 4 was linked to antinuclear antibody (ANA) and anti–double stranded DNA (dsDNA) antibody (Ab) production. In this investigation, two congenic strains, NZM2328.C57L/Jc1 (NZM.C57Lc1) and NZM2328.C57L/Jc4 (NZM.C57Lc4), were generated by replacing the respective genetic intervals containing either Cgnz1 or Adnz1 with those from C57L/J, a nonlupus-prone strain. The NZM.C57Lc1 females had markedly reduced incidence of chronic glomerulonephritis and severe proteinuria. NZM.C57Lc4 females had chronic glomerulonephritis and severe proteinuria without circulating ANA, anti-dsDNA, and antinucleosome Ab. These data confirm the linkage analysis. Unexpectedly, NZM.C57Lc1 females had little anti-dsDNA and related Ab, suggesting the presence of a second locus Adnz2 on chromosome 1. The diseased NZM.C57Lc4 kidneys had immune complexes by immunofluorescence and electron microscopy. The eluates from these kidneys did not contain ANA, anti-dsDNA, and antinucleosome Ab, indicative of the presence of non–anti-dsDNA nephritogenic Ab. Thus, breaking tolerance to dsDNA and chromatin is not required for the pathogenesis of lupus nephritis. These results reaffirm that anti-dsDNA and related Ab production and chronic glomerulonephritis are under independent genetic control. These findings have significant implications in the pathogenesis of systemic lupus erythematosus

Influence of Combined Transcranial Direct Current Stimulation and Motor Training on Corticospinal Excitability in Children With Unilateral Cerebral Palsy

Combined non-invasive brain stimulation (NIBS) and rehabilitation interventions have the potential to improve function in children with unilateral cerebral palsy (UCP), however their effects on developing brain function are not well understood. In a proof-of-principle study, we used single-pulse transcranial magnetic stimulation (TMS) to measure changes in corticospinal excitability and relationships to motor performance following a randomized controlled trial consisting of 10 days of combined constraint-induced movement therapy (CIMT) and cathodal transcranial direct current stimulation (tDCS) applied to the contralesional motor cortex. Twenty children and young adults (mean age = 12 years, 9 months, range = 7 years, 7 months, 21 years, 7 months) with UCP participated. TMS testing was performed before, after, and 6 months after the intervention to measure motor evoked potential (MEP) amplitude and cortical silent period (CSP) duration. The association between neurophysiologic and motor outcomes and differences in excitability between hemispheres were examined. Contralesional MEP amplitude decreased as hypothesized in five of five participants receiving active tDCS immediately after and 6 months after the intervention, however no statistically significant differences between intervention groups were noted for MEP amplitude [mean difference = −323.9 μV, 95% CI = (−989, 341), p = 0.34] or CSP duration [mean difference = 3.9 ms, 95% CI = (−7.7, 15.5), p = 0.51]. Changes in corticospinal excitability were not statistically associated with improvements in hand function after the intervention. Across all participants, MEP amplitudes measured in the more-affected hand from both contralesional (mean difference = −474.5 μV) and ipsilesional hemispheres (−624.5 μV) were smaller compared to the less-affected hand. Assessing neurophysiologic changes after tDCS in children with UCP provides an understanding of long-term effects on brain excitability to help determine its potential as a therapeutic intervention. Additional investigation into the neurophysiologic effects of tDCS in larger samples of children with UCP are needed to confirm these findings

Bis(4-amino­pyridinium) bis(hydrogen oxalate) monohydrate

In the title compound, 2C5H7N2 +·2C2HO4 −·H2O, the asymmetric unit consists of an amino­pyridinium cation, an oxalic actetate anion and a half-molecule of water, which lies on a two-fold rotation axis. The crystal packing is consolidated by inter­molecular O—H⋯O, N—H⋯O and C—H⋯O hydrogen bonds. The mol­ecules are linked into an infinite one dimensional chain along [010]

4-Amino­pyridinium hydrogen succinate

In the title salt, C5H7N2 +·C4H5O4 −, the asymmetric unit comprises an amino­pyridinium cation and a hydrogen succinate anion as protonation of the aromatic N atom of the 4-amino­pyridine mol­ecule has occurred. The crystal packing is stabilized by inter­molecular O—H⋯O and N—H⋯O hydrogen bonds that lead to a two-dimensional array. Short C—H⋯O contacts are also present

2-Amino­pyridinium (2-amino­pyridine)trichloridonickelate(II)

In the title compound, (C5H7N2)[NiCl3(C5H6N2)], the NiII atom is four-coordinated by three chloride anions and one N atom of a 2-amino­pyridine ligand, forming a distorted tetra­hedral coordination. In the crystal structure, cations and complex anions are linked into chains along the a, b and c axes by N—H⋯Cl hydrogen bonds, leading to the formation of a three-dimensional framework

Color Confinement, Quark Pair Creation and Dynamical Chiral-Symmetry Breaking in the Dual Ginzburg-Landau Theory

We study the color confinement, the $q$-$\bar q$ pair creation and the dynamical chiral-symmetry breaking of nonperturbative QCD by using the dual Ginzburg-Landau theory, where QCD-monopole condensation plays an essential role on the nonperturbative dynamics in the infrared region. As a result of the dual Meissner effect, the linear static quark potential, which characterizes the quark confinement, is obtained in the long distance within the quenched approximation. We obtain a simple expression for the string tension similar to the energy per unit length of a vortex in the superconductivity physics. The dynamical effect of light quarks on the quark confining potential is investigated in terms of the infrared screening effect due to the $q$-$\bar q$ pair creation or the cut of the hadronic string. The screening length of the potential is estimated by using the Schwinger formula for the $q$-$\bar q$ pair creation. We introduce the corresponding infrared cutoff to the strong long-range correlation factor in the gluon propagator as a dynamical effect of light quarks, and obtain a compact formula of the quark potential including the screening effect in the infrared region. We investigate the dynamical chiral-symmetry breaking by using the Schwinger-Dyson equation, where the gluon propagator includes the nonperturbative effect related toComment: 37 pages, plain TeX (using `phyzzx' macro), (( 8 figures - available on request from [email protected] )

Lepton Dipole Moments and Rare Decays in the CP-violating MSSM with Nonuniversal Soft-Supersymmetry Breaking

We investigate the muon anomalous magnetic dipole moment (MDM), the muon electric dipole moment (EDM) and the lepton-flavour-violating decays of the $\tau-$lepton, $\tau \to \mu \gamma$ and $\tau\to 3\mu$, in the CP-violating Minimal Supersymmetric Standard Model (MSSM) with nonuniversal soft-supersymmetry breaking. We evaluate numerically the muon EDM and the branching ratios $B(\tau \to \mu\gamma)$ and $B(\tau \to 3\mu)$, after taking into account the experimental constraints from the electron EDM and muon MDM. Upon imposition of the experimental limits on our theoretical predictions for the aforementioned branching ratios and the muon MDM, we obtain an upper bound of about $10^{-23} e\cdot cm$ on the muon EDM which lies well within the explorable reach of the proposed experiment at BNL.Comment: Latex, 26 pages, 8 figures, accepted for publication in Phys. Rev.

Impact of KRAS mutation status on the efficacy of immunotherapy in lung cancer brain metastases

Immune checkpoint inhibitors (ICIs) have resulted in improved outcomes in non-small cell lung cancer (NSCLC) patients. However, data demonstrating the efficacy of ICIs in NSCLC brain metastases (NSCLCBM) is limited. We analyzed overall survival (OS) in patients with NSCLCBM treated with ICIs within 90 days of NSCLCBM diagnosis (ICI-90) and compared them to patients who never received ICIs (no-ICI). We reviewed 800 patients with LCBM who were diagnosed between 2010 and 2019 at a major tertiary care institution, 97% of whom received stereotactic radiosurgery (SRS) for local treatment of BM. OS from BM was compared between the ICI-90 and no-ICI groups using the Log-Rank test and Cox proportional-hazards model. Additionally, the impact of KRAS mutational status on the efficacy of ICI was investigated. After accounting for known prognostic factors, ICI-90 in addition to SRS led to significantly improved OS compared to no-ICI (12.5 months vs 9.1, p \u3c 0.001). In the 109 patients who had both a known PD-L1 expression and KRAS status, 80.4% of patients with KRAS mutation had PD-L1 expression vs 61.9% in wild-type KRAS patients (p = 0.04). In patients without a KRAS mutation, there was no difference in OS between the ICI-90 vs no-ICI cohort with a one-year survival of 60.2% vs 54.8% (p = 0.84). However, in patients with a KRAS mutation, ICI-90 led to a one-year survival of 60.4% vs 34.1% (p = 0.004). Patients with NSCLCBM who received ICI-90 had improved OS compared to no-ICI patients. Additionally, this benefit appears to be observed primarily in patients with KRAS mutations that may drive the overall benefit, which should be taken into account in the development of future trials