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This study confirmed the change in functional composition and alcohol-induced acute liver injury in Aloe arborescens after fermentation. An acute liver injury was induced by administration of ethanol (3 g/kg/day) to C57BL/6J mice for 5 days. A fermented A. arborescens Miller leaf (FAAL) extract was orally administered 30 minutes before ethanol treatment. After fermentation, the emodin content was approximately 13 times higher than that of the raw material. FAAL extract significantly attenuated ethanol-induced aspartate aminotransferase, alanine aminotransferase, and triglyceride increases in serum and liver tissue. Histological analysis revealed that FAAL extract inhibits inflammatory cell infiltration and fat accumulation in liver tissues. The cytochrome P450 2E1, superoxide dismutase, and glutathione (GSH), which involved in alcohol-induced oxidative stress, were effectively regulated by FAAL extract in serum and liver tissues, except for GSH. FAAL also maintained the antioxidant defense system by upregulating heme oxygenase 1 and nuclear factor erythroid 2-related factor 2 protein expression. In addition, FAAL extract inhibited the decrease in alcohol dehydrogenase and aldehyde dehydrogenase activity, which promoted alcohol metabolism and prevented the activation of inflammatory response. Our results suggest that FAAL could be used as a potential therapeutic agent for ethanol-induced acute liver injury.

In situ CuI-mediated cyclization methodology helped yield benzimidazoles with different substitution manner, such as 1,2-diarylbenzimidazoles (4 and 5) and 1-arylbenzimidazoles (6-15). The result of structure-activity relationship (SAR) study confirmed the significance of the 5,6,7-trimethoxybenzimidazole moiety, and the representative derivatives (8-10) exhibited marked antiproliferative activity against A549, HCT-116, and PC-3 cells; in addition, they are able to inhibit the polymerization of tubulin. Among them, compound 10 inhibited the growth of A549, HCT-116, and PC-3 cells with a mean IC 50 value of 0.07 μM, and its IC 50 value of tubulin polymerization is 0.26 μM., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Four new alkaloids, hippobrines A-D ( 1 - 4 ), along with three new polyacetylenes, hippobrenes A-C ( 5 - 7 ), were isolated from Hippobroma longiflora . Compounds 1 - 3 possess an unprecedented carbon skeleton. All of the new structures were determined by analyzing their mass and NMR spectroscopic data. The absolute configurations of 1 and 2 were confirmed by single-crystal X-ray analyses, and the absolute configurations of 3 and 7 were deduced using their ECD spectra. Plausible biogenetic pathways of 1 and 4 were proposed. In regard to bioactivities, all compounds ( 1 - 7 ) exhibited weak antiangiogenic activity against human endothelial progenitor cells, with IC 50 values ranging from 21.1 ± 1.1 to 44.0 ± 2.3 μg/mL.

Maternal embryonic leucine zipper kinase (MELK) is a member of the AMPK (AMP-activated protein kinase) protein family, which is widely and highly expressed in multiple cancer types. Through direct and indirect interactions with other targets, it mediates various cascades of signal transduction processes and plays an important role in regulating tumor cell survival, growth, invasion and migration and other biological functions. Interestingly, MELK also plays an important role in the regulation of the tumor microenvironment, which can not only predict the responsiveness of immunotherapy, but also affect the function of immune cells to regulate tumor progression. In addition, more and more small molecule inhibitors have been developed for the target of MELK, which exert important anti-tumor effects and have achieved excellent results in a number of clinical trials. In this review, we outline the structural features, molecular biological functions, potential regulatory mechanisms and important roles of MELK in tumors and tumor microenvironment, as well as substances targeting MELK. Although many molecular mechanisms of MELK in the process of tumor regulation are still unknown, it is worth affirming that MELK is a potential tumor molecular therapeutic target, and its unique superiority and important role provide clues and confidence for subsequent basic research and scientific transformation., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to report., (Copyright © 2023 Elsevier B.V. All rights reserved.)

GPR84 is a proinflammatory G protein-coupled receptor that mediates myeloid immune cell functions. Blocking GPR84 with antagonists is a promising approach for treating inflammatory and fibrotic diseases. Previously, a GPR84 antagonist 604c , with a symmetrical phosphodiester structure, has displayed promising efficacy in a mouse model of ulcerative colitis. However, the low blood exposure resulting from physicochemical properties prevented its uses in other inflammatory diseases. In this study, a series of unsymmetrical phosphodiesters with lower lipophilicity were designed and tested. The representative compound 37 exhibited a 100-fold increase in mouse blood exposure compared to 604c while maintaining in vitro activity. In a mouse model of acute lung injury, 37 (30 mg/kg, po) significantly reduced the infiltration of proinflammatory cells and the release of inflammatory cytokines and ameliorated pathological changes equally or more effectively than N -acetylcysteine (100 mg/kg, po). These findings suggest that 37 is a promising candidate for treating lung inflammation.

To eliminate internal defects of grains developed during melt-cast charging, the formation mechanism and the trend of crystal morphology of internal defects of 2,4,6-trinitrotoluene and 2,4-dinitroanisole-based melt-cast explosives under different process conditions were simulated. The effects of solidification treatment on melt-cast explosive molding quality were investigated by combining pressurized feeding, head insulation, and water bath cooling. The single pressurized treatment technology results showed that grains were exposed to layer-by-layer solidification from outside to inside, resulting in V-shaped shrink areas of the contract cavity in the core. The defect area was proportional to the treatment temperature. However, the combination of treatment technologies, such as head insulation and water bath cooling, promoted longitudinal gradient solidification of the explosive and controllable migration of its internal defects. Moreover, the combined treatment technologies effectively improved the heat transfer efficiency of the explosive with the help of a water bath to reduce the solidification time, thus achieving highly efficient equal-material manufacturing of microdefect or zero-defect grains., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

This study aimed to identify abnormal brain regions and imaging indices of vascular cognitive impairment (VCI) and explore specific imaging diagnostic markers of VCI. In this study, 24 patients with VCI were allocated to the VCI group and 25 healthy subjects were assigned to the healthy control (HC) group. Demographic data and neuropsychological test scores were compared using SPSS 25.0. The structural and functional imaging data were post-processed and statistically analyzed using CAT12, DPARSF and SPM12 software, based on the MATLAB platform. The structural and functional indices of gray matter volume (GMV) and regional homogeneity (ReHo) were obtained, and inter-group data were analyzed using an independent-sample t test. Sex, age, years of education, and total brain volume were used as covariates. Compared to the HC group, the GMV of VCI in the VCI group decreased significantly in the rectus muscles of the bilateral gyrus, left superior temporal gyrus, left supplementary motor area (SMA), right insula, right superior temporal gyrus, right anterior cuneiform lobe, and right anterior central gyrus (PRECG) (P < .05, FWE correction), without GMV enlargement in the brain area. ReHo decreased in the right inferior temporal gyrus (ITG), right parahippocampal gyrus, and left temporal pole (middle temporal gyrus, right lingual gyrus, left posterior central gyrus, and right middle temporal gyrus), the areas of increased ReHo were the left caudate nucleus, left rectus gyrus, right anterior cingulate gyrus and lateral cingulate gyrus (P < .05, FWE correction). Correlation analysis showed that the GMV of the left superior temporal gyrus was positively correlated with the Montreal Cognitive Assessment (MoCA) score (P < .05), and the GMV of the right insula was positively correlated with the MESE and long delayed memory scores (P < .05). There was a significant positive correlation between the ReHo and short-term delayed memory scores in the middle temporal gyrus of the left temporal pole (P < .05). The volume of GMV and ReHo decreased in VCI patients, suggesting that impairment of brain structure and function in specific regions is the central mechanism of cognitive impairment in these patients. Meanwhile, the functional indices of some brain regions were increased, which may be a compensatory mechanism for the cognitive impairment associated with VCI., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: To study the effect of diurnal temperature range on the number of elderly inpatients with ischemic stroke in Hunan Province. Method: Demographic and disease data, meteorological data, air quality data, population, economic and health resource data of elderly inpatients with ischemic stroke were collected in 122 districts/counties of Hunan Province from January to December 2019. The relationships between the diurnal temperature range and the number of elderly inpatients with ischemic stroke were analyzed by using the distributed lag non-linear model, including the cumulative lag effect of the diurnal temperature range in different seasons, extremely high diurnal temperature range and extremely low diurnal temperature range. Results: In 2019, 152 875 person-times were admitted to the hospital for ischemic stroke in the elderly in Hunan Province. There was a non-linear relationship between the diurnal temperature range and the number of elderly patients with ischemic stroke, with different lag periods. In spring and winter, with the decrease in diurnal temperature range, the risk of admission of elderly patients with ischemic stroke increased ( P trend <0.001, P trend =0.002);in summer, with the increase in diurnal temperature range, the risk of admission of elderly patients with ischemic stroke increased ( P trend =0.024);in autumn, the change in the diurnal temperature range would not cause a change in admission risk ( P trend =0.089). Except that the lag effect of the extremely low diurnal temperature range in autumn was not obvious, the lag effect occurred in other seasons under extremely low and extremely high diurnal temperature ranges. Conclusion: The high diurnal temperature range in summer and the low diurnal temperature range in spring and winter will increase the risk of admission of elderly patients with ischemic stroke, and the risk of admission of elderly patients with ischemic stroke will lag under the extremely low and extremely high diurnal temperature ranges in the above three seasons.

This retrospective study evaluated the characteristics and response of subretinal hyperreflective material (SHRM) to anti-vascular endothelial growth factor (VEGF) treatment in eyes with myopic choroidal neovascularization (CNV). The visual acuity (VA) was assessed at 3, 6, and 12 months after initiating anti-VEGF treatment in 116 patients (119 eyes) with SHRM and myopic CNV. Multimodal imaging, including color fundus photography, fluorescein angiography (FA), and optical coherence tomography angiography (OCT-A), were performed. We compared type 2 neovascularization (NV) (n = 64), subretinal hyperreflective exudation (SHE) (n = 37), NV with hemorrhage (n = 15), and fibrosis (n = 3). The type 2 NV group, and NV with hemorrhage groups showed significant VA improvement after 12 months of treatment (p < 0.05 in both groups); the SHE group failed to show improvement (p = 0.366). All groups showed a significant reduction in central foveal thickness after 12 months of treatment (all p < 0.05). The SHE group had a significantly higher incidence of interrupted ellipsoid zone than the other groups (p < 0.05). Myopic CNV can present as SHRM on OCT-A. Visual prognoses vary in different SHRM types. OCT-A and FA may help predict the outcomes of different subtypes of myopic CNV. SHE is predictive of outer retinal layer atrophy in patients with various SHRM types., (© 2023. The Author(s).)

Wastewater-based epidemiology (WBE) represents an efficient approach for public pathogen surveillance as it provides early warning of disease outbreaks; however, it has not yet been applied to dengue virus (DENV), which might cause endemics via mosquito spread. In this study, a working platform was established to provide direct virus recovery and qPCR quantification from wastewater samples that were artificially loaded with target DENV serotypes I to IV and noncognate spike control viral particles. The results showed qPCR efficiencies of 91.2 %, 94.8 %, 92.6 % and 88.7 % for DENV I, II, III, and IV, respectively, and a broad working range over 6 orders of magnitude using the preferred primer sets. Next, the results revealed that the ultrafiltration method was superior to the skimmed milk flocculation method for recovering either DENV or control viral particles from wastewater. Finally, DENV-2 was loaded simultaneously with the noncognate spike control and could be recovered at comparable levels either in PBS or in wastewater, indicating the applicability of noncognate spike control particles to reflect the efficiency of experimental steps. In conclusion, our data suggest that DENV particles in wastewater could be recovered and quantitatively detected in absolute amounts, indicating the feasibility of DENV surveillance using the WBE approach., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Horizontal neck wrinkles develop during the aging process., Aims: This study assessed the effectiveness of a comprehensive approach to treating horizontal neck wrinkles using non-cross-linked hyaluronic acid injection and smooth absorbable PPDO (Poly p-dioxanon) thread insertion., Methods: Ten patients with horizontal neck wrinkles were treated with hyaluronic acid injection and thread-lifting. The clinical outcomes were evaluated six months after treatment., Results: The median global aesthetic improvement scale scores evaluated by plastic surgeons and the patients were 4.3 ± 0.8 (3-5) and 4.1 ± 0.7 (3-5), respectively, at six months post-treatment. Five (50%) patients strongly agreed, and three subjects (30%) agreed that their horizontal neck wrinkles had improved following treatment. No serious adverse events, including infections, lumps, irregularities, or the Tyndall effect, occurred during treatment., Conclusion: This study revealed that a comprehensive approach using hyaluronic acid and thread-lifting provided satisfactory and effective clinical outcomes in treating horizontal neck wrinkles., Level of Evidence Iv: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors http://www.springer.com/00266 ., (© 2022. The Author(s).)

Phytochemical investigation of the fruits of Crataegus pinnatifida Bunge led to the isolation of four pairs enantiomeric benzofuran lignans ( 1a / 1b - 4a / 4b ) including four undescribed compounds ( 1a , 2b , 3b and 4b ). Their structures were determined by extensive spectroscopic methods and the absolute configurations were further determined by the comparison of experimental and calculated ECD spectra. All the enantiomeric lignans were evaluated for their inhibitory activities to tyrosinase. Among them, compound 4a showed moderate inhibition activity (IC 50 = 0.54 mM).

Background: The role of macrophages in the pathogenesis of nonalcoholic steatohepatitis (NASH) is complex and unclear., Methods: Single-cell RNA sequencing was performed on nonparenchymal cells isolated from NASH and control mice. The expression of Vsig4 + macrophages was verified by qPCR, flow cytometry and immunohistochemistry. Primary hepatic macrophages were cocultured with primary hepatocytes or hepatic stellate cells (LX2) cells by Transwell to detect immunofluorescence and oil red O staining., Results: Two main single macrophage subsets were identified that exhibited a significant change in cell percentage when NASH occurred: resident Kupffer cells (KCs; Cluster 2) and lipid-associated macrophages (LAMs; Cluster 13). Nearly 82% of resident single KCs in Cluster 2 specifically expressed Cd163, and an inhibited subgroup of Cd163 + resident single-KCs was suggested to be protective against NASH. Similar to Cd163, Vsig4 was both enriched in and specific to Cluster 2. The percentage of Vsig4 + -KCs was significantly decreased in NASH in vivo and in vitro. Hepatocytes and hepatic stellate cells produced less lipid droplet accumulation, proinflammatory protein (TNF-α) and profibrotic protein (α-SMA) in response to coculture with Vsig4 + -KCs than in those cocultured with lipotoxic KCs., Conclusions: A subgroup of Vsig4 + resident single-KCs was shown to improve hepatic inflammation and fibrosis in NASH., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Introduction: Combined phacovitrectomy is gaining popularity due to efficiency and immediate visual improvement. However, concerns regarding erroneous intraocular lens (IOL) calculation in combination surgery are increasing, such as myopic shift owing to a thick macula and consequent underestimation of the axial length. Therefore, this study aimed to compare the refractive outcomes of combined phacovitrectomy in patients with highly myopic and non-highly myopic eyes., Methods: A retrospective chart review was performed on patients who received combined phacoemulsification, intraocular lens implantation, and small gauge pars plana vitrectomy for cataract and macular pathologies in highly myopic and non-highly myopic eyes. Pre- and postoperative evaluation and ocular parameters were recorded, and analyses were performed using the Student's t test and regression analysis., Results: A total of 133 patients with macular pathologies, including myopic tractional maculopathy, macular hole, and epiretinal membrane, were enrolled. SRK II or SRK/T models were used for calculating IOL. The mean absolute error of refraction change was 0.65 D; 83.5% of patients were within 1-D error, 57.9% within 0.5-D error, and 35.3% within 0.25-D error, with SRK/T showing better precision and yielding more myopic shift. Furthermore, the predictive accuracy of SRK II or SRK/T was better in patients with non-highly myopic eyes. Moreover, Barrett's universal II formula was not superior to SRK II or SRK/T in the prediction of postoperative refractive error (p = 0.48)., Conclusion: Refractive outcomes were satisfactory in the cohort of patients with highly myopic eyes. The combined implementation of SRK II and SRK/T was not inferior to Barrett's universal II formula in predicting satisfactory refractive outcomes. Combination surgery can be an option for patients with both cataract and macular pathologies., (© 2023. The Author(s).)

New therapeutic approaches are needed for metastatic osteosarcoma (OS), as survival rates remain low despite surgery and chemotherapy. Epigenetic changes, such as histone H3 methylation, play key roles in many cancers including OS, although the underlying mechanisms are not clear. In this study, human OS tissue and OS cell lines displayed lower levels of histone H3 lysine trimethylation compared with normal bone tissue and osteoblast cells. Treating OS cells with the histone lysine demethylase inhibitor 5-carboxy-8-hydroxyquinoline (IOX-1) dose-dependently increased histone H3 methylation and inhibited cellular migratory and invasive capabilities, suppressed matrix metalloproteinase expression, reversed epithelial-to-mesenchymal transition by increasing levels of epithelial markers E-cadherin and ZO-1 and decreasing the expression of mesenchymal markers N-cadherin, vimentin, and TWIST, and also reduced stemness properties. An analysis of cultivated MG63 cisplatin-resistant (MG63-CR) cells revealed lower histone H3 lysine trimethylation levels compared with levels in MG63 cells. Exposing MG63-CR cells to IOX-1 increased histone H3 trimethylation and ATP-binding cassette transporter expression, potentially sensitizing MG63-CR cells to cisplatin. In conclusion, our study suggests that histone H3 lysine trimethylation is associated with metastatic OS and that IOX-1 or other epigenetic modulators present promising strategies to inhibit metastatic OS progression., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Wheat sharp eyespot is a serious disease caused by the phytopathogens Rhizoctonia cerealis and R. solani . Some species in the genus Streptomyces have been identified as potential biocontrol agents against phytopathogens. In this investigation, the physiological, biochemical, phylogenetic, and genomic characteristics of strain HU2014 indicate that it is a novel Streptomyces sp. most closely related to Streptomyces albireticuli . Strain HU2014 exhibited strong antifungal activity against R. cerealis G11 and R. solani YL-3. Ultraperformance liquid chromatography-mass spectrometry on the four extracts from the extracellular filtrate of strain HU2014 identified 10 chemical constituents in the Natural Products Atlas with high match levels (more than 90%). In an antifungal efficiency test on wheat sharp eyespot, two extracts significantly reduced the lesion areas on bean leaves infected by R. solani YL-3. The drenching of wheat in pots with spore suspension of strain HU2014 demonstrated a control efficiency of 65.1% against R. cerealis G11 (compared with 66.9% when treated by a 30% hymexazol aqueous solution). Additionally, in vitro and pot experiments demonstrated that strain HU2014 can produce indoleacetic acid, siderophores, extracellular enzymes, and solubilized phosphate, and it can promote plant growth. We conclude that strain HU2014 could be a valuable microbial resource for growth promotion of wheat and biological control of wheat sharp eyespot.

Telomeres, which are located at the ends of eukaryotic chromosomes, are crucial for genomic maintenance. Most telomeric DNA is composed of tandemly repeated guanine (G)-rich sequences, which form G-quadruplexes (G4s). The structures and dynamics of telomeric G4s are essential for telomere functioning and helpful for G4-based biosensing. However, they are far from being understood, especially for plants. In this contribution, the folding, environment-induced G4 dynamics, and protein-catalyzed unfolding of plant telomeric G4s were comprehensively studied. It was found that diverse plant telomeric sequences from land plants to green algae could fold into G4 structures. In addition, 5'-proximal ssDNA but not 3'-proximal ssDNA drove conversion of anti-parallel G4 structures to parallel structures, and both 5' and 3' ssDNA decreased the stability of G4s in dilute solution. Furthermore, molecular crowding promoted the formation of parallel structures for three-layer but not for two-layer G4s, and increased the stability of all selected G4s. Finally, AtRecQ2 helicase resolved the stable parallel structure of typical plant telomeric G4 in crowded solution, but ssDNA binding protein AtRPA did not. Furthermore, AtRecQ2 unwound the structure more efficiently in the presence of AtRPA. The results may expand our understanding on the structures and dynamics of plant telomeric G4s., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Two-dimensional covalent-organic frameworks (2D COFs) have recently emerged as great prospects for their applications as new photocatalytic platforms in solar-to-hydrogen conversion; nevertheless, their inefficient solar energy capture and fast charge recombination hinder the improvement of photocatalytic hydrogen production performance. Herein, two photoactive three-component donor-π-acceptor (TCDA) materials were constructed using a multicomponent synthesis strategy by introducing electron-deficient triazine and electron-rich benzotrithiophene moieties into frameworks through sp 2 carbon and imine linkages, respectively. Compared with two-component COFs, the novel TCDA-COFs are more convenient in regulating the inherent photophysical properties, thereby realizing outstanding photocatalytic activity for hydrogen evolution from water. Remarkably, the first sp 2 carbon-linked TCDA-COF displays an impressive hydrogen evolution rate of 70.8 ± 1.9 mmol g -1 h -1 with excellent reusability in the presence of 1 wt % Pt under visible-light illumination (420-780 nm). Utilizing the combination of diversified spectroscopy and theoretical prediction, we show that the full π-conjugated linkage not only effectively broadens the visible-light harvesting of COFs but also enhances charge transfer and separation efficiency.

Lung cancer is an extremely common cancer and metastatic lung cancer has a greatly low survival rate. Lymphangiogenesis is essential for the development and metastasis of lung cancer. The adipokine angiopoietin-like protein 2 (ANGPTL2) regulates tumor progression and metastasis, although the functions of ANGPTL2 in lung cancer are unknown. Analysis of data from TCGA genomics program, the GEPIA web server and the Oncomine database revealed that higher levels of ANGPTL2 expression were correlated with progressive disease and lymph node metastasis. ANGPTL2 enhanced VEGF-A-dependent lymphatic endothelial cell (LEC) tube formation and migration. Integrin α5β1, p38 and nuclear factor (NF)-κB signaling mediated ANGPTL2-regulated lymphangiogenesis. Importantly, overexpression ANGPTL2 facilitated tumor growth and lymphangiogenesis in vivo . Thus, ANGPTL2 is a promising therapeutic object for treating lung cancer.

The thin-wall heat pipe is an efficient heat transfer component that has been widely used in the field of heat dissipation of high-power electronic equipment in recent years. In this study, the orange peel morphology defect of thin-wall heat pipes after bending deformation was analyzed both for the macro-3D profile and for the micro-formation mechanism. The morphology and crystal orientations of the grains and annealing twins were carefully characterized utilizing optical metallography and the electron backscatter diffraction technique. The results show that after high-temperature sintering treatment, the matrix grains of the heat pipe are seriously coarsened and form a strong Goss texture, while certain annealing twins with the unique copper orientation are retained. The distribution of the Schmid factor value subjected to the uniaxial stress indicates that inhomogeneity in the intergranular deformation exists among the annealing twins and matrix grains. The annealing twin exhibits a "hard-oriented" component during the deformation; thus, it plays a role as a barrier and hinders the slipping of dislocation. As the strain accumulates, part of the annealing twins may protrude from the surface of the heat pipe, forming a large-scale fluctuation of the surface as the so-called "orange peel" morphology. The 3D profile shows the bulged twins mostly perpendicular to the drawing direction, about 200-300 in width and 10-20 μm in height.

Neovascular age-related macular degeneration (AMD) is described as abnormal angiogenesis in the retina and the leaking of fluid and blood that generates a huge, dark, blind spot in the center of the visual field, causing severe vision loss in over 90% of patients. Bone marrow-derived endothelial progenitor cells (EPCs) contribute to pathologic angiogenesis. Gene expression profiles downloaded from the eyeIntegration v1.0 database for healthy retinas and retinas from patients with neovascular AMD identified significantly higher levels of EPC-specific markers (CD34, CD133) and blood vessel markers (CD31, VEGF) in the neovascular AMD retinas compared with healthy retinas. Melatonin is a hormone that is mainly secreted by the pineal gland, and is also produced in the retina. Whether melatonin affects vascular endothelial growth factor (VEGF)-induced EPC angiogenesis in neovascular AMD is unknown. Our study revealed that melatonin inhibits VEGF-induced stimulation of EPC migration and tube formation. By directly binding with the VEGFR2 extracellular domain, melatonin significantly and dose-dependently inhibited VEGF-induced PDGF-BB expression and angiogenesis in EPCs via c-Src and FAK, NF-κB and AP-1 signaling. The corneal alkali burn model demonstrated that melatonin markedly inhibited EPC angiogenesis and neovascular AMD. Melatonin appears promising for reducing EPC angiogenesis in neovascular AMD.

Objective: To examine the short-term curative effect with minimally invasive right infra-axillary thoracotomy for transaortic modified Morrow procedure. Methods: The clinical data of 60 patients who underwent video-assisted thoracoscopic transaortic modified Morrow procedure from August 2021 to August 2022 at Department of Cardiovascular Surgery, Zhejiang Provincial People's Hospital were retrospectively analyzed. There were 31 males and 29 females, with the age ( M (IQR)) of 54.0(22.3) years (range: 15 to 71 years). The echocardiography confirmed the diagnosis of moderate mitral regurgitation in 30 patients, and severe mitral regurgitation in 13 patients. Systolic anterior motion (SAM) was present preoperatively in 54 patients. All 60 patients underwent transaortic modified Morrow procedure through a right infra-axillary thoracotomy using femorofemoral cardiopulmonary bypass. Surgical procedures mainly included transverse aortic incision, exposure of left ventricular outflow tract (LVOT), septal myectomy, and correction of the abnormal mitral valve and subvalvular structures. Results: All 60 patients underwent the programmatic procedures successfully without conversion to full sternotomy. The cardiopulmonary bypass time was (142.0±32.1) minutes (range: 89 to 240 minutes), while the cross-clamp time was (95.0±23.5) minutes (range: 50 to 162 minutes). The patients had a postoperative peak LVOT gradient of 7.0 (5.0) mmHg (range: 0 to 38 mmHg) (1 mmHg=0.133 kPa). A total of 57 patients were extubated on the operating table. The drainage volume in the first 24 h was (175.9±57.0) ml (range: 60 to 327 ml). The length of intensive care unit stay was 21.0 (5.8)h (range: 8 to 120 h) and postoperative hospital stay was 8 (5) days (range: 5 to 19 days). The postoperative septal thickness was 11 (2) mm (range: 8 to 14 mm). All patients had no iatrogenic ventricular septal perforation or postoperative residual SAM. The patients were followed up for 4 (9) months (range: 1 to 15 months), and none of them needed cardiac surgery again due to valve dysfunction or increased peak LVOT gradient during follow-up. Conclusion: Using a video-assisted thoracoscopic transaortic modified Morrow procedure through a right infra-axillary minithoracotomy can provide good visualization of the LVOT and hypertrophic ventricular septum, ensure optimal exposure of the mitral valve in the presence of complex mitral subvalvular structures, so that allows satisfactory short-term surgical results.

The zero-magnetic-field nonlinear Hall effect (NLHE) refers to the second-order transverse current induced by an applied alternating electric field; it indicates the topological properties of inversion-symmetry-breaking crystals. Despite several studies on the NLHE induced by the Berry-curvature dipole in Weyl semimetals, the direct current conversion by rectification is limited to very low driving frequencies and cryogenic temperatures. The nonlinear photoresponse generated by the NLHE at room temperature can be useful for numerous applications in communication, sensing, and photodetection across a high bandwidth. In this study, observations of the second-order NLHE in type-II Dirac semimetal CoTe 2 under time-reversal symmetry are reported. This is determined by the disorder-induced extrinsic contribution on the broken-inversion-symmetry surface and room-temperature terahertz rectification without the need for semiconductor junctions or bias voltage. It is shown that remarkable photoresponsivity over 0.1 A W -1 , a response time of approximately 710 ns, and a mean noise equivalent power of 1 pW Hz -1/2 can be achieved at room temperature. The results open a new pathway for low-energy photon harvesting via nonlinear rectification induced by the NLHE in strongly spin-orbit-coupled and inversion-symmetry-breaking systems, promising a considerable impact in the field of infrared/terahertz photonics., (© 2023 The Authors. Advanced Materials published by Wiley-VCH GmbH.)

Patients with chronic kidney disease (CKD) who are being treated with immunosuppressive medications are at risk for developing Pneumocystis jirovecii pneumonia (PCP). We attempted to characterize the clinical aspects of PCP in CKD patients in order to alert high-risk patients with bad prognosis. A retrospective study of CKD patients was conducted from June 2018 to June 2022. Based on PCP diagnostic criteria, these patients were divided into PCP and non-PCP groups. Using univariate and multivariate logistic regression analysis, risk indicators were evaluated, and nomogram and decision tree were developed. Of the CKD patients screened for Pneumocystis carinii nucleic acid, 1512 were included. Two-hundred forty four (16.14%) were diagnosed with PCP. Of the PCP, 88.5% was receiving glucocorticoid (GC) therapy, of which 66.3% received more than 0.5 mg/kg GC. Multivariate analysis showed that membranous nephropathy (OR 2.35, 95% CI 1.45-3.80), immunosuppressive therapy (OR 1.94, 95% CI 1.06-3.69), and ground glass opacity of CT scanning (OR 1.71, 95% CI 1.10-2.65) were associated with increased risk of Pneumocystis carinii infection. The AUC of nomogram based on logistics regression was 0.78 (0.75-0.81). The mortality in patients with PCP was 32.40%. Univariate analysis and decision tree showed that pulmonary insufficiency (PO 2 : OR 0.98, 95% CI 0.96-1.00), elevated APTT (OR 1.07, 95% CI 1.04-1.11), and reduced hemoglobin (OR 0.97, 95% CI 0.96-0.98) were associated with poor prognosis. PCP is not rare in CKD patients, particularly in those treated with immunosuppressive therapy. Considering the high mortality of the cases, further studies on the prevention and management of these patients are needed., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The vast majority of seasonal influenza vaccines administered each year are derived from virus propagated in eggs using technology that has changed little since the 1930s. The immunogenicity, durability, and breadth of response would likely benefit from a recombinant nanoparticle-based approach. Although the E2 protein nanoparticle (NP) platform has been previously shown to promote effective cell-mediated responses to peptide epitopes, it has not yet been reported to deliver whole protein antigens. In this study, we synthesized a novel maleimido tris-nitrilotriacetic acid (NTA) linker to couple protein hemagglutinin (HA) from H1N1 influenza virus to the E2 NP, and we evaluated the HA-specific antibody responses using protein microarrays. We found that recombinant H1 protein alone is immunogenic in mice but requires two boosts for IgG to be detected and is strongly IgG1 (Th2) polarized. When conjugated to E2 NPs, IgG2c is produced leading to a more balanced Th1/Th2 response. Inclusion of the Toll-like receptor 4 agonist monophosphoryl lipid A (MPLA) significantly enhances the immunogenicity of H1-E2 NPs while retaining the Th1/Th2 balance. Interestingly, broader homo- and heterosubtypic cross-reactivity is also observed for conjugated H1-E2 with MPLA, compared to unconjugated H1 with or without MPLA. These results highlight the potential of an NP-based delivery of HA for tuning the immunogenicity, breadth, and Th1/Th2 balance generated by recombinant HA-based vaccination. Furthermore, the modularity of this protein-protein conjugation strategy may have utility for future vaccine development against other human pathogens.

Hydrogel shape memory and actuating functionalities are heavily pursued and have found great potential in various application fields. However, their combination for more flexible and complicated morphing behaviors is still challenging. Herein, it is reported that by controlling the light-initiated polymerization of active hydrogel layers on shape memory hydrogel substrates, advanced morphing behaviors based on programmable hydrogel shapes and actuating trajectories are realized. The formation and photo-reduction-induced dissociation of Fe 3+ -carboxylate coordination endow the hydrogel substrates with the shape memory functionality. The photo-reduced Fe 2+ ions can diffuse from the substrates into the monomer solutions to initiate the polymerization of the thermally responsive active layers, whose actuating temperatures and amplitudes can be facially tuned by controlling their thicknesses and compositions. One potential application, a shape-programmable 3D hook that can lift an object with a specific shape, is also unveiled. The demonstrated strategy is extendable to other hydrogel systems to realize more versatile and complicated actuating behaviors., (© 2022 Wiley-VCH GmbH.)

The study of interactions between proteins and surfactants is of relevance in a diverse range of applications including food, enzymatic detergent formulation, and drug delivery. In spite of sodium dodecyl sulfate (SDS)-induced unfolding has been studied in detail at the protein level, deciphering the conformation-activity relationship of a recombinant γ-glutamyltranspeptidase (BlrGGT) from Bacillus licheniformis remains important to understand how the transpeptidase activity is related to its conformation. In this study, we examined the enzyme catalysis and conformational transition of BlrGGT in the presence of SDS. Enzymatic assays showed that the transpeptidase activity of BlrGGT was greatly affected by SDS in a concentration-dependent manner with approximately 90% inactivation at 6 mM. Native polyacrylamide gel electrophoresis of SDS-treated samples clearly revealed that the heterodimeric enzyme was apparently dissociated into two different subunits at concentrations above 2 mM. The study of enzyme kinetics showed that SDS can act as a mixed-type inhibitor to reduce the catalytic efficiency of BlrGGT. Moreover, the t 1/2 value of the enzyme at 55 °C was greatly reduced from 495.1 min to 7.4 min in the presence of 1 mM SDS. The I 3 /I 1 ratio of pyrene excimer fluorescence emission changed around 3.7 mM SDS in the absence of BlrGGT and the inflection point of enzyme samples was reduced to less than 2.7 mM. The Far-UV CD spectrum of the native enzyme had two negative peaks at 208 and 222 nm, respectively; however, both negative peaks increased in magnitude with increasing SDS concentration and reached maximal values at above 4.0 mM. The intrinsic fluorescence spectra of tryptophan further demonstrated that the SDS-induced enzyme conformational transition occurred at approximately 5.1 mM. Tween 20 significantly suppressed the interaction of BlrGGT with SDS by forming mixed micelles at a molar ratio of 1.0. Taken together, this study definitely promotes our better understanding of the relationship between the conformation and catalysis of BlrGGT., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The factors associated with suicide attempts in major depressive disorder (MDD) patients with comorbid glucose disturbances remain unclear. To the best of our knowledge, this is the first study with a large sample size to examine risk factors of suicide attempts in first-episode drug-naïve (FEDN) MDD patients with comorbid glucose disturbances, including clinically relevant factors, metabolic parameters, and thyroid hormone levels. A total of 1718 FEDN MDD patients were enrolled. The Hamilton Depression Scale (HAMD), Hamilton Anxiety Scale (HAMA), and Positive and Negative Syndrome Scale (PANSS) were used to assess the clinical symptoms of patients. Fasting blood glucose, metabolic parameters, and thyroid hormone levels were measured. After controlling for HAMA and HAMD scores, the suicide attempt rate was 1.88 times higher in MDD patients with glucose disturbances than in MDD patients without glucose disturbances. Compared to non-suicide attempters, suicide attempters among the MDD patients with glucose disturbances had higher scores on HAMD and HAMA, PANSS positive symptoms, as well as higher levels of systolic and diastolic blood pressure, TC, LDL-C, thyroid stimulating hormone (TSH), TgAb, and thyroid peroxidases antibody (TPOAb). The combination of positive symptom score, HDL-C, systolic blood pressure, and marital status distinguished suicide attempters from non-suicide attempters. In addition, HAMA score, HAMD score, and TPOAb were associated with the number of suicide attempts in MDD patients with comorbid glucose disturbances. Our results suggest a high incidence of suicide attempts in MDD patients with comorbid glucose disturbances. Several clinically relevant factors, metabolic parameters, and thyroid hormone function have an impact on suicide attempts in MDD patients with comorbid glucose disturbances., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Both osteoporosis and cardiovascular disease (CVD) share similar pathways in pathophysiology and are intercorrelated with increased morbidity and mortality in elderly women. Although denosumab and raloxifene are the current guideline-based pharmacological treatments, their impacts on cardiovascular protection are yet to be examined. This study aimed to compare mortality rate and cardiovascular events between denosumab and raloxifene in osteoporotic women. Risks of CVD development and all-cause mortality were estimated using Cox proportional hazard regression. A total of 7972 (3986 in each group) women were recruited between January 2003 and December 2018. No significant difference between denosumab and raloxifene was observed in composite CVDs, myocardial infarction, or congestive heart failure. However, comparison of the propensity score matched cohorts revealed that patients with proportion of days covered (PDC) ≥60% had lower incidence of ischemic stroke in the denosumab group than that in the raloxifene group (aHR 0.68; 95% CI 0.47-0.98; p = 0.0399). In addition, all-cause mortality was lower in the denosumab group than in the raloxifene group (aHR 0.59; 95% CI 0.48-0.72; p = 0.001), except in patients aged <65 y/o in this cohort study. We concluded that denosumab is superior to raloxifene in lowering risks of all-cause mortality and certain ischemic strokes in osteoporotic women.

This study was aimed at identifying the bioactive components of the crude and stir-baked hawthorn for invigorating spleen and promoting digestion, respectively, to clarify the processing mechanism of hawthorn by applying the partial least squares(PLS) algorithm to build the spectrum-effect relationship model. Firstly, different polar fractions of crude and stir-baked hawthorn aqueous extracts and combinations of different fractions were prepared, respectively. Then, the contents of 24 chemical components were determined by ultra-high performance liquid chromatography-mass spectrometry. The effects of different polar fractions of crude hawthorn and stir-baked hawthorn aqueous extracts and combinations of different fractions were evaluated by measuring the gastric emptying rate and small intestinal propulsion rate. Finally, the PLS algorithm was used to establish the spectrum-effect relationship model. The results showed that there were significant differences in the contents of 24 chemical components for different polar fractions of crude and stir-baked hawthorn aqueous extracts and combinations of different fractions, and the gastric emptying rate and small intestinal propulsion rate of model rats were improved by administration of different polar fractions of crude and stir-baked hawthorn aqueous extracts and combinations of different fractions. The bioactive components of crude hawthorn identified by PLS models were vitexin-4″-O-glucoside, vitexin-2″-O-rhamnoside, neochlorogenic acid, rutin, gallic acid, vanillic acid, citric acid, malic acid, quinic acid and fumaric acid, while neochlorogenic acid, cryptochlorogenic acid, rutin, gallic acid, vanillic acid, citric acid, quinic acid and fumaric acid were the bioactive components of stir-baked hawthorn. This study provided data support and scientific basis for identifying the bioactive components of crude and stir-baked hawthorn, and clarifying the processing mechanism of hawthorn.

Posttranslational protein S-palmitoylation regulates the localization and function of its target proteins involved in diverse cellular processes including meiosis. In this study, we demonstrate that S-palmitoylation mediated by Erf2-Erf4 and Akr1 palmitoylacyltransferases is required at multiple meiotic stages in the fission yeast Schizosaccharomyces pombe We find that S-palmitoylation by Erf2-Erf4 is required for Ras1 localization at the cell periphery to enrich at the cell conjugation site for mating pheromone response. In the absence of Erf2 or Erf4, mutant cells are sterile. A role of Akr1 S-palmitoylating the nuclear fusion protein Tht1 to function in karyogamy is identified. We demonstrate that S-palmitoylation stabilizes and localizes Tht1 to ER, interacting with Sey1 ER fusion GTPase for proper meiotic nuclear fusion. In akr1 , tht1 , or sey1 mutant, meiotic cells, haploid nuclei are unfused with subsequent chromosome segregation defects. Erf2-Erf4 has an additional substrate of the spore coat protein Isp3. In the absence of Erf2, Isp3 is mislocalized from the spore coat. Together, these results highlight the versatility of the cellular processes in which protein S-palmitoylation participates., (© 2023 Pham et al.)

Cancer vaccine immunotherapy facilitates the immune system's recognition of tumor-associated antigens, and the biomolecular design of these vaccines using nanoparticles is one important approach towards obtaining strong anti-tumor responses. Following activation of dendritic cells (DCs), a robust CD8+ T cell-mediated adaptive immune response is critical for tumor elimination. While the role of efficient antigen-presenting myeloid DCs (mDCs) is conventionally attributed towards vaccine efficacy, participation by highly cytokine-producing plasmacytoid DCs (pDCs) is less understood and is often overlooked. We examined vaccines based on the E2 protein nanoparticle platform that delivered encapsulated TLR9 agonist bacterial-like DNA (CpG1826 or CpG1018) or TLR7 agonist viral ssRNA to determine their efficacy over free agonists in activating both mDCs and pDCs for antigen presentation. Although mDCs were only activated by nanoparticle-encapsulated TLR9 agonists, pDCs were activated by all the individually tested constructs, and CpG1826 was shown to induce pDC cytokine production. Transfer of secreted factors from pDCs that were stimulated with a vaccine formulation comprising peptide antigen and CpG1826 enhanced mDC display of the antigen, particularly when delivered in nanoparticles. Only when treated with nanoparticle-conjugated vaccine could pDCs secrete factors to induce antigen display on naïve mDCs. These results reveal that pDCs can aid mDCs, highlighting the importance of activating both pDCs and mDCs in designing effective cancer vaccines, and demonstrate the advantage of using nanoparticle-based vaccine delivery.

The exotic electronic properties of topological semimetals (TSs) have opened new pathways for innovative photonic and optoelectronic devices, especially in the highly pursuit terahertz (THz) band. However, in most cases Dirac fermions lay far above or below the Fermi level, thus hindering their successful exploitation for the low-energy photonics. Here, low-energy type-II Dirac fermions in kitkaite (NiTeSe) for ultrasensitive THz detection through metal-topological semimetal-metal heterostructures are exploited. Furthermore, a heterostructure combining two Dirac materials, namely, graphene and NiTeSe, is implemented for a novel photodetector exhibiting a responsivity as high as 1.22 A W -1 , with a response time of 0.6 µs, a noise-equivalent power of 18 pW Hz -0.5 , with outstanding stability in the ambient conditions. This work brings to fruition of Dirac fermiology in THz technology, enabling self-powered, low-power, room-temperature, and ultrafast THz detection., (© 2022 Wiley-VCH GmbH.)

Aim: To explore the effect of pathogenesis-based individualised thrombectomy on the clinical results and prognoses of acute intracranial large-artery occlusion., Material and Methods: A total of 151 patients were included in this prospective study and divided into the control group (stent thrombectomy, 53 cases), a direct aspiration first pass technique (ADAPT) group (52 cases) and the stent group (stent thrombectomy or a combination of stent thrombectomy and ADAPT, 46 cases) based on whether stent or ADAPT was used. We compared and analysed the patients? general information, the National Institutes of Health Stroke Scale (NHISS) score at admission, the time between the end of arteriography and revascularisation, the number of thrombectomies, the modified Rankin scale (mRS) score at three months and complications in the three groups., Results: Compared with the control group, the time between the end of arteriography and revascularisation in the ADAPT group was significantly reduced (p < 0.05), and the patency rate after one thrombectomy significantly increased (p < 0.05). The positive prognosis rate was significantly increased in the stent and ADAPT groups compared with the control group (p < 0.05)., Conclusion: The application of the ADAPT technique in patients with embolism-induced cerebral infarction can reduce the time of revascularisation. The use of stents in patients with atherosclerosis-induced cerebral infarction can increase the patency rate after one thrombectomy.

Graphene-like 2D coordination polymers (GCPs) have been of central research interest in recent decades with significant impact in many fields. According to classical coordination chemistry, Cu(II) can adopt the dsp 2 hybridization to form square planar coordination geometry, but not Cu(I); this is why so far, there has been few 2D layered structures synthesized from Cu(I) precursors. Herein a pair of isostructural GCPs synthesized by the coordination of benzenehexathiol (BHT) ligands with Cu(I) and Cu(II) ions, respectively, is reported. Spectroscopic characterizations indicate that Cu(I) and Cu(II) coexist with a near 1:1 ratio in both GCPs but remain indistinguishable with a fractional oxidation state of +1.5 on average, making these two GCPs a unique pair of Creutz-Taube mixed-valence 2D structures. Based on density functional theory calculations, an intramolecular pseudo-redox mechanism is further uncovered whereby the radicals on BHT ligands can oxidize Cu(I) or reduce Cu(II) ions upon coordination, thus producing isostructures with distinct electron configurations. For the first time, it is demonstrated that using Cu(I) or Cu(II), one can achieve 2D isostructures, indicating an unusual fact that a neutral periodic structure can host a different number of total electrons as ground states, which may open a new chapter for 2D materials., (© 2022 Wiley-VCH GmbH.)

Background: Cinobufacini, a sterilized hot water extract of dried toad skin, had significant effect against several human cancers. However, there are few studies reporting the effect of cinobufacini on pancreatic cancer., Purpose: To investigate the effects of cinobufacini on the progress of pancreatic ductal adenocarcinoma and the underlying mechanisms., Methods: Cell counting, EdU incorporation and flow Cytometry were performed to evaluate the effect of cinobufacini on cell cycle and growth. MIA-PaCa2 cells were implanted into the nude mice to determine whether cinobufacini represses PDAC progression in vivo. Luciferase reporter assay, western blotting and qPCR were carried out to measure the activity of NF-κB pathway and the alteration of YEATS2 and TAK1. Ectopic gene expression introduced by plasmids was used to verify the molecular mechanism., Results: Our results showed that cinobufacini induced cell cycle arrest and inhibited the growth of PDAC cell in vitro, and repressed MIA-derived PDAC in vivo. Cinobufacini inhibited the phosphorylation of IKK, IκB and NF-κB p65 in PDAC cells. Furthermore, cinobufacini decreased the abundance of intracellular YEATS2 and total TAK1 protein in a time- and dose dependent manner. Ectopic expression of YEATS2 re-elevated the level of TAK1 and phosphorylated IKKα/β, IκBα and p65 after cinobufacini treatment in PANC-1 cells., Conclusion: Cinobufacini retards the growth and progression of PDAC in vitro and in vivo through YEATS2/TAK1/NF-κB axis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier GmbH. All rights reserved.)

Cancer vaccines displaying tumor-associated antigens (TAAs) train the immune system for enhanced tumor recognition and elimination. Nanoparticle-based cancer vaccines are ingested and processed by dendritic cells, which subsequently activate antigen-specific cytotoxic T cells, allowing them to identify and eliminate tumor cells displaying these TAAs. Here, we describe the procedures to conjugate TAA and adjuvant to a model protein nanoparticle platform (E2), followed by assessment of vaccine performance. Utilizing a syngeneic tumor model, the efficacy of in vivo immunization was determined by cytotoxic T lymphocyte assays and IFN-γ ELISpot ex vivo assays to measure tumor cell lysis and TAA-specific activation, respectively. In vivo tumor challenge directly allows evaluation of anti-tumor response and survival over time., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Lysozyme is a natural protein with a good bacteriostatic effect, but its poor inhibition of Gram-negative bacteria limits its development potential as a natural preservative. Therefore, the modification of natural lysozyme to expand the antimicrobial spectrum become the focus of lysozyme study. Egg white lysozyme has low cost, rich content in nature, is easy to obtain, strong stability, and high enzyme activity, so it can be applied in the modification of lysozyme. Egg white lysozyme was modified by chemical methods using organic acids. Caffeic acid and p-coumaric acid in organic acids were used as modifiers, and 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride and N-hydroxy succinimide were used as dehydration condensation agents during modification. A certain degree of modified lysozyme was obtained through appropriate modification conditions. The antibacterial properties and structure of the obtained two organic acid-modified lysozymes were compared with natural enzymes. The results showed that compared with the native enzyme, the activity of modified lysozyme decreased, but the inhibitory effect on Gram-negative bacteria was enhanced. The minimum inhibitory concentrations of caffeic acid-modified enzyme and p-coumaric acid-modified enzyme on Escherichia coli and Pseudomonas aeruginosa were 0.5 mg/mL and 0.75 mg/mL, respectively. However, the antibacterial ability of modified lysozyme to Gram-positive bacteria was lower than that of the natural enzyme. The minimum inhibitory concentration of caffeic acid-modified enzyme and p-coumaric acid-modified enzyme to Staphylococcus aureus and Bacillus subtilis was 1.25 mg/mL. The peak fitting results of the amide-I band absorption peak in the infrared spectroscopy showed that the content of the secondary structure of the two modified enzymes obtained after modification was different from that of natural enzymes. In the study, two organic acids were used to modify egg white lysozyme, which enhanced the enzyme's inhibition of Gram-negative bacteria, and analyzed the mechanisms for the change in the enzyme's antibacterial ability from the perspective of the structural change of the modified enzyme, providing a new idea for lysozyme modification.

In this study, a marine brown alga Sargassum cristaefolium -derived fungal strain, Penicillium sumatraense SC29, was isolated and identified. Column chromatography of the extracts from liquid fermented products of the fungal strain was carried out and led to the isolation of six compounds. Their structures were elucidated by spectroscopic analysis and supported by single-crystal X-ray diffraction as four previously undescribed ( R )-3-hydroxybutyric acid and glycolic acid derivatives, namely penisterines A ( 1 ) and C-E ( 3 - 5 ) and penisterine A methyl ether ( 2 ), isolated for the first time from natural resources, along with ( R )-3-hydroxybutyric acid ( 6 ). Of these compounds identified, penisterine E ( 5 ) was a unique 6/6/6-tricyclic ether with an acetal and two hemiketal functionalities. All the isolates were subjected to in vitro anti-angiogenic assays using a human endothelial progenitor cell (EPCs) platform. Among these, penisterine D ( 4 ) inhibited EPC growth, migration, and tube formation without any cytotoxic effect. Further, in in vivo bioassays, the percentages of angiogenesis of compound 3 on Tg ( fli1 :EGFP) transgenic zebrafish were 54% and 37% as the treated concentration increased from 10.2 to 20.4 µg/mL, respectively, and the percentages of angiogenesis of compound 4 were 52% and 41% as the treated concentration increased from 8.6 to 17.2 µg/mL, respectively. The anti-angiogenic activity of penisterine D ( 4 ) makes it an attractive candidate for further preclinical investigation.

Objective: Codonopsis Radix and Polygonati Rhizoma (CRPR) has a good hypoglycemic effect. The aims of the present study were to investigate the effect of CRPR on high-fat/high-sugar diet (HFHSD)- and streptozotocin (STZ)-induced type 2 diabetes mellitus (T2DM) mice as well as to investigate the involved mechanism., Methods: A T2DM mouse model was generated by combining HFHSD and STZ. After the model was established, normal and model groups received the same volume of normal saline intragastrically, and the negative control group was treated with metformin (200 mg/kg·BW). The low, medium, and high CRPR groups received four consecutive weeks of oral gavage with CRPR doses of 2.5, 5, and 10 g/kg·BW, respectively, during the course of the study. Body weight and fasting blood glucose (FBG) were measured on a weekly basis. Enzyme-linked immunosorbent assay (ELISAs) were used to evaluate the serum and liver samples. Hematoxylin and eosin (H&E) staining was utilized to observe the pathological status of the liver and pancreas. Western blot (WB) analysis was performed to evaluate the protein expression levels of PI3K, p-PI3K, AKT, and p-AKT., Results: Compared to model mice, each treatment group had significantly elevated levels of FBG, total cholesterol (TC), and triacylglycerol (TG) ( P< 0.01 and P< 0.05, respectively). The levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were significantly reduced in the treatment groups compared to the model group ( P< 0.01). Compared to the model group, fasting insulin (FINS) levels were elevated in all groups of CRPR ( P< 0.05), and there were significantly higher levels of high-density lipoprotein cholesterol (HDL-C) in both the low-dose and high-dose CRPR groups ( P< 0.05). H&E staining indicated that CRPR treatment reduced organ enlargement, improved liver lipid accumulation, and repaired islet injury in T2DM mice. Moreover, WB analysis demonstrated that all CRPR groups significantly upregulated the protein expression of IRS1, p-GSK3β, PI3K, p-Akt and p-FOXO1( P< 0.05) as well as significantly downregulated p-IRS1 and FOXO1 protein expression ( P <0.05)., Conclusion: The present study demonstrated that CRPR effectively improves the metabolic disturbance of lipids, repairs damaged liver tissues, repairs damaged pancreatic tissues, and reduces insulin resistance (IR) in T2DM mice. The mechanism of action may be associated with upregulation of the IRS1/PI3K/AKT signaling pathway and inhibition of IRS1 phosphorylation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Mao, Song, Pan, Li, Wang, Feng and Zhang.)

One undescribed C 40 terpenoid, calomacroquinoic acid; four undescribed diterpenes, 5α,6α-epoxy-7α-hydroxyferruginol, 15-ethoxysugiol, 7-methoxy-6,7-secoabieta-8,11,13-triene-6,12-diol, and ethyl 7,8-secoabieta-11,14-dioxo-7-ate; two compounds isolated from Nature for the first time, 6β,7α-dihydroxyferruginol and 12-O-methyltaxochinon; and six known compounds were successfully identified from the bark of Taiwan incense cedar Calocedrus formosana. Structures of all isolates were elucidated by physical data (appearance, ultraviolet, infrared, specific rotation, and X-ray) and spectroscopic data (1D and 2D nuclear magnetic resonance, and high-resolution electron ionization mass spectrometry). The biosynthetic pathway of calomacroquinoic acid is also described in the current study. Nitric oxide production in lipopolysaccharide (LPS)-stimulated BV-2 microglia cells was inhibited by 6,7-dehydroferruginol, 7α,11-dihydroxy-12-methoxy-8,11,13-abietriene, and trans-communic acid. Altogether, the bark of C. formosana possessed several potential natural therapeutics against inflammation-related neuronal diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier Ltd.)

The pathogenesis of ulcerative colitis (UC) is unclear. House dust mite (HDM) is associated with immune inflammation in the body. This study is designed to identify the association between HDM and UC clinical symptoms. UC patients ( n  = 86) and non-UC control (NC) subjects ( n  = 64) were recruited. Colon lavage fluids (CLF) were collected from HDM skin prick test positive patients during colonoscopy, and analyzed by immunological approaches. HDM was detected in fecal samples, which was positively correlated with UC clinical symptoms. HDM-specific eosinophils and Th2 cells were detected in CLF, which could be specifically activated by exposing to HDM in the culture. Direct exposure to HDM induced eosinophil activation in the colon of UC patients. UC patients displayed elevated levels of Th2 cytokines in the serum. UC clinical symptom scores were positively correlated with serum levels of Th2 cytokines. HDM was detected in UC patients' stools, which was positively correlated with UC clinical symptoms. Direct exposure to HDM could trigger eosinophilic activation of the colon.

I-motifs are four-strand noncanonical secondary structures formed by cytosine (C)-rich sequences in living cells. The structural dynamics of i-motifs play essential roles in many cellular processes, such as telomerase inhibition, DNA replication, and transcriptional regulation. In cells, the structural dynamics of the i-motif can be modulated by the interaction of poly(C)-binding proteins (PCBPs), and the interaction is closely related to human health, through modulating the transcription of oncogenes and telomere stability. Therefore, the mechanisms of how PCBPs interact with i-motif structures are fundamentally important. However, the underlying mechanisms remain elusive. I-motif structures in the promoter of the c-MYC oncogene can be unfolded by heterogeneous nuclear ribonucleoprotein K (hnRNP K), a PCBP, to activate its transcription. Here, we selected this system as an example to comprehensively study the unfolding mechanisms. We found that the promoter sequence containing 5 C-runs preferred folding into type-1245 to type-1234 i-motif structures based on their folding stability, which was further confirmed by single-molecule FRET. In addition, we first revealed that the c-MYC i-motif structure was discretely resolved by hnRNP K through two intermediate states, which were assigned to the opposite hairpin and neighboring hairpin, as further confirmed by site mutations. Furthermore, we found all three KH (hnRNP K homology) domains of hnRNP K could unfold the c-MYC i-motif structure, and KH2 and KH3 were more active than KH1. In conclusion, this study may deepen our understanding of the interactions between i-motifs and PCBPs and may be helpful for drug development., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The prognostic impact of obesity on patients with atrial fibrillation (AF) remains under-evaluated and controversial., Methods: Patients with AF from the Gulf Survey of Atrial Fibrillation Events (Gulf SAFE) registry were included, who were recruited from six countries in the Middle East Gulf region and followed for 12 months. A multivariable model was established to investigate the association of obesity with clinical outcomes, including stroke or systemic embolism (SE), bleeding, admission for heart failure (HF) or AF, all-cause mortality, and a composite outcome. Restricted cubic splines were depicted to illustrate the relationship between body mass index (BMI) and outcomes. Sensitivity analysis was also conducted., Results: A total of 1,804 patients with AF and recorded BMI entered the final analysis (mean age 56.2 ± 16.1 years, 47.0% female); 559 (31.0%) were obese (BMI over 30 kg/m 2 ). In multivariable analysis, obesity was associated with reduced risks of stroke/systematic embolism [adjusted odds ratio (aOR) 0.40, 95% confidence interval (CI), 0.18-0.89], bleeding [aOR 0.44, 95%CI, 0.26-0.74], HF admission (aOR 0.61, 95%CI, 0.41-0.90) and the composite outcome (aOR 0.65, 95%CI, 0.50-0.84). As a continuous variable, higher BMI was associated with lower risks for stroke/SE, bleeding, HF admission, all-cause mortality, and the composite outcome as demonstrated by the accumulated incidence of events and restricted cubic splines. This "protective effect" of obesity was more prominent in some subgroups of patients., Conclusion: Among patients with AF, obesity and higher BMI were associated with a more favorable prognosis in the Gulf SAFE registry. The underlying mechanisms for this obesity "paradox" merit further exploration., Competing Interests: Author NA was employed by Hamad Medical Corporation. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Li, Xie, Alsheikh-Ali, AlMahmeed, Sulaiman, Asaad, Liu, Zubaid and Lip.)

New treatments for chondrosarcoma are extremely important. Chondrosarcoma is a primary malignant bone tumor with a very unfavorable prognosis. High-grade chondrosarcoma has a high potential to metastasize to any organ in the body. Platelet-derived growth factor (PDGF) is a potent angiogenic factor that promotes tumor angiogenesis and metastasis. The adipocytokine visfatin promotes metastatic potential of chondrosarcoma; however, the role of visfatin in angiogenesis in human chondrosarcoma is unclear. We report that the levels of PDGF-C expression were positively correlated with tumor stages, significantly higher than the levels of expression in normal cartilage. Visfatin increased PDGF-C expression and endothelial progenitor cell (EPC) angiogenesis through the PI3K/Akt/mTOR signaling pathway, and dose-dependently down-regulated the synthesis of miR-1264, which targets the 3'-UTR of PDGF-C. Additionally, we discovered inhibition of visfatin or PDGF-C in chondrosarcoma tumors significantly reduced tumor angiogenesis and size. Our results indicate that visfatin inhibits miR-1264 production through the PI3K/Akt/mTOR signaling cascade, and thereby promotes PDGF-C expression and chondrosarcoma angiogenesis. Visfatin may be worth targeting in the treatment of chondrosarcoma angiogenesis.