A novel fully human anti-NT-ANGPTL3 antibody from phage display library exhibits potent ApoB, TG, and LDL-C lowering activities in hyperlipidemia mice.

Dyslipidemia is characterized by elevated plasma levels of low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), and TG-rich lipoprotein (TGRLs) in circulation, and is closely associated with the incidence and development of cardiovascular disease. Angiopoietin-like protein 3 (ANGPTL3) deficiency has been identified as a cause of familial combined hypolipidemia in humans, which allows it to be an important therapeutic target for reducing plasma lipids. Here, we report the discovery and characterization of a novel fully human antibody F1519-D95aA against N-terminal ANGPTL3 (NT-ANGPTL3), which potently inhibits NT-ANGPTL3 with a KD as low as 9.21 nM. In hyperlipidemic mice, F1519-D95aA shows higher apolipoprotein B (ApoB) and TG-lowering, and similar LDL-C reducing activity as compared to positive control Evinacumab (56.50% vs 26.01% decrease in serum ApoB levels, 30.84% vs 25.28% decrease in serum TG levels, 23.32% vs 22.52% decrease in serum LDLC levels, relative to vehicle group). Molecular docking and binding energy calculations reveal that the F1519-D95aA-ANGPTL3 complex (10 hydrogen bonds, -65.51 kcal/mol) is more stable than the Evinacumab-ANGPTL3 complex (4 hydrogen bonds, -63.76 kcal/mol). Importantly, F1519-D95aA binds to ANGPTL3 with different residues in ANGPTL3 from Evinacumab, suggesting that F1519-D95aA may be useful for the treatment of patients resistant to Evinacumab. In conclusion, F1519-D95aA is a novel fully human anti-NT-ANGPTL3 antibody with potent plasma ApoB, TG, and LDL-C lowering activities, which can potentially serve as a therapeutic agent for hyperlipidemia and relevant cardiovascular diseases.

Evidence of a large current of transcranial alternating current stimulation directly to deep brain regions.

Deep brain regions such as hippocampus, insula, and amygdala are involved in neuropsychiatric disorders, including chronic insomnia and depression. Our recent reports showed that transcranial alternating current stimulation (tACS) with a current of 15 mA and a frequency of 77.5 Hz, delivered through a montage of the forehead and both mastoids was safe and effective in intervening chronic insomnia and depression over 8 weeks. However, there is no physical evidence to support whether a large alternating current of 15 mA in tACS can send electrical currents to deep brain tissue in awake humans. Here, we directly recorded local field potentials (LFPs) in the hippocampus, insula and amygdala at different current strengths (1 to 15 mA) in 11 adult patients with drug-resistant epilepsy implanted with stereoelectroencephalography (SEEG) electrodes who received tACS at 77.5 Hz from 1 mA to 15 mA at 77.5 Hz for five minutes at each current for a total of 40 min. For the current of 15 mA at 77.5 Hz, additional 55 min were applied to add up a total of 60 min. Linear regression analysis revealed that the average LFPs for the remaining contacts on both sides of the hippocampus, insula, and amygdala of each patient were statistically associated with the given currents in each patient (p < 0.05-0.01), except for the left insula of one subject (p = 0.053). Alternating currents greater than 7 mA were required to produce significant differences in LFPs in the three brain regions compared to LFPs at 0 mA (p < 0.05). The differences remained significant after adjusting for multiple comparisons (p < 0.05). Our study provides direct evidence that the specific tACS procedures are capable of delivering electrical currents to deep brain tissues, opening a realistic avenue for modulating or treating neuropsychiatric disorders associated with hippocampus, insula, and amygdala.

Synthesis of Dihydroquinoxalinones from Biomass-Derived Keto Acids and o-Phenylenediamines.

A novel catalyst-free cascade amination/cyclization/reduction reaction was developed for the synthesis of various Dihydroquinoxalinones under mild conditions from accessible biomass-derived keto acids and 1,2-phenylenediamines with ammonia borane as a hydrogen donor. This single-step approach enables a simple and eco-friendly route toward the direct synthesis of 12 kinds of Dihydroquinoxalinones in moderate to excellent yields in the green solvent dimethyl carbonate. The results of deuterium-labeling experiments and density function calculations demonstrate that the reductive process proceeds along a double hydrogen transfer pathway. An acceptable yield of Dihydroquinoxalinone can be afforded in a gram-scale experiment, illustrating the practicality of the as-reported reaction system.

Discovery of novel cGAS inhibitors based on natural flavonoids.

Cyclic GMP-AMP synthase (cGAS) plays an important role in the inflammatory response. It has been reported that aberrant activation of cGAS is associated with a variety of immune-mediated inflammatory disorders. The development of small molecule inhibitors of cGAS has been considered as a promising therapeutic strategy for the diseases. Flavonoids, a typical class of natural products, are known for their anti-inflammatory activities. Although cGAS is closely associated with inflammation, the potential effects of natural flavonoid compounds on cGAS have been rarely studied. Therefore, we screened an in-house natural flavonoid library by pyrophosphatase (PPiase) coupling assay and identified novel cGAS inhibitors baicalein and baicalin. Subsequently, crystal structures of the two natural flavonoids in complex with human cGAS were determined, which provide mechanistic insight into the anti-inflammatory activities of baicalein and baicalin at the molecular level. After that, a virtual screening based on the crystal structures of baicalein and baicalin in complex with human cGAS was performed. As a result, compound C20 was identified to inhibit both human and mouse cGAS with IC50 values of 2.28 and 1.44 µM, respectively, and its detailed interactions with human cGAS were further revealed by the X-ray crystal structure determination. These results demonstrate the potential of natural products used as hits in drug discovery and provide valuable hints for further development of cGAS inhibitors.

Real-Time Segmentation of Unstructured Environments by Combining Domain Generalization and Attention Mechanisms.

This paper presents a focused investigation into real-time segmentation in unstructured environments, a crucial aspect for enabling autonomous navigation in off-road robots. To address this challenge, an improved variant of the DDRNet23-slim model is proposed, which includes a lightweight network architecture and reclassifies ten different categories, including drivable roads, trees, high vegetation, obstacles, and buildings, based on the RUGD dataset. The model's design includes the integration of the semantic-aware normalization and semantic-aware whitening (SAN-SAW) module into the main network to improve generalization ability beyond the visible domain. The model's segmentation accuracy is improved through the fusion of channel attention and spatial attention mechanisms in the low-resolution branch to enhance its ability to capture fine details in complex scenes. Additionally, to tackle the issue of category imbalance in unstructured scene datasets, a rare class sampling strategy (RCS) is employed to mitigate the negative impact of low segmentation accuracy for rare classes on the overall performance of the model. Experimental results demonstrate that the improved model achieves a significant 14% increase mIoU in the invisible domain, indicating its strong generalization ability. With a parameter count of only 5.79M, the model achieves mAcc of 85.21% and mIoU of 77.75%. The model has been successfully deployed on a a Jetson Xavier NX ROS robot and tested in both real and simulated orchard environments. Speed optimization using TensorRT increased the segmentation speed to 30.17 FPS. The proposed model strikes a desirable balance between inference speed and accuracy and has good domain migration ability, making it applicable in various domains such as forestry rescue and intelligent agricultural orchard harvesting.

Underwater image enhancement using adaptive color restoration and dehazing.

Underwater images captured by optical cameras can be degraded by light attenuation and scattering, which leads to deteriorated visual image quality. The technique of underwater image enhancement plays an important role in a wide range of subsequent applications such as image segmentation and object detection. To address this issue, we propose an underwater image enhancement framework which consists of an adaptive color restoration module and a haze-line based dehazing module. First, we employ an adaptive color restoration method to compensate the deteriorated color channels and restore the colors. The color restoration module consists of three steps: background light estimation, color recognition, and color compensation. The background light estimation determines the image is blueish or greenish, and the compensation is applied in red-green or red-blue channels. Second, the haze-line technique is employed to remove the haze and enhance the image details. Experimental results show that the proposed method can restore the color and remove the haze at the same time, and it also outperforms several state-of-the-art methods on three publicly available datasets. Moreover, experiments on an underwater object detection dataset show that the proposed underwater image enhancement method is able to improve the accuracy of the subsequent underwater object detection framework.

Effects of Alprostadil Combined with Edaravone on Inflammation, Oxidative Stress and Pulmonary Function in Patients with Traumatic Hemorrhagic Shock.

The study aimed to explore the roles of alprostadil combined with edaravone in inflammation, oxidative stress and Pulmonary function in patients with traumatic hemorrhagic shock (HS). 80 patients with traumatic HS treated in Feicheng Hospital Affiliated to Shandong First Medical University and Tai'an City Central Hospital from January 2018 to January 2022 were enrolled and divided into observation group (n=40) and control group (n=40) according to the randomized control method.  Patients in the control group were given alprostadil alone (5 g alprostadil + 10 mL normal saline) in addition to conventional treatment, while those in the observation group received edaravone (30 mg edaravone + 250 mL normal saline) on the basis of treatment in the control group. The patients in both groups were treated via intravenous infusion once a day for 5 days. 24 hours (h) after resuscitation, venous blood were collected to detect serum biochemical indicators such as blood urea nitrogen (BUN), aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Enzyme-linked immunosorbent assay (ELISA) was conducted to determine serum inflammatory factors. Lung lavage fluid was collected to examine pulmonaryfunction indicators such as myeloperoxidase (MPO) and matrix metalloproteinase-9 (MMP-9) activity and to observe the oxygenation index (OI). Blood pressure was measured at admission and 24 h after surgery. The observation group had significantly lowered serum BUN, AST and ALT (p<0.05), the content of serum interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) as well as oxidative stress indexes like superoxide dismutase (SOD) and malondialdehyde (MDA) (p<0.05) and pulmonary function indicators (p<0.05) but overtly increased content of SOD and OI. Furthermore, the blood pressure in the observation group dropped to 30 mmHg at admission and rose to the normal range. Alprostadil combined with edaravone effectively reduces inflammatory factors and improves oxidative stress and pulmonary function in patients with traumatic HS, whose efficacy is significantly better than that of alprostadil alone.

Identification of Cysteine 270 as a Novel Site for Allosteric Modulators of SARS-CoV-2 Papain-Like Protease.

The coronavirus papain-like protease (PLpro ) plays an important role in the proteolytic processing of viral polyproteins and the dysregulation of the host immune response, providing a promising therapeutic target. However, the development of inhibitors against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) PLpro is challenging owing to the restricted S1/S2 sites in the substrate binding pocket. Here we report the discovery of two activators of SARS-CoV-2 PLpro and the identification of the unique residue, cysteine 270 (C270), as an allosteric and covalent regulatory site for the activators. This site is also specifically modified by glutathione, resulting in protease activation. Furthermore, a compound was found to allosterically inhibit the protease activity by covalent binding to C270. Together, these results elucidate an unrevealed molecular mechanism for allosteric modulation of SARS-CoV-2 PLpro and provid a novel site for allosteric inhibitors design.

What coronavirus 3C-like protease tells us: From structure, substrate selectivity, to inhibitor design.

The emergence of a variety of coronaviruses (CoVs) in the last decades has posed huge threats to human health. Especially, the ongoing pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to more than 70 million infections and over 1.6 million of deaths worldwide in the past few months. None of the efficacious antiviral agents against human CoVs have been approved yet. 3C-like protease (3CLpro ) is an attractive target for antiviral intervention due to its essential role in processing polyproteins translated from viral RNA, and its conserved structural feature and substrate specificity among CoVs in spite of the sequence variation. This review focuses on all available crystal structures of 12 CoV 3CLpro s and their inhibitors, and intends to provide a comprehensive understanding of this protease from multiple aspects including its structural features, substrate specificity, inhibitor binding modes, and more importantly, to recapitulate the similarity and diversity among different CoV 3CLpro s and the structure-activity relationship of various types of inhibitors. Such an attempt could gain a deep insight into the inhibition mechanisms and drive future structure-based drug discovery targeting 3CLpro s.

Post-COVID-19 Epidemic: Allostatic Load among Medical and Nonmedical Workers in China.

BACKGROUND: As the fight against the COVID-19 epidemic continues, medical workers may have allostatic load. OBJECTIVE: During the reopening of society, medical and nonmedical workers were compared in terms of allostatic load. METHODS: An online study was performed; 3,590 Chinese subjects were analyzed. Socio-demographic variables, allostatic load, stress, abnormal illness behavior, global well-being, mental status, and social support were assessed. RESULTS: There was no difference in allostatic load in medical workers compared to nonmedical workers (15.8 vs. 17.8%; p = 0.22). Multivariate conditional logistic regression revealed that anxiety (OR = 1.24; 95% CI 1.18-1.31; p < 0.01), depression (OR = 1.23; 95% CI 1.17-1.29; p < 0.01), somatization (OR = 1.20; 95% CI 1.14-1.25; p < 0.01), hostility (OR = 1.24; 95% CI 1.18-1.30; p < 0.01), and abnormal illness behavior (OR = 1.49; 95% CI 1.34-1.66; p < 0.01) were positively associated with allostatic load, while objective support (OR = 0.84; 95% CI 0.78-0.89; p < 0.01), subjective support (OR = 0.84; 95% CI 0.80-0.88; p < 0.01), utilization of support (OR = 0.80; 95% CI 0.72-0.88; p < 0.01), social support (OR = 0.90; 95% CI 0.87-0.93; p < 0.01), and global well-being (OR = 0.30; 95% CI 0.22-0.41; p < 0.01) were negatively associated. CONCLUSIONS: In the post-COVID-19 epidemic time, medical and nonmedical workers had similar allostatic load. Psychological distress and abnormal illness behavior were risk factors for it, while social support could relieve it.

Oral multivalent epitope vaccine, based on UreB, HpaA, CAT, and LTB, for prevention and treatment of Helicobacter pylori infection in C57BL / 6 mice.

BACKGROUND: As the resistance of Helicobacter pylori to traditional triple therapy is gradually revealed, an increasing number of people are focusing on vaccine treatments for H. pylori infection. Epitope vaccines are a promising strategy for the treatment of H. pylori infection, and multivalent vaccines will be more effective than monovalent vaccines. MATERIALS AND METHODS: In this study, we designed a multivalent vaccine named LHUC, which consists of the adjuvant LTB as well as three Th cell epitopes (HpaA154-171 , UreB237-251, and UreB546-561 ) and five B-cell epitopes (UreB349-363 , UreB327-334 , CAT394-405 , CAT387-397, and HpaA132-141 ) from UreB, HpaA, and catalase. In BALB/c mice, the specificity and immunogenicity of the fusion peptide LHUC and the neutralization of H. pylori urease and catalase by the specific IgG elicited by LHUC were evaluated. The preventive and therapeutic effects of LHUC were evaluated in C57BL/6 mice infected with H. pylori. RESULTS: The results showed that compared with LTB and PBS, LHUC induced specific IgG and IgA antibody production in mice, and IgG antibodies significantly inhibited the H. pylori urease and catalase activities in vitro. Additionally, by detecting the levels of IFN-γ, IL-4, and IL-17 in lymphocyte supernatants, we proved that LHUC could activate Th1, Th2, and Th17 mixed T-cell immune responses in vivo. Finally, a C57BL/6 mouse model of gastric infection with H. pylori was established. The results showed that compared with the effects of LTB and PBS, the prevention and treatment effects of oral inoculation with LHUC significantly inhibited bacterial colonization. CONCLUSIONS: In conclusion, LHUC, a multivalent vaccine based on multiple H. pylori antigens, is a promising and safe vaccine that can effectively reduce the colonization of H. pylori in the stomach.

Lunasin attenuates oxidant-induced endothelial injury and inhibits atherosclerotic plaque progression in ApoE-/- mice by up-regulating heme oxygenase-1 via PI3K/Akt/Nrf2/ARE pathway.

Oxidative stress-induced vascular endothelial cell (VEC) injury is a major mechanism in the initiation and development of atherosclerosis. Lunasin, a soybean-derived 43-aa peptide, has been previously shown to possess potent antioxidant and anti-inflammatory activities other than its established anticancer activities. This study investigated the effects of lunasin on protecting VECs from oxidative damage and inhibiting atherosclerotic plaque progression in apolipoprotein E-deficient (ApoE-/-) mice and explored its underlying mechanism. Biochemical and histologic analyses were performed by using EA.hy926 human VECs and a high-fat diet (HFD) ApoE-/- mouse atherosclerosis model. Our data indicated that lunasin attenuated H2O2-induced, mitochondria-dependent endothelial apoptosis via down-regulating Bax and up-regulating Bcl-2, inhibiting the mitochondrial depolarization, and reducing the release of cytochrome c, as well as decreasing the activation of caspase-9 and caspase-3 in vitro and in vivo. Mechanic studies showed that lunasin significantly up-regulated heme oxygenase-1 via the PI3K/Akt/nuclear factor erythroid 2-related factor 2/antioxidant response element pathway, and reduced H2O2-induced ROS production in VECs, thereby attenuating oxidant-induced endothelial injury and inhibiting atherosclerotic plaque progression in ApoE-/- mice. In conclusion, our in vitro and in vivo data suggest that lunasin protects VECs from oxidative damage by enhancing heme oxygenase-1 expression via activation of the PI3K/Akt/nuclear factor erythroid 2-related factor 2/antioxidant response element pathway and inhibiting mitochondria-dependent apoptosis, thereby effectively attenuating atherosclerosis in HFD-fed ApoE-/- mice. Lunasin may act as a potential therapeutic agent for the prevention and treatment of atherosclerosis.-Gu, L., Ye, P., Li, H., Wang, Y., Xu, Y., Tian, Q., Lei, G., Zhao, C., Gao, Z., Zhao, W., Tan, S. Lunasin attenuates oxidant-induced endothelial injury and inhibits atherosclerotic plaque progression in ApoE-/- mice by up-regulating heme oxygenase-1 via PI3K/Akt/Nrf2/ARE pathway.

Mental Health and Psychosocial Problems of Medical Health Workers during the COVID-19 Epidemic in China.

OBJECTIVE: We explored whether medical health workers had more psychosocial problems than nonmedical health workers during the COVID-19 outbreak. METHODS: An online survey was run from February 19 to March 6, 2020; a total of 2,182 Chinese subjects participated. Mental health variables were assessed via the Insomnia Severity Index (ISI), the Symptom Check List-revised (SCL-90-R), and the Patient Health Questionnaire-4 (PHQ-4), which included a 2-item anxiety scale and a 2-item depression scale (PHQ-2). RESULTS: Compared with nonmedical health workers (n = 1,255), medical health workers (n = 927) had a higher prevalence of insomnia (38.4 vs. 30.5%, p < 0.01), anxiety (13.0 vs. 8.5%, p < 0.01), depression (12.2 vs. 9.5%; p< 0.04), somatization (1.6 vs. 0.4%; p < 0.01), and obsessive-compulsive symptoms (5.3 vs. 2.2%; p < 0.01). They also had higher total scores of ISI, GAD-2, PHQ-2, and SCL-90-R obsessive-compulsive symptoms (p ≤ 0.01). Among medical health workers, having organic disease was an independent factor for insomnia, anxiety, depression, somatization, and obsessive-compulsive symptoms (p < 0.05 or 0.01). Living in rural areas, being female, and being at risk of contact with COVID-19 patients were the most common risk factors for insomnia, anxiety, obsessive-compulsive symptoms, and depression (p < 0.01 or 0.05). Among nonmedical health workers, having organic disease was a risk factor for insomnia, depression, and obsessive-compulsive symptoms (p < 0.01 or 0.05). CONCLUSIONS: During the COVID-19 outbreak, medical health workers had psychosocial problems and risk factors for developing them. They were in need of attention and recovery programs.

In Silico Screening-Based Discovery of Novel Inhibitors of Human Cyclic GMP-AMP Synthase: A Cross-Validation Study of Molecular Docking and Experimental Testing.

Cyclic GMP-AMP synthase (cGAS) has been recently uncovered to be a promising therapeutic target for immune-associated diseases. Until now, only a few inhibitors have been identified through high-throughput screening campaigns. Here, we reported the discovery of novel inhibitors for the catalytic domain of human cGAS (h-cGASCD) by virtual screening for the first time. To generate a reliable docking mode, we first obtained a high-resolution crystal structure of h-cGASCD in complex with PF-06928215, a known inhibitor of h-cGAS, followed by molecular dynamics simulations on this complex structure. Four fragment hits were identified by the virtual screening together with a thermal shift assay. The crystal structures of these four compounds in complex with h-cGASCD were subsequently determined, and the binding modes of the compounds were similar to those predicted by molecular docking, supporting the reliability of the docking model. In addition, an enzyme activity assay identified compound 18 (IC50 = 29.88 ± 3.20 µM) from the compounds predicted by the virtual screening. A similarity search of compound 18 followed by a second virtual screening led to the discovery of compounds S2 (IC50 = 13.1 ± 0.09 µM) and S3 (IC50 = 4.9 ± 0.26 µM) as h-cGAS inhibitors with improved potency. Therefore, the present study not only provides the validated hit compounds for further development of h-cGAS inhibitors but also demonstrates a cross-validation study of virtual screening, in vitro experimental assays, and crystal structure determination.

Discovery of Ubiquitin-Specific Protease 7 (USP7) Inhibitors with Novel Scaffold Structures by Virtual Screening, Molecular Dynamics Simulation, and Biological Evaluation.

USP7 has been regarded as a potential therapeutic target for cancer. In this study, virtual screening, molecular dynamics (MD) simulation, and biological evaluation have been applied for the discovery of novel USP7 inhibitors targeting the catalytic active site. Among the obtained compounds, compound 12 with a novel scaffold structure exhibited certain USP7 inhibitory activity (Ub-AMC assay IC50 = 18.40 ± 1.75 µM, Ub-Rho assay IC50 = 7.75 µM). The binding affinity between USP7CD (USP7 catalytic domain) and this hit compound was confirmed with a KD value of 4.46 ± 0.86 µM. Preliminary in vitro studies disclosed its antiproliferative activity on human prostate cancer cell line LNCaP with an IC50 value of 15.43 ± 3.49 µM. MD simulation revealed the detailed differences of protein-ligand interactions between USP7CD and the ligands, including the reference compound ALM4 and compound 12, providing some important information for improving the bioactivity of 12. This hit compound will serve as a promising starting point for facilitating the further discovery of novel USP7 inhibitors.

Anti-SARS-CoV-2 activities in vitro of Shuanghuanglian preparations and bioactive ingredients.

Human infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19) and there is no cure currently. The 3CL protease (3CLpro) is a highly conserved protease which is indispensable for CoVs replication, and is a promising target for development of broad-spectrum antiviral drugs. In this study we investigated the anti-SARS-CoV-2 potential of Shuanghuanglian preparation, a Chinese traditional patent medicine with a long history for treating respiratory tract infection in China. We showed that either the oral liquid of Shuanghuanglian, the lyophilized powder of Shuanghuanglian for injection or their bioactive components dose-dependently inhibited SARS-CoV-2 3CLpro as well as the replication of SARS-CoV-2 in Vero E6 cells. Baicalin and baicalein, two ingredients of Shuanghuanglian, were characterized as the first noncovalent, nonpeptidomimetic inhibitors of SARS-CoV-2 3CLpro and exhibited potent antiviral activities in a cell-based system. Remarkably, the binding mode of baicalein with SARS-CoV-2 3CLpro determined by X-ray protein crystallography was distinctly different from those of known 3CLpro inhibitors. Baicalein was productively ensconced in the core of the substrate-binding pocket by interacting with two catalytic residues, the crucial S1/S2 subsites and the oxyanion loop, acting as a "shield" in front of the catalytic dyad to effectively prevent substrate access to the catalytic dyad within the active site. Overall, this study provides an example for exploring the in vitro potency of Chinese traditional patent medicines and effectively identifying bioactive ingredients toward a specific target, and gains evidence supporting the in vivo studies of Shuanghuanglian oral liquid as well as two natural products for COVID-19 treatment.

Hybrid patterns from directed self-assembly of diblock copolymers by chemical patterns.

The surface affinity is a critical factor for controlling the formation of monolayer nanostructures in block copolymer thin films. In general, strong surface affinity tends to induce the formation of domains with low spontaneous curvature. Abiding by this principle, we propose a facile chemoepitaxial scheme for producing large-scale ordered hybrid patterns by the directed self-assembly of diblock copolymers. The guiding chemical pattern is designed as periodic stripes with alternately changing surface affinities. As a consequence, two different geometries of domains are formed on the stripes with different affinities. The self-assembly process of block copolymers guided by the stripe patterns is investigated using cell dynamics simulations based on time-dependent Ginzburg-Landau theory, and the kinetic stability diagram is estimated. Hybrid patterns are successfully achieved with both cylinder-forming and sphere-forming diblock copolymers. In the cylinder-forming system, the major hybrid pattern exhibiting a considerable stability window is composed of parallel cylinders and perforated lamellae, while it is composed of monolayer spheres and parallel cylinders in the other system. Encouragingly, the chemoepitaxial method is valid till the period of the guiding pattern is a large multiple of the domain spacing. The chemoepitaxial scheme demonstrated in this work serves as a nice supplement to the graphoepitaxial one proposed in our previous work.

Hybrid line-dot nanopatterns from directed self-assembly of diblock copolymers by trenches.

We demonstrate that the directed self-assembly of AB diblock copolymers by periodic trenches can be used to fabricate large-scale ordered hybrid line-dot nanopatterns in addition to a defect-free dot nanopattern. The formation of line or dot nanopatterns in thin films with proper surface affinities is controlled by the film thickness, which is modulated by a topographic pattern consisting of steps and trenches. Two kinds of line-dot nanopatterns are achieved with cylinder-forming and sphere-forming copolymers, respectively. One kind of hybrid nanopatterns is composed of perpendicularly standing cylinders (dots) on the steps and parallel monolayer cylinders (lines) within the trenches, while the dots of the other kind are replaced by monolayer spheres on the steps. The thermodynamic stability region of target hybrid nanopatterns is identified by constructing two-dimensional phase diagrams with respect to two control parameters of step height and film thickness using self-consistent field theory. Furthermore, a process window of the line-dot nanopatterns is estimated using cell dynamics simulations based on time-dependent Ginzburg-Landau theory, confirming their feasibility in kinetics.

Surface-projection-based transperineal cognitive fusion targeted biopsy of the prostate: an original technique with a good cancer detection rate.

BACKGROUND: To report a new standardized cognitive fusion technique on transperineal targeted biopsy (TB) of prostate, and to evaluate its efficacy for cancer detection combined with systematic biopsy (SB) . METHODS: We present a retrospective review of consecutive patients undergoing multiparametric magnetic resonance (mpMRI) imaging of the prostate with subsequent transperineal prostate biopsy from January 2016 to December 2018. A free-hand 12-core SB was performed for each patient. PI-RADS 3-5 lesions were further targeted for biopsy with our TB technique. Firstly, a central point of suspicious lesion (B') was registered cognitively on a transverse section of transrectal ultrasound (TRUS). Then, biopsy gun punctured vertically through a fixed pioneer site (A) on skin of perineum, and deep into the TRUS section to get A'. Next, targeted site (B), the surface-projection of B', would be determined on skin of perineum by A and distance from B' to A'. Finally, puncture through B to reach B'. Pathological findings of SB and TB were analyzed. RESULTS: A total of 126 patients underwent transperineal prostate biopsy (47 SB only, 79 SB + TB). The age of the patients was 68.7 ± 9.2 years. The median preoperative PSA value was 11.8 ng/mL. Preoperative prostate volume was 60.5 ± 50.0 mL. The numbers of patients with PI-RADS scores of 1 through 5 were 4, 43, 27, 21 and 31, respectively. The overall detection rate of cancer was 61/126 (48.4%), and it was significantly higher in the combination cohort (56/79, 70.9%) compared with the SB only cohort (5/47, 10.6%, p<0.001). When focused on the combination cohort, TB detected a similar overall rate of PCa (53/79, 67.1% vs 52/79, 65.8%; p = 0.87) compared with SB. The clinically significant PCa (csPC) detection rate was 52/79 (65.8%), while for TB and SB the csPC/PC rate was 51/53 (96.2%) and 48/52 (92.3%), respectively(p = 0.44). TB demonstrated a better sampling performance (positive rate for each core) compared with SB (51.0% vs 31.3%, p < 0.001). CONCLUSIONS: Surface-projection-based transperineal cognitive fusion targeted biopsy of the prostate has a good efficacy in detecting PCa.

Lunasin Improves the LDL-C Lowering Efficacy of Simvastatin via Inhibiting PCSK9 Expression in Hepatocytes and ApoE-/- Mice.

Statins are the most popular therapeutic drugs to lower plasma low density lipoprotein cholesterol (LDL-C) synthesis by competitively inhibiting hydroxyl-3-methyl-glutaryl-CoA (HMG-CoA) reductase and up-regulating the hepatic low density lipoprotein receptor (LDLR). However, the concomitant up-regulation of proprotein convertase subtilisin/kexin type 9 (PCSK9) by statin attenuates its cholesterol lowering efficacy. Lunasin, a soybean derived 43-amino acid polypeptide, has been previously shown to functionally enhance LDL uptake via down-regulating PCSK9 and up-regulating LDLR in hepatocytes and mice. Herein, we investigated the LDL-C lowering efficacy of simvastatin combined with lunasin. In HepG2 cells, after co-treatment with 1 µM simvastatin and 5 µM lunasin for 24 h, the up-regulation of PCSK9 by simvastatin was effectively counteracted by lunasin via down-regulating hepatocyte nuclear factor 1α (HNF-1α), and the functional LDL uptake was additively enhanced. Additionally, after combined therapy with simvastatin and lunasin for four weeks, ApoE-/- mice had significantly lower PCSK9 and higher LDLR levels in hepatic tissues and remarkably reduced plasma concentrations of total cholesterol (TC) and LDL-C, as compared to each monotherapy. Conclusively, lunasin significantly improved the LDL-C lowering efficacy of simvastatin by counteracting simvastatin induced elevation of PCSK9 in hepatocytes and ApoE-/- mice. Simvastatin combined with lunasin could be a novel regimen for hypercholesterolemia treatment.