1.42A crystal structure of mini-IGF-1(2): an analysis of the disulfide isomerization property and receptor binding property of IGF-1 based on the three-dimensional structure

Insulin and insulin-like growth factor 1 (IGF-1) share a homologous sequence, a similar three-dimensional structure and weakly overlapping biological activity, but IGF-1 folds into two thermodynamically stable disulfide isomers, while insulin folds into one unique stable tertiary structure. This is a very interesting phenomenon in which one amino acid sequence encodes two three-dimensional structures, and its molecular mechanism has remained unclear for a long time. In this study, the crystal structure of mini-IGF-1(2), a disulfide isomer of an artificial analog of IGF-1, was solved by the SAD/SIRAS method using our in-house X-ray source. Evidence was found in the structure showing that the intra-A-chain/domain disulfide bond of some molecules was broken; thus, it was proposed that disulfide isomerization begins with the breakdown of this disulfide bond. Furthermore, based on the structural comparison of IGF-1 and insulin, a new assumption was made that in insulin the several hydrogen bonds formed between the N-terminal region of the B-chain and the intra-A-chain disulfide region of the A-chain are the main reason for the stability of the intra-A-chain disulfide bond and for the prevention of disulfide isomerization, while Phe B1 and His B5 are very important for the formation of these hydrogen bonds. Moreover, the receptor binding property of IGF-1 was analyzed in detail based on the structural comparison of mini-IGF-1(2), native IGF-1, and small mini-IGF-1.     

A green and effective method for the determination of metalaxyl enantiomers in tobacco and soil by supercritical fluid chromatography–tandem mass spectrometry

We reported a new methodology for the stereoselective determination of metalaxyl enantiomers in tobacco and soil. The QuEChERS (quick, easy, cheap, effective, rugged, and safe) method was used for the extraction and clean-up of the tobacco and soil samples. Separation of the metalaxyl enantiomers was performed on an ACQUITY UPC2 Trefoil CEL1 chiral column coupled with supercritical fluid chromatography with tandem mass spectrometry (SFC-MS/MS), and the run time was only 5 minutes. Under the optimized conditions, the recoveries for the enantiomers were between 78.2% and 93.3% with intraday relative standard deviations (RSDs) ranging from 1.1% to 5.4%. The limit of detection (LOD) for the enantiomers in tobacco and soil varied from 0.005 to 0.007 mg/kg, and the limit of quantitation (LOQ) ranged from 0.017 to 0.020 mg/kg. In this method, only a small amount of methanol was consumed to obtain a rapid stereoselective separation. This proposed method showed good accuracy and precision and might be suitable for fast enantioselective determination of metalaxyl in food and environmental samples. The developed method was further validated by application to the analysis of authentic samples.     

BMP2/7 heterodimer enhances osteogenic differentiation of rat BMSCs via ERK signaling compared with respective homodimers

Bone morphogenetic protein (BMP)2/7 heterodimer shows greater efficacy in enhancing bone regeneration. However, the precise mechanism and the role of mitogen-activated protein kinase (MAPK) signaling network in BMP2/7-driven osteogenesis remain ambiguous. In this study, we evaluated the effects of BMP2/7 heterodimers on osteoblastic differentiation in rat bone marrow mesenchymal stem cells (BMSCs), with the aim to elaborate how MAPKs might be involved in this cellular process by treatment of rat BMSCs with BMP2/-7 with a special signal-pathway inhibitor. We found that BMP2/7 heterodimer induced a much stronger osteogenic response in rat BMSCs compared with either homodimer. Most interestingly, extracellular signal-regulated kinase (ERK) demonstrated a highly sustained phosphorylation and activation in the BMP2/7 heterodimer treatment groups, and inhibition of ERK cascades using U0126 special inhibitor that significantly reduced the activity of ALP and calcium mineralization to a substantial degree in rat BMSCs treated with BMP2/7 heterodimers. Collectively, we demonstrate that BMP2/7 heterodimer shows a potent ability to stimulate osteogenesis in rat BMSCs. The activated ERK signaling pathway involved in this process may contribute partially to an increased osteogenic potency of heterodimeric BMP2/7 growth factors.     

Disparities in distribution of COVID-19 vaccines across US counties: A geographic information system–based cross-sectional study

BackgroundThe US Centers for Disease Control and Prevention has repeatedly called for Coronavirus Disease 2019 (COVID-19) vaccine equity. The objective our study was to measure equity in the early distribution of COVID-19 vaccines to healthcare facilities across the US. Specifically, we tested whether the likelihood of a healthcare facility administering COVID-19 vaccines in May 2021 differed by county-level racial composition and degree of urbanicity.Methods and findingsThe outcome was whether an eligible vaccination facility actually administered COVID-19 vaccines as of May 2021, and was defined by spatially matching locations of eligible and actual COVID-19 vaccine administration locations. The outcome was regressed against county-level measures for racial/ethnic composition, urbanicity, income, social vulnerability index, COVID-19 mortality, 2020 election results, and availability of nontraditional vaccination locations using generalized estimating equations.Across the US, 61.4% of eligible healthcare facilities and 76.0% of eligible pharmacies provided COVID-19 vaccinations as of May 2021. Facilities in counties with >42.2% non-Hispanic Black population (i.e., > 95th county percentile of Black race composition) were less likely to serve as COVID-19 vaccine administration locations compared to facilities in counties with <12.5% non-Hispanic Black population (i.e., lower than US average), with OR 0.83; 95% CI, 0.70 to 0.98, p = 0.030. Location of a facility in a rural county (OR 0.82; 95% CI, 0.75 to 0.90, p < 0.001, versus metropolitan county) or in a county in the top quintile of COVID-19 mortality (OR 0.83; 95% CI, 0.75 to 0.93, p = 0.001, versus bottom 4 quintiles) was associated with decreased odds of serving as a COVID-19 vaccine administration location.There was a significant interaction of urbanicity and racial/ethnic composition: In metropolitan counties, facilities in counties with >42.2% non-Hispanic Black population (i.e., >95th county percentile of Black race composition) had 32% (95% CI 14% to 47%, p = 0.001) lower odds of serving as COVID administration facility compared to facilities in counties with below US average Black population. This association between Black composition and odds of a facility serving as vaccine administration facility was not observed in rural or suburban counties. In rural counties, facilities in counties with above US average Hispanic population had 26% (95% CI 11% to 38%, p = 0.002) lower odds of serving as vaccine administration facility compared to facilities in counties with below US average Hispanic population. This association between Hispanic ethnicity and odds of a facility serving as vaccine administration facility was not observed in metropolitan or suburban counties.Our analyses did not include nontraditional vaccination sites and are based on data as of May 2021, thus they represent the early distribution of COVID-19 vaccines. Our results based on this cross-sectional analysis may not be generalizable to later phases of the COVID-19 vaccine distribution process.ConclusionsHealthcare facilities in counties with higher Black composition, in rural areas, and in hardest-hit communities were less likely to serve as COVID-19 vaccine administration locations in May 2021. The lower uptake of COVID-19 vaccinations among minority populations and rural areas has been attributed to vaccine hesitancy; however, decreased access to vaccination sites may be an additional overlooked barrier.

Inmaculada Hernandez and colleagues investigate the disparities in early-phase distribution of COVID-19 Vaccines across U.S. Counties.     

中期因子在相关疾病发病机制和治疗中的研究进展

中期因子(Midkine,MK),是一种分泌型肝素结合性生长因子,具有促进细胞有丝分裂、诱导细胞恶化、促进微血管生成、抑制细胞凋亡、促进炎症介质趋化、促纤溶等功能特点;经研究发现,当机体处于健康状态时中期因子除了肾脏及小肠上皮少量表达,其他部位极少表达,但机体出现疾病时,中期因子在体内的表达明显增多,如在多种恶性肿瘤、动脉粥样硬化、各类炎症、糖尿病肾病、高血压及COPD等疾病中均监测到中期因子的高表达,进一步研究发现上述疾病的发生发展与中期因子的功能特点密切相关;近年有学者利用MK在疾病发生发展中的功能特点对疾病进行治疗,特别是MK在肿瘤领域的治疗已成为研究热点,本文结合国内外的最新研究现状就MK与相关疾病的发病机制及治疗作一简要概述,并提出进一步研究的设想。