Zinc(ii)-mediated stereoselective construction of 1,2-cis 2-azido-2-deoxy glycosidic linkage: assembly of Acinetobacter baumannii K48 capsular pentasaccharide derivative.

The capsular polysaccharide (CPS) is a major virulence factor of the pathogenic Acinetobacter baumannii and a promising target for vaccine development. However, the synthesis of the 1,2-cis-2-amino-2-deoxyglycoside core of CPS remains challenging to date. Here we develop a highly α-selective ZnI2-mediated 1,2-cis 2-azido-2-deoxy chemical glycosylation strategy using 2-azido-2-deoxy glucosyl donors equipped with various 4,6-O-tethered groups. Among them the tetraisopropyldisiloxane (TIPDS)-protected 2-azido-2-deoxy-d-glucosyl donor afforded predominantly α-glycoside (α : ß = >20 : 1) in maximum yield. This novel approach applies to a wide acceptor substrate scope, including various aliphatic alcohols, sugar alcohols, and natural products. We demonstrated the versatility and effectiveness of this strategy by the synthesis of A. baumannii K48 capsular pentasaccharide repeating fragments, employing the developed reaction as the key step for constructing the 1,2-cis 2-azido-2-deoxy glycosidic linkage. The reaction mechanism was explored with combined experimental variable-temperature NMR (VT-NMR) studies and mass spectroscopy (MS) analysis, and theoretical density functional theory calculations, which suggested the formation of covalent α-C1GlcN-iodide intermediate in equilibrium with separated oxocarbenium-counter ion pair, followed by an SN1-like α-nucleophilic attack most likely from separated ion pairs by the ZnI2-activated acceptor complex under the influence of the 2-azido gauche effect.

Stably Grafting Polymer Brushes on Both Active and Inert Surfaces Using Tadpole-Like Single-Chain Particles with an Interactive "Head".

We report a "grafting to" method for stably grafting high-molecular-weight polymer brushes on both active and inert surfaces using tadpole-like single-chain particles (TSCPs) with an interactive "head" as grafting units. The TSCPs can be efficiently synthesized through intrachain cross-linking one block of a diblock copolymer; the "head" is the intrachain cross-linked single-chain particle, and the "tail" is a linear polymer chain that has a contour length up to micrometers. When grafted to a surface, the "head", integrating numerous interacting groups, can synergize multiple weak interactions with the surface, thereby enabling stable grafting of the "tail" on both active and traditionally challenging inert surfaces. Because the structural parameters and composition of the "heads" and "tails" can be separately adjusted over a wide range, the interactivity of the "heads" with the surface and properties of the brushes can be controlled orthogonally, accomplishing surface brushes that cannot be achieved by existing methods.

Synchronous Endometrial and Ovarian Endometrioid Carcinoma With MUTYH Germline Mutation: A Case Report With Genetic Analysis.

Synchronous endometrial and ovarian endometrioid carcinoma, which simultaneously involves the endometrium and ovary, is a relatively rare entity among gynecological cancers. Precise diagnosis and risk stratification are crucial for disease management. We present a unique case of a 40-year-old woman diagnosed with synchronous endometrial and ovarian endometrioid carcinoma carrying a monoallelic pathogenic MUTYH germline variant. Despite the histological morphology of the right ovarian tumor exhibiting some differences compared to the uterine tumor, we identified three identical somatic mutations shared between the uterine tumor and right ovarian tumor, along with four additional mutations exclusive to the uterine tumor, through the utilization of massively parallel sequencing of a 196-gene panel. These findings enabled us to elucidate the clonal relatedness and potential clonal evolution of the tumor across the two anatomical sites. Furthermore, in accordance with the 2023 FIGO staging system, the patient was diagnosed with Stage IIIB2 uterine cancer, and consequently, adjuvant radiation and chemotherapy were administered after surgery. She is being followed periodically and is normal 15 months after surgery. To the best of our knowledge, this study presents the first case of a patient with synchronous endometrial and ovarian endometrioid carcinoma harboring a monoallelic pathogenic MUTYH germline variant.

Immune protection of three serine protease inhibitors vaccine in mice against Rhipicephalus sanguineus.

Bioactive molecules in tick saliva are considered to be key to successful feeding and further the transmission of tick-borne pathogens. Problems such as pathogen transmission and animal weight loss result in tick infestation can cause tremendous economic losses to the livestock industry. Therefore, the development of a universal tick vaccine is urgently needed. In this paper, three serine protease inhibitor (serpin) proteins RMS-3, L7LRK7 and L7LTU1 were analyzed with bioinformatics methods. Subsequently the proteins were expressed and purified, and inoculated into Kunming mice for immune protection analysis. The amino acid sequence similarities between RMS-3, L7LRK7 and L7LTU1 were up to 90% in Rhipicephalus sanguineus. The recombinant RMS-3 + L7LRK7 + L7LTU1 showed anticoagulant reaction function and could inhibit the activity of CD4+ lymphocytes, when inoculated into Kunming mice. Additionally, After the immunized mice were challenged with Rhipicephalus sanguineus, the percentage of larvae and nymphs that were fully engorged dropped to 40.87% (P < 0.05) and 87.68% (P > 0.05) in the RmS-3 + L7LRK7 immune group, 49.57% (P < 0.01) and 52.06% (P < 0.05) in the RmS-3 + L7LTU1 group, and 45.22% (P < 0.05) and 60.28% (P < 0.05) in the RmS-3 + L7LRK7 + L7LTU1 immune group, in comparison with the control group. These data indicate that RmS-3 + L7LRK7 + L7LTU1 has good immune protection and has the potential to be developed into a vaccine against the larvae and nymphs of R. sanguineus.

B(C6F5)3-Catalyzed Stereoselective 1,2-cis Arabinofuranosylation with a Conformationally Constrained Donor.

Compared with stereoselective glycosylation methods mainly addressed on the preparation of pyranose glycosides, the furanosylation has been more limited, especially for the 1,2-cis arabinofuranosylation. Herein, we report a novel stereoselective 1,2-cis-arabinofuranosylation strategy using a conformationally restricted 3,5-O-xylylene-protected arabinofuranosyl donor on activation with B(C6F5)3 for desired targets in moderate to excellent yields and ß-stereoselectivity. The effectiveness of the 1,2-cis-arabinofuranosylation strategy was demonstrated successfully with various acceptors, including carbohydrate alcohols.

Zonisamide attenuates pressure overload-induced myocardial hypertrophy in mice through proteasome inhibition.

Myocardial hypertrophy is a pathological thickening of the myocardium which ultimately results in heart failure. We previously reported that zonisamide, an antiepileptic drug, attenuated pressure overload-caused myocardial hypertrophy and diabetic cardiomyopathy in murine models. In addition, we have found that the inhibition of proteasome activates glycogen synthesis kinase 3 (GSK-3) thus alleviates myocardial hypertrophy, which is an important anti-hypertrophic strategy. In this study, we investigated whether zonisamide prevented pressure overload-caused myocardial hypertrophy through suppressing proteasome. Pressure overload-caused myocardial hypertrophy was induced in mice by trans-aortic constriction (TAC) surgery. Two days after the surgery, the mice were administered zonisamide (10, 20, 40 mg·kg-1·d-1, i.g.) for four weeks. We showed that zonisamide administration significantly mitigated impaired cardiac function. Furthermore, zonisamide administration significantly inhibited proteasome activity as well as the expression levels of proteasome subunit beta types (PSMB) of the 20 S proteasome (PSMB1, PSMB2 and PSMB5) and proteasome-regulated particles (RPT) of the 19 S proteasome (RPT1, RPT4) in heart tissues of TAC mice. In primary neonatal rat cardiomyocytes (NRCMs), zonisamide (0.3 µM) prevented myocardial hypertrophy triggered by angiotensin II (Ang II), and significantly inhibited proteasome activity, proteasome subunits and proteasome-regulated particles. In Ang II-treated NRCMs, we found that 18α-glycyrrhetinic acid (18α-GA, 2 mg/ml), a proteasome inducer, eliminated the protective effects of zonisamide against myocardial hypertrophy and proteasome. Moreover, zonisamide treatment activated GSK-3 through inhibiting the phosphorylated AKT (protein kinase B, PKB) and phosphorylated liver kinase B1/AMP-activated protein kinase (LKB1/AMPKα), the upstream of GSK-3. Zonisamide treatment also inhibited GSK-3's downstream signaling proteins, including extracellular signal-regulated kinase (ERK) and GATA binding protein 4 (GATA4), both being the hypertrophic factors. Collectively, this study highlights the potential of zonisamide as a new therapeutic agent for myocardial hypertrophy, as it shows potent anti-hypertrophic potential through the suppression of proteasome.