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• An effective wind turbine tower model with lumped mass and foundation stiffness is developed. • Critical wind speed of frequency lock-in is mainly affected by structural sizes near tower top. • Lumped mass and foundation stiffness mainly affect frequency lock-in range rather than response amplitude. • The prediction of vortex-induced vibration range is validated by wind tunnel experiment. Vortex-induced vibration (VIV) of wind turbine tower is a common occurrence in practical engineering, significantly impacting the safety and reliability of structure. An effective method is developed to investigate the VIV characteristics of a wind turbine tower with an elastic foundation and a lumped mass. To simulate the fluid–structure interaction, the van der Pol equation is utilized. The equations of motion of wind turbine tower, accounting for aerodynamic force, are established using Hamilton's principle and the assumed mode method, and they are solved by the method of multiple scales. Modal functions of the wind turbine tower are obtained through the finite element method (FEM). The analysis further explores the influences of various parameters on the VIV characteristics of wind turbine tower. The results show that the VIV occurs within the frequency lock-in and multi-value ranges, and the critical wind speeds are mainly determined by the diameters of the segments near the tower top. Moreover, as the lumped mass increases or the foundation stiffness decreases, the occurrence of VIV shifts to lower wind speeds. A wind tunnel experiment of a scaled wind turbine tower model validates the frequency lock-in range of the VIV analysis results. [ABSTRACT FROM AUTHOR]

Sanguinarine (Sang) is a natural alkaloid and distributed in several plants of Papaveraceae. The antitumor, antioxidant, antimicrobial and anti-inflammatory effects of Sang were extensively reported, but its speciality and mechanism against Lepidoptera insects were still unknown. In this study, detailed toxicological parameters of Sang against silkworms, Bombyx mori (B. mori), were determined by a toxicological test. Then, a nuclear magnetic resonance-based (NMR) metabolomics method was adopted to analyze the changes in hemolymph metabolites of silkworms after feeding Sang. The growth of fourth-instar larvae was significantly ceased by the oral administration of 0.05–0.3% Sang and vast deaths appeared in 0.3% Sang group on Day 4 and Day 5. The quantitative analysis of metabolites indicated that trehalose and citrate levels in hemolymph were increased after 24 h of feeding 0.3% Sang, whereas the concentrations of pyruvate, succinate, malate and fumarate were decreased. In addition, the enzymatic determination and reverse transcription quantitative PCR (RT-qPCR) showed that the trehalase (THL) activity and the transcriptional level of one gene coding THL were uniformly weakened by 0.3% Sang. One of the important mechanisms of Sang against silkworms might be interpreted as follows. Sang impaired trehalose hydrolysis, reduced THL activity and transcription, and led to the inhibition of energy metabolism, consequent antigrowth and high lethality in larvae of B. mori. Our findings offered new insights into the insecticidal effect of Sang from the perspective of energy metabolism and provided the basis for the application of Sang in the control of Lepidoptera pests. Unlabelled Image • The defensive roles of sanguinarine against the Lepidoptera insect were still unknown. • Sanguinarine significantly inhibited the growth of fourth-instar Bombyx mori larvae. • Sanguinarine targeted on trehalase and induced the systemic inhibition of energy metabolism in silkworms. • This study provided the basis for the application of Sang in the control of Lepidoptera pests. [ABSTRACT FROM AUTHOR]

Abstract The strategy of using multipotential stem cells like bone mesenchymal stromal cells (BMSCs) for nerve tissue engineering is proven feasible. The promotion effects on neural transdifferentiation of BMSCs from factors including nerve growth factor (NGF), laminin and electrical stimulation (ES) have been reported, while it is not known if these factors can achieve a strong synergetic impact when the cells are cultured on conductive substrates. In this study, it was identified that any single factor (NGF, laminin, or conductive substrate) combined with ES demonstrated the capacity to induce BMSCs transdifferentiating into neural cells, while the efficiency was found in the order of NGF > laminin > conductive substrate. The combination of any two of the factors would be more efficient in inducing the neural transdifferentiation than individual factor. As expected, the strongest promotion in inducing BMSCs to transdifferentiate into neural cells was identified when BMSCs were cultured on laminin-treated conductive nanofibrous mesh in the presence of NGF and under proper ES simultaneously, showing significant synergetic efficiency from these multiple factors. Studies on the Notch-1 signaling pathway, a main negative regulator of neurogenesis, revealed these factors sharing a similar molecular mechanism in regulating the neural transdifferentiation of BMSCs. The results suggested that satisfactory nerve regeneration might be achievable if these synergetic multiple factors could be involved in nerve guidance conduit design, especially, when BMSCs were applied as co-implanted cells. Graphical abstract fx1 Highlights • Neural transdifferentiation of BMSCs are studied by incorporating multiple promoting factors. • The promoting factors include nerve growth factor, laminin, conductive nanofibers and electrical stimulation. • These four factors demonstrate strong synergetic promotion in inducing the neural transdifferentiation of BMSCs. • Notch-1 signaling pathway is involved in the transdifferentiation process. [ABSTRACT FROM AUTHOR]

In this study, we extracted the polysaccharides from Hizikia fusiforme (HFPs) and evaluated their effects on the immune response of the mud crab Scylla paramamosain. Compositional analysis revealed that HFPs were composed mainly of mannuronic acid (49.05%) and fucose (22.29%) as sulfated polysaccharides, and the sugar chain structure was β-type. These results indicated that HFPs have potential antioxidant and immunostimulation activity in vivo or in vitro assays. Through this research, we found that HFPs inhibited viral replication in white spot syndrome virus (WSSV)-infected crabs and promoted phagocytosis of Vibrio alginolyticus by hemocytes. Quantitative PCR results showed that HFPs up-regulated the expression levels of astakine , crustin , myosin , MCM7 , STAT , TLR , JAK , CAP , and p53 in crab hemocytes. HFPs also promoted the activities of superoxide dismutase and acid phosphatase and the hemolymph antioxidant activities of crabs. HFPs maintained peroxidase activity after WSSV challenge, thereby providing protection against oxidative damage caused by the virus. HFPs also promoted apoptosis of hemocytes after WSSV infection. In addition, HFPs significantly enhanced the survival rate of WSSV-infected crabs. All results confirmed that HFPs improved the innate immunity of S. paramamosain by enhancing the expression of antimicrobial peptides, antioxidant enzyme activity, phagocytosis, and apoptosis. Therefore, HFPs have potential for use as therapeutic or preventive agents to regulate the innate immunity of mud crabs and protect them against microbial infection. • Hizikia fusiforme polysaccharides supplement significantly reduced the mortality of S. paramamosain caused by WSSV infection. • H. fusiforme polysaccharides significantly promoted the apoptosis of hemocyte in S. paramamosain. • The WSSV copy numbers were reduced by H. fusiforme polysaccharides supplement in S. paramamosain. [ABSTRACT FROM AUTHOR]

Lead (Pb) induces male infertility in vertebrates. Whether lead is related to reproductive abnormalities in aquatic invertebrates remains uncertain. In this work, effects of Pb on the sperm quality and oxidative stress of the freshwater crab Sinopotamon henanense were investigated after 3, 5 and 7 d exposure to different Pb concentrations (0, 3.675, 7.35, 14.7, 29.4 and 58.8 mg/L). Sperm quality indices including sperm plasma-membrane integrity and acrosomal-membrane integrity were measured by flow cytometry. DNA integrity was measured by fluorescence microscopy. The results showed that Pb levels in sperm increased significantly upon Pb exposure in most treated groups, sperm plasma-membrane integrity, acrosomal-membrane integrity, and DNA integrity were reduced at higher concentrations after 5 d and 7 d. Oxidative stress of sperm induced by Pb was reflected in significant up-regulation of reactive oxygen species (ROS) levels after 3, 5 and 7 d. A significant reduction of the total antioxidant capacity levels occurred after exposure to 14.7 mg/L Pb and above at 7 d compared to the control. The results of oxidative damage to lipids, proteins and DNA of sperm showed that malondialdehyde, protein carbonylation and DNA–protein crosslinks were increased in a concentration- and time-dependent manner. Our findings document that Pb can induce harmful effects on several reproductive endpoints in a freshwater crab. [ABSTRACT FROM AUTHOR]

Lead (Pb) is one of the most toxic environmental pollutants and known to exert multiple toxic effects including gonadotoxic and spermiotoxic effects. In order to understand toxic mechanisms of lead (Pb) on the testes and the accessory glands of crabs, we investigated Pb accumulation in testes and accessory glands and the survival rate of sperms of freshwater crab, Sinopotamon henanense . The tissue damaging effects of Pb was also investigated by histopathological examination and analyses of antioxidant enzymes as well as lipid peroxidation. Crabs were exposed to different Pb concentrations (0, 3.675, 7.35, 14.7, 29.4 and 58.8 mg/L) for 3, 5 and 7 days. The results showed that Pb levels in testes and accessory glands increased significantly following Pb exposure for 5 and 7 days in almost all treated groups, and survival rate of sperm decreased with increasing Pb concentrations at 5 and 7 days. Morphological changes identified histologically were discovered in testes, including a disordered arrangement of germ cells, a decreased number of sperm in the lumina of the seminiferous tubules, extensive necrosis in the germinal layer of the seminiferous tubules, etc. At the same time, histological abnormalities were discovered in accessory glands, the wall cells were separated from the basement membrane, and wall cells were missing partly. The activities of SOD, GPx and CAT in testes showed no statistically significant changes compared to the control for 3 days, and initially increased and subsequently decreased with increasing Pb concentrations at 5 and 7 days. The antioxidant enzyme activities in accessory glands initially increased and subsequently decreased with increasing Pb concentrations and Pb exposure. This was accompanied with an increase in malondialdehyde (MDA) content in a concentration-dependent manner. These results showed that acute Pb exposure led to a reduction of survival rate of sperm and harmful effects at the cellular level of crab testes and accessory glands, which are most likely linked to Pb-induced oxidative stress. [ABSTRACT FROM AUTHOR]

A hydrothermal fabrication of ZnO nanorod-based grating patterns on Si substrates is reported. The arrays of optical fiber cores were manually assembled as templates with nominal pitches of 250 μm and 375 μm. The profiles of the templates and the grating patterns were extracted and quantitatively characterized based on micrographs of scanning electron microscopy (SEM) and Image Processing Toolbox of MATLAB. The errors of the actual pitches and the parallelism demonstrate that the process capability of manually assembling the optical fiber cores can meet the quality requirement of the templates. The critical dimensions (CDs) show that the size of the trough formed by the template and the Si substrate determines the location of the grating pattern. The characteristic parameters, including line edge roughness (LER), line width roughness (LWR), skewness (Sk), kurtosis (Ku), and correlation length ( ζ ), exhibit that the three-phase contact lines among the trapped air bubble, ZnO seed solution, and Si substrate (or the optical fiber core) decide the form of the grating pattern. The research found that larger nominal pitch of the template resulted in larger size of the trough which further led to less CD, and higher hydrophilicity of the Si surfaces resulted in smoother profiles whilst lower hydrophilicity of the optical fiber core surfaces led to rougher ones. [ABSTRACT FROM AUTHOR]

[Display omitted] • Fragment based drug discovery. • A series of novel CDK4/6 selective inhibitors with anti-breast cancer activities. • Small molecule deconstruction and structure activity relationship based on descriptor method. • Discovery of a new potential binding mode of small molecule& CDK4/6 mediated by Ile12. CDK4/6 were attractive chemotherapeutic targets for the treatment of malignant tumors, CDK4/6 selective inhibitors have made outstanding contributions in the treatment of breast cancer. However, these inhibitors share a single skeleton of N -(pyridin-2-yl) pyrimidin-2-amine which cannot overcome the side effects in clinical application. In our previous study, an N' - acetylpyrrolidine-1-carbohydrazide was hit as the initial fragment by analyzing the active site characteristics of CDK6. Two series of N -(pyridin-3-yl) proline were obtained by fragment growth method. The QSAR study was carried out according to the in vitro activities data against CDK4/6, and two compounds 7c and 7p with potent inhibitory activities were found to interact with CDK4 in different binding conformation. They showed potential inhibition of cell proliferation against the breast cancer cell, and 7c exhibited promised anti-breast cancer effect in vivo. [ABSTRACT FROM AUTHOR]

Abstract: As a γ-secretase inhibitor, DAPT has been widely used to evaluate the biological behaviors and Notch signaling pathway in various cells. This study was aimed to examine the effects of DAPT on the growth and vitamin D3 induced osteogenesis in adipose derived stem cells (ASCs). The cells were treated with or without DAPT and induced to osteoblastic lineage in the presence of vitamin D3. Alizarin red staining and real-time PCR results indicated that the addition of DAPT to vitamin D3 treatments enhanced osteogenesis in ASCs. According to the fold increase and colony-forming unit assay results, the cells cultured in DAPT exhibited lower proliferation rate than those cultured in control medium. Hey1, expressed in the nucleus of ASCs to act as a transcriptional repressor, was downregulated when Notch signaling was inhibited by DAPT. Whereas the expression of Runx2 increased in the nucleus of osteogenic induced ASCs after DAPT treatment. This study demonstrated that DAPT reduced the proliferation and enhanced the osteogenesis in ASCs via regulation of Notch and Runx2 expression. [Copyright &y& Elsevier]

Abstract: The utility of polymer standards for the calibration of average molecular mass estimates often is limited by the polydispersity—the breadth of the size distribution—of the standard. Here monodisperse synthetic hyaluronan (or hyaluronic acid [HA]) complexes in the approximately 1- to 8-megadalton (MDa) range were prepared in two steps. First, synchronized stoichiometrically controlled in vitro reactions yielded linear narrow size distribution biotinylated HA chains. Second, streptavidin protein was added at substoichiometric levels to prepare a series of complexes with one, two, three, or four HA chains per streptavidin molecule. The dendritic-like molecules approximate the mobility of natural linear HA chains on agarose gels, making the complexes useful as defined size standards for high-molecular weight HA preparations. [Copyright &y& Elsevier]

Abstract: To investigate Nogo-B expression changes in mouse heart microvascular endothelial H5V cell line induced by lysophosphatidylcholine. Cells were incubated with different concentrations of lysoPC for the same incubation time and with 10 μmol/l lysoPC at different incubation times. Protein and mRNA expression levels of Nogo-B1 and Nogo-B2 were measured with Western blotting and semiquantitative RT-PCR, respectively. Nogo-B1 protein was detected in normal H5V cells by Western blotting. When H5V cells were incubated with lysoPC, Nogo-B1 protein level decreased, and the lowest point fell to 20% of the original level induced by 20 μmol/l lysoPC for 24 h. Incubation of H5V cells with lysoPC of different concentrations or at different time points caused little change in Nogo-B1 mRNA expression level, except for a 50% decrease in 20 μmol/l lysoPC at 24 h, while a transient change was observed in Nogo-B2 mRNA level. These results demonstrate that Nogo-B1 protein expression could be down-regulated with increasing concentrations of lysoPC and lapse of incubation time, though no mRNA transcription down-regulation occurred. However, mRNA expression level of Nogo-B2 showed a transient up-regulation induced by lysoPC. We conclude that the two subtypes of Nogo-B may play different roles in the endothelial cell injury process. [Copyright &y& Elsevier]

• Electrophysiological functional connectivity (FC) within the rat default mode network (DMN) is highly dynamic. • Dynamic FC could be further extracted into distinct spatial patterns using factor analysis; some of these patterns are state-dependent. • The observed spatial patterns and their temporal contributions are modulated by sleep. Resting-state studies have typically assumed constant functional connectivity (FC) between brain regions, and these parameters of interest provide meaningful descriptions of the functional organization of the brain. A number of studies have recently provided evidence pointing to dynamic FC fluctuations in the resting brain, especially in higher-order regions such as the default mode network (DMN). The neural activities underlying dynamic FC remain poorly understood. Here, we recorded electrophysiological signals from DMN regions in freely behaving rats. The dynamic FCs between signals within the DMN were estimated by the phase locking value (PLV) method with sliding time windows across vigilance states [quiet wakefulness (QW) and slow-wave and rapid eye movement sleep (SWS and REMS)]. Factor analysis was then performed to reveal the hidden patterns within the DMN. We identified distinct spatial FC patterns according to the similarities between their temporal dynamics. Interestingly, some of these patterns were vigilance state-dependent, while others were independent across states. The temporal contributions of these patterns fluctuated over time, and their interactive relationships were different across vigilance states. These spatial patterns with dynamic temporal contributions and combinations may offer a flexible framework for efficiently integrating information to support cognition and behavior. These findings provide novel insights into the dynamic functional organization of the rat DMN. [ABSTRACT FROM AUTHOR]

Abstract: In this study, we present an efficient phosphorylation-free and ligase-free PCR-based multiple site-directed mutagenesis that allows simultaneous mutations up to six distal sites. This method could be extended to any plasmid DNA that is isolated from dam+ Escherichia coli strains, and the results showed that the simultaneously mutagenic efficiencies of quadruple mutation and sextuple mutation were up to 80% and 40%, respectively. [Copyright &y& Elsevier]

Abstract: In this study, we report a novel megaprimed and ligase-free, PCR-based, site-directed mutagenesis method modified from the QuikChange site-directed mutagenesis (QCM). One mutagenic oligonucleotide and one universal flanking primer were used to produce the complementary megaprimers that were then used to amplify the whole plasmid template. This method yields a mutagenesis efficiency (∼90%) similar to that of QCM but uses only one mutagenic oligonucleotide instead of two of them, and the length of the oligonucleotide could be shorter. This method can be further extended to double mutations that are located at distant sites by using two mutagenic oligonucleotides and even to site saturation mutagenesis by introducing randomized codons. [Copyright &y& Elsevier]

Improving the electrocatalytic performance of MOF materials has attracted great attention, among which more efforts have been devoted to introduce different transition metal elements to improve the performance of MOFs. However, the introduction of non-metallic elements is often overlooked. Herein, we have synthesized three new isostructural 2D polyhalogenated Co-MOFs [Co(X 4 -pta)(bpy)(H 2 O) 2 n (X 4 -H 2 pta = tetrahalogenphthalic acid, X = F, Cl and Br, bpy = 4,4′-dipyridyl). To explore the influence of different halogen substituted isostructural Co(II)-based MOFs on electrochemical hydrogen evolution reaction (HER). Research shows that HER activity of pure Co–Cl 4 -MOF is distinctly superior to that of the pure Co–Br 4 -MOF and Co–F 4 -MOF. Notably, addition of acetylene black (AB) can improve the conductivity of pure Co-X 4 -MOFs, resulting in enhancing HER performance for the composites in an acidic medium. Among them, the AB&Co–Cl 4 -MOF(3:4) exhibits the best HER performance owing to its smaller overpotential of 283 mV at the current density of 10 mA cm-2, lower Tafel slope of 86mV·dec-1 and a long-term durability with a period of 24 h. The results demonstrate that introducing halogen elements into the MOFs is an efficient strategy for enhanced electrocatalytic HER. The H atoms on the benzene ring of H 2 pta ligand can be modulated by introducing halogens into Co-MOF, causing the expedited electrochemical hydrogen evolution reaction (HER). Research shows that HER activity of pure Co–Cl 4 -MOF is distinctly superior to that of the pure Co–Br 4 -MOF and Co–F 4 -MOF. Image 1 • Three new isostructural 2D polyhalogenated Co(II)-based MOFs has been constructed from mixed ligands. • The halogen elements are introduced into the cobalt-based catalyst, it has some positive effect on catalysis. • The MOF containing chlorine with high electronegativity showed higher HER activity than bromine. [ABSTRACT FROM AUTHOR]

Herein, we designed a metal-coordinated carrier-free nanodrug (USFe3+LA NPs) with near sphere shape by co-assembling of UA, SRF, Fe3+, low molecular weight protamine (LMWP), and epithelial cell adhesion molecule (EpCAM) aptamer via a facile self-assembly method to improve the efficacy of chemotherapy monotherapy and achieve synergistic therapy. USFe3+LA NPs could inhibit tumor metastasis by inhibiting the intercellular adhesion molecule-1 (ICAM-1) and vascular endothelial growth factor (VEGF) expression. In addition, USFe3+LA NPs could enhance immune response and sensitize tumors to immune checkpoint inhibitors PD-L1 antibody. It was demonstrated that USFe3+LA NPs significantly inhibited tumor growth and metastasis, showing that this nano-delivery system synergistically enhanced its anti-tumor effect. These nanodrugs will provide a new strategy for combined chemotherapy, CDT, ferroptosis, and immunotherapy. [Display omitted] The heterogeneity of hepatocellular carcinoma (HCC) and the complexity of the tumor microenvironment (TME) pose challenges to efficient drug delivery and the antitumor efficacy of combined or synergistic therapies. Herein, a metal-coordinated carrier-free nanodrug (named as USFe3+ LA NPs) was developed for ferroptosis-mediated multimodal synergistic anti-HCC. Natural product ursolic acid (UA) was incorporated to enhance the sensitivity of tumor cells to sorafenib (SRF). Surface decoration of cell penetration peptide and epithelial cell adhesion molecule aptamer facilitated the uptake of USFe3+ LA NPs by HepG2 cells. Meanwhile, Fe3+ ions could react with intracellular hydrogen peroxide, generating toxic hydroxyl radical (·OH) for chemodynamical therapy (CDT) and amplified ferroptosis by cystine/glutamate antiporter system (System X c −), which promoted the consumption of glutathione (GSH) and inhibited the expression of glutathione peroxidase 4 (GPX4). Notably, these all-in-one nanodrugs could inhibit tumor metastasis and induced immunogenic cell death (ICD). Last but not least, the nanodrugs demonstrated favorable biocompatibility, augmenting the immune response against the programmed death-ligand 1 (PD-L1) by increasing cytotoxic T cell infiltration. In vivo studies revealed significant suppression of tumor growth and distant metastasis. Overall, our work introduced a novel strategy for applications of metal-coordinated co-assembled carrier-free nano-delivery system in HCC combination therapy, especially in the realms of cancer metastasis prevention and immunotherapy. [ABSTRACT FROM AUTHOR]

[Display omitted] The effectiveness of chemotherapeutic agents for hepatocellular carcinoma (HCC) is unsatisfactory because of tumor heterogeneity, multidrug resistance, and poor target accumulation. Therefore, multimodality-treatment with accurate drug delivery has become increasingly popular. Herein, a cell penetrating peptide-aptamer dual modified-nanocomposite (USILA NPs) was successfully constructed by coating a cell penetrating peptide and aptamer onto the surface of sorafenib (Sora), ursolic acid (UA) and indocyanine green (ICG) condensed nanodrug (USI NPs) via one-pot assembly for targeted and synergistic HCC treatment. USILA NPs showed higher cellular uptake and cytotoxicity in HepG2 and H22 cells, with a high expression of epithelial cell adhesion molecule (EpCAM). Furthermore, these NPs caused more significant mitochondrial membrane potential reduction and cell apoptosis. These NPs could selectively accumulate at the tumor site of H22 tumor-bearing mice and were detected with the help of ICG fluorescence; moreover, they retarded tumor growth better than monotherapy. Thus, USILA NPs can realize the targeted delivery of dual drugs and the integration of diagnosis and treatment. Moreover, the effects were more significant after co-administration of iRGD peptide, a tumor-penetrating peptide with better penetration promoting ability or programmed cell death ligand 1 (PD-L1) antibody for the reversal of the immunosuppressive state in the tumor microenvironment. The tumor inhibition rates of USILA NPs + iRGD peptide or USILA NPs + PD-L1 antibody with good therapeutic safety were 72.38 % and 67.91 % compared with control, respectively. Overall, this composite nanosystem could act as a promising targeted tool and provide an effective intervention strategy for enhanced HCC synergistic treatment. [ABSTRACT FROM AUTHOR]

[Display omitted] Tumor microenvironment (TME) stimuli-responsive nanoassemblies are emerging as promising drug delivery systems (DDSs), which acquire controlled release by structural transformation under exogenous stimulation. However, the design of smart stimuli-responsive nanoplatforms integrated with nanomaterials to achieve complete tumor ablation remains challenging. Therefore, it is of utmost importance to develop TME-based stimuli-responsive DDSs to enhance drug-targeted delivery and release at tumor sites. Herein, we proposed an appealing strategy to construct fluorescence-mediated TME stimulus-responsive nanoplatforms for synergistic cancer therapy by assembling photosensitizers (PSs) carbon dots (CDs), chemotherapeutic agent ursolic acid (UA), and copper ions (Cu2+). First, UA nanoparticles (UA NPs) were prepared by self-assembly of UA, then UA NPs were assembled with CDs via hydrogen bonding force to obtain UC NPs. After combining with Cu2+, the resulting particles (named UCCu2+ NPs) exhibited quenched fluorescence and photosensitization due to the aggregation of UC NPs. Upon entering the tumor tissue, the photodynamic therapy (PDT) and the fluorescence function of UCCu2+ were recovered in response to TME stimulation. The introduction of Cu2+ triggered the charge reversal of UCCu2+ NPs, thereby promoting lysosomal escape. Furthermore, Cu2+ resulted in additional chemodynamic therapy (CDT) capacity by reacting with hydrogen peroxide (H 2 O 2) as well as by consuming glutathione (GSH) in cancer cells through a redox reaction, hence magnifying intracellular oxidative stress and enhancing the therapeutic efficacy due to reactive oxygen species (ROS) therapy. In summary, UCCu2+ NPs provided an unprecedented novel approach for improving the therapeutic efficacy through the three-pronged (chemotherapy, phototherapy, and heat-reinforced CDT) attacks to achieve synergistic therapy. [ABSTRACT FROM AUTHOR]

Diabetic nephropathy (DN) is one of the most important complications of diabetes mellitus (DM) and has become the second cause of end-stage renal disease (ESRD). This study intends to investigate the molecular mechanism of increased mitochondrial fission in podocytes under the effect of high glucose (HG), and to preliminarily study the role of mitochondrial fission factor (MFF)-mediated mitochondrial fission in podocyte injury of DN. In vitro studies, we found that HG induced increased mitochondrial fission and podocyte damage. At the same time MFF mRNA and protein levels was increased, suggesting that MFF was transcriptional upregulated under HG conditions. Consistent with this, in vivo studies found that mitochondrial fission was also significantly increased in podocytes of diabetic nephropathy mice, and MFF expression was up-regulated. Therefore, our study proves that mitochondrial fission increases in podocytes under DM both in vitro and in vivo, and the up-regulation of MFF expression may be one of the reasons for the increase of mitochondrial fission. After inhibiting the expression of MFF, the survival rate of podocytes was significantly decreased under HG conditions, suggesting that MFF may play a protective role in podocyte injury in DN. • High glucose stimulation caused podocyte damage and increased mitochondrial fission. • The expression of mitochondrial fission factor was significantly up-regulated after high glucose stimulation. • Mitochondrial fission factor was protective against high glucose-stimulated podocytes. [ABSTRACT FROM AUTHOR]

Abstract: Ischaemia leads to increased proliferation of progenitors in the subependymal zone (SEZ) neurogenic niche of the adult brain and to generation and migration of newborn neurons. Here we investigated the spatiotemporal characteristics of the mitotic activity of adult neural stem and progenitor cells in the SEZ during the sub-acute and chronic post-ischaemic phases. Ischaemia was induced by performing a 1h unilateral middle cerebral artery occlusion (MCAO) and tissue was collected 4/5weeks and 1year after the insult. Neural stem cells (NSCs) responded differently from their downstream progenitors to MCAO, with NSCs being activated only transiently whilst progenitors remain activated even at 1year post-injury. Importantly, mitotic activation was observed only in the affected areas of the niche and specifically in the dorsal half of the SEZ. Analysis of the topography of mitoses, in relation to the anatomy of the lesion and to the position of ependymal cells and blood vessels, suggested an interplay between lesion-derived recruiting signals and the local signals that normally control proliferation in the chronic post-ischaemic phase. [Copyright &y& Elsevier]

• The first meta-analysis of risk factors for anxiety for PWE. • Identified several factors associated with an increased risk of anxiety in PWE. • Further prospective cohort studies are needed to investigate risk factors of anxiety in PWE to help improve quality of life. Epilepsy is a very common neurological disease, and it is important to focus on both controlling seizures and alleviating the psychological problems associated with this disease.Anxiety is an important risk factor for epilepsy and seriously affects the quality of life of patients with epilepsy (PWE). However, several risk factors for anxiety in PWE are relatively controversial and understudied. This meta-analysis was performed to identify potential risk factors for anxiety in PWE with the aim of reducing the incidence of anxiety and improving the quality of life among the individuals. The PubMed, Embase and Cochrane Library databases were systematically searched up to July 2023 to find eligible original English studies. All the search results were reviewed based on our inclusion and exclusion criteria. We calculated the combined odds ratios (ORs), standard mean differences (SMDs) and their corresponding 95% confidence intervals (CIs) to evaluate the effect of the included risk factors on anxiety in PWE. Twenty-four studies involving 5,403 PWE were ultimately included. The pooled results of our meta-analysis showed that female sex (OR = 1.67; 95 % CI: 1.30,2.15; p < 0.001), unmarried/divorced/widowed (OR = 0.83; 95 % CI: 0.72,0.96; p = 0.011), low socioeconomic status (OR = 0.47; 95 % CI: 0.33,0.67; p < 0.001), education levels below high school (OR = 1.74; 95 % CI: 1.36,2.23; p < 0.001), a history of trauma (OR = 2.53; 95 % CI: 1.69,3.78; p < 0.001), monotherapy (OR = 0.49; 95 % CI: 0.39,0.62; p < 0.001), AED-induced psychiatric side effects (OR = 2.45; 95 % CI: 1.20,4.98); p = 0.014), depression (OR = 5.45 95 % CI: 2.49,11.94; p < 0.001), a history of suicide (OR = 3.56; 95 % CI: 1.72,7.38; p = 0.001), and illness-related shame (OR = 2.76; 95 % CI: 2.17,3.52; p < 0.001) were risk factors for anxiety. This meta-analysis showed that female, unmarried, low socioeconomic status, education level below senior high school, a history of trauma, monotherapy, AED-induced psychiatric side effects, depression, a history of suicide, and shame were risk factors for anxiety in PWE. However, further research is needed to determine the effect of other potential risk factors on anxiety in PWE. In addition, most of the studies included in this meta-analysis were not uniform in scale, and the risk factors were not comprehensive; therefore, larger prospective studies in different countries are needed to further investigate these risk factors. [ABSTRACT FROM AUTHOR]

Abstract: The cDNA of goose interferon-α (goIFN-α) was amplified from PHA stimulated PBMCs of goose by RT-PCR. The cDNA encodes a 30-amino acid signal peptide and a 161-amino acid mature protein, respectively. Recombinant mature goIFN-α (rgoIFN-α) expressed by prokaryotic and eukaryotic system possessed antiviral activity that was neutralized by rabbit anti-rgoIFN-α antibody in vitro. On the other hand, rgoIFN-α lacks intrinsic macrophage activating factor (MAF) activity, peripheral blood leukocyte-derived macrophages (PBLMs) could not produce nitric oxide (NO) by stimulate with rgoIFN-α as compared to stimulate with recombinant mature goIFN-γ (rgoIFN-γ) that was a powerful NO stimulant in vitro. [Copyright &y& Elsevier]

Abstract: Vezf1 is an early development gene that encodes a zinc finger transcription factor. In the developing embryo, Vezf1 is expressed in the yolk sac mesoderm and the endothelium of the developing vasculature and, in addition, in mesodermal and neuronal tissues. Targeted inactivation of Vezf1 in mice reveals that it acts in a closely regulated, dose-dependent fashion on the development of the blood vascular and lymphatic system. Homozygous mutant embryos display vascular remodeling defects and loss of vascular integrity leading to localized hemorrhaging. Ultrastructural analysis shows defective endothelial cell adhesion and tight junction formation in the mutant vessels. Moreover, in heterozygous embryos, haploinsufficiency is observed that is characterized by lymphatic hypervascularization associated with hemorrhaging and edema in the jugular region; a phenotype reminiscent of the human congenital lymphatic malformation syndrome cystic hygroma. [Copyright &y& Elsevier]

Glioma is one of the most malignant tumors worldwide. This study was aimed to study the effect of miR-379–5p/MGST1 on cell proliferation, migration, invasion and EMT in glioma. RT-qPCR detected the expression of miR-379–5p and MGST1 in RNA level in glioma cell lines. Bioinformatic analysis was made to explore the associations between miR-379–5p and MGST1 while survival analysis was made with regards to MGST1 expression in glioma patients. Western blot analysis was applied to measure the EMT changes. MTT examined the cell viability. Transwell was used to detect the cellular invasion and migration. The binding sites between miR-379–5p and MGST1 were validated by luciferase reporter assays. miR-379–5p expression was lower in glioma cells. MiR-379–5p increase inhibited the viability, migration, invasion and EMT while inhibition of miR-379–5p showed a reverse effect. MGST1 inhibition curbed the cell functions. MiR-379–5p targeted and regulated MGST1 expression. Lower MGST1 is related to higher survival rate. miR-379–5p could regulate glioma cell viability, migration, invasion and EMT through MGST1, suggesting that miR-379–5p/MGST1 axis might function in the regulation of glioma progression. • MiR-379–5p was down-regulated in glioma tissues and cell lines. • Upregulation of miR-379–5p inhibited the viability, migration and invasion of U87 and U251 cells. • MGST1 was targeted and mediated by miR-379–5p in glioma cells. • MGST1 downregulation was associated with higher survival rate in GBM patients. • MGST1 could restore the cell viability, migration, invasion inhibited by miR-379–5p. [ABSTRACT FROM AUTHOR]

• Valproic acid (VPA)-induced encephalopathy is a rare but serious complication of VPA therapy. • Valproic acid-induced encephalopathy is associated with hyperammonemia and carnitine deficiency. • In EEG, a burst suppression pattern is seen VPA-induced encephalopathy, resembling severe encephalopathy. • VPA-induced encephalopathy is treated by VPA discontinuation, L-carnitine supplementation, and extracorporeal treatment. Valproic acid (VPA), or sodium valproate, is a commonly used medication for seizure disorders, migraines, and mental illness. Although VPA is relatively safe, it still has several adverse effects; among these, VPA-induced encephalopathy is the most serious. Valproic acid-induced encephalopathy mainly manifests as acute or subacute encephalopathy and has been associated with hyperammonemia, L-carnitine deficiency, and urea cycle enzyme dysfunction. Delayed identification of VPA-induced encephalopathy could be potentially fatal. Here, we perform an extensive review of relevant literature pertaining to VPA-induced encephalopathy, including its epidemiology, clinical features, possible pathophysiology, risk factors, diagnosis, and treatment. [ABSTRACT FROM AUTHOR]

Primary Hypertriglyceridemia refers to a loss-of-function genetic defect which prevents the triglyceride (TG) in chylomicrons (CM) from lipolysis, leading to the accumulation of TG. The mutation of lipoprotein lipase (LPL) gene has been recognized as the main cause of primary hypertriglyceridemia. Recently, a new LPL gene mutation p.C310R(c. T928C) was identified in a family with hypertriglyceridemia. The proband was manifested by severe hypertriglyceridemia and diabetes. Skeletal muscle is the major LPL-synthesizing tissue and insulin response target tissue. However, little is known about the effects of LPL gene mutation on skeletal muscle. This study is intended to observe the effects of LPL-C310R mutation on glycolipid metabolism and skeletal muscle. We found that a significantly decreased LPL plasma concentration, activity and the expression levels in skeletal muscle were observed in Lpl C310R/+ mice comparing to wild type mice. Those mutant mice also exhibited increased fasting plasma TG, free fat acids (FFA) and insulin, as well as FFA in muscle, and decreased glucose tolerance. Enhanced expression of BIP and elevated phosphorylation of IRE1α were observed in skeletal muscle, suggesting increased endoplasmic reticulum stress (ERS). Consistent with this, increased phosphorylation of JNK was also observed. Meanwhile, remarkably enhanced phosphorylation of IRS-1 (Ser307) and decreased phosphorylation of AKT were observed in skeletal muscle of mutant mice, suggesting impaired insulin signaling. Significant lipid deposition and morphological changes in endoplasmic reticulum and mitochondria were observed in the skeletal muscle of mutant mice but not in wild type control. Results demonstrate Lpl C310R mutation caused impaired glucose tolerance, ER stress and impaired insulin signaling in skeletal muscle. • A new LPL gene mutation p.C310R(c. T928C) was identified in a family with hypertriglyceridemia. • Lpl-C310R knockin led to decrease of LPL concentration in plasma and the expression levels in skeletal muscle. • Lpl-C310R knockin resulted in impaired glucose tolerance, elevated free fatty acid levels in plasma and muscle. • Lpl-C310R knockin caused ER stress and impaired insulin signaling in skeletal muscle. [ABSTRACT FROM AUTHOR]

• During the COVID-19 pandemic, diagnostic and treatment delay is an important issue in epilepsy. • Epilepsy specialists' prescription habits changed during the COVID-19 pandemic. • There are many potential reasons for increased seizure frequency during the COVID-19 pandemic. During the coronavirus disease 2019 (COVID-19) pandemic, the global population experienced changes in diagnosis and treatment patterns. The aim of this study was to evaluate the influence of the COVID-19 pandemic on people with epilepsy (PWE) and epilepsy specialists in China. We retrospectively evaluated newly diagnosed PWE from January 2018 to January 2022 at Shanxi Bethune Hospital. The clinical characteristics of PWE and the prescription habits of epilepsy specialists were analyzed. We also explored changes in seizure control among PWE as a result of the COVID-19 pandemic and assessed the possible causes. After excluding 49 PWE who were lost to follow-up, 421 PWE were included in the study. They were divided into a prepandemic group and a pandemic group, with December 2019 as the boundary. By comparing the two groups, we found that the duration between first symptom detection and diagnosis was longer in the pandemic group than in the prepandemic group. Epilepsy specialists preferred prescribing the fast-acting antiepileptic drug levetiracetam (LEV) in the pandemic group. During the COVID-19 pandemic, 49.57% of PWE reported difficulties in accessing their epilepsy healthcare provider, and 26.96% reported that appointments with their providers occurred as usual. A lack of anti-seizure medication (ASM) availability was reported by 32.17% of subjects. An increase in seizure frequency was noted in 25.22% of the PWE during the pandemic. The factors increasing seizure frequency during the pandemic were fear of COVID-19, exacerbation of mental states, sleep deprivation, cancelation of regular medical visits, difficulties accessing epilepsy healthcare providers, and a lack of ASM availability. The COVID-19 pandemic exposed PWE to harmful consequences mainly due to medical shortages and worse life states. During the pandemic, there were delays in the diagnosis of PWE, and doctors' prescription habits changed. We must consider the lessons learned during this period of social restrictions and employ recent technological advances to improve treatment for PWE. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract Artemisinin (Qinghaosu) and its semi-synthetic derivatives have been demonstrated to alleviate neuroinflammatory response in the central nerve system (CNS). In this review, we summarized that artemisinins are capable to treat neuroinflammtion-related CNS diseases in both direct (via regulating inflammatory process in the CNS, exerting anti-oxidative stress and neuroprotective effect, and preventing Aβ accumulation) and indirect (via maintaining BBB integrity, suppressing systemic inflammation and alleviating intestinal inflammtion) manner. However, the precise mechanism of their anti-neuroinflammatory effects and potential neurotoxicity, which hindered further progress in these aspects, remains unclear. We suggest that further understanding of the PK/PD properties and structure-action relationship of atemisinin and its derivatives will facilitate the development of new therapeutics with better curative effects and safety. [ABSTRACT FROM AUTHOR]

The remarkable regenerative capacity of the zebrafish has made it an important model organism for studying heart regeneration. However, current loss-of-function studies are limited by a lack of conditional-knockout and effective gene-knockdown methods for the adult heart. Here, we report a novel siRNA knockdown method facilitated by poly(ethylene glycol)-b-poly( d , l -lactide) (PEG–PLA) nanoparticles. The siRNA-encapsulated nanoparticles successfully entered cells and resulted in remarkable gene-specific knockdown in the adult heart. This effect was demonstrated by down-regulation of the Aldh1a2 and Dusp6 proteins after intrapleural delivery of nanoparticle-encapsulated siRNAs. Furthermore, siRNA-mediated knockdown of Aldh1a2 was sufficient to inhibit myocardial proliferation and decrease the numbers of Gata4-positive cardiomyocytes after ventricular resection. Therefore, the results of this work demonstrate that nanoparticle-facilitated siRNA delivery provides an alternative tool for loss-of-function studies of genes in the adult heart in particular and other organs in general in the adult zebrafish. [ABSTRACT FROM AUTHOR]

Marek׳s disease virus (MDV) is a representative alpha herpes virus able to induce rapid-onset T-cell lymphoma in its natural host and regarded as an ideal model for the study of virus-induced tumorigenesis. Recent studies have shown that the mdv1-miR-M4-5p, a viral analog of cellular miR-155, is critical for MDV׳s oncogenicity. However, the precise mechanism whereby it was involved in MD lymphomagenesis remained unknown. We have presently identified the host mRNA targets of mdv1-miR-M4-5 and identified the latent TGF-β binding protein 1 (LTBP1) as a critical target for it. We found that during MDV infection, down-regulation of LTBP1 expression by mdv1-miR-M4-5p led to a significant decrease of the secretion and activation of TGF-β1, with suppression of TGF-β signaling and a significant activation of expression of c-Myc, a well-known oncogene which is critical for virus-induced tumorigenesis. Our findings reveal a novel and important mechanism of how mdv1-miR-M4-5p potentially contributes to MDV-induced tumorigenesis. [ABSTRACT FROM AUTHOR]

Abstract: Inflammation is an important contributing mechanism in ischemic brain injury. The current study elucidates a previously unexplored role of Fas ligand (FasL) in post-stroke inflammatory responses that is independent of its well-known effect in triggering apoptosis. Focal cerebral ischemia was induced for 2h by right middle cerebral artery occlusion (MCAO) in FasL mutant (gld) and wild-type mice. FasL mutation profoundly reduced brain damage and improved neurological performance from 6 to 72h after ischemic stroke. The production of inflammatory cytokines in the brain was attenuated in gld mice after ischemia in the absence of dramatic change in inflammatory cell apoptosis. FasL mutation attenuated the recruitment of peripheral inflammatory cells (neutrophil) and inhibited the activation of residential glial cells (microglia and astrocyte). FasL mutation reduced CD8+ T cells and turned the Th1/Th2 balance towards Th2 in the brain and peripheral blood after cerebral ischemia. In contrast to cerebral ischemia, the molecular and cellular inflammatory changes induced by intracerebroventricular injection of lipopolysaccharide (LPS) were also attenuated in gld mice. Moreover, the soluble FasL (sFasL) and phospho-SAPK/JNK were decreased in gld mice, suggesting that the inflammatory role of FasL in experimental stroke might relate to sFasL and the c-Jun N-terminal kinase (JNK) signaling pathway. Taken together, our data suggest a novel role of FasL in the damaging inflammatory responses associated with cerebral ischemia. Neutralization of FasL may be a novel therapeutic strategy to suppress post-stroke inflammation and improve the long-term outcomes of stroke. [Copyright &y& Elsevier]

Abstract: The molecular mass of the polysaccharide hyaluronan (HA) is an important determinant of its biological activity and physicochemical properties. One method currently used for the analysis of the molecular mass distribution of an HA sample is gel electrophoresis. In the current work, an improved agarose gel electrophoresis method for analysis of high molecular mass HA is presented and validated. HA mobility in 0.5% agarose minigels was found to be linearly related to the logarithm of molecular mass in the range from approximately 200 to 6000kDa. A sample load of 2.5μg for polydisperse HA samples was employed. Densitometric scanning of stained gels allowed analysis of the range of molecular masses present in the sample as well as calculation of weight-average and number-average values. The method was validated for a polydisperse HA sample with a weight-average molecular mass of approximately 2000kDa. Excellent agreement was found between the weight-average molecular mass determined by electrophoresis and that determined by rheological measurement of the solution viscosity. The revised method was then used to show that heating solutions of HA at 100°C, followed by various cooling procedures, had no effect on the HA molecular mass distribution. [Copyright &y& Elsevier]

The effect of vagus nerve stimulation (VNS), an important auxiliary therapy for treating drug-resistant epilepsy (DRE), on autonomic nerve function is still controversial. Heart rate variability is a widely used indicator of autonomic nerve function. To clarify the relationship between VNS and heart rate variability (HRV), we performed a meta-analysis to systematically evaluate the effect of VNS on HRV in patients with epilepsy. We performed a systematic review by searching the following online databases: PubMed, Web of Science, EMBASE and the Cochrane Library. The key search terms were "vagal nerve stimulation," "epilepsy" and "heart rate variability". Other features of VNS in patients with epilepsy include postoperative changes in low-frequency (LF), high-frequency (HF) and low-frequency/high-frequency (LF/HF) heart rate variability, which were used as evaluation indices, and the Newcastle-Ottawa Quality Assessment Scale and Stata 14.0 statistical software were used for literature quality evaluation and meta-analysis. Twelve studies published in English were obtained, and 229 patients with epilepsy who underwent VNS were ultimately included after elimination of duplicate articles and those that did not meet the inclusion criteria. Regarding LF heart rate variability, in the response subgroup, patients with DRE with VNS presented a lower value (-0.58) before surgery than after surgery, with a 95% confidence interval (CI) ranging from −1.00 to −0.15. For HF heart rate variability, patients with DRE with VNS had a lower value (-0.45) before surgery than after surgery in the response subgroup, with a 95% CI ranging from −0.74 to −0.17. No differences were found for LF/HF values or the LF and HF values of other subgroups. VNS has little effect on the balance of sympathetic and parasympathetic nerve activity and would not be expected to cause cardiovascular autonomic dysfunction in patients with DRE. For patients with DRE, VNS can control seizures and has little effect on autonomic nervous function. [ABSTRACT FROM AUTHOR]

Abstract: For the proper development of vertebrate embryos as well as for survival of the adult organism, it is essential to form a functional vascular system. Molecules involved in this process are members of highly conserved families of proteins that exert conserved functions across species. Bone morphogenetic proteins (BMP) are extracellular factors that are regulated by extracellular modulators and bind to BMP receptors, which in turn activate intracellular signaling cascades. BMPs are necessary not only for induction of endothelial and hematopoietic lineages but also for further endothelial and hematopoietic cell differentiation. Previously, we identified BMPER (BMP endothelial cell precursor derived regulator) and demonstrated its spatiotemporal expression at sites of vasculogenesis and direct modulation of BMP activity. To directly investigate the role of BMPER in vascular development, we cloned the BMPER ortholog in zebrafish (zbmper). It is expressed at sites of high BMP activity, including vascular precursor cells located in the aortic arches and the intermediate cell mass during zebrafish embryonic development. Knockdown of zbmper results in a dorsalized phenotype, a reduced number of gata1 expressing hematopoietic precursor cells and of circulating blood cells as well as in a vascular phenotype. The generation of the caudal vein is compromised and the pattern guiding of the intersomitic vessels is disturbed, indicating that zbmper is required for early steps in vascular pattern formation and hematopoiesis in zebrafish. [Copyright &y& Elsevier]

Thrombosis initiated by abnormal platelet aggregation is a pivotal pathological event that precedes most cases of cardiovascular diseases (CVD). Recently, growing evidence indicates that platelet could be a potential target for CVD prevention. However, as the conventional antithrombotic management strategy, applications of current antiplatelet agents are somewhat limited by their various side effects, such as bleeding risk and drug resistance. Hence, efforts have been made to search for agents as complementary therapies. Ginsenoside, the principal active component extracted from Panax ginseng , has gained much attention for its regulations on multiple crucial events of platelet aggregation. From structural characteristics to clinical applications, this review anatomized the intrinsic structure-function relationship of antiplatelet potency of ginsenosides, and the involved signal pathways were specifically summarized. Additionally, the emphasis was placed on clinical studies that investigate the antithrombotic efficacy of ginsenosides in the treatment of CVD. Further, a broad overview of approaches for improving the bioavailability of ginsenosides was concluded. Limitations and prospects of current studies were also discussed. This study may provide some new insights into the systematic understanding of ginsenosides in CVD treatment and lay a foundation for future research. [ABSTRACT FROM AUTHOR]

• Homoerythrina alkaloid derivatives bearing a triazole moiety as PARP-1 inhibitors have been synthesized. • Compound 10n exhibited the most potent activity against A549 cells. • Compound 10n was intrinsic apoptosis induced by cell cycle arrest in the S phase. A series of homoerythrina alkaloid derivatives containing a 1,2,3-triazole moiety as PARP-1 inhibitors were designed and synthesized. And their anti-proliferative activity was further evaluated. Compound 10n had excellent activity to inhibit proliferation of A549 cells (IC 50 = 1.89 μM), which was higher than harringtonine (IC 50 = 10.55 μM), pemetrexed (IC 50 = 3.39 μM), and rucaparib (IC 50 = 4.91 μM). Furthermore, the selectivity index of compound 10n was higher than rucaparib and pemetrexed for lung cancer cells. Flow cytometry analysis showed that compound 10n significantly arrested the cell cycle in the S phase, then induced apoptosis of A549 cells (apoptosis rate is 46%), which effectively inhibited cell proliferation. Simultaneously, western blot analysis revealed that compound 10n could prevent the biosynthesis of PAR. Further analysis results revealed that compound 10n could inhibit the expression of cyclin A, down-regulate the expression of bcl-2/bax, activate caspase-3, and ultimately induce apoptosis of A549 cells. All the results indicated that compound 10n had potential research value as a novel PARP-1 inhibitor in antitumor, and it provided a new reference for further development of PARP-1 inhibitors. [ABSTRACT FROM AUTHOR]