Publications by authors named "Yu Lu"

1,577 Publications

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Retinal Microvasculature and Choriocapillaris Flow Deficit in Relation to Serum Uric Acid Using Swept-Source Optical Coherence Tomography Angiography.

Transl Vis Sci Technol 2022 Aug;11(8)

Department of Rheumatology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.

Purpose: To explore the relationship between serum uric acid (SUA) and retinochoroidal microcirculation in the Chinese population.

Methods: This prospective cross-sectional study was conducted among the residents of Guangzhou, southern China. A commercially available optical coherence tomography angiography (OCTA) device was used to obtain the superficial vessel density (SVD) and deep vessel density in the retina and the choriocapillaris flow deficit (CFD) in the macular region. Univariable and multivariable linear regression models were used to assess the association of hyperuricemia and SUA levels with OCTA parameters.

Results: A total of 638 participants with normal SUA and 296 participants with hyperuricemia were included in the study. Parafoveal SVD was significantly reduced among the participants with hyperuricemia compared to participants with normal SUA (P < 0.001), while the parafoveal CFD was higher in hyperuricemic participants than those of normal SUA levels (P = 0.007). After adjusting for potential confounders, greater SUA levels was associated with lower SVD (β = -0.078; P < 0.001) and greater CFD (β = 0.015; P = 0.011). Gender difference analysis indicated that a 10-µmol/L increase in SUA levels among the female participants led to a 0.144 decrease in SVD (P < 0.001), but it was not statistically significant for the male participants (P = 0.653).

Conclusions: An elevated uric acid level and its fluctuations were independently associated with impaired retinal and choroidal microcirculation using OCTA in the study population. Women appear to be more sensitive to high SUA levels than men.

Translational Relevance: Elevating uric acid concentration may play a role in the development and progression of cardiovascular diseases through microvascular alteration, as demonstrated by OCTA parameters.
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http://dx.doi.org/10.1167/tvst.11.8.9DOI Listing
August 2022

Targeting autophagy regulation in NLRP3 inflammasome-mediated lung inflammation in COVID-19.

Clin Immunol 2022 Aug 6:109093. Epub 2022 Aug 6.

Sichuan Key Medical Laboratory of New Drug Discovery and Druggability Evaluation, Materia Medica, Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, School of Pharmacy; Education Ministry Key Laboratory of Medical Electrophysiology, School of Preclinical Medicine, Southwest Medical University, Luzhou 646000, China; State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa 99078, Macau SAR, China. Electronic address:

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Emerging evidence indicates that the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome is activated, which results in a cytokine storm at the late stage of COVID-19. Autophagy regulation is involved in the infection and replication of SARS-CoV-2 at the early stage and the inhibition of NLRP3 inflammasome-mediated lung inflammation at the late stage of COVID-19. Here, we discuss the autophagy regulation at different stages of COVID-19. Specifically, we highlighted the therapeutic potential of autophagy activators in COVID-19 by inhibiting the NLRP3 inflammasome, thereby avoiding the cytokine storm. We hope this review provides enlightenment for the use of autophagy activators targeting the inhibition of the NLRP3 inflammasome, specifically the combinational therapy of autophagy modulators with the inhibitors of the NLRP3 inflammasome, antiviral drugs, or anti-inflammatory drugs in the fight against COVID-19.
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http://dx.doi.org/10.1016/j.clim.2022.109093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9356669PMC
August 2022

Dysfunction of Ras-GAP protein AfgapA contributes to hypoxia fitness in Aspergillus fumigatus.

Curr Genet 2022 Aug 8. Epub 2022 Aug 8.

Medical Mycology Research Center, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8673, Japan.

The filamentous fungus Aspergillus fumigatus is the most important pathogenic fungus among Aspergillus species associated with aspergillosis. A. fumigatus must adapt to hypoxic microenvironments to survive and thrive in human lungs. To gain further insights into hypoxic adaptation, we generated a laboratory-evolved strain (Afs35-G20) harboring hypoxia fitness, and identified a nonsense mutation in AfgapA encoding a Ras-GAP protein, which could result in the deletion of 22 amino acids at the C-terminus. We investigated the role of AfgapA in hypoxia fitness by constructing Afs35-G20-AfgapA, and ∆AfgapA. Indeed, the hypoxia fitness of Afs35-G20 was reversed by introducing AfgapA. ∆AfgapA exhibited greater hypoxia fitness and hypervirulence in the silkworm infection model, indicating that AfgapA is responsible for hypoxia fitness, particularly in liquid cultures. Taken together, the AfgapA dysfunction may lead to the downregulation of its Ras substrate(s), reflecting several phenotypes such as increased hypoxia fitness, hypervirulence, poor conidiation, and conidial pigmentation. Here, we report the function of a Ras-GAP protein AfgapA in A. fumigatus for the first time.
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http://dx.doi.org/10.1007/s00294-022-01249-9DOI Listing
August 2022

Prophage Diversity Across and Verotoxin-Producing in Agricultural Niches of British Columbia, Canada.

Front Microbiol 2022 22;13:853703. Epub 2022 Jul 22.

Food, Nutrition and Health, The University of British Columbia, Vancouver, BC, Canada.

Prophages have long been regarded as an important contributor to the evolution of and Verotoxin-producing (VTEC), members of the that cause millions of cases of foodborne illness in North America. In . Typhimurium, prophages provide many of the genes required for invasion; similarly, in VTEC, the Verotoxin-encoding genes are located in cryptic prophages. The ability of prophages to quickly acquire and lose genes have driven their rapid evolution, leading to highly diversified populations of phages that can infect distantly-related bacterial hosts. To defend against foreign genetic materials (i.e., phages), bacteria have evolved Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) immunity, consisting of variable spacer regions that match short nucleic acid sequences of invaders previously encountered. The number of spacer regions varies widely amongst , and there is currently no clear consensus if the accumulation of spacers is linked to genomic prophage abundance. Given the immense prophage diversity and contribution to bacterial host phenotypes, we analyzed the prophage sequences within 118 strains of and VTEC, 117 of which are of agricultural origin. Overall, 130 unique prophage sequences were identified and they were found to be remarkably diverse with <50% nucleotide similarity, particularly with the Gifsy-1 group which was identified in several serovars and interestingly, a strain of VTEC. Additionally, we identified a novel plasmid-like phage that carried antibiotic resistance and bacteriocin resistance genes. The strains analyzed carried at least six distinct spacers which did not possess homology to prophages identified in the same genome. In fact, only a fraction of all identified spacers (14%) possessed significant homology to known prophages. Regression models did not discern a correlation between spacer and prophage abundance in our strains, although the relatively high number of spacers in our strains (an average of 27 in and 19 in VTEC) suggest that high rates of infection may occur in agricultural niches and be a contributing driver in bacterial evolution. Cumulatively, these results shed insight into prophage diversity of and VTEC, which will have further implications when informing development of phage therapies against these foodborne pathogens.
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http://dx.doi.org/10.3389/fmicb.2022.853703DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9355379PMC
July 2022

Evaluation of skeletal muscle perfusion changes in patients with peripheral artery disease before and after percutaneous transluminal angioplasty using multiparametric MR imaging.

Magn Reson Imaging 2022 Aug 4. Epub 2022 Aug 4.

Department of Radiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. Electronic address:

Purpose: To evaluate muscle perfusion in patients with peripheral artery disease (PAD) before and after percutaneous transluminal angioplasty (PTA) of the limb by means of MR arterial spin labeling (ASL) and intravoxel incoherent motion (IVIM) under the resting state.

Methods: Twenty-eight patients with lower extremity PAD were enrolled. Skeletal muscles in lower extremities were examined at rest by using ASL and IVIM at 3.0 T. Imaging metrics, including blood flow (BF), perfusion fraction f, diffusion coefficient D, and pseudodiffusion coefficient D, were measured in the anterior, lateral, soleus, and gastrocnemius muscle groups. Paired t-test was used to compare the imaging parameters before and after PTA. Pearson correlation analysis was conducted between imaging parameter changes and ankle brachial index (ABI) changes after PTA.

Results: ABI was significantly improved after PTA (P < 0.001). For ASL and IVIM imaging, significant changes were noted in ASL-BF and IVIM-D values in the lateral, soleus, and gastrocnemius muscle groups (all P < 0.0125) when comparing pre- and postoperative measurements. Changes in ASL-BF and IVIM-f values in the anterior muscle group, and in IVIM-D value in the anterior and soleus muscle groups after PTA, and were found to be significantly correlated with ABI improvement (all P < 0.05).

Conclusion: Multiparametric MR techniques including ASL and IVIM can detect the perfusion changes of lower limb tissue before and after PTA in patients with PAD under resting state.
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http://dx.doi.org/10.1016/j.mri.2022.08.001DOI Listing
August 2022

Molecular mechanism of Rhubarb in the treatment of non-small cell lung cancer based on network pharmacology and molecular docking technology.

Authors:
Ye-Ru Tan Yu Lu

Mol Divers 2022 Aug 6. Epub 2022 Aug 6.

The First Affiliated Hospital, Department of General Practice, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.

Non-small cell lung cancer (NSCLC) is one of the leading causes of death in the world. Rhubarb, a traditional Chinese medicine, has been widely used in the treatment of inflammatory and autoimmune diseases. This study aimed to investigate the possible mechanism of the rhubarb herb in the treatment of NSCLC by means of network pharmacology and molecular docking and to provide a theoretical basis for experiments and clinical application of traditional Chinese medicine for treating lung cancer. The main active chemical components and targets of rhubarb were screened through Swiss Target Prediction, TargetNet, and Traditional Chinese Medicine Systems Pharmacology (TCMSP) database. The protein-protein interaction (PPI) network was built via an in-depth exploration of the relationships between the proteins. The enrichment analyses of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were applied to predict the potential roles in the pathogenesis of NSCLC via the R package cluster Profiler. Potential targets and active ingredients associated with anti-tumor effects of rhubarb were screened by reverse molecular docking. By searching databases and literature, a total of 295 targets were found for the 21 active ingredients in rhubarb. There were 68 common target genes associated with NSCLC, of which 9 are derived from FDA-approved drugs. GO Gene Set Enrichment Analysis (GSEA) explored up to 1103 biological processes, 62 molecular functions, and 18 cellular components. KEGG GSEA explored 65 basic pathways, and 71 disease pathways. Four key targets (JUN, EGFR, BCL2, and JAK2) were screened through the protein-protein interaction network, target-pathway network, and FDA drug-target network. Molecular docking results showed that these key targets had relatively strong binding activities with rhubarb's active ingredients. The present study explored the potential pharmacological mechanisms of rhubarb on NSCLC, promoting the clinical application of rhubarb in treating NSCLC, and providing references for advanced research.
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http://dx.doi.org/10.1007/s11030-022-10501-wDOI Listing
August 2022

Construction and validation of the Dalian emotional movement open-source set (DEMOS).

Behav Res Methods 2022 Aug 5. Epub 2022 Aug 5.

Research Center of Brain and Cognitive Neuroscience, Liaoning Normal University, Dalian, 116029, China.

Human body movements are important for emotion recognition and social communication and have received extensive attention from researchers. In this field, emotional biological motion stimuli, as depicted by point-light displays, are widely used. However, the number of stimuli in the existing material library is small, and there is a lack of standardized indicators, which subsequently limits experimental design and conduction. Therefore, based on our prior kinematic dataset, we constructed the Dalian Emotional Movement Open-source Set (DEMOS) using computational modeling. The DEMOS has three views (i.e., frontal 0°, left 45°, and left 90°) and in total comprises 2664 high-quality videos of emotional biological motion, each displaying happiness, sadness, anger, fear, disgust, and neutral. All stimuli were validated in terms of recognition accuracy, emotional intensity, and subjective movement. The objective movement for each expression was also calculated. The DEMOS can be downloaded for free from https://osf.io/83fst/ . To our knowledge, this is the largest multi-view emotional biological motion set based on the whole body. The DEMOS can be applied in many fields, including affective computing, social cognition, and psychiatry.
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http://dx.doi.org/10.3758/s13428-022-01887-4DOI Listing
August 2022

Characteristics and sources analysis of ambient volatile organic compounds in a typical industrial park: Implications for ozone formation in 2022 Asian Games.

Sci Total Environ 2022 Aug 1:157746. Epub 2022 Aug 1.

College of Environment, Zhejiang University of Technology, Hangzhou 310014, China.

In this study, volatile organic compounds (VOCs) at a major industrial park in Yangtze River Delta Region, China, along with an urban site had been investigated for three years (2018-2020). The daily-mean concentration of total 97 VOCs in the industrial park (224.3 ± 139.1 μg/m) was about twice that of urban site (112.0 ± 64.2 μg/m). Halohydrocarbons were predominant VOCs species at both sites accounting for 39.0 % and 32.2 % in industrial and urban sites, respectively. Annual-average concentrations of total VOCs slowed down gradually in industrial park, while that of the urban site increased annually. Evident seasonal and diurnal variations were observed for VOCs concentration in both sites. Higher VOCs concentrations appeared in summer for industrial park, and high concentrations generally appeared at 8:00 and 19:00-20:00 in two sites. Diagnostic ratios of m/p-xylene to ethylbenzene indicated vehicle emissions and solvent volatilization were main sources of VOCs in industrial site during winter. Further positive matrix factorization identified fuel usage and industry source as major sources in industrial park and urban site, respectively. Ozone formation potential calculations showed aromatics contributed most to ozone formation, and benzyl chloride was a key species when its concentration was high. Further empirical kinetic modeling approach revealed ozone formation in industrial park was in VOCs-limited regime. Through air mass trajectory analysis, air pollutants especially ozone from industrial park will be transported to stadiums by northeast wind during the 2022 Asian Games. The reductions in VOCs emissions from industrials are highly recommended for ozone control in 2022 Asian Games.
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http://dx.doi.org/10.1016/j.scitotenv.2022.157746DOI Listing
August 2022

Superior Efficacy of a TBI-166, Bedaquiline, and Pyrazinamide Combination Regimen in a Murine Model of Tuberculosis.

Antimicrob Agents Chemother 2022 Aug 4:e0065822. Epub 2022 Aug 4.

Beijing Key Laboratory of Drug Resistance Tuberculosis Research, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China.

TBI-166, derived from riminophenazine analogues, shows more potent anti-TB activity than clofazimine and is being assessed against tuberculosis (TB) in a phase IIa clinical trial in China. Preclinical regimen studies containing TBI-166 will support the phase IIb clinical trials of TBI-166. In the present study, we compared the efficacy in three murine TB models of an all-oral drug-resistant TB drug regimen of TBI-166 with bedaquiline (BDQ) and pyrazinamide (PZA) with the first-line regimen of isoniazid (INH) with rifampin (RFP) and PZA (HRZ regimen), the most effective reported TBI-166-containing regimen of TBI-166 with BDQ and linezolid (LZD), and the Nix-TB clinical trial regimen of BDQ with pretomanid and LZD (BPaL regimen). In the C3HeB/FeJ murine TB model, for the TBI-166+BDQ+PZA regimen, the lungs of mice were culture negative at 4 weeks, and there were no relapses at 8 weeks of treatment. The reduction in bacterial burden and relapse rate were greater than those of the HRZ regimen and the TBI-166+BDQ+LZD regimen. Compared with the BPaL regimen, the TBI-166+BDQ+PZA regimen had similar or stronger early bactericidal activity, bactericidal activity, and sterilizing activity in the BALB/c murine TB model. The bacterial burden in the TBI-166+BDQ+PZA regimen group decreased significantly more than that in the BPaL regimen group and was almost or totally relapse free (<13.33% after 8 weeks). In conclusion, oral short-course three-drug regimens, including TBI-166 with high efficacy, were identified. The TBI-166+BDQ+PZA regimen is recommended for further study in a TBI-166 phase IIb clinical trial.
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http://dx.doi.org/10.1128/aac.00658-22DOI Listing
August 2022

Targeting microglial autophagic degradation of the NLRP3 inflammasome for identification of thonningianin A in Alzheimer's disease.

Inflamm Regen 2022 Aug 3;42(1):25. Epub 2022 Aug 3.

Sichuan Key Medical Laboratory of New Drug Discovery and Drugability Evaluation, Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, Key Laboratory of Medical Electrophysiology of Ministry of Education, School of Pharmacy, Southwest Medical University, Luzhou, 646000, China.

Background: NLRP3 inflammasome-mediated neuroinflammation plays a critical role in the pathogenesis and development of Alzheimer's disease (AD). Microglial autophagic degradation not only decreases the deposits of extracellular Aβ fibrils but also inhibits the activation of NRLP3 inflammasome. Here, we aimed to identify the potent autophagy enhancers from Penthorum chinense Pursh (PCP) that alleviate the pathology of AD via inhibiting the NLRP3 inflammasome.

Methods: At first, autophagic activity-guided isolation was performed to identify the autophagy enhancers in PCP. Secondly, the autophagy effect was monitored by detecting LC3 protein expression using Western blotting and the average number of GFP-LC3 puncta per microglial cell using confocal microscopy. Then, the activation of NLRP3 inflammasome was measured by detecting the protein expression and transfected fluorescence intensity of NLRP3, ASC, and caspase-1, as well as the secretion of proinflammatory cytokines. Finally, the behavioral performance was evaluated by measuring the paralysis in C. elegans, and the cognitive function was tested by Morris water maze (MWM) in APP/PS1 mice.

Results: Four ellagitannin flavonoids, including pinocembrin-7-O-[4″,6″-hexahydroxydiphenoyl]-glucoside (PHG), pinocembrin-7-O-[3″-O-galloyl-4″,6″-hexahydroxydiphenoyl]-glucoside (PGHG), thonningianin A (TA), and thonningianin B (TB), were identified to be autophagy enhancers in PCP. Among these, TA exhibited the strongest autophagy induction effect, and the mechanistic study demonstrated that TA activated autophagy via the AMPK/ULK1 and Raf/MEK/ERK signaling pathways. In addition, TA effectively promoted the autophagic degradation of NLRP3 inflammasome in Aβ(1-42)-induced microglial cells and ameliorated neuronal damage via autophagy induction. In vivo, TA activated autophagy and improved behavioral symptoms in C. elegans. Furthermore, TA might penetrate the blood-brain barrier and could improve cognitive function and ameliorate the Aβ pathology and the NLRP3 inflammasome-mediated neuroinflammation via the AMPK/ULK1 and Raf/MEK/ERK signaling pathways in APP/PS1 mice.

Conclusion: We identified TA as a potent microglial autophagy enhancer in PCP that promotes the autophagic degradation of the NLRP3 inflammasome to alleviate the pathology of AD via the AMPK/ULK1 and Raf/MEK/ERK signaling pathways, which provides novel insights for TA in the treatment of AD.
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http://dx.doi.org/10.1186/s41232-022-00209-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9347127PMC
August 2022

Design, Synthesis, and Biological Evaluation of Pyrrole-2-carboxamide Derivatives as Mycobacterial Membrane Protein Large 3 Inhibitors for Treating Drug-Resistant Tuberculosis.

J Med Chem 2022 Aug 1;65(15):10534-10553. Epub 2022 Aug 1.

Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Chinese Academy of Medical Sciences Key Laboratory of Anti-DR TB Innovative Drug Research, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, 1 Xian Nong Tan Street, Beijing 100050, P. R. China.

In this work, pyrrole-2-carboxamides were designed with a structure-guided strategy based on the crystal structure of MmpL3 and a pharmacophore model. The structure-activity relationship studies revealed that attaching phenyl and pyridyl groups with electron-withdrawing substituents to the pyrrole ring and attaching bulky substituents to the carboxamide greatly improved anti-TB activity. Most compounds showed potent anti-TB activity (MIC < 0.016 μg/mL) and low cytotoxicity (IC > 64 μg/mL). Compound displayed excellent activity against drug-resistant tuberculosis, good microsomal stability, almost no inhibition of the hERG K channel, and good efficacy. Furthermore, the target of the pyrrole-2-carboxamides was identified by measuring their potency against expressing wild-type and mutated variants of the gene from () and determining their effect on mycolic acid biosynthesis using a [C] acetate metabolic labeling assay. The present study provides new MmpL3 inhibitors that are promising anti-TB agents.
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http://dx.doi.org/10.1021/acs.jmedchem.2c00718DOI Listing
August 2022

Secoisolariciresinol diglucoside-derived metabolite, enterolactone, attenuates atopic dermatitis by suppressing Th2 immune response.

Int Immunopharmacol 2022 Jul 29;111:109039. Epub 2022 Jul 29.

Department of Medical Laboratory, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, Guangdong 510515, China; Microbiome Medicine Center, Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University,Guangzhou, Guangdong 510282, China. Electronic address:

Atopic dermatitis (AD) is a severe inflammatory skin disease caused by a combination of genetic, immune, and environmental factors. Intestinal microbiome disorders and changes in the immune microenvironment are associated with AD. We observed that gut bacterial metabolite enterolactone (ENL) was significantly reduced in AD model mice. Notably, patients with early childhood-onset AD exhibited decreased sera ENL level compared to the healthy controls, and the ENL level was negatively correlated with the SCORAD index. Secoisolariciresinol-diglycoside (SDG) is a natural dietary lignan of flaxseeds that can be converted by intestinal bacteria to ENL. Repeated applications of 2,4-dinitrochlorobenzene (DNCB) were performed on the ear and dorsal skin of mice to induce AD-like symptoms and skin lesions. Oral administration of SDG significantly decreased serum IgE levels and limited skin inflammation in the DNCB-induced AD mice. In addition, SDG treatment strongly limited the Th2 responses in AD mice. Moreover, we demonstrated that the IL-4 production was significantly suppressed by ENL under Th2 polarization conditions via the JAK-STAT6 signaling pathway in a concentration-dependent manner. We concluded that SDG and its derived metabolite ENL ameliorated AD development by reducing the Th2 immune response. These results suggested that SDG and ENL might be exploited as potential therapeutic candidates for AD treatment.
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http://dx.doi.org/10.1016/j.intimp.2022.109039DOI Listing
July 2022

Cooling Field Dependence of Exchange Bias in Mn-Doped Metal- Organic Framework [NH(CH)][FeFe(HCOO)].

J Phys Chem Lett 2022 Aug 29;13(31):7185-7190. Epub 2022 Jul 29.

National Laboratory of Solid State Microstructures and Department of Physics, Nanjing University, Nanjing210093, People's Republic of China.

Herein, an intriguing exchange bias (EB) effect manifesting itself from positive to negative with an increase in the cooling field () is reported in the single crystal of Mn-doped metal-organic framework (MOF) [NH(CH)][FeFe(HCOO)] () by finely tuning the exchange interactions between the magnetic ions. Note that the doping ratio of Mn relative to the total metal ions is about 15%. Negative magnetization and EB below the compensation temperature were both observed in , and the EB field () changes its sign from positive to negative when is larger than ∼10 kOe. The abnormal dependence of EB can be interpreted explicitly by a combination of negative magnetization and couplings among the ions of Fe, Fe, and Mn with varying the . This work demonstrates a tunable EB in MOFs, in favor of designing novel magnetic devices.
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http://dx.doi.org/10.1021/acs.jpclett.2c01844DOI Listing
August 2022

The Function of FoxK Transcription Factors in Diseases.

Front Physiol 2022 12;13:928625. Epub 2022 Jul 12.

Department of Pathology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.

Forkhead box (FOX) transcription factors play a crucial role in the regulation of many diseases, being an evolutionarily conserved superfamily of transcription factors. In recent years, FoxK1/2, members of its family, has been the subject of research. Even though FoxK1 and FoxK2 have some functional overlap, increasing evidence indicates that the regulatory functions of FoxK1 and FoxK2 are not the same in various physiological and disease states. It is important to understand the biological function and mechanism of FoxK1/2 for better understanding pathogenesis of diseases, predicting prognosis, and finding new therapeutic targets. There is, however, a lack of comprehensive and systematic analysis of the similarities and differences of FoxK1/2 roles in disease, prompting us to perform a literature review.
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http://dx.doi.org/10.3389/fphys.2022.928625DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9314541PMC
July 2022

In-situ fabrication of active interfaces towards FeSe as advanced performance anode for sodium-ion batteries.

J Colloid Interface Sci 2022 Jul 21;627:922-930. Epub 2022 Jul 21.

School of Materials and Energy, Guangdong University of Technology, Guangzhou 510006, Guangdong, China. Electronic address:

Transition metal selenides have gained enormous interest as anodes for sodium ion batteries (SIBs). Nonetheless, their large volume expansion causing poor rate and inferior cycle stability during Na insertion/extraction process hinders their further applications in SIBs. Herein, a confined-regulated interfacial engineering strategy towards the synthesis of FeSe microparticles coated by ultrathin nitrogen-doped carbon (NC) is demonstrated ([email protected]). The strong interfacial interaction between FeSeand NC endows [email protected] with fast electron/Na transport kinetics and outstanding structural stability, delivering unexceptionable rate capability (364 mAh/gat 10 A/g) and preeminent cycling durability (capacity retention of 100 % at 1 A/g over 1000 cycles). Furthermore, variousex situcharacterization techniques and density functional theory (DFT) calculations have been applied to demonstrate the Na storage mechanism of [email protected] The assembled NaV(PO)[email protected]//[email protected] full cell also displays a high capacity of 241 mAh/gat 1 A/g with the capacity retention of nearly 100 % over 2000 cycles, and delivers a supreme energy density of 135 Wh kg and a topmost power density of 495 W kg, manifesting the latent applications of [email protected] in the fast charging SIBs.
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http://dx.doi.org/10.1016/j.jcis.2022.07.094DOI Listing
July 2022

Design of Metal-Based Slippery Liquid-Infused Porous Surfaces (SLIPSs) with Effective Liquid Repellency Achieved with a Femtosecond Laser.

Micromachines (Basel) 2022 Jul 22;13(8). Epub 2022 Jul 22.

State Key Laboratory for Manufacturing System Engineering and Shaanxi Key Laboratory of Photonics Technology for Information, School of Electronic Science and Engineering, Xi'an Jiaotong University, Xi'an 710049, China.

Slippery liquid-infused porous surfaces (SLIPSs) have become an effective method to provide materials with sliding performance and, thus, achieve liquid repellency, through the process of infusing lubricants into the microstructure of the surface. However, the construction of microstructures on high-strength metals is still a significant challenge. Herein, we used a femtosecond laser with a temporally shaped Bessel beam to process NiTi alloy, and created uniform porous structures with a microhole diameter of around 4 µm, in order to store and lock lubricant. In addition, as the lubricant is an important factor that can influence the sliding properties, five different lubricants were selected to prepare the SLIPSs, and were further compared in terms of their sliding behavior. The temperature cycle test and the hydraulic pressure test were implemented to characterize the durability of the samples, and different liquids were used to investigate the possible failure under complex fluid conditions. In general, the prepared SLIPSs exhibited superior liquid repellency. We believe that, in combination with a femtosecond laser, slippery liquid-infused porous surfaces are promising for applications in a wide range of areas.
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http://dx.doi.org/10.3390/mi13081160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9332264PMC
July 2022

A Combination Method of Costal Cartilage Injection Techniques for Augmentation Rhinoplasty.

J Craniofac Surg 2022 Jul 26. Epub 2022 Jul 26.

17th Department of Plastic Surgery, Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shi-Jing-Shan District, Beijing, China.

Background: The multiple toothpick-shaped costal cartilage (MTCC) injection technique was introduced as an improvement based on the free diced costal cartilage (FDCC) injection technique for augmentation rhinoplasty. However, radix irregularities may occur when using the MTCC technique. Considering that the FDCC grafts are easier to shape at the nasal radix, we adopted a combination method of the 2 techniques to achieve natural and smooth contour.

Methods: Four patients accepted this method for augmentation rhinoplasty. Through a unilateral marginal incision, the costal cartilage grafts were injected for nasal augmentation at the subperiosteal plane. The FDCC grafts and the MTCC grafts were used for nasal radix and dorsum augmentation, respectively. Nasal contour was adjusted by external shaping. The follow-up ranged from 24 to 43 months.

Results: All patients were satisfied with the surgical outcome. There were no major complications occurred during the follow-up. One patient underwent rasping revision due to her own beauty-appreciation changes.

Conclusions: The combination method can take advantages of the FDCC and MTCC injection techniques. It can effectively lower the incidence of contour irregularities and graft displacement. Meanwhile, it is easy to perform without special procedure, and is time-saving and cartilage-saving.
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http://dx.doi.org/10.1097/SCS.0000000000008807DOI Listing
July 2022

Qualitative and quantitative mass spectrometry comparison of characteristic galactosyl lactose isomers from goat milk at different lactation stages.

J Dairy Sci 2022 Jul 18. Epub 2022 Jul 18.

Shaanxi Natural Carbohydrate Resource Engineering Research Center, College of Food Science and Technology, Northwest University, Xi'an 710069, China. Electronic address:

Galactooligosaccharides are composed mainly of galactosyl lactose, which is important for infant growth and as a functional food additive. Although galactosyl lactose is abundant in goat milk, its complex structure has hindered the separation and analysis of its isomers. In this study, 5 isomers of goat milk galactosyl lactose were separated by HPLC: β6'-galactosyl lactose (β6'-GL), α6'-galactosyl lactose (α6'-GL), β4'-galactosyl lactose (β4'-GL), α3'-galactosyl lactose (α3'-GL), and β3'-galactosyl lactose (β3'-GL). This composition differs from that of commercial galactooligosaccharide products, which comprise mainly β-configuration oligosaccharides. The isomers were then qualitatively and quantitatively compared at different lactation stages using online HPLC-mass spectrometry. Relative quantitative analysis showed that the total content of the 5 galactosyl lactose isomers was highest in transitional goat milk. Specifically, β3'-GL was the main isomer in colostrum and α3'-GL was the main isomer in transitional and mature milk. β6'-Galactosyl lactose and β4'-GL tended to increase and then decrease during lactation. Moreover, α3'-GL content was 2 times higher than in colostrum and 10 times higher in transitional milk than in mature milk; in contrast, for β3'-GL, the values were 5 and 2 times higher, respectively. Absolute quantitative analysis revealed that β3'-GL was the most abundant isomers in colostrum (32.3 mg/L), and α3'-GL was the most abundant in transitional milk (88.1 mg/L) and mature milk (36.3 mg/L). These findings provide an important quantitative basis for understanding the relationship between structure and function of galactosyl lactose in goat milk, as well as its exploitation as a functional food.
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http://dx.doi.org/10.3168/jds.2021-21701DOI Listing
July 2022

High-throughput screening for amyloid- binding natural small-molecules based on the combinational use of biolayer interferometry and UHPLC-DAD-Q/TOF-MS/MS.

Acta Pharm Sin B 2022 Apr 4;12(4):1723-1739. Epub 2021 Sep 4.

Sichuan Key Medical Laboratory of New Drug Discovery and Druggability Evaluation, Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, School of Pharmacy, Education Ministry Key Laboratory of Medical Electrophysiology, Southwest Medical University, Luzhou 646000, China.

Discovery of drugs rapidly and effectively is an important aspect for Alzheimer's disease (AD). In this study, a novel high-throughput screening (HTS) method aims at screening the small-molecules with amyloid- (A) binding affinity from natural medicines, based on the combinational use of biolayer interferometry (BLI) and ultra-high-performance liquid chromatography coupled with diode-array detector and quadrupole/time-of-flight tandem mass spectrometry (UHPLC-DAD-Q/TOF-MS/MS) has been firstly developed. Briefly, the components in natural medicines disassociated from biotinylated A were collected to analyze their potential A binding affinity by UHPLC-DAD-Q/TOF-MS/MS. Here, baicalein was confirmed to exhibit the highest binding affinity with A in . Moreover, polyporenic acid C (PPAC), dehydrotumulosic acid (DTA), and tumulosic acid (TA) in Kai-Xin-San (KXS) were also identified as potent A inhibitors. Further bioactivity validations indicated that these compounds could inhibit A fibrillation, improve the viability in A-induced PC-12 cells, and decrease the A content and improve the behavioral ability in . The molecular docking results confirmed that PPAC, DTA, and TA possessed good binding properties with A. Collectively, the present study has provided a novel and effective HTS method for the identification of natural inhibitors on A fibrillation, which may accelerate the process on anti-AD drugs discovery and development.
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http://dx.doi.org/10.1016/j.apsb.2021.08.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9279722PMC
April 2022

Biodegradable magnesium alloys for orthopaedic applications.

Biomater Transl 2021 28;2(3):214-235. Epub 2021 Sep 28.

School of Metallurgy and Materials, University of Birmingham, Birmingham, UK.

There is increasing interest in the development of bone repair materials for biomedical applications. Magnesium (Mg)-based alloys have a natural ability to biodegrade because they corrode in aqueous media; they are thus promising materials for orthopaedic device applications in that the need for a secondary surgical operation to remove the implant can be eliminated. Notably, Mg has superior biocompatibility because Mg is found in the human body in abundance. Moreover, Mg alloys have a low elastic modulus, close to that of natural bone, which limits stress shielding. However, there are still some challenges for Mg-based fracture fixation. The degradation of Mg alloys in biological fluids can be too rapid, resulting in a loss of mechanical integrity before complete healing of the bone fracture. In order to achieve an appropriate combination of bio-corrosion and mechanical performance, the microstructure needs to be tailored properly by appropriate alloy design, as well as the use of strengthening processes and manufacturing techniques. This review covers the evolution, current strategies and future perspectives of Mg-based orthopaedic implants.
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http://dx.doi.org/10.12336/biomatertransl.2021.03.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9255811PMC
September 2021

The Key Role of Magnetic Resonance Imaging in the Detection of Neurodegenerative Diseases-Associated Biomarkers: A Review.

Mol Neurobiol 2022 Jul 12. Epub 2022 Jul 12.

Sichuan Key Medical Laboratory of New Drug Discovery and Druggability Evaluation, Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, Southwest Medical University, Luzhou, 646000, China.

Neurodegenerative diseases (NDs), including chronic disease such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and multiple sclerosis, and acute diseases like traumatic brain injury and ischemic stroke are characterized by progressive degeneration, brain tissue damage and loss of neurons, accompanied by behavioral and cognitive dysfunctions. So far, there are no complete cures for NDs; thus, early and timely diagnoses are essential and beneficial to patients' treatment. Magnetic resonance imaging (MRI) has become one of the advanced medical imaging techniques widely used in the clinical examination of NDs due to its non-invasive diagnostic value. In this review, research published in English in current decade from PubMed electronic database on the use of MRI to detect specific biomarkers of NDs was collected, summarized, and discussed, which provides valuable suggestions for the early diagnosis, prevention, and treatment of NDs in the clinic.
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http://dx.doi.org/10.1007/s12035-022-02944-xDOI Listing
July 2022

Molecular-Scale Plasmon Trapping via a Graphene-Hybridized Tip-Substrate System.

Materials (Basel) 2022 Jul 1;15(13). Epub 2022 Jul 1.

State Key Laboratory for Manufacturing System Engineering and Shaanxi Key Laboratory of Photonics Technology for Information, School of Electronic Science and Engineering, Xi'an Jiaotong University, Xi'an 710049, China.

We theoretically investigated the plasmon trapping stability of a molecular-scale Au sphere via designing Au nanotip antenna hybridized with a graphene sheet embedded Silica substrate. A hybrid plasmonic trapping model is self-consistently built, which considers the surface plasmon excitation in the graphene-hybridized tip-substrate system for supporting the scattering and gradient optical forces on the optical diffraction-limit broken nanoscale. It is revealed that the plasmon trapping properties, including plasmon optical force and potential well, can be unprecedentedly adjusted by applying a graphene sheet at proper Fermi energy with respect to the designed tip-substrate geometry. This shows that the plasmon potential well of 218 kT at room temperature can be determinately achieved for trapping of a 10 nm Au sphere by optimizing the surface medium film layer of the designed graphene-hybridized Silica substrate. This is explained as the crucial role of graphene hybridization participating in plasmon enhancement for generating the highly localized electric field, in return augmenting the trapping force acting on the trapped sphere with a deepened potential well. This study can be helpful for designing the plasmon trapping of very small particles with new routes for molecular-scale applications for molecular-imaging, nano-sensing, and high-sensitive single-molecule spectroscopy, etc.
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http://dx.doi.org/10.3390/ma15134627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9267308PMC
July 2022

Comparative Mass Spectrometry Analysis and Immunomodulatory Effects of Casein Glycomacropeptide -Glycans in Bovine and Caprine Whey Powder.

J Agric Food Chem 2022 Jul 8;70(28):8746-8754. Epub 2022 Jul 8.

Shaanxi Natural Carbohydrate Resource Engineering Research Center, College of Food Science and Technology, Northwest University, Xi'an 710069, China.

Casein glycomacropeptide carries various -glycan modifications, which, together with variations in the amino acid composition of the glycopeptide, may result in different biological activities. In this study, -glycans of casein glycomacropeptide from bovine and caprine whey powder were qualitatively and quantitatively analyzed by LC-UV-ESI-MS/MS, and their immune activities and regulatory mechanisms were compared. -Glycans' total content was 1.54 times higher in bovine than in caprine glycomacropeptide. The glycoform H1N1S2 (H: hexose; N: -acetylgalactosamine; and S: -acetylneuraminic acid) accounted for nearly 50% of total glycomacropeptide -glycans in bovine milk but less than 20% in caprine milk. Bovine glycomacropeptide glycosylation promoted the immune activity of RAW264.7 cells, which may be linked to a higher content of disialylated -glycans. Glycomacropeptide from both milk sources significantly upregulated the mRNA expression of IL-1α, TNF-α, and IL-10 in RAW264.7 cells and activated the MAPK immunomodulatory signaling pathway. This study demonstrates the possible use of casein glycomacropeptide as an immunomodulatory agent.
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http://dx.doi.org/10.1021/acs.jafc.1c07975DOI Listing
July 2022

EPR-based enzymatic activity detection of endogenous caspase-3 in apoptosis cell lysates.

Chem Commun (Camb) 2022 Jul 28;58(61):8528-8531. Epub 2022 Jul 28.

High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei, Anhui, 230031, China.

Caspase-3 plays a vital role in cell apoptosis and related diseases. The detection and characterization of endogenous active caspase-3 are of immense value not only for mechanism studies of apoptosis but also for the diagnosis and treatment of apoptosis-related diseases. Here, an electron paramagnetic resonance (EPR)-based enzymatic assay was developed for the detection of caspase-3 activity both and in apoptosis cells. This assay uses a sandwich-like probe composed of a caspase-3-specific peptide segment (DEVD) conjugated to an EPR-detectable nitroxide spin label and magnetic beads (MBs). Cleavage of the "Nitroxide-Peptide-MBs" sandwich probe caspase-3 will release the nitroxide, which is readily detected by EPR after magnetic separation, resulting in a distinct EPR "off/on" transition. This assay takes advantage of the specific cleavage of DEVD-containing peptides by caspase-3 for high specificity, magnetic beads for fast magnetic separation, and EPR spectroscopy for considerably high detection sensitivity (LODs for caspase-3 are 116 nM at 60 min and 58 nM at 120 min). Importantly, the assay was proven to be compatible with complex biological samples and can detect the endogenous active caspase-3, thereby providing potential applications in the screening of protease-targeted drugs and the diagnosis of protease-associated diseases.
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http://dx.doi.org/10.1039/d2cc02361jDOI Listing
July 2022

Plant invasion reconstructs soil microbial assembly and functionality in coastal salt marshes.

Mol Ecol 2022 Jul 5. Epub 2022 Jul 5.

Qilu University of Technology (Shandong Academy of Sciences), Ji' nan, China.

Microbiologically driven ecosystem processes can be profoundly altered by alien plant invasions. There is limited understanding of the ecological mechanisms orchestrating different microbial constituents and their roles in emerging functional properties under plant invasions. Here, we investigated soil microbial communities and functions using high-throughput amplicon sequencing and GeoChip technology, respectively, along a chronological gradient of smooth cordgrass invasion in salt marshes located in the Yellow River Estuary, China. We found a positive correlation between microbial diversity and the duration age of invasion, and both bacterial and fungal communities showed consistent changes with invasion. Soil microbial metabolic potential, as indicated by the abundance of microbial functional genes involved in biogeochemical cycling, decreased in response to invasion. As a consequence, declining soil microbial metabolisms as a result of plant invasion facilitated carbon accumulation in invaded salt marshes. Bacteria and fungi exhibited distinct contributions to assembly processes along the invasion gradient: bacterial communities were mainly driven by selection and dispersal limitation, while fungi were dramatically shaped by stochastic processes. Soil microbial-mediated functions were taxon-specific, as indicated by community-function relationships. This study demonstrates the distinct contributions of microbial constituents to microbial community assembly and functions and sheds light on the implications of plant invasion on microbiologically driven ecosystem processes in coastal wetlands.
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http://dx.doi.org/10.1111/mec.16600DOI Listing
July 2022

Citri Reticulatae Semen extract promotes healthy aging and neuroprotection via autophagy induction in Caenorhabditis elegans.

J Gerontol A Biol Sci Med Sci 2022 Jul 5. Epub 2022 Jul 5.

Sichuan Key Medical Laboratory of New Drug Discovery and Drugability Evaluation, Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, Key Laboratory of Medical Electrophysiology of Ministry of Education, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China.

Nutrition intervention has emerged as a potential strategy to delay aging and promote healthy longevity. Citri Reticulatae Semen (CRS) has diverse beneficial effects and has been used for thousands of years to treat pain. However, the health benefits of CRS in prolonging healthspan and improving aging-related diseases and the exact mechanisms remain poorly characterized. In this study, Caenorhabditis elegans (C. elegans) was used as a model organism to study the anti-aging and healthspan promoting activities of 75% ethanol extract of CRS (CRSE). The results showed that treatment with CRSE at 1000 μg/mL significantly extended the lifespan of worms by 18.93% without detriment to healthspan and fitness, as evidenced by the delayed aging-related phenotypes and increased body length and width and reproductive output. In addition, CRSE treatment enhanced the ability of resistance under heat, oxidative, and pathogenic bacterial stress. Consistently, heat shock proteins and antioxidant enzyme-related and pathogenesis-related (PR) genes were up-regulated by CRSE treatment. Furthermore, CRSE supplementation also improved α-synuclein, 6-OHDA, and polyQ40-induced pathologies in transgenic C. elegans models of Parkinson's disease (PD) and Huntington's disease (HD). The mechanistic study demonstrated that CRSE induced autophagy in worms, while the RNAi knockdown of 4 key autophagy-related genes including lgg-1, bec-1, vps-34, and unc-51 remarkably abrogated the beneficial effects of CRSE on the extending of lifespan and healthspan and neuroprotection, demonstrating that CRSE exerts beneficial effects via autophagy induction in worms. Together, our current findings provide new insights into the practical application of CRS for the prevention of aging and aging-related diseases.
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http://dx.doi.org/10.1093/gerona/glac136DOI Listing
July 2022

Impaired Sensitivity to Thyroid Hormones Is Associated With Elevated Blood Glucose in Coronary Heart Disease.

Front Endocrinol (Lausanne) 2022 15;13:895843. Epub 2022 Jun 15.

Tianjin University of Traditional Chinese Medicine, Tianjin, China.

Context: Thyroid hormones influence glucose homeostasis through central and peripheral regulation. To date, the association between thyroid hormone sensitivity and elevated blood glucose (EBG) in patients with coronary heart disease (CHD) remains unknown. The purpose of this study was to investigate the association between thyroid hormone sensitivity and risk of EBG in patients with CHD, and to further explore their association in different sexes and ages.

Methods: This large multicenter retrospective study included 30,244 patients with CHD (aged 30-80 years) between 1 January 2014 and 30 September 2020. Parameters representing central and peripheral sensitivity to thyroid hormones were calculated. Central sensitivity to thyroid hormones was assessed by calculating the Thyroid Feedback Quantile-based Index (TFQI), Thyroid-stimulating Hormone Index (TSHI), and Thyrotropin Thyroxine Resistance Index (TT4RI), and Parametric Thyroid Feedback Quantile-based Index (PTFQI); peripheral sensitivity to thyroid hormones was evaluated using the ratio of free triiodothyronine (FT3) /free thyroxine (FT4). Taking normal glucose tolerance (NGT) as a reference, logistic regression was used to analyse the relationship between central and peripheral thyroid hormone sensitivity and EBG in patients with CHD.

Results: Among the 30,244 participants, 15,493 (51.23%) had EBG. The risk of EBG was negatively correlated with TSHI (OR: 0.91; 95%CI: 0.91 to 0.92; < 0.001), TT4RI (OR: 0.99; 95% CI: 0.99 to 0.99; <0.001), TFQI (OR: 0.82; 95%CI: 0.80 to 0.84; 0.001) and PTFQI (OR: 0.76; 95%CI: 0.74 to 0.78; <0.001). Compared to males and patients aged 60 and below, the OR value for EBG was lower in females and in patients aged over 60 years old. Conversely, EBG risk was positively associated with FT3/FT4 (OR: 1.08; 95% CI: 1.07 to 1.09; 0.001) and in the sex-categorized subgroups, males had higher OR values than females.

Conclusions: This study showed that thyroid hormone sensitivity is significantly associated with EBG in patients with CHD. This association is higher in females than in males, and the association in those aged over 60 years old is higher than that in patients aged 60 years and below.
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http://dx.doi.org/10.3389/fendo.2022.895843DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9240192PMC
June 2022

Changes in target ability of nanoparticles due to protein corona composition and disease state.

Asian J Pharm Sci 2022 May 4;17(3):401-411. Epub 2022 Apr 4.

Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610064, China.

Many studies have shown the influence of protein corona (PC) on the active targeting capability of ligand-modified nanoparticles; however, the influence of clinical status on PC composition and targeting capacity is rarely discussed. In this study, when transferrin-modified PEGylated polystyrene nanoparticles (Tf-PNs) is intravenously injected into mice with non-small cell lung cancer (NSCLC) comorbid with type 2 diabetes mellitus (T2DM), more Tf-PNs accumulated in the tumor tissue than in those of NSCLC model mice. This indicated that PC derived from different states of disease changed the active targeting ability of Tf-PNs. To explain the occurrence of this phenomenon, our analysis of PC from different disease states revealed that Tf (transferrin) modification had no significant effect on the formation of PC, and that the PC from the NSCLC comorbid with T2DM model contained more proteins like fibrin and clusterin. This work demonstrates the impacts of comorbidity, such as with T2DM, on the active targeting capability of ligand-modified nanoparticles, and the results promote the application of nanoparticles for precision medicine.
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http://dx.doi.org/10.1016/j.ajps.2022.03.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9237596PMC
May 2022

The splicing factor RBM17 drives leukemic stem cell maintenance by evading nonsense-mediated decay of pro-leukemic factors.

Nat Commun 2022 Jul 4;13(1):3833. Epub 2022 Jul 4.

Department of Medicine, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada.

Chemo-resistance in acute myeloid leukemia (AML) patients is driven by leukemic stem cells (LSCs) resulting in high rates of relapse and low overall survival. Here, we demonstrate that upregulation of the splicing factor, RBM17 preferentially marks and sustains LSCs and directly correlates with shorten patient survival. RBM17 knockdown in primary AML cells leads to myeloid differentiation and impaired colony formation and in vivo engraftment. Integrative multi-omics analyses show that RBM17 repression leads to inclusion of poison exons and production of nonsense-mediated decay (NMD)-sensitive transcripts for pro-leukemic factors and the translation initiation factor, EIF4A2. We show that EIF4A2 is enriched in LSCs and its inhibition impairs primary AML progenitor activity. Proteomic analysis of EIF4A2-depleted AML cells shows recapitulation of the RBM17 knockdown biological effects, including pronounced suppression of proteins involved in ribosome biogenesis. Overall, these results provide a rationale to target RBM17 and/or its downstream NMD-sensitive splicing substrates for AML treatment.
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http://dx.doi.org/10.1038/s41467-022-31155-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9250932PMC
July 2022

Scenarios and sustainability of the economy-nitrogen-resource-environment system using a system dynamic model on the Qinghai-Tibet Plateau.

J Environ Manage 2022 Sep 28;318:115623. Epub 2022 Jun 28.

Faculty of Geographical Science, Beijing Normal University, Beijing, 100875, China.

Nitrogen (N) plays a vital role in the development of crop production and animal husbandry in agricultural and pastoral areas. However, the irrational utilization of N resources and subsequent environmental issues with rapid economic development has attracted wide public attention. Coordinating the economy-N-resource-environment (ENRE) system is of great importance for regional sustainable development. In this study, the dynamics of the ENRE system of a typical agricultural and pastoral area on the Qinghai-Tibet Plateau (QTP) were simulated using the VENSIM software from 1998 to 2018. Four typical scenarios (current development scenario, economic development scenario, environment protection scenario and resource optimization scenario) are established to assess the sustainability level and the coupling coordination degrees (CCDs) of the three subsystems, i.e., the economy, N-resource and environment subsystems from 2019 to 2030. Our study indicates that the N flow-based system dynamics (SD) model connects the different subsystems of the ENRE system together well and allows different scenario simulations. From 2019 to 2030, the ENRE system is at a weak sustainability level during the simulation period, and the three subsystems are at slightly unbalanced stages of development in terms of CCD level. The sustainability and CCD levels of the four examined scenarios are as follows: resource optimization scenario > economic development scenario > environment protection scenario >current development scenario, with average values of 0.45, 0.37; 0.42, 0.36; 0.41, 0.35; and 0.39, 0.34, respectively. Under the resource optimization scenario, reducing N inputs to food production and consumption and reducing the planting area of cash crops can effectively improve the N use efficiency of the food chain in the N-resource subsystem (15.34% from 2019 to 2030 on average). Our results provide a reference for promoting sustainable development and formulating policies in agricultural and pastoral regions.
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http://dx.doi.org/10.1016/j.jenvman.2022.115623DOI Listing
September 2022
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