Lewis Acid Catalyzed Cycloaddition of Bicyclobutanes with Ynamides for the Synthesis of Polysubstituted 2-Amino-bicyclo[2.1.1]hexenes.

Synthesis of bicyclic scaffolds has gained significant attention in drug discovery due to their potential to mimic benzene bioisosteres. Here, we present a mild and scalable Sc(OTf)3-catalyzed [3+2] cycloaddition of bicyclo[1.1.0]butanes (BCBs) with ynamides, yielding a diverse array of polysubstituted 2-amino-bicyclo[2.1.1]hexenes in good to excellent yields. These products offer valuable starting materials for the construction of novel functionalized bicyclo[1.1.0]butanes. Preliminary mechanistic studies indicate that the reaction involves a nucleophilic addition of ynamides to bicyclo[1.1.0]butanes, followed by an intramolecular cyclization of in situ generated enolate and keteniminium ion. We expect that these findings will encourage utilization of complex bioisosteres and foster further investigation into BCB-based cycloaddition chemistry.

Diagnosis and Treatment of Radioactive Iodine-Induced Sialadenitis: A 10-Year Endoscopic Experience.

OBJECTIVES: The aim of this study was to explore the endoscopic characteristics of radioactive iodine-induced sialadenitis (RAIS), and to evaluate the treatment outcomes of endoscopic intervention for RAIS. STUDY DESIGN: Retrospective case series. METHODS: Eighty-two consecutive patients (11 males and 71 females) diagnosed as RAIS from Nov. 2012 to Sep. 2023 were retrospectively included. All patients underwent endoscopic exploration and intervention of the affected glands. The endoscopic features were collected, and treatment outcomes were followed-up and evaluated through post to pre-operative comparisons of gland status. RESULTS: Overall, endoscopic procedures were undertaken for 162 parotid glands (PGs) and 62 submandibular glands (SMGs). Endoscopy showed severe lumen stricture (49.3%) and ductal atresia (23.5%) in PGs, as well as severe stenosis of the anterior duct and ectasia of the proximal duct (59.7%) in SMGs. During a median six months' follow-up, the treatment outcomes of PGs were evaluated as "improvement" in 23.4%，"lesion maintenance" in 45.1% and "lesion aggravation" in 31.5% of the glands. As for SMGs, the treatment outcomes were scored as "improvement"in 29.0%，"lesion maintenance"in 54.8%, and"lesion aggravation"in 16.1% of the glands. No significant differences of treatment outcomes were found relative to RAI treatment sessions and cumulative dosage. CONCLUSION: RAIS is characteristic of severe lumen stricture and ductal atresia in PGs, and stenosis of the distal duct and ectasia of the proximal duct in SMGs. Endoscopy can alleviate clinical symptoms of RAIS and help to preserve the gland function. LEVEL OF EVIDENCE: 4 Laryngoscope, 2024.

Identifying the risk factors of ICU-acquired fungal infections: clinical evidence from using machine learning.

Background: Fungal infections are associated with high morbidity and mortality in the intensive care unit (ICU), but their diagnosis is difficult. In this study, machine learning was applied to design and define the predictive model of ICU-acquired fungi (ICU-AF) in the early stage of fungal infections using Random Forest. Objectives: This study aimed to provide evidence for the early warning and management of fungal infections. Methods: We analyzed the data of patients with culture-positive fungi during their admission to seven ICUs of the First Affiliated Hospital of Chongqing Medical University from January 1, 2015, to December 31, 2019. Patients whose first culture was positive for fungi longer than 48 h after ICU admission were included in the ICU-AF cohort. A predictive model of ICU-AF was obtained using the Least Absolute Shrinkage and Selection Operator and machine learning, and the relationship between the features within the model and the disease severity and mortality of patients was analyzed. Finally, the relationships between the ICU-AF model, antifungal therapy and empirical antifungal therapy were analyzed. Results: A total of 1,434 cases were included finally. We used lasso dimensionality reduction for all features and selected six features with importance ≥0.05 in the optimal model, namely, times of arterial catheter, enteral nutrition, corticosteroids, broadspectrum antibiotics, urinary catheter, and invasive mechanical ventilation. The area under the curve of the model for predicting ICU-AF was 0.981 in the test set, with a sensitivity of 0.960 and specificity of 0.990. The times of arterial catheter (p = 0.011, OR = 1.057, 95% CI = 1.053-1.104) and invasive mechanical ventilation (p = 0.007, OR = 1.056, 95%CI = 1.015-1.098) were independent risk factors for antifungal therapy in ICU-AF. The times of arterial catheter (p = 0.004, OR = 1.098, 95%CI = 0.855-0.970) were an independent risk factor for empirical antifungal therapy. Conclusion: The most important risk factors for ICU-AF are the six time-related features of clinical parameters (arterial catheter, enteral nutrition, corticosteroids, broadspectrum antibiotics, urinary catheter, and invasive mechanical ventilation), which provide early warning for the occurrence of fungal infection. Furthermore, this model can help ICU physicians to assess whether empiric antifungal therapy should be administered to ICU patients who are susceptible to fungal infections.

Ligamentum Teres Tears and Increased Combined Anteversion Are Associated With Hip Microinstability in Patients With Borderline Dysplasia.

PURPOSE: To investigate the differences in the prevalence of ligamentum teres (LT) tears and other radiographic measurements in borderline dysplasia of the hip (BDDH) with/without microinstability and to evaluate the associations between these imaging findings and the prevalence of microinstability in patients with BDDH. METHODS: This was a retrospective study of symptomatic patients with BDDH (18° ≤ lateral center-edge angle <25°) treated with arthroscopy in our hospital between January 2016 and December 2021. These patients were divided into the BDDH with microinstability (mBDDH) group and the stable BDDH (nBDDH) group. The radiographic parameters associated with hip joint stability, such as the state of LT, acetabular versions, femoral neck version, Tönnis angle, combined anteversions, and anterior/posterior acetabular coverage, were reviewed and analyzed. RESULTS: There were 54 patients (49 female/5 male, 26.7 ± 6.9 years) in the mBDDH group and 81 patients (74 female/7 male, 27.2 ± 7.7 years) in the nBDDH group. The mBDDH group had greater LT tear (43/54 vs 5/81) and general laxity rates, increased femoral neck version, acetabular version and combined anteversion (52.4 ± 5.9 vs 41.5 ± 7.1 at 3-o'clock level) than the nBDDH group. Binary logistic regression showed that LT tears (odds ratio 6.32, 95% confidence interval 1.38-28.8; P = .02; R2 = .458) and combined anteversion at the 3-o'clock level (odds ratio 1.42, 95% confidence interval 1.09-1.84; P < .01; R2 = .458) were independent predictors of microinstability in patients with BDDH. The cutoff value of combined anteversion at 3-o'clock level was 49.5°. In addition, LT tear was correlated with increased combined anteversion at 3-o'clock level in patients with BDDH (P < .01, η2 = 0.29). CONCLUSIONS: LT tears and increased combined anteversion at the 3-o'clock level on the acetabular clockface were associated with hip microinstability in patients with BDDH, suggesting that patients with BDDH and LT tears might have a greater prevalence of anterior microinstability. LEVEL OF EVIDENCE: Level III, case‒control study.

ITRAQ-based proteomics analysis of human ectopic endometrial stromal cells treated by Maqian essential oil.

BACKGROUND: Endometriosis is a common and complex syndrome characterized by the presence of endometrial-like tissue outside the uterus. Chinese medicine has been recently found to show good efficacy in treating endometriosis. Our previous results revealed that Maqian fruit essential oil (MQEO) could inhibit the proliferation and induce apoptosis of ectopic endometrial stromal cells (EESCs), but the mechanisms remain unclear. In this study, we aim to explore the molecular mechanism of MQEO's specific effects in EESCs. METHODS: We conducted a quantitative proteomics analysis by iTRAQ on EESCs treated with MQEO or DMSO. Then deep analysis was performed based on differentially expressed proteins, including Gene Ontology enrichment analysis, pathway enrichment analysis and protein interaction analysis. Candidate protein targets were subsequently verified by western blotting. RESULTS: Among 6575 identified proteins, 435 proteins exhibited altered expression levels in MQEO-treated EESCs. Of these proteins, most were distributed in signal transduction as well as immune system and the most significantly altered pathway was complement and coagulation cascades. Moreover, two differentially expressed proteins (Heme oxygenase 1 and Acyl-CoA 6-desaturase) were verified and they can be potential biomarkers for endometriosis treatment. CONCLUSIONS: Our proteomic analysis revealed distinct protein expression patterns induced by MQEO treatment in EESCs, highlighting the potential of MQEO for endometriosis treatment and biomarker discovery.

Long non-coding RNA X-Inactive Specific Transcript (XIST) interacting with USF2 promotes osteogenic differentiation of periodontal ligament stem cells through regulation of WDR72 transcription.

BACKGROUND: Periodontal ligament stem cells (PDLSCs) are the most potential cells in periodontal tissue regeneration and bone tissue regeneration. Our prior work had revealed that WD repeat-containing protein 72 (WDR72) was crucial for osteogenic differentiation of PDLSCs. Here, we further elucidated its underlying mechanism in PDLSC osteogenic differentiation. METHODS: Human PDLSCs, isolated and identified by flow cytometry, were prepared for osteogenic differentiation induction. Levels of WDR72, long non-coding RNA X-Inactive Specific Transcript (XIST), upstream stimulatory factor 2 (USF2), and osteogenic marker genes (Runx2, Osteocalcin, and Collagen I) in human PDLSCs and clinical specimens were detected by RT-qPCR. Protein expressions of WDR72, Runx2, Osteocalcin, and Colla1 were tested by Western blot. The interactions among the molecules were verified by RIP, RNA pull-down, ChIP, and luciferase reporter assays. Osteogenic differentiation was evaluated by alkaline phosphatase (ALP) and alizarin red staining (ARS). RESULTS: WDR72 was decreased in periodontal tissues of periodontitis patients, and overexpression reversed TNF-α-mediated suppressive effects on PDLSC osteogenic differentiation. Mechanically, XIST recruited the enrichment of USF2 to the WDR72 promoter region, thereby positively regulating WDR72. WDR72 silencing overturned XIST-mediated biological effects in PDLSCs. CONCLUSION: WDR72, regulated by the XIST/USF2 axis, enhances osteogenic differentiation of PDLSCs, implying a novel strategy for alleviating periodontitis.

Confirmation of eosinophilic sialodochitis by terminal duct biopsy.

OBJECTIVE: To analyse the histopathological features of eosinophilic sialodochitis by using terminal duct biopsy. METHODS: Sixty-five patients with suspected eosinophilic sialodochitis and four with chronic obstructive sialadenitis were prospectively enrolled. Clinical features, laboratory tests and sialograms were comparatively analysed. Terminal duct biopsy of the parotid or submandibular glands was performed concomitantly with endoscopy-assisted duct dilatation to determine the histopathological features of eosinophilic sialodochitis. RESULTS: Based on eosinophil quantification, the samples of suspected patients were scored as 'definite', 'highly suspected' and 'negative' in 26 (40%), 15 (23.1%) and 24 (36.9%) cases, respectively. Gland types and peripheral blood eosinophil counts were significantly different among these three groups. The proportions of itching glands, mucus plug exudations and elevated immunoglobulin E levels were higher in the 'definite' group than in the other two groups; however, the intergroup differences were insignificant. The primary pathological features of eosinophilic sialodochitis were abundant eosinophils and lymphocytes infiltrated around the duct, degranulation of eosinophils, extensive fibrosis and scattered mastocytes. Periductal eosinophils were not found in cases of chronic obstructive sialadenitis. CONCLUSION: Our findings suggest that terminal duct biopsy is safe and valuable for the pathological confirmation of eosinophilic sialodochitis, and can be used simultaneously with endoscopy-assisted duct dilatation.

Predictive validation of existing bleeding and thromboembolic scores in elderly patients with comorbid atrial fibrillation and acute coronary syndrome.

BACKGROUND: The validation of various risk scores in elderly patients with comorbid atrial fibrillation (AF) and acute coronary syndrome (ACS) has not been reported. The present study compared the predictive performance of existing risk scores in these patients. METHODS: A total of 1252 elderly patients with AF and ACS comorbidities (≥ 65 years old) were consecutively enrolled from January 2015 to December 2019. All patients were followed up for one year. The predictive performance of risk scores in predicting bleeding and thromboembolic events was calculated and compared. RESULTS: During the 1-year follow-up, 183 (14.6%) patients had thromboembolic events, 198 (15.8%) patients had BARC class ≥ 2 bleeding events, and 61 (4.9%) patients had BARC class ≥ 3 bleeding events. For the BARC class ≥ 3 bleeding events, discrimination of the existing risk scores was low to moderate, PRECISE-DAPT (C-statistic: 0.638, 95% CI: 0.611-0.665), ATRIA (C-statistic: 0.615, 95% CI: 0.587-0.642), PARIS-MB (C-statistic: 0.612, 95% CI: 0.584-0.639), HAS-BLED (C-statistic: 0.597, 95% CI: 0.569-0.624) and CRUSADE (C-statistic: 0.595, 95% CI: 0.567-0.622). However, the calibration was good. PRECISE-DAPT showed a higher integrated discrimination improvement (IDI) than PARIS-MB, HAS-BLED, ATRIA, and CRUSADE (P < 0.05) and the best decision curve analysis (DCA). For thromboembolic events, the discrimination of GRACE (C-statistic: 0.636, 95% CI: 0.608-0.662) was higher than CHA2DS2-VASc (C-statistic: 0.612, 95% CI: 0.584-0.639), OPT-CAD (C-statistic: 0.602, 95% CI: 0.574-0.629) and PARIS-CTE (C-statistic: 0.595, 95% CI: 0.567-0.622). The calibration was good. Compared to OPT-CAD and PARIS-CTE, the IDI of the GRACE score slightly improved (P < 0.05). However, NRI analysis showed no significant difference. DCA showed that the clinical practicability of thromboembolic risk scores was similar. CONCLUSIONS: The discrimination and calibration of existing risk scores in predicting 1-year thromboembolic and bleeding events were unsatisfactory in elderly patients with comorbid AF and ACS. PRECISE-DAPT showed higher IDI and DCA than other risk scores in predicting BARC class ≥ 3 bleeding events. The GRACE score showed a slight advantage in predicting thrombotic events.

Carnobacterium maltaromaticum boosts intestinal vitamin D production to suppress colorectal cancer in female mice.

Carnobacterium maltaromaticum was found to be specifically depleted in female patients with colorectal cancer (CRC). Administration of C. maltaromaticum reduces intestinal tumor formation in two murine CRC models in a female-specific manner. Estrogen increases the attachment and colonization of C. maltaromaticum via increasing the colonic expression of SLC3A2 that binds to DD-CPase of this bacterium. Metabolomic and transcriptomic profiling unveils the increased gut abundance of vitamin D-related metabolites and the mucosal activation of vitamin D receptor (VDR) signaling in C. maltaromaticum-gavaged mice in a gut microbiome- and VDR-dependent manner. In vitro fermentation system confirms the metabolic cross-feeding of C. maltaromaticum with Faecalibacterium prausnitzii to convert C. maltaromaticum-produced 7-dehydrocholesterol into vitamin D for activating the host VDR signaling. Overall, C. maltaromaticum colonizes the gut in an estrogen-dependent manner and acts along with other microbes to augment the intestinal vitamin D production to activate the host VDR for suppressing CRC.

Design, synthesis and evaluation of a myricetin and nobiletin hybrid compound for alleviating hyperuricemia based on metabolomics and gut microbiota.

Hyperuricemia (HUA) is the fourth most common basic metabolic disease that can cause damage to multiple organs throughout the body. In this study, a hybrid compound consisting of myricetin and nobiletin was synthesized and its biological activity was evaluated. We named the hybrid compound MNH, and its structure was confirmed by spectroscopy. This study used serum metabolomics profiling with LC/MS and 16S rRNA gene sequencing analysis to explore the anti-HUA efficacy of MNH on a yeast paste-induced mouse model. The results showed that serum uric acid (UA), creatinine (CRE) and urea nitrogen (BUN) levels were significantly decreased after the intervention of MNH. The efficacy of MNH in lowering UA was somewhat greater than that of myricetin and nobiletin. In addition, MNH could repair the renal histopathological damage. Moreover, serum metabolomics demonstrated that MNH regulated the metabolic pathways involved in glycerophospholipid metabolism, arachidonic acid metabolism and alanine etc. Furthermore, MNH supplementation restored the composition of gut microbiota with remarkable reductions in Lactobacillus and Limosilactobacillus and significant elevations in norank_f_Muribaculaceae and Bacteroides at the genus level. Taken together, these results indicated that MNH might represent a protective effect against HUA via modulating gut microbiota and metabolomics.

Correction: Formal synthesis of cyclotheonellazole A.

Correction for 'Formal synthesis of cyclotheonellazole A' by Bohua Long et al., Org. Biomol. Chem., 2023, https://doi.org/10.1039/d3ob00038a.

Concise Enantioselective Total Synthesis of Isopavine Alkaloids.

Herein, we report a concise asymmetric total synthesis of isopavine alkaloids, which feature a special azabicyclo[3.2.2]nonane tetracyclic skeleton. The key steps include iridium-catalyzed asymmetric hydrogenation of unsaturated carboxylic acids, Curtius rearrangement, and Eschweiler-Clarke methylation, which enable an enantioselective approach to isopavine alkaloids in 6-7 linear steps. Furthermore, for the first time, isopavine alkaloids, especially (-)-reframidine (3), are found to display effective antiproliferative effects on various cancer cell lines.

MiR-130a-3p regulates FUNDC1-mediated mitophagy by targeting GJA1 in myocardial ischemia/reperfusion injury.

Understanding the complex pathogenesis in myocardial ischemia/reperfusion (I/R) injury (IRI) is an urgent problem in clinical trials. Increasing pieces of evidence have suggested that miRNAs are involved in the occurrence and development of heart diseases by regulating mitochondria-related gene expression. Mitochondria have been acknowledged as the key triggers of cardiac I/R injury. However, the potential impact of miR-130a on mitochondria remains unclear in myocardial IRI. Exploring the regulatory mechanism of miR-130a on mitochondria may provide a new target for IRI therapy. In the present study, we found that miR-130a significantly increased in acute myocardial infarction (AMI) patients and myocardial I/R rats. MiR-130a could downregulate the viability of cardiomyocytes and the knockdown of miR-130a could protect the viability of cardiomyocytes under hypoxia-reoxygenation (HR). Over-expression of miR-130a resulted in mitochondrial dysfunction. It was evidenced by decreases in mitochondrial ATP production, mitochondrial membrane potential (MMP), and an increase in reactive oxygen species (ROS) production. However, suppression of miR-130a could protect against mitochondrial damage, show elevation of mitochondrial ATP production rate and MMP, and reduce ROS production. We further explored the effect of miR-130a on the mitochondrial quality control (QMC) system by determining mitochondrial-protein-specific proteases and analyzed mitochondrial morphology by fluorescence imaging and electron microscopy, respectively. It was noted that miR-130a could suppress mitochondrial fusion and FUNDC1-mediated mitophagy to accelerate myocardial IRI. Moreover, we investigated the potential miR-130a targeted mitochondria-related genes to understand the regulatory mechanism of miR-130a in the setting of myocardial IRI. It was revealed that miR-130a targeted GJA1, and GJA1 rescued IRI by enhancing ATP production rate and oxidative phosphorylation, meanwhile protecting cell viability, MMP, and activating mitophagy. In addition, the knockdown of miR-130a significantly activated FUNDC1-mediated mitophagy, while the knockdown of GJA1 reversed the relevant response. Collectively, our findings suggest that miR-130a regulates FUNDC1-mediated mitophagy by targeting GJA1 in myocardial IRI.

Primulalizipingensis (Primulaceae), a new species from Sichuan, China.

A new species, Primulalizipingensis W.B.Ju, L.Y.He & X.F.Gao, found in Shimian County, Sichuan, China, is described and illustrated. It is morphologically similar to P.rhodochroa and P.socialis, but can be distinguished from them in having shorter plants covering with white farinose, leaf margin sharply dentate above the middle, the leaf blade becomes papery after drying, scapes obsolete, the bract linear-lanceolate to subulate, solitary at the base of the pedicel, and the white hairs present inside the corolla tube.

Mechanism of heroin promoting addiction and relapse in progeny of male rats by inhibiting promoter methylation of imprinted gene H19 by down-regulating DNMT3a / 中国药理学通报

Aim To investigate the effect of heroin use in male rats of F0 generation on heroin addiction and relapse in rats of Fl generation and the underlying mechanism. Methods Male rats of F0 generation were treated with different doses of heroin (1, 3, 9 mg • kg

Predictive validation of existing bleeding and thromboembolic scores in elderly patients with comorbid atrial fibrillation and acute coronary syndrome / 老年心脏病学杂志（英文版）

BACKGROUND@#The validation of various risk scores in elderly patients with comorbid atrial fibrillation (AF) and acute coronary syndrome (ACS) has not been reported. The present study compared the predictive performance of existing risk scores in these patients.@*METHODS@#A total of 1252 elderly patients with AF and ACS comorbidities (≥ 65 years old) were consecutively enrolled from January 2015 to December 2019. All patients were followed up for one year. The predictive performance of risk scores in predicting bleeding and thromboembolic events was calculated and compared.@*RESULTS@#During the 1-year follow-up, 183 (14.6%) patients had thromboembolic events, 198 (15.8%) patients had BARC class ≥ 2 bleeding events, and 61 (4.9%) patients had BARC class ≥ 3 bleeding events. For the BARC class ≥ 3 bleeding events, discrimination of the existing risk scores was low to moderate, PRECISE-DAPT (C-statistic: 0.638, 95% CI: 0.611-0.665), ATRIA (C-statistic: 0.615, 95% CI: 0.587-0.642), PARIS-MB (C-statistic: 0.612, 95% CI: 0.584-0.639), HAS-BLED (C-statistic: 0.597, 95% CI: 0.569-0.624) and CRUSADE (C-statistic: 0.595, 95% CI: 0.567-0.622). However, the calibration was good. PRECISE-DAPT showed a higher integrated discrimination improvement (IDI) than PARIS-MB, HAS-BLED, ATRIA, and CRUSADE (P < 0.05) and the best decision curve analysis (DCA). For thromboembolic events, the discrimination of GRACE (C-statistic: 0.636, 95% CI: 0.608-0.662) was higher than CHA2DS2-VASc (C-statistic: 0.612, 95% CI: 0.584-0.639), OPT-CAD (C-statistic: 0.602, 95% CI: 0.574-0.629) and PARIS-CTE (C-statistic: 0.595, 95% CI: 0.567-0.622). The calibration was good. Compared to OPT-CAD and PARIS-CTE, the IDI of the GRACE score slightly improved (P < 0.05). However, NRI analysis showed no significant difference. DCA showed that the clinical practicability of thromboembolic risk scores was similar.@*CONCLUSIONS@#The discrimination and calibration of existing risk scores in predicting 1-year thromboembolic and bleeding events were unsatisfactory in elderly patients with comorbid AF and ACS. PRECISE-DAPT showed higher IDI and DCA than other risk scores in predicting BARC class ≥ 3 bleeding events. The GRACE score showed a slight advantage in predicting thrombotic events.

Design, synthesis and biological evaluation of a novel colchicine-magnolol hybrid for inhibiting the growth of Lewis lung carcinoma in Vitro and in Vivo.

Colchicine is a bioactive alkaloid originally from Colchicum autumnale and possesses excellent antiproliferative activity. However, colchicine-associated severe toxicity, gastrointestinal side effects in particular, limits its further therapeutic use. In the current study, we thus designed and synthesized a novel hybrid (CMH) by splicing colchicine and magnolol, a multifunctional polyphenol showing favorable gastrointestinal protection. The antitumor activity of CMH in Lewis lung carcinoma (LLC) was then evaluated in vitro and in vivo. Biologically, CMH inhibited the growth of LLC cells with an IC50 of 0.26 µM, 100 times more potently than cisplatin (26.05 µM) did. Meanwhile, the cytotoxicity of CMH was 10-fold lower than that of colchicine in normal human lung cells (BEAS-2B). In C57BL/6 mice xenograft model, CMH (0.5 mg/kg) worked as efficacious as colchicine (0.5 mg/kg) to inhibit tumor growth and 2 times more potently than cisplatin (1 mg/kg). In terms of mortality, 7 out of 10 mice died in colchicine group (0.75 mg/kg), while no death was observed in groups receiving CMH or cisplatin at 0.75 mg/kg. Mechanistic studies using Western blot revealed that CMH dose-dependently suppressed the protein expression of phosphorylated ERK. Molecular docking analysis further indicated that CMH was well fitted in the colchicine binding site of tubulin and formed several hydrogen bonds with tubulin protein. These results enable our novel hybrid CMH as a potential antineoplastic agent with lower toxicity, and provide perquisites for further investigation to confirm the therapeutic potentiality of this novel hybrid.

Efficient synthesis of novel colchicine-magnolol hybrids and evaluation of their inhibitory activity on key proteases of 2019-nCoV replication and acute lung injury.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 or 2019-nCoV), is a life-threatening infectious condition. Acute lung injury is a common complication in patients with COVID-19. 3-chymotrypsin-like protease (3CLpro) of 2019-nCoV and neutrophil elastase are critical targets of COVID-19 and acute lung injury, respectively. Colchicine and magnolol are reported to exert inhibitory effects on inflammatory response, the severe comorbidity in both COVID-19 and acute lung injury. We thus designed and synthesized a series of novel colchicine-magnolol hybrids based on a two-step synthetic sequence. It was found that these novel hybrids provided unexpected inhibition on 3CLpro and neutrophil elastase, a bioactivity that colchicine and magnolol did not possess. These findings not only provide perquisites for further in vitro and in vivo investigation to confirm the therapeutic potentiality of novel colchicine-magnolol hybrids, but also suggest that the concurrent inhibition of 3CLpro and neutrophil elastase may enable novel colchicine-magnolol hybrids as effective multi-target drug compounds.

[Characteristics of extreme temperature variation in the Loess Plateau and its correlation with average temperature]. / é»„åœŸé«˜åŽŸæžç«¯æ°”æ¸©å˜åŒ–ç‰¹å¾åŠå ¶ä¸Žå¹³å‡æ°”æ¸©çš„ç›¸å ³æ€§.

In recent decades, extreme climate occurred frequently on the Loess Plateau. It is thus particularly important to study and predict the occurrence of extreme climate. Available researches on extreme climate mainly focus on the changing characteristics of the event itself, but ignore the correlation between average temperature and its changing trend. We used linear trend estimation, Mann-Kendall test, sliding t test and Pearson correlation analy-sis to study the variation trend of extreme temperature and its correlation with average temperature on the Loess Plateau based on the daily maximum temperature, minimum temperature and average temperature data of 79 meteo-rological stations from 1986 to 2019. The results showed that the extreme warmth index in the Loess Plateau region showed a significant upward trend, the extreme cold index showed a significant downward trend, and the frequency of extreme high temperature events increased. Most of the extreme temperature indices had abrupt changes in the middle and late 1990s and in 2012, and the extreme temperature showed a downward trend from 1998 to 2012, which better responded to the phenomenon of global warming hiatus. The increasing trend of mean temperature in the gully region, the rocky mountain region and the valley plain region was more obvious than that in other regions. The stations with large trend of extreme temperature index almost all occurred in the region with large increases of mean temperature. The increases of average temperature in small increments increased the frequency of extreme high temperature event, with the change range of extreme low temperature and its rate being greater than the extreme high temperature. Climate warming on extreme temperature index had a different effect, small changes in the average temperature in the Loess Plateau made the climate transfer towards the direction of more frequent heat.

What Factors Are Associated With Postoperative Ischiofemoral Impingement After Bernese Periacetabular Osteotomy in Developmental Dysplasia of the Hip?

BACKGROUND: Any abnormal structures that contribute to the narrowing of the ischiofemoral space could induce ischiofemoral impingement. Bernese periacetabular osteotomy (PAO) medializes the hip center and, therefore, decreases contact stress on the cartilage in developmental dysplasia of the hip (DDH). However, medialization of the hip center might also narrow the ischiofemoral space, which may increase the risk of postoperative ischiofemoral impingement in patients with acetabular dysplasia who are undergoing PAO. Furthermore, the dysplastic hip has less ischiofemoral space and less space for the quadratus femoris. A few studies have focused on the amount of medialization of the hip center, but the proportion of postoperative ischiofemoral impingement after PAO has not been investigated. QUESTIONS/PURPOSES: (1) What proportion of patients develop ischiofemoral impingement after undergoing unilateral PAO for DDH? (2) What radiographic factors are associated with postoperative ischiofemoral impingement in patients who underwent PAO for DDH? (3) How much hip center medialization is safe so as to avoid postoperative ischiofemoral impingement during PAO? METHODS: Between 2014 and 2016, we treated 265 adult patients who had symptomatic residual acetabular dysplasia (lateral center-edge angle less than 20°) using PAO. During that time, we generally offered PAO to patients with acetabular dysplasia when the patients had no advanced osteoarthritis (Tönnis grade < 2). Of those, we considered only patients who underwent primary PAO without femoral osteotomy as potentially eligible. Based on that, 65% (173 of 265) were eligible; a further 9% (24 of 265) were excluded due to leg length discrepancy, spine disorders, or joint replacement in the contralateral side, and another 6% (17 of 265) of patients were lost before the minimum study follow-up of 2 years or had incomplete datasets, leaving 50% (132 of 265) for analysis in this retrospective study at a mean of 2.70 ± 0.71 years. The diagnosis of ischiofemoral impingement was defined by symptoms, MRI, and diagnostic ischiofemoral injection. We ascertained the percentage of patients with this diagnosis to answer the first research question. To answer the second question, we divided the patients into two groups: PAO patients with ischiofemoral impingement and PAO patients without ischiofemoral impingement. The demographic data and preoperative imaging parameters of patients in both groups were compared. There were statistical differences in acetabular version, ischial angle, neck-shaft angle, the presence of positive coxa profunda sign, McKibbin index, ischiofemoral space, quadratus femoris space, anterior acetabular section angle, and the net amount of hip center medialization. To investigate potential factors associated with postoperative ischiofemoral impingement in patients who underwent PAO, these factors underwent binary logistic regression analysis. To answer the third question, the cutoff value of the net amount of hip center medialization was evaluated using receiver operator characteristic curve and the Youden index method. RESULTS: We found that 26% (35 of 132) of PAO dysplastic hips had postoperative ischiofemoral impingement. After controlling for confounding variables such as acetabular version, ischial angle, femoral neck version, McKibbin index, and ischiofemoral space, we found that an increasing neck-shaft angle (odds ratio 1.14 [95% confidence interval 1.01 to 1.29]; p = 0.03), a positive coxa profunda sign (OR 0.13 [95% CI 0.03 to 0.58]; p < 0.01), and an increasing net amount of hip center medialization (OR 2.76 [95% CI 1.70 to 4.47]; p < 0.01) were associated with postoperative ischiofemoral impingement in patients with DDH who underwent PAO (R 2 = 0.73). The cutoff values of neck-shaft angle was 138.4°. The cutoff values of the net amount of hip center medialization was 1.9 mm. CONCLUSIONS: Postoperative ischiofemoral impingement could occur in patients with acetabular dysplasia who have undergone PAO after hip center medialization. An increasing neck-shaft angle, a positive coxa profunda sign on preoperative imaging, and excessive medialization of the hip center are factors associated with ischiofemoral impingement development in these patients. Therefore, we suggest that physicians measure the ischiofemoral space on a preoperative CT when patients with DDH have an increasing neck-shaft angle (> 138.4°) or a positive coxa profunda sign on radiological imaging. During PAO, the amount of hip center medialization should be carefully controlled to keep these patients from developing postoperative ischiofemoral impingement. LEVEL OF EVIDENCE: Level III, therapeutic study.