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Minimizing the ratio of ionizable lipid in lipid nanoparticles for in vivo base editing

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National Science Review 2024年第6期11卷 285-293页

作者： Qiubing Chen Xuebin Wang Yizhou Zhang Ming Tian Junyi Duan Ying Zhang Hao Yin Departments of Urology and Laboratory Medicine Frontier Science Center for Immunology and Metabolism Medical Research InstituteZhongnan Hospital of Wuhan UniversityWuhan University State Key Laboratory of Virology Tai Kang Center for Life and Medical Sciences Tai Kang Medical SchoolWuhan University Department of Rheumatology and Immunology Zhongnan Hospital of Wuhan UniversityWuhan University Wuhan Research center for Infectious Diseases and Cancer Chinese Academy of Medical Sciences RNA Institute Wuhan University

Lipid nanoparticles(LNPs) have gained clinical approval as carriers for both siRNA and mRNA. Among the crucial components of LNPs, ionizable lipids play a pivotal role in determining the efficiency of RNA delivery. In this study, we synthesized a series of ionizable lipids, denoted as HTO, with a higher count of hydroxyl groups compared to SM-102. Remarkably, LNPs based on HTO12 lipid demonstrated comparable mRNA delivery efficiency and biosafety to those based on SM-102. However, the former reduced the ratio of ionizable lipid/total lipids to mRNA in LNPs by 2.5 times compared to SM-102. The HTO12 LNP efficiently encapsulated adenine base editor mRNA and sgRNA targeting Pcsk9, leading to substantial gene editing within the liver of mice and effective reduction of the target protein. Our study underscores that ionizable lipids with multiple hydroxyl groups may facilitate an improved lipid-to-mRNA ratio to minimize the dosage of ionizable lipids for in vivo delivery.

关键词： ionizable lipid lipid nanoparticle mRNA delivery base editor delivery Pcsk9

Decision-Making and Management of Self-Care in Persons with Traumatic Spinal Cord Injuries: A Preliminary Study

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Journal of Behavioral and Brain Science 2024年第2期14卷 47-63页

作者： Paul E. Plonski Jasmin Vassileva Ryan Shahidi Paul B. Perrin William Carter Lance L. Goetz Amber Brochetti James M. Bjork Institute for Drug and Alcohol Studies Virginia Commonwealth University Richmond VA USA Richmond veterans affairs medical center Richmond VA USA Department of Psychiatry Virginia Commonwealth University Richmond VA USA Department of Psychology Virginia Commonwealth University Richmond VA USA Department of Physical Medicine and Rehabilitation Virginia Commonwealth University Richmond VA USA Department of Spinal Cord Injury Cleveland Veterans Affairs Medical Center Cleveland OH USA Department of Pharmacology and Toxicology Virginia Commonwealth University Richmond VA USA

Patients and physicians understand the importance of self-care following spinal cord injury (SCI), yet many individuals with SCI do not adhere to recommended self-care activities despite logistical supports. Neurobehavioral determinants of SCI self-care behavior, such as impulsivity, are not widely studied, yet understanding them could inform efforts to improve SCI self-care. We explored associations between impulsivity and self-care in an observational study of 35 US adults age 18 - 50 who had traumatic SCI with paraplegia at least six months before assessment. The primary outcome measure was self-reported self-care. In LASSO regression models that included all neurobehavioral measures and demographics as predictors of self-care, dispositional measures of greater impulsivity (negative urgency, lack of premeditation, lack of perseverance), and reduced mindfulness were associated with reduced self-care. Outcome (magnitude) sensitivity, a latent decision-making parameter derived from computationally modeling successive choices in a gambling task, was also associated with self-care behavior. These results are preliminary;more research is needed to demonstrate the utility of these findings in clinical settings. Information about associations between impulsivity and poor self-care in people with SCI could guide the development of interventions to improve SCI self-care and help patients with elevated risks related to self-care and secondary health conditions.

关键词： Spinal Cord Injury Self-Care Decision-Making Paraplegia Impulsive Behavior Health Care

Current knowledge for the risk factors of early permanent pacemaker implantation following transcatheter aortic valve replacement and what is next for the primary prevention?

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World Journal of Cardiology 2024年第2期16卷 54-57页

作者： Gen-Min Lin Wei-Chun Huang Chih-Lu Han Department of Medicine Hualien Armed Forces General HospitalHualien 970Taiwan Cardiovascular center Kaohsiung Veterans General HospitalKaohsiung 81346Taiwan Department of Medicine Taipei Veterans General HospitalTaipei 112Taiwan

In this editorial,we comprehensively summarized the preoperative risk factors of early permanent pacemaker implantation after transcatheter aortic valve replacement(TAVR)among patients with severe aortic stenosis from several renowned clinical studies and focused on the primary prevention of managing the modifiable factors,e.g.,paroxysmal atrial fibrillation before the TAVR.

关键词： Permanent pacemaker implantation Transcatheter aortic valve replacement Interventricular conduction delay Diabetes Supraventricular arrhythmia

Reduction of epinephrine in the lumbar spinal cord following repetitive blast-induced traumatic brain injury in rats

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Neural Regeneration Research 2024年第7期19卷 1548-1552页

作者： Shigeharu Tsuda Mustafa Golam Jiamei Hou Kevin K.W.Wang Floyd J.Thompson Prodip Bose Brain Rehabilitation Research center Malcom Randall VA Medical CenterNorth Florida/South Georgia Veterans Health SystemGainesvilleFLUSA Department of Anesthesiology College of MedicineUniversity of FloridaGainesvilleFLUSA Department of Emergency Medicine University of FloridaGainesvilleFLUSA Department of Neuroscience University of FloridaGainesvilleFLUSA Department of Neurology University of FloridaGainesvilleFLUSA

Traumatic brain inju ry-induced unfavorable outcomes in human patients have independently been associated with dysregulated levels of monoamines,especially epinephrine,although few preclinical studies have examined the epinephrine level in the central nervous system after traumatic brain *** has been shown to regulate the activities of spinal motoneurons as well as increase the heart rate,blood pressure,and blood flow to the hindlimb ***,the purpose of the present study was to determine the impact of repeated blast-induced traumatic brain injury on the epinephrine levels in seve ral function-s pecific central nervous system regions in *** three repeated blast injuries at 3-day intervals,the hippocampus,motor cortex,locus coeruleus,vestibular nuclei,and lumbar spinal cord were harvested at post-injury day eight and processed for epinephrine assays using a high-sensitive electrochemical detector cou pled with high-performance liquid *** results showed that the epinephrine levels were significantly decreased in the lumbar spinal cord tissues of blast-induced traumatic brain injury animals compared to the levels detected in age-and sex-matched sham *** other function-specific central nervous system regions,although the epinephrine levels were slightly altered following blast-induced tra u matic brain injury,they were not statistically *** results suggest that blast injury-induced significant downregulation of epinephrine in the lumbar spinal cord could negatively impact the motor and cardiovascular *** is the first repo rt to show altered epinephrine levels in the spinal cord following repetitive mild blast-induced traumatic brain injury.

关键词： balance blood flow cardiovascular system central nervous system epinephrine ischemic damage lumbar spinal cord muscle tone repeated blast spasticity traumatic brain injury

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SARS-CoV-2 spike protein-ACE2 interaction increases carbohydrate sulfotransferases and reduces N-acetylgalactosamine-4-sulfatase by p38 MAPK

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Signal Transduction and Targeted Therapy 2024年第3期9卷 1174-1185页

作者： Sumit Bhattacharyya Joanne K.Tobacman Jesse Brown VA medical center and University of Illinois at Chicago ChicagoIL 60612USA

Immunostaining in lungs of patients who died with CovID-19 infection showed increased intensity and distribution of chondroitin sulfate and decline in N-acetylgalactostamine-4-sulfatase(Arylsulfatase B;ARSB).To explain these findings,human small airway epithelial cells were exposed to the SARS-CoV-2 spike protein receptor binding domain(SPRBD)and transcriptional mechanisms were ***-p38 MAPK and phospho-SMAD3 increased following exposure to the SPRBD,and their inhibition suppressed the promoter activation of the carbohydrate sulfotransferases CHST15 and CHST11,which contributed to chondroitin sulfate *** in ARSB was mediated by phospho-38 MAPK-induced N-terminal Rb phosphorylation and an associated increase in Rb-E2F1 binding and decline in E2F1 binding to the ARSB *** increases in chondroitin sulfotransferases were inhibited when treated with phospho-p38-MAPK inhibitors,SMAD3(SIS3)inhibitors,as well as antihistamine desloratadine and antibiotic *** the mouse model of carrageenan-induced systemic inflammation,increases in phosphop38 MAPK and expression of CHST15 and CHST11 and declines in DNA-E2F binding and ARSB expression occurred in the lung,similar to theobserved effects in this SPRBD model of COVID-19 *** accumulation of chondroitin sulfates is associated with fibrotic lung conditions and diffuse alveolar damage,increased attention to p38-MAPK inhibition may be beneficial in amelioratingCovid-19infections.

关键词： ACE2 lung inhibited

Genome-wide Studies Reveal Genetic Risk Factors for Hepatic Fat Content

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Genomics, Proteomics & Bioinformatics 2024年第2期22卷 57-68页

作者： Yanni Li Eline H.van den Berg Alexander Kurilshikov Dasha V.Zhernakova Ranko Gacesa Shixian Hu Esteban A.Lopera-Maya Alexandra Zhernakova Lifelines Cohort Study Vincent E.de Meijer Serena Sanna Robin P.F.Dullaart Hans Blokzijl Eleonora A.M.Festen Jingyuan Fu Rinse K.Weersma Department of Gastroenterology and Hepatology University of GroningenUniversity Medical Center GroningenGroningen 9713 GZThe Netherlands Department of Genetics University of GroningenUniversity Medical Center GroningenGroningen 9713 GZThe Netherlands Department of Gastroenterology and Hepatology Tianjin Medical University General HospitalTianjin Medical UniversityTianjin 300052China Laboratory of Genomic Diversity Center for Computer TechnologiesITMO UniversitySaint Petersburg 199034Russia Institute of Precision Medicine the First Affiliated HospitalSun Yat-sen UniversityGuangzhou 510080China Department of Surgery Section of Hepatobiliary Surgery and Liver TransplantationUniversity of GroningenUniversity Medical Center GroningenGroningen 9713 GZThe Netherlands Department of Endocrinology University of GroningenUniversity Medical Center GroningenGroningen 9713 GZThe Netherlands Department of Pediatrics University of GroningenUniversity Medical Center GroningenGroningen 9713 GZThe Netherlands 不详

Genetic susceptibility to metabolic associated fatty liver disease(MAFLD)is complex and poorly *** characterization of the genetic background of hepatic fat content would provide insights into disease etiology and causality of risk *** performed genome-wide association study(GWAS)on two noninvasive definitions of hepatic fat content:magnetic resonance imaging proton density fat fraction(MRI-PDFF)in 16,050 participants and fatty liver index(FLI)in 388,701 participants from the United Kingdom(UK)Biobank(UKBB).Heritability,genetic overlap,and similarity between hepatic fat content phenotypes were analyzed,and replicated in 10,398 participants from the University medical center Groningen(UMCG)Genetics Lifelines Initiative(UGLI).Meta-analysis of GWASs of MRI-PDFF in UKBB revealed five statistically significant loci,including two novel genomic loci harboring CREB3L1(rs72910057-T,P=5.40E−09)and GCM1(rs1491489378-T,P=3.16E−09),respectively,as well as three previously reported loci:PNPLA3,TM6SF2,and *** of FLI in UKBB identified 196 genome-wide significant loci,of which 49 were replicated in UGLI,with top signals in ZPR1(P=3.35E−13)and FTO(P=2.11E−09).Statistically significant genetic correlation(rg)between MRI-PDFF(UKBB)and FLI(UGLI)GWAS results was found(rg=0.5276,P=1.45E−03).Novel MRI-PDFF genetic signals(CREB3L1 and GCM1)were replicated in the FLI *** identified two novel genes for MRI-PDFF and 49 replicable loci for *** a difference in hepatic fat content assessment between MRI-PDFF and FLI,a substantial similar genetic architecture was *** is identified as an easy and reliable approach to study hepatic fat content at the population level.

关键词： Hepatic fat content MAFLD Genome-wide association study Fatty liver index Magnetic resonance imaging proton density fat fraction

Modifications in aroma characteristics of'Merlot'dry red wines aged in American,French and Slovakian oak barrels with different toasting degrees

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Food Science and Human Wellness 2024年第1期13卷 381-391页

作者： Haocheng Lu Binhao Cheng Yibin Lan Changqing Duan Fei He center for Viticulture and Enology College of Food Science and Nutritional EngineeringChina Agricultural UniversityBeijing 100083China Key Laboratory of Viticulture and Enology Ministry of Agriculture and Rural AffairsBeijing 100083China

Aging in oak barrels is widely used in enology which could bring flavor changes and aromatic complexity to *** the present study,the aroma compounds were analyzed from the‘Merlot’dry red wines,which were fermented in two types of fermenters(stainless steel tank and rotated oak barrel)and aged in six types of oak barrels(three geographic origins×two toasting degrees)for different time(0,3,6 and 9 months,respectively).Results showed that 30 volatiles were associated with barrels and increased during oak *** fermenters could influence the intensities of the toast,leathery,smoky,fruity,floral and caramel *** concentration of whisky lactone,eugenol,cis-isoeugenol,and the intensities of the toast and spicy aromas were highest in the wines aged in American oak and were lowest in the wines aged in French oak *** concentrations of guaiacol,syringol,trans-isoeugenol,furfural alcohol,vanilla,cis-whisky lactone enabled the medium toasting barrels to be distinguished from the light toasting *** compounds originating from the barrels could be used to distinguish the types of different barrels,but the other general grape-derived and fermentation-derived volatiles could *** fermenters,oak species and toasting degrees of the barrels all had significant effects on the aroma profiles of the aged‘Merlot’dry red wines,but the influence of the geographic origin was not obvious.

关键词： Wine Aroma Oak Barrel Oak species Toasting degrees Geographic origin Aging

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Gas-propelled nanomotors alleviate colitis through the regulation of intestinal immunoenvironment-hematopexis-microbiota circuits

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Acta Pharmaceutica Sinica B 2024年第6期14卷 2732-2747页

作者： Bo Xiao Yuqi Liang Ga Liu Lingshuang Wang Zhan Zhang Libin Qiu Haiting Xu Sean Carr Xiaoxiao Shi Rui LReis Subhas CKundu Zhenghua Zhu Department of Gastroenterology the First Affiliated Hospital of Nanchang UniversityNanchang 330006China College of Sericulture Textileand Biomass SciencesSouthwest UniversityChongqing 400715China Department of Neurology School of MedicineEmory UniversityAtlantaGA 30322USA Atlanta veterans affairs medical center DecaturGA 30033USA Department of Surgery School of MedicineEmory UniversityAtlantaGA 30322USA Bs Research Group I3Bs—Research Institute on BiomaterialsBiodegradables and BiomimeticsUniversity of MinhoHeadquarters of the European Institute of Excellence on Tissue Engineering and Regenerative MedicineAveParkBarcoGuimaraes 4805-017Portugal

The progression of ulcerative colitis(UC)is associated with immunologic derangement,intestinal hemorrhage,and microbiota *** traditional medications mainly focus on mitigating inflammation,it remains challenging to address multiple ***,a versatile gas-propelled nanomotor was constructed by mild fusion of post-ultrasonic CaO_(2) nanospheres with Cu_(2)O *** resulting CaO_(2)–Cu_(2)O possessed a desirable diameter(291.3 nm)and a uniform size *** could be efficiently internalized by colonic epithelial cells and macrophages,scavenge intracellular reactive oxygen/nitrogen species,and alleviate immune reactions by pro-polarizing macrophages to the anti-inflammatory M2 *** nanomotor was found to penetrate through the mucus barrier and accumulate in the colitis mucosa due to the driving force of the generated oxygen *** administration of CaO_(2)–Cu_(2)O could stanch the bleeding,repair the disrupted colonic epithelial layer,and reduce the inflammatory responses through its interaction with the genes relevant to blood coagulation,anti-oxidation,wound healing,and ***,it restored intestinal microbiota balance by elevating the proportions of beneficial bacteria(e.g.,Odoribacter and Bifidobacterium)and decreasing the abundances of harmful bacteria(e.g.,Prevotellaceae and Helicobacter).Our gas-driven CaO_(2)–Cu_(2)O offers a promising therapeutic platform for robust treatment of UC via the rectal route.

关键词： Nanomotor Anti-inflammation Blood coagulation Immune regulation Hematopexis Microbiota rebalance Ulcerative colitis Rectal administration

A vision system based on CNN-LSTM for robotic citrus sorting Author links open overlay panel

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Information Processing in Agriculture 2024年第1期11卷 14-25页

作者： Yonghua Yu Xiaosong An Jiahao Lin Shanjun Li Yaohui Chen College of Engineering Huazhong Agricultural UniversityWuhan 430070China Key Laboratory of Agricultural Equipment in Mid-Lower Yangtze River Ministry of Agriculture and Rural AffairsWuhan 430070China National R&D center for Citrus Preservation Wuhan 430070China Citrus Mechanization Research Base Ministry of Agriculture and Rural AffairsWuhan 430070China

Compared with manual sorting of citrus fruit,vision-based sorting solutions can help achieve higher accuracy and *** this study,we present a vision system based on CNN-LSTM,which can cooperate with robotic grippers for real-time sorting and is readily applicable to various citrus processing plants.A CNN-based detector was adopted to detect the defective oranges in view and temporarily classify them into corresponding types,and an LSTM-based predictor was used to predict the position of the oranges in a future frame based on image sequential *** fusion of CNN and LSTM networks enabled the system to track defective ones during rotation and identify their true types,and their future path was also predicted which is vital for predictive control of visually guided robotic *** detection accuracy of 94.1%was obtained based on experimental results,and the error for path prediction was within 4.33 pixels 40 frames *** average time to process a frame was between 28 and 62 frames per second,which also satisfied real-time *** results proved the potential of the proposed system for automated citrus sorting with good precision and efficiency,and it can be readily extended to other fruit crops featuring high versatility.

关键词： Deep learning Long short-term memory Vision system Online citrus sorting Path prediction