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Abstract The gamma-type inhibitor of snake venom phospholipase A 2 (PLIγ) is expressed extensively in livers of both venomous and non-venomous snakes. It is not clear why PLIγs from different snake species possess diverse activities. To obtain high activity PLIγs and interpret the sequence-function relationships, we used DNA shuffling to hybridize the PLIγs of Sinonatrix annularis (saPLIγ) and Elaphe carinata (ecPLIγ). Chimera PLIγs (cPLIγ) of ∼550 bp were obtained by a series of gene manipulations including DNase I digestion, primer-free PCR, and PCR amplification with PLIγs primer pair. After successful insertion of cPLIγs into pCANTAB5e phage vector, the transformed TG1 strain of Esherichia coli was achieved. The cPLIγ phage library was produced and panned in a five-pace snake venom-coated immune tube. Three high affinity cPLIγ isoforms survived two rounds of panning. Prokaryote expression by the pET28c vector was employed for production of the three cPLIγs and the two parental PLIγs. These all showed anti-hemorrhage activity with cPLIγ 2 demonstrating superior inhibition to the parent PLIγs. Sequence alignment showed that the three kinds of cPLIγ were produced by gene splicing of S. annularis and E. carinata at different sites. Primary sequence changes brought regional changes in secondary and tertiary structure, which may explain the differences in PLIγ activity. Highlights • PLIγ can neutralize snake venom PLA2s, and is regarded as a promising antivenom candidate. • DNA shuffling and phage surface display is an effective way for PLIγ directed evolution. • The chimera PLIγ 2 showed even superior anti-hemorrhage activity than the parent PLIγs. • The α-helix of 150–155aa was believed to be correlative to the activity of PLIγ. [ABSTRACT FROM AUTHOR]

SaPLIγ is a natural phospholipase A 2 (PLA 2 ) inhibitor, isolated from Sinonatrix annularis, that has been demonstrated to protect against envenomation by other venomous snakes. As snake venom PLA 2 s and mammalian secretory PLA 2 s are similar, saPLIγ is thought to have potential to alleviate inflammatory reactions in which PLA 2 s act as a key enzyme for arachidonic acid release. The aim of this study was to investigate the anti-inflammatory effects and mechanisms of action of saPLIγ in an animal model of carrageenan-induced acute inflammation. The results indicated that saPLIγ inhibited PLA 2 subtypes extensively, especially IIA-PLA 2 , in a dose-dependent manner. Paw swelling in mice was reduced markedly by intraperitoneal saPLIγ 2 .5 mg/kg, and the effect was significantly better than observed with dexamethasone at the same dose. Lower neutrophil infiltration and tissue edema was observed in the paws of saPLIγ-treated mice. Additionally, carrageenan-induced cyclooxygenase- 2 (COX- 2 ) and pro-inflammatory cytokines (TNFα and IL-1β) were also significantly down-regulated by saPLIγ in a dose-dependent manner. These results suggested that saPLIγ had effective anti-inflammatory effects in vivo, and these were produced by blocking mammalian IB, IIA, V and X sPLA2 subtypes. [ABSTRACT FROM AUTHOR]

[Display omitted] • A venom affinity column was constructed and adapted for active inhibitors mining. • Venom inhibitors and toxin receptors were identified in the serum and liver of the snake species S. annularis. • Fifteen toxins from D. acutus venom were pooled using venom binding proteins-affinity column Various snake species and snake predators have natural neutralization against snake toxins, which their antidotal abilities are commonly attributed to the intrinsic inhibitors produced by the liver, e.g., phospholipase A 2 inhibitor (PLI) and metalloproteinase inhibitor (SVMPI). Sinonatrix annularis was found to possess broad-spectrum neutralization to different snake venoms in our lab. Although the anti-venom compound PLIγ has been previously characterized in our laboratory, the mechanism of resistance of S. annularis to snake venoms remains obscure. In this research, a venom affinity chromatography was constructed by immobilizing D. acutus venom to NHS-agarose beads and applied for antitoxins mining from S. annularis. The binding capacity of the venom column was validated using a self-prepared rabbit antivenom against D. acutus. Serum and liver homogenate of S. annularis were then applied to the column, the bound components were profiled using SDS-PAGE and mass spectrometry. PLIs, snake venom metalloproteins inhibitor (SVMPI), small serum protein (SSP), heat shock proteins, etc were identified. To identify their toxin targets in D. acutus venom, a reverse separation was conducted by coupling the fractionated S. annularis serum proteins to NHS-agarose beads. Fifteen toxins of five families were captured and identified as follows: PLA 2 s, metalloproteinases, cysteine-rich secretory proteins, snake venom serine proteinases, and C-type lectins. These discoveries increased our understanding of the capacity and mechanism of the natural neutralization of S. annularis to snake venom. These natural inhibitors are medically significant due to their powerful and broad antidotal activities, which may provide alternative and promising drug candidates for snakebite treatment. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the most common neurodegenerative disease characterized by cognitive impairment with few therapeutic options. Despite many failures in developing AD treatment during the past 20 years, significant advances have been achieved in passive immunotherapy of AD very recently. Here, we review characteristics, clinical trial data, and mechanisms of action for monoclonal antibodies (mAbs) targeting key players in AD pathogenesis, including amyloid-β (Aβ), tau and neuroinflammation modulators. We emphasized the efficacy of lecanemab and donanemab on cognition and amyloid clearance in AD patients in phase III clinical trials and discussed factors that may contribute to the efficacy and side effects of anti-Aβ mAbs. In addition, we provided important information on mAbs targeting tau or inflammatory regulators in clinical trials, and indicated that mAbs against the mid-region of tau or pathogenic tau have therapeutic potential for AD. In conclusion, passive immunotherapy targeting key players in AD pathogenesis offers a promising strategy for effective AD treatment. ● Passive immunotherapy is a major strategy under clinical development for AD treatment. ● Monoclonal antibodies against Aβ including lecanemab and donanemab showed significant efficacy in phase III clinical trials. ● ARIA and brain atrophy cannot be ignored in Aβ-targeted immunotherapy. ● Passive immunotherapy targeting tau and neuroinflammation is at an early stage of development. [ABSTRACT FROM AUTHOR]

The properties and spectrum of the highly charged tungsten ions draw more and more attention, due to its potential application in the next generation fusion reactor. The transition wavelength and rate of the magnetic-dipole transition between the levels of the ground configuration of W53+ ion in the range of 10 − 20 nm were calculated by Dirac–Fock–Slater (DFS) method with a local central potential and Multi-Configuration Dirac-Hartree-Fock (MCDHF) method, respectively. The results are consistent with the previous EBIT experimental data and other theoretical data. A collisional-radiative model was constructed, and the spectrum of magnetic-dipole transition of W53+ ion observed on EBIT (Y. Ralchenko et al., Phys. Rev. A. 83 , 032517, 2011) was reproduced theoretically. Another two new transitions near the wavelength of 16.683 nm and 18.018 nm are also assigned to the M1 transition of W53+ ion. • The EBIT spectrum of W53+ ion was reproduced and analyzed by CRM with accurate atomic data. • The new M1 transition between the ground configuration of W53+ ions were assigned to the experimental spectrum. • The MCDHF transition wavelength was used instead of DFS results to get better agreement with the experiments. [ABSTRACT FROM AUTHOR]

• The electron correlation model was constructed for double K hole states of highly charged Xe q + ions. • The multi-configuration Dirac-Hartree-Fock method was used with electron correlation, Breit and QED effects corrections. • The spectator electron effects on the transition energy shift was determined to be 240 eV per 2p spectator electron. • The synthetic spectrum of the bare Xe ions interacting with carbon target were provided. The double electron E1 transition energies, probabilities, and oscillator strengths between the 2 s 2 p n and 1 s 2 2 p n − 1 (1 ≤ n ≤ 6) configurations of Xe q + (47 ≤ q ≤ 52) ions with different spectator electrons have been calculated based on the multi-configuration Dirac-Hartree-Fock method. A reasonable electron correlation model is constructed with the aid of the active space method. The finite mass of nuclear, Breit interaction and QED effects have also been included. The calculated results are in good agreement with the available data. The theoretical spectra of different spectator electrons of the double K hole state have been predicted. The spectator electron effects on the transition spectra have been analyzed in detail. The present results will be helpful for analyzing the high energy X-ray spectrum observed from the interaction between high energy highly charged ions and the surface. [ABSTRACT FROM AUTHOR]

• A systematic study of spatiotemporal evolution of extreme ultraviolet spectra in laser-produced silver (Ag) plasmas is performed with aid of a spatio-temporally resolved emission spectroscopy and multiconfiguration Hartree-Fock calculations. • Complex spectral structures were accurately revealed based on the assumption of a normalized Boltzmann distribution among the excited states and a steady-state collision-radiative model, which are dominated from the contributions of 4p and 4d excitations of Ag7+–Ag13+ ions. • Theoretical plasma-state parameters near the target surface at the initial stage of the laser-produced Ag plasma were determined via the steady-state collision-radiation model. Experimental and theoretical analyses are reported for the spatiotemporal evolution of extreme ultraviolet spectra in laser-produced silver (Ag) plasmas. The time-resolved spectra were acquired 1.5 mm from the target surface. The 4p and 4d excitations of Ag7+–Ag13+ ions were calculated with the aid of multiconfiguration Hartree-Fock calculations. The spectral line distributions of transitions in the dominant 4p and 4d excitation configurations and their variations with the degree of ionization were analyzed. Complex spectral structures were accurately revealed based on the assumption of a normalized Boltzmann distribution among the excited states and a steady-state collision-radiative model. Experimental peak origins were identified by comparing experimental and simulated spectra. These results will provide data for energy-level structures of highly-charged ions of middle- and high-Z elements and their radiative characteristics in plasmas. [ABSTRACT FROM AUTHOR]