Existence of a complete holomorphic vector field via the Kähler–Einstein metric

In this paper, we study the existence of a complete holomorphic vector field on a strongly pseudoconvex complex manifold admitting a negatively curved complete Kähler–Einstein metric and a discrete sequence of automorphisms. Using the method of potential scaling, we will show that there is a potential function of the Kähler–Einstein metric whose differential has a constant length. Then, we will construct a complete holomorphic vector field from the gradient vector field of the potential function.

     

Synthesis of Moracin C and Its Derivatives with a 2-arylbenzofuran Motif and Evaluation of Their PCSK9 Inhibitory Effects in HepG2 Cells

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key factor in several cardiovascular diseases, as it is responsible for the elevation of circulating low-density lipoprotein cholesterol (LDL-C) levels in blood plasma by direct interaction with the LDL receptor. The development of orally available drugs to inhibit this PCSK9-LDLR interaction is a highly desirable objective. Here, we report the synthesis of naturally occurring moracin compounds and their derivatives with a 2-arylbenzofuran motif to inhibit PCSK9 expression. In addition, we discuss a short approach involving the three-step synthesis of moracin C and a divergent method to obtain various analogs from one starting material. Among the tested derivatives, compound 7 (97.1%) was identified as a more potent inhibitor of PCSK9 expression in HepG2 cells than berberine (60.9%). These results provide a better understanding of the structure–activity relationships of moracin derivatives for the inhibition of PCSK9 expression in human hepatocytes.     

Investigation on the magnetic and Mössbauer spectroscopy of 57Fe doped LiMnPO4

Journal of Radioanalytical and Nuclear Chemistry - The 57Fe doped LiMnPO4 cathode with potential applications in Li-ion batteries was prepared by solid-state reaction. The magnetic susceptibility...     

Synthesis and structure of the medium-pore zeolite PST-35 with two interconnected cages of unusual orthorhombic shape

The search for new zeolite structures and compositions remains important in synthetic materials science due to the high impact on developing new chemical technologies, as well as on improving existing ones. Herein we present the synthesis and structure of PST-35, a novel medium-pore germanosilicate (Si/Ge = 2.1–6.6) zeolite, achieved by combining the excess fluoride approach and the unique structure directing ability of Ge in the presence of 1,2,3-triethylimidazolium ions as an organic structure-directing agent. PST-35 contains a zig-zag 10-ring (4.6 × 6.7 Å) channel system constructed of strictly alternating large 28-hedral ([4⁸·5⁸·6⁸·8²·10²]) and smaller 18-hedral ([4⁶·5⁴·6⁴·8²·10²]) cages of anomalous orthorhombic shape. The PST-35 structure is built from the connection of pst-35 layers consisting of small 8-hedral ([4³·5⁴·6]) cages, previously unobserved zeolite building layers, through single 4-rings.

A medium-pore zeolite containing 2 novel orthorhombic-shaped cages was synthesized by combining the tendency of Ge to form double 4-ring units with the structure-directing ability of 1,2,3-triethylimidazolium ions under excess fluoride conditions.     

Syringaresinol Alleviates Oxaliplatin-Induced Neuropathic Pain Symptoms by Inhibiting the Inflammatory Responses of Spinal Microglia

Oxaliplatin-induced peripheral neuropathy (OIPN) is a serious side effect that impairs the quality of life of patients treated with the chemotherapeutic agent, oxaliplatin. The underlying pathophysiology of OIPN remains unclear, and there are no effective therapeutics. This study aimed to investigate the causal relationship between spinal microglial activation and OIPN and explore the analgesic effects of syringaresinol, a phytochemical from the bark of Cinnamomum cassia, on OIPN symptoms. The causality between microglial activation and OIPN was investigated by assessing cold and mechanical allodynia in mice after intrathecal injection of the serum supernatant from a BV-2 microglial cell line treated with oxaliplatin. The microglial inflammatory response was measured based on inducible nitric oxide synthase (iNOS), phosphorylated extracellular signal-regulated kinase (p-ERK), and phosphorylated nuclear factor-kappa B (p-NF-κB) expression in the spinal dorsal horn. The effects of syringaresinol were tested using behavioral and immunohistochemical assays. We found that oxaliplatin treatment activated the microglia to increase inflammatory responses, leading to the induction of pain. Syringaresinol treatment significantly ameliorated oxaliplatin-induced pain and suppressed microglial expression of inflammatory signaling molecules. Thus, we concluded that the analgesic effects of syringaresinol on OIPN were achieved via the modulation of spinal microglial inflammatory responses.     

Establishment of a humanized animal model of systemic sclerosis in which T helper-17 cells from patients with systemic sclerosis infiltrate and cause fibrosis in the lungs and skin

Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by inflammation, microangiopathy, and progressive fibrosis in the skin and internal organs. To evaluate the pathophysiologic mechanisms and efficacies of potential therapeutics for SSc, a preclinical model recapitulating the disease phenotypes is needed. Here, we introduce a novel animal model for SSc using immunodeficient mice injected with peripheral blood mononuclear cells (PBMCs) from SSc patients. Human PBMCs acquired from SSc patients and healthy controls were transferred into NOD.Cg-Prkdc^scidIl2rg^tm1Wjl (NSG) mice with concurrent bleomycin injection. Blood, skin, and lung tissues were acquired and analyzed after PBMC engraftment. In addition, we investigated whether the humanized murine model could be used to assess the efficacy of potential therapeutics for SSc. Human PBMCs from SSc patients and healthy controls were engrafted into the blood, skin, and lung tissues of NSG mice. Histological analysis of affected tissues from mice treated with SSc PBMCs (SSc hu-mice) demonstrated substantial inflammation, fibrosis and vasculopathy with human immune cell infiltration and increased expression of IL-17, TGF-β, CCL2, CCL3, and CXCL9. The proportions of circulating and tissue-infiltrating T helper 17 (Th17) cells were elevated in SSc hu-mice. These cells showed increased expression of CXCR3 and phosphorylated STAT3. SSc hu-mice treated with rebamipide and other potential Th17-cell-modulating drugs presented significantly reduced tissue fibrosis. Mice injected with patient-derived PBMCs show promise as an animal model of SSc.Subject terms: Autoimmunity, Autoimmune diseases     

An Fc variant with two mutations confers prolonged serum half-life and enhanced effector functions on IgG antibodies

The pH-selective interaction between the immunoglobulin G (IgG) fragment crystallizable region (Fc region) and the neonatal Fc receptor (FcRn) is critical for prolonging the circulating half-lives of IgG molecules through intracellular trafficking and recycling. By using directed evolution, we successfully identified Fc mutations that improve the pH-dependent binding of human FcRn and prolong the serum persistence of a model IgG antibody and an Fc-fusion protein. Strikingly, trastuzumab-PFc29 and aflibercept-PFc29, a model therapeutic IgG antibody and an Fc-fusion protein, respectively, when combined with our engineered Fc (Q311R/M428L), both exhibited significantly higher serum half-lives in human FcRn transgenic mice than their counterparts with wild-type Fc. Moreover, in a cynomolgus monkey model, trastuzumab-PFc29 displayed a superior pharmacokinetic profile to that of both trastuzumab-YTE and trastuzumab-LS, which contain the well-validated serum half-life extension Fcs YTE (M252Y/S254T/T256E) and LS (M428L/N434S), respectively. Furthermore, the introduction of two identified mutations of PFc29 (Q311R/M428L) into the model antibodies enhanced both complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity activity, which are triggered by the association between IgG Fc and Fc binding ligands and are critical for clearing cancer cells. In addition, the effector functions could be turned off by combining the two mutations of PFc29 with effector function-silencing mutations, but the antibodies maintained their excellent pH-dependent human FcRn binding profile. We expect our Fc variants to be an excellent tool for enhancing the pharmacokinetic profiles and potencies of various therapeutic antibodies and Fc-fusion proteins.Subject terms: Antibody therapy, Molecularly targeted therapy, Drug development