Synthesis of tertiary alkylphosphonate oligonucleotides through light-driven radical-polar crossover reactions

光エネルギーで新しい化学修飾核酸を合成 --核酸リン原子の第三級アルキル化に成功--. 京都大学プレスリリース. 2023-11-01.Chemical modification of nucleotides can improve the metabolic stability and target specificity of oligonucleotide therapeutics, and alkylphosphonates have been employed as charge-neutral replacements for naturally-occurring phosphodiester backbones in these compounds. However, at present, the alkyl moieties that can be attached to phosphorus atoms in these compounds are limited to methyl groups or primary/secondary alkyls, and such alkylphosphonate moieties can degrade during oligonucleotide synthesis. The present work demonstrates the tertiary alkylation of the phosphorus atoms of phosphites bearing two 2’-deoxynuclosides. This process utilizes a carbocation generated via a light-driven radical-polar crossover mechanism. This protocol provides tertiary alkylphosphonate structures that are difficult to synthesize using existing methods. The conversion of these species to oligonucleotides having charge-neutral alkylphosphonate linkages through a phosphoramidite-based approach was also confirmed in this study

Admission systolic blood pressure as a prognostic predictor of acute decompensated heart failure: A report from the KCHF registry

[Background] Admission systolic blood pressure has emerged as a predictor of postdischarge outcomes of patients with acute decompensated heart failure; however, its validity in varied clinical conditions of this patient subset is unclear. The aim of this study was to further explore the prognostic value of admission systolic blood pressure in patients with acute decompensated heart failure. [Methods] The Kyoto Congestive Heart Failure (KCHF) registry is a prospective, observational, multicenter cohort study enrolling consecutive patients with acute decompensated heart failure from 19 participating hospitals in Japan. Clinical characteristics at baseline and prognosis were examined by the following value range of admission systolic blood pressure: <100, 100–139, and ≥140 mmHg. The primary outcome measure was defined as all-cause death after discharge. Subgroup analyses were done for prior hospitalization for heart failure, hypertension, left ventricular ejection fraction, and medications at discharge. We excluded patients with acute coronary syndrome or insufficient data. [Results] We analyzed 3564 patients discharged alive out of 3804 patients hospitalized for acute decompensated heart failure. In the entire cohort, lower admission systolic blood pressure was associated with poor outcomes (1-year cumulative incidence of all-cause death: <100 mmHg, 26.8%; 100–139 mmHg, 20.2%; and ≥140 mmHg, 15.1%, p<0.001). The magnitude of the effect of lower admission systolic blood pressure for postdischarge all-cause death was greater in patients with prior hospitalization for heart failure, heart failure with reduced left ventricular ejection fraction, and β-blocker use at discharge than in those without. [Conclusions] Admission systolic blood pressure is useful for postdischarge risk stratification in patients with acute decompensated heart failure. Its magnitude of the effect as a prognostic predictor may differ across clinical conditions of patients

Identification of the Neogenin-Binding Site on the Repulsive Guidance Molecule A

Repulsive guidance molecule (RGM) is a membrane-bound protein that was originally identified as an axon guidance molecule in the chick retinotectal system. RGMa, one of the 3 isoforms found in mammals, is involved in laminar patterning, cephalic neural tube closure, axon guidance, and inhibition of axonal regeneration. In addition to its roles in the nervous system, RGMa plays a role in enhancing helper T-cell activation. Binding of RGM to its receptor, neogenin, is considered necessary to transduce these signals; however, information on the binding of RGM to neogenin is limited. Using co-immunoprecipitation studies, we have identified that the RGMa region required for binding to neogenin contains amino acids (aa) 259–295. Synthesized peptide consisting of aa 284–293 directly binds to the extracellular domain (ECD) of recombinant neogenin, and addition of this peptide inhibits RGMa-induced growth cone collapse in mouse cortical neurons. Thus, we propose that this peptide is a promising lead in finding reagents capable of inhibiting RGMa signaling

Magnetized Fast Isochoric Laser Heating for Efficient Creation of Ultra-High-Energy-Density States

The quest for the inertial confinement fusion (ICF) ignition is a grand challenge, as exemplified by extraordinary large laser facilities. Fast isochoric heating of a pre-compressed plasma core with a high-intensity short-pulse laser is an attractive and alternative approach to create ultra-high-energy-density states like those found in ICF ignition sparks. This avoids the ignition quench caused by the hot spark mixing with the surrounding cold fuel, which is the crucial problem of the currently pursued ignition scheme. High-intensity lasers efficiently produce relativistic electron beams (REB). A part of the REB kinetic energy is deposited in the core, and then the heated region becomes the hot spark to trigger the ignition. However, only a small portion of the REB collides with the core because of its large divergence. Here we have demonstrated enhanced laser-to-core energy coupling with the magnetized fast isochoric heating. The method employs a kilo-tesla-level magnetic field that is applied to the transport region from the REB generation point to the core which results in guiding the REB along the magnetic field lines to the core. 7.7 $\pm$ 1.3 % of the maximum coupling was achieved even with a relatively small radial area density core ($\rho R$ $\sim$ 0.1 g/cm$^2$). The guided REB transport was clearly visualized in a pre-compressed core by using Cu-$K_\alpha$ imaging technique. A simplified model coupled with the comprehensive diagnostics yields 6.2\% of the coupling that agrees fairly with the measured coupling. This model also reveals that an ignition-scale areal density core ($\rho R$ $\sim$ 0.4 g/cm$^2$) leads to much higher laser-to-core coupling ($>$ 15%), this is much higher than that achieved by the current scheme

Alkylated alkali lignin for compatibilizing agents of carbon fiber reinforced plastics with polypropylene

金沢大学理工研究域生命理工学系As an alternative to petroleum-based compatibilizing agents, we developed lignin derivatives for compatibilizing agents of carbon fiber-reinforced plastics that have thermoplasticity. In this study, alkyl chains were introduced into alkali lignin at various ratios to optimize the compatibility of the lignin derivatives with both polypropylene and carbon fiber. The interfacial shear strength between the two materials was improved from 8.2 to 17.2 MPa by mixing with the optimized lignin derivative. The value is comparable to that achieved with a typical petroleum-based compatibilizing agent (18.3 MPa).Embargo Period 6 monthsThis paper has supplementary information