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1. Selective and Reversible Ligand Assembly on the DNA and RNA Repeat Sequences in Myotonic Dystrophy

   https://doi.org/10.1002/cbic.202200260  

   Krueger, Sarah B. ; Lanzendorf, Amie N. ; Jeon, Hyoeun ; Zimmerman, Steven C. ( July 2022 , ChemBioChem)

   Small molecule targeting of DNA and RNA sequences has come into focus as a therapeutic strategy for diseases such as myotonic dystrophy type 1 (DM1), a trinucleotide repeat disease characterized by RNA gain‐of‐function. Herein, we report a novel template‐selected, reversible assembly of therapeutic agentsin situvia aldehyde‐amine condensation. Rationally designed small molecule targeting agents functionalized with either an aldehyde or an amine were synthesized and screened against the target nucleic acid sequence. The assembly of fragments was confirmed by MALDI‐MS in the presence of DM1‐relevant nucleic acid sequences. The resulting hit combinations of aldehyde and amine inhibited the formation of r(CUG)^expin vitro in a cooperative manner at low micromolar levels and rescued mis‐splicing defects in DM1 model cells. This reversible template‐selected assembly is a promising approach to achieve cell permeable and multivalent targeting viain situsynthesis and could be applied to other nucleic acid targets.

    

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2. Realizability of iso-g2 processes via effective pair interactions

   https://doi.org/10.1063/5.0130679  

   Wang, Haina ; Stillinger, Frank H. ; Torquato, Salvatore ( December 2022 , The Journal of Chemical Physics)

   An outstanding problem in statistical mechanics is the determination of whether prescribed functional forms of the pair correlation function g2(r) [or equivalently, structure factor S(k)] at some number density ρ can be achieved by many-body systems in d-dimensional Euclidean space. The Zhang–Torquato conjecture states that any realizable set of pair statistics, whether from a nonequilibrium or equilibrium system, can be achieved by equilibrium systems involving up to two-body interactions. To further test this conjecture, we study the realizability problem of the nonequilibrium iso-g2 process, i.e., the determination of density-dependent effective potentials that yield equilibrium states in which g2 remains invariant for a positive range of densities. Using a precise inverse algorithm that determines effective potentials that match hypothesized functional forms of g2(r) for all r and S(k) for all k, we show that the unit-step function g2, which is the zero-density limit of the hard-sphere potential, is remarkably realizable up to the packing fraction ϕ = 0.49 for d = 1. For d = 2 and 3, it is realizable up to the maximum “terminal” packing fraction ϕc = 1/2d, at which the systems are hyperuniform, implying that the explicitly known necessary conditions for realizability are sufficient up through ϕc. For ϕ near but below ϕc, the large-r behaviors of the effective potentials are given exactly by the functional forms exp[ − κ(ϕ)r] for d = 1, r−1/2 exp[ − κ(ϕ)r] for d = 2, and r−1 exp[ − κ(ϕ)r] (Yukawa form) for d = 3, where κ−1(ϕ) is a screening length, and for ϕ = ϕc, the potentials at large r are given by the pure Coulomb forms in the respective dimensions as predicted by Torquato and Stillinger [Phys. Rev. E 68, 041113 (2003)]. We also find that the effective potential for the pair statistics of the 3D “ghost” random sequential addition at the maximum packing fraction ϕc = 1/8 is much shorter ranged than that for the 3D unit-step function g2 at ϕc; thus, it does not constrain the realizability of the unit-step function g2. Our inverse methodology yields effective potentials for realizable targets, and, as expected, it does not reach convergence for a target that is known to be non-realizable, despite the fact that it satisfies all known explicit necessary conditions. Our findings demonstrate that exploring the iso-g2 process via our inverse methodology is an effective and robust means to tackle the realizability problem and is expected to facilitate the design of novel nanoparticle systems with density-dependent effective potentials, including exotic hyperuniform states of matter.

    

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3. VERTICO. IV. Environmental Effects on the Gas Distribution and Star Formation Efficiency of Virgo Cluster Spirals

   https://doi.org/10.3847/1538-4357/ac9d3c  

   Villanueva, Vicente ; Bolatto, Alberto D. ; Vogel, Stuart ; Brown, Tobias ; Wilson, Christine D. ; Zabel, Nikki ; Ellison, Sara ; Stevens, Adam R. H. ; Jiménez Donaire, María Jesús ; Spekkens, Kristine ; et al ( December 2022 , The Astrophysical Journal)

   We measure the molecular-to-atomic gas ratio,R_mol, and the star formation rate (SFR) per unit molecular gas mass, SFE_mol, in 38 nearby galaxies selected from the Virgo Environment Traced in CO (VERTICO) survey. We stack ALMA¹²CO (J= 2−1) spectra coherently using Hivelocities from the VIVA survey to detect faint CO emission out to galactocentric radiir_gal∼ 1.2r₂₅. We determine the scale lengths for the molecular and stellar components, finding a ∼3:5 relation compared to ∼1:1 in field galaxies, indicating that the CO emission is more centrally concentrated than the stars. We computeR_molas a function of different physical quantities. While the spatially resolvedR_molon average decreases with increasing radius, we find that the mean molecular-to-atomic gas ratio within the stellar effective radiusR_e,R_mol(r<R_e), shows a systematic increase with the level of Hi, truncation and/or asymmetry (H_Iperturbation). Analysis of the molecular- and the atomic-to-stellar mass ratios withinR_e,$R_{\star }^{\mathrm{mol}}(r<R_e)$and$R_{\star }^{\mathrm{atom}}(r<R_e)$, shows that VERTICO galaxies have increasingly lower$R_{\star }^{\mathrm{atom}}(r<R_e)$for larger levels of H_Iperturbation (compared to field galaxies matched in stellar mass), but no significant change in$R_{\star }^{\mathrm{m}\mathrm{o}\mathrm{l}}(r<R_e)$. We also measure a clear systematic decrease of the SFE_molwithinR_e, SFE_mol(r<R_e), with increasingly perturbed Hi. Therefore, compared to field galaxies from the field, VERTICO galaxies are more compact in CO emission in relation to their stellar distribution, but increasingly perturbed atomic gas increases theirR_moland decreases the efficiency with which their molecular gas forms stars.

    

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4. Calcium mediated static and dynamic allostery in S100A12 : Implications for target recognition by S100 proteins

   https://doi.org/10.1002/pro.4955  

   Wang, Qian ; DiForte, Christopher ; Aleshintsev, Aleksey ; Elci, Gianna ; Bhattacharya, Shibani ; Bongiorno, Angelo ; Gupta, Rupal ( March 2024 , Protein Science)

   Structure and functions of S100 proteins are regulated by two distinct calcium binding EF hand motifs. In this work, we used solution‐state NMR spectroscopy to investigate the cooperativity between the two calcium binding sites and map the allosteric changes at the target binding site. To parse the contribution of the individual calcium binding events, variants of S100A12 were designed to selectively bind calcium to either the EF‐I (N63A) or EF‐II (E31A) loop, respectively. Detailed analysis of the backbone chemical shifts for wildtype protein and its mutants indicates that calcium binding to the canonical EF‐II loop is the principal trigger for the conformational switch between ‘closed’ apo to the ‘open’ Ca²⁺‐bound conformation of the protein. Elimination of binding in S100‐specific EF‐I loop has limited impact on the calcium binding affinity of the EF‐II loop and the concomitant structural rearrangement. In contrast, deletion of binding in the EF‐II loop significantly attenuates calcium affinity in the EF‐I loop and the structure adopts a ‘closed’ apo‐like conformation. Analysis of experimental amide nitrogen (¹⁵N) relaxation rates (R₁,R₂, and¹⁵N–{¹H} NOE) and molecular dynamics (MD) simulations demonstrate that the calcium bound state is relatively floppy with pico–nanosecond motions induced in functionally relevant domains responsible for target recognition such as the hinge domain and the C‐terminal residues. Experimental relaxation studies combined with MD simulations show that while calcium binding in the EF‐I loop alone does not induce significant motions in the polypeptide chain, EF‐I regulates fluctuations in the polypeptide in the presence of bound calcium in the EF‐II loop. These results offer novel insights into the dynamic regulation of target recognition by calcium binding and unravels the role of cooperativity between the two calcium binding events in S100A12.

    

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5. TOI-3785 b: A Low-density Neptune Orbiting an M2-dwarf Star

   https://doi.org/10.3847/1538-3881/acd8bf  

   Powers, Luke C. ; Libby-Roberts, Jessica ; Lin, Andrea S. J. ; Cañas, Caleb I. ; Kanodia, Shubham ; Mahadevan, Suvrath ; Ninan, Joe P. ; Stefánsson, Guđmundur ; Gupta, Arvind F. ; Jones, Sinclaire ; et al ( July 2023 , The Astronomical Journal)

   Using both ground-based transit photometry and high-precision radial velocity spectroscopy, we confirm the planetary nature of TOI-3785 b. This transiting Neptune orbits an M2-Dwarf star with a period of ∼4.67 days, a planetary radius of 5.14 ± 0.16R_⊕, a mass of${14.95}_{-3.92}^{+4.10}$M_⊕, and a density of$\rho ={0.61}_{-0.17}^{+0.18}$g cm⁻³. TOI-3785 b belongs to a rare population of Neptunes (4R_⊕<R_p< 7R_⊕) orbiting cooler, smaller M-dwarf host stars, of which only ∼10 have been confirmed. By increasing the number of confirmed planets, TOI-3785 b offers an opportunity to compare similar planets across varying planetary and stellar parameter spaces. Moreover, with a high-transmission spectroscopy metric of ∼150 combined with a relatively cool equilibrium temperature ofT_eq= 582 ± 16 K and an inactive host star, TOI-3785 b is one of the more promising low-density M-dwarf Neptune targets for atmospheric follow up. Future investigation into atmospheric mass-loss rates of TOI-3785 b may yield new insights into the atmospheric evolution of these low-mass gas planets around M dwarfs.

    

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