Structures of Mithramycin Analogues Bound to DNA and Implications for Targeting Transcription Factor FLI1

Transcription factors have been considered undruggable, but this paradigm has been recently challenged. DNA binding natural product mithramycin (MTM) is a potent antagonist of oncogenic transcription factor EWS–FLI1. Structural details of MTM recognition of DNA, including the FLI1 binding sequence GGA(A/T), are needed to understand how MTM interferes with EWS–FLI1. We report a crystal structure of an MTM analogue MTM SA–Trp bound to a DNA oligomer containing a site GGCC, and two structures of a novel analogue MTM SA–Phe in complex with DNA. MTM SA–Phe is bound to sites AGGG and GGGT on one DNA, and to AGGG and GGGA(T) (a FLI1 binding site) on the other, revealing how MTM recognizes different DNA sequences. Unexpectedly, at sub-micromolar concentrations MTMs stabilize FLI1–DNA complex on GGAA repeats, which are critical for the oncogenic function of EWS–FLI1. We also directly demonstrate by nuclear magnetic resonance formation of a ternary FLI1–DNA–MTM complex on a single GGAA FLI1/MTM binding site. These biochemical and structural data and a new FLI1–DNA structure suggest that MTM binds the minor groove and perturbs FLI1 bound nearby in the major groove. This ternary complex model may lead to development of novel MTM analogues that selectively target EWS–FLI1 or other oncogenic transcription factors, as anti-cancer therapeutics

Magnetic interference patterns in long disordered Josephson junctions

We study a diffusive superconductor - normal metal - superconductor (SNS) junction in an external magnetic field. In the limit of a long junction, we find that the form of the dependence of the Josephson current on the field and on the length of the junction depends on the ratio between the junction width and the length associated with the magnetic field. A certain critical ratio between these two length scales separates two different regimes. In narrow junctions, the critical current exhibits a pure decay as a function of the junction length or of the magnetic field. In wide junctions, the critical current exhibits damped oscillations as a function of the same parameters. This damped oscillating behavior differs from the Fraunhofer pattern typical for short or tunnel junctions. In wide and long junctions, superconducting pair correlations and supercurrent are localized along the edges of the junction.Comment: 9 pages, 4 figures, minor modifications corresponding to the published versio

Sequential nonadiabatic excitation of large molecules and ions driven by strong laser fields

Electronic processes leading to dissociative ionization of polyatomic molecules in strong laser fields are investigated experimentally, theoretically, and numerically. Using time-of-flight ion mass spectroscopy, we study the dependence of fragmentation on laser intensity for a series of related molecules and report regular trends in this dependence on the size, symmetry, and electronic structure of a molecule. Based on these data, we develop a model of dissociative ionization of polyatomic molecules in intense laser fields. The model is built on three elements: (i) nonadiabatic population transfer from the ground electronic state to the excited-state manifold via a doorway (charge-transfer) transition; (ii) exponential enhancement of this transition by collective dynamic polarization of all electrons, and (iii) sequential energy deposition in both neutral molecules and resulting molecular ions. The sequential nonadiabatic excitation is accelerated by a counterintuitive increase of a large molecule's polarizability following its ionization. The generic theory of sequential nonadiabatic excitation forms a basis for quantitative description of various nonlinear processes in polyatomic molecules and ions in strong laser fields.Peer reviewed: YesNRC publication: Ye

Accurate Calculations of Rotationally Inelastic Scattering Cross Sections Using Mixed Quantum/Classical Theory

For computational treatment of rotationally inelastic scattering of molecules, we propose to use the mixed quantum/classical theory, MQCT. The old idea of treating translational motion classically, while quantum mechanics is used for rotational degrees of freedom, is developed to the new level and is applied to Na + N2 collisions in a broad range of energies. Comparison with full-quantum calculations shows that MQCT accurately reproduces all, even minor, features of energy dependence of cross sections, except scattering resonances at very low energies. The remarkable success of MQCT opens up wide opportunities for computational predictions of inelastic scattering cross sections at higher temperatures and/or for polyatomic molecules and heavier quenchers, which is computationally close to impossible within the full-quantum framework

Evidence for the classical integrability of the complete AdS(4) x CP(3) superstring

We construct a zero-curvature Lax connection in a sub-sector of the superstring theory on AdS(4) x CP(3) which is not described by the OSp(6|4)/U(3) x SO(1,3) supercoset sigma-model. In this sub-sector worldsheet fermions associated to eight broken supersymmetries of the type IIA background are physical fields. As such, the prescription for the construction of the Lax connection based on the Z_4-automorphism of the isometry superalgebra OSp(6|4) does not do the job. So, to construct the Lax connection we have used an alternative method which nevertheless relies on the isometry of the target superspace and kappa-symmetry of the Green-Schwarz superstring.Comment: 1+26 pages; v2: minor typos corrected, acknowledgements adde

Negative Kaons in Dense Baryonic Matter

Kaon polarization operator in dense baryonic matter of arbitrary isotopic composition is calculated including s- and p-wave kaon-baryon interactions. The regular part of the polarization operator is extracted from the realistic kaon-nucleon interaction based on the chiral and 1/N_c expansion. Contributions of the Lambda(1116), Sigma(1195), Sigma*(1385) resonances are taken explicitly into account in the pole and regular terms with inclusion of mean-field potentials. The baryon-baryon correlations are incorporated and fluctuation contributions are estimated. Results are applied for K- in neutron star matter. Within our model a second-order phase transition to the s-wave K- condensate state occurs at rho_c \gsim 4 \rho_0 once the baryon-baryon correlations are included. We show that the second-order phase transition to the p-wave $K^-$ condensate state may occur at densities $\rho_c \sim 3\div 5 \rho_0$ in dependence on the parameter choice. We demonstrate that a first-order phase transition to a proton-enriched (approximately isospin-symmetric) nucleon matter with a p-wave K- condensate can occur at smaller densities, \rho\lsim 2 \rho_0. The transition is accompanied by the suppression of hyperon concentrations.Comment: 41 pages, 24 figures, revtex4 styl

General model for retroviral capsid pattern recognition by TRIM5 proteins

Permission to archive final published versionRestriction factors are intrinsic cellular defense proteins that have evolved to block microbial infections. Retroviruses such as HIV-1 are restricted by TRIM5 proteins, which recognize the viral capsid shell that surrounds, organizes, and protects the viral genome. TRIM5α uses a SPRY domain to bind capsids with low intrinsic affinity (KD of >1 mM) and therefore requires higher-order assembly into a hexagonal lattice to generate sufficient avidity for productive capsid recognition. TRIMCyp, on the other hand, binds HIV-1 capsids through a cyclophilin A domain, which has a well-defined binding site and higher affinity (KD of ∼10 μM) for isolated capsid subunits. Therefore, it has been argued that TRIMCyp proteins have dispensed with the need for higher-order assembly to function as antiviral factors. Here, we show that, consistent with its high degree of sequence similarity with TRIM5α, the TRIMCyp B-box 2 domain shares the same ability to self-associate and facilitate assembly of a TRIMCyp hexagonal lattice that can wrap about the HIV-1 capsid. We also show that under stringent experimental conditions, TRIMCyp-mediated restriction of HIV-1 is indeed dependent on higher-order assembly. Both forms of TRIM5 therefore use the same mechanism of avidity-driven capsid pattern recognitionYe

Histone H3 Localizes to the Centromeric DNA in Budding Yeast

During cell division, segregation of sister chromatids to daughter cells is achieved by the poleward pulling force of microtubules, which attach to the chromatids by means of a multiprotein complex, the kinetochore. Kinetochores assemble at the centromeric DNA organized by specialized centromeric nucleosomes. In contrast to other eukaryotes, which typically have large repetitive centromeric regions, budding yeast CEN DNA is defined by a 125 bp sequence and assembles a single centromeric nucleosome. In budding yeast, as well as in other eukaryotes, the Cse4 histone variant (known in vertebrates as CENP-A) is believed to substitute for histone H3 at the centromeric nucleosome. However, the exact composition of the CEN nucleosome remains a subject of debate. We report the use of a novel ChIP approach to reveal the composition of the centromeric nucleosome and its localization on CEN DNA in budding yeast. Surprisingly, we observed a strong interaction of H3, as well as Cse4, H4, H2A, and H2B, but not histone chaperone Scm3 (HJURP in human) with the centromeric DNA. H3 localizes to centromeric DNA at all stages of the cell cycle. Using a sequential ChIP approach, we could demonstrate the co-occupancy of H3 and Cse4 at the CEN DNA. Our results favor a H3-Cse4 heterotypic octamer at the budding yeast centromere. Whether or not our model is correct, any future model will have to account for the stable association of histone H3 with the centromeric DNA

Observational study of pimecrolimus 1% cream for prevention of transcutaneous sensitization in children with atopic dermatitis during their first year of life

IntroductionEpidermal barrier dysfunction in children with atopic dermatitis can cause transcutaneous sensitization to allergens and allergic diseases. We evaluated the effectiveness of an early-intervention algorithm for atopic dermatitis treatment, utilizing pimecrolimus for long-term maintenance therapy, in reducing transcutaneous sensitization in infants.MethodThis was a single-center cohort observational study that enrolled children aged 1-4 months with family history of allergic diseases, moderate-to-severe atopic dermatitis, and sensitization to ≥ 1 of the investigated allergens. Patients who sought medical attention at atopic dermatitis onset (within 10 days) were group 1 “baseline therapy with topical glucocorticoids with subsequent transition to pimecrolimus as maintenance therapy”; patients who sought medical attention later were group 2 “baseline and maintenance therapy with topical glucocorticoids, without subsequent use of pimecrolimus”. Sensitization class and level of allergen-specific immunoglobulin E were determined at baseline, and 6 and 12 months of age. Atopic dermatitis severity was evaluated using the Eczema Area and Severity Index score at baseline and 6, 9 and 12 months of age.ResultsFifty-six and 52 patients were enrolled in groups 1 and 2, respectively. Compared with group 2, group 1 demonstrated a lower level of sensitization to cow's milk protein, egg white and house dust mite allergen at 6 and 12 months of age, and a more pronounced decrease in atopic dermatitis severity at 6, 9 and 12 months of age. No adverse events occurred.DiscussionThe pimecrolimus-containing algorithm was effective in treating atopic dermatitis and prophylaxis of early forms of allergic diseases in infants.Trial registrationhttps://clinicaltrials.gov/NCT04900948, retrospectively registered, 25 May 2021