3-Amide-ß-carbolines block the cell cycle by targeting CDK2 and DNA in tumor cells potentially as anti-mitotic agents.

ß-Carboline alkaloids are natural and synthetic products with outstanding antitumor activity. C3 substituted and dimerized ß-carbolines exert excellent antitumor activity. In the present research, 37 ß-carboline derivatives were synthesized and characterized. Their cytotoxicity, cell cycle, apoptosis, and CDK2- and DNA-binding affinity were evaluated. ß-Carboline monomer M3 and dimer D4 showed selective activity and higher cytotoxicity in tumor cells than in normal cells. Structure-activity relationships (SAR) indicated that the amide group at C3 enhanced the antitumor activity. M3 blocked the A549 (IC50 = 1.44 ± 1.10 µM) cell cycle in the S phase and inhibited A549 cell migration, while D4 blocked the HepG2 (IC50 = 2.84 ± 0.73 µM) cell cycle in the G0/G1 phase, both of which ultimately induced apoptosis. Furthermore, associations of M3 and D4 with CDK2 and DNA were proven by network pharmacology analysis, molecular docking, and western blotting. The expression level of CDK2 was downregulated in M3-treated A549 cells and D4-treated HepG2 cells. Moreover, M3 and D4 interact with DNA and CDK2 at sub-micromolar concentrations in endothermic interactions caused by entropy-driven adsorption processes, which means that the favorable entropy change (ΔS > 0) overcomes the unfavorable enthalpy change (ΔH > 0) and drives the spontaneous reaction (ΔG < 0). Overall, these results clarified the antitumor mechanisms of M3 and D4 through disrupting the cell cycle by binding DNA and CDK2, which demonstrated the potential of M3 and D4 as novel antiproliferative drugs targeting mitosis.

A Dual-Threshold Algorithm for Ice-Covered Lake Water Level Retrieval Using Sentinel-3 SAR Altimetry Waveforms.

Satellite altimetry has been proven to measure water levels in lakes and rivers effectively. The Sentinel-3A satellite is equipped with a dual-frequency synthetic aperture radar altimeter (SRAL), which allows for inland water levels to be measured with higher precision and improved spatial resolution. However, in regions at middle and high latitudes, where many lakes are covered by ice during the winter, the non-uniformity of the altimeter footprint can substantially impact the accuracy of water level estimates, resulting in abnormal readings when applying standard SRAL synthetic aperture radar (SAR) waveform retracking algorithms (retrackers). In this study, a modified method is proposed to determine the current surface type of lakes, analyzing changes in backscattering coefficients and brightness temperature. This method aligns with ground station observations and ensures consistent surface type classification. Additionally, a dual-threshold algorithm that addresses the limitations of the original bimodal algorithm by identifying multiple peaks without needing elevation correction is introduced. This innovative approach significantly enhances the precision of equivalent water level measurements for ice-covered lakes. The study retrieves and compares the water level data of nine North American lakes covered by ice from 2016-2019 using the dual-threshold and the SAMOSA-3 algorithm with in situ data. For Lake Athabasca, Cedar Lake, Great Slave Lake, Lake Winnipeg, and Lake Erie, the root mean square error (RMSE) of SAMOSA-3 is 39.58 cm, 46.18 cm, 45.75 cm, 42.64 cm, and 6.89 cm, respectively. However, the dual-threshold algorithm achieves an RMSE of 6.75 cm, 9.47 cm, 5.90 cm, 7.67 cm, and 5.01 cm, respectively, representing a decrease of 75%, 79%, 87%, 82%, and 27%, respectively, compared to SAMOSA-3. The dual-threshold algorithm can accurately estimate water levels in ice-covered lakes during winter. It offers a promising prospect for achieving long-term, continuous, and high-precision water level measurements for middle- and high-latitude lakes.

Evaluating the Performance of Seven Ongoing Satellite Altimetry Missions for Measuring Inland Water Levels of the Great Lakes.

Satellite altimetry can provide long-term water level time series for water bodies lacking hydrological stations. Few studies have evaluated the performance of HY-2C and Sentinel-6 satellites in inland water bodies, as they have operated for less than 1 and 2 years, respectively. This study evaluated the measured water level accuracy of CryoSat-2, HY-2B, HY-2C, ICESat-2, Jason-3, Sentinel-3A, and Sentinel-6 in the Great Lakes by in-situ data of 12 hydrological stations from 1 January 2021 to 1 April 2022. Jason-3 and Sentinel-6 have the lowest mean root-mean-square-error (RMSE) of measured water level, which is 0.07 m. The measured water level of Sentinel-6 satellite shows a high correlation at all passing stations, and the average value of all correlation coefficients (R) is also the highest among all satellites, reaching 0.94. The mean RMSE of ICESat-2 satellite is slightly lower than Jason-3 and Sentinel-6, which is 0.09 m. The stability of the average deviation (bias) of the ICESat-2 is the best, with the maximum bias only 0.07 m larger than the minimum bias. ICESat-2 satellite has an exceptionally high spatial resolution. It is the only satellite among the seven satellites that has retrieved water levels around twelve stations. HY-2C satellite has the highest temporal resolution, with a temporal resolution of 7.5 days at station 9075014 in Huron Lake and an average of 10 days in the Great Lakes region. The results show that the seven altimetry satellites currently in operation have their own advantages and disadvantages, Jason-3 and Sentinel-6 have the highest accuracy, ICESat-2 has higher accuracy and the highest spatial resolution, and HY-2C has the highest temporal resolution, although it is less accurate. In summary, with full consideration of accuracy and space-time resolution, the ICESat-2 satellite can be used as the benchmark to achieve the unification of multi-source data and establish water level time series.

Acinetobacter baumannii outer membrane protein A induces HeLa cell autophagy via MAPK/JNK signaling pathway.

Autophagy is an evolutionary conserved self-balancing process that plays an important role in maintaining cellular homeostasis via the clearance of damaged organelles and misfolded proteins. Infection-triggered autophagy specifically inhibits the invasion of intracellular bacterial replication and hence protects the cells from microbial infections. It has been reported that Acinetobacter baumannii trigger cell autophagy. However, the role of its virulence protein OmpA remains unclear. Therefore, this study aimed to explore the effects of Acinetobacter baumannii OmpA on cell autophagy and its underlying molecular mechanisms. The results showed that OmpA induced autophagy in HeLa and RAW264.7 cells, increased LC3BII expression, and hindered p62 degradation. Moreover, OmpA triggered incomplete autophagy by interfering the fusion of autophagosomes with lysosomes. Besides, OmpA activated MAPK/JNK signaling pathway and enhanced the phosphorylation levels of JNK, p38, and ERK, c-Jun. Inhibition of JNK signaling pathway suppressed OmpA-induced autophagy in HeLa cells. Ab wild-type strains carrying OmpA triggered incomplete autophagy and resulted in a large number of IL-1ß production. Ab-△OmpA strain (OmpA gene mutation) restored autophagic flux and reduced the accumulation of p62 and the release of IL-1ß in HeLa cells. Rapamycin activated autophagy to inhibit OmpA-induced IL-1ß secretion and protect HeLa cells from inflammatory damage. Collectively, these results suggest that OmpA can induce autophagy in HeLa cells through MAPK/JNK signaling pathway. Pre-treatment with Rapamycin activates autophagy and protects against cell death.

Surgical treatment of syphilitic superficial femoral artery aneurysm: a rare case report.

BACKGROUND: Arterial aneurysm is a known complication of syphilis, but the occurrence of femoral artery aneurysm secondary to the syphilitic disease has never been reported. CASE PRESENTATION: The present study described a 60-year-old Chinese male who presented with two aneurysms in the middle and lower segment of the right superficial femoral artery causing the symptoms of pain, coldness and numbness in the right lower limb. This case was diagnosed with syphilitic superficial femoral aneurysm because of positive syphilitic testing and the inflammatory cell infiltration around the adventitial vasa vasorum under the pathological examination. Anti-syphilis treatment, stent graft implantation and open surgery were attempted to eliminate the syphilis and aneurysm, which was ultimately successful, with no symptoms after a follow-up of 3 months. CONCLUSION: Combined open and endovascular repair may be effective and safe for treatment of syphilitic femoral artery aneurysms.

[Species identification and absolute quantification of biological samples by droplet digital PCR].

OBJECTIVE: To test droplet digital PCR for species identification and absolute quantification of biological sample. METHODS: Specific primers and probes for human mtDNA encoding gene ND4 and 16S rRNA were designed, and the species-specificity was assessed on DNA samples derived from human and common animals. To determine the sensitivity and stability of droplet digital PCR for species identification and absolute quantification, gradient dilution series of recombinant plasmid and 16 human DNA samples were analyzed. RESULTS: Human recombinant plasmid FAM (ND4) could be used in detecting the samples of human. And the results of detecting were consistent with all levels of diluted concentrations. Droplet digital PCR was able to detect low and single copy of target DNA. CONCLUSION: Droplet digital PCR, with high sensitivity and specificity, is fully amenable for species identification and absolute quantification of biological samples, also it can be applied on routine forensic examination.

Syntaxin17 Restores Lysosomal Function and Inhibits Pyroptosis Caused by Acinetobacter baumannii.

Acinetobacter baumannii (A. baumannii) causes autophagy flux disorder by degrading STX17, resulting in a serious inflammatory response. It remains unclear whether STX17 can alter the inflammatory response process by controlling autolysosome function. This study aimed to explore the role of STX17 in the regulation of pyroptosis induced by A. baumannii. Our findings indicate that overexpression of STX17 enhances autophagosome degradation, increases LAMP1 expression, reduces Cathepsin B release, and improves lysosomal function. Conversely, knockdown of STX17 suppresses autophagosome degradation, reduces LAMP1 expression, augments Cathepsin B release, and accelerates lysosomal dysfunction. In instances of A. baumannii infection, overexpression of STX17 was found to improve lysosomal function and reduce the expression of mature of GSDMD and IL-1ß, along with the release of LDH, thus inhibiting pyroptosis caused by A. baumannii. Conversely, knockdown of STX17 led to increased lysosomal dysfunction and further enhanced the expression of mature of GSDMD and IL-1ß, and increased the release of LDH, exacerbating pyroptosis induced by A. baumannii. These findings suggest that STX17 regulates pyroptosis induced by A. baumannii by modulating lysosomal function.

Path analysis of regional logistics and economy coordinated development: An fsQCA approach.

The coordinated development of regional logistics and the economy is crucial for regional economic progress and for reducing regional development disparities. This study applies regional coordinated development theory and coupling theory, utilizing the Coupling Coordination Degree Model (CCDM) to analyze data from 31 provinces and cities in China in 2021, with the analysis results serving as the outcome variable. Additionally, we use data from four dimensions: infrastructure investment (II), technological innovation (TI), industrial structure (IS), and human capital (HC), as the conditional variables, conducting a multi-factor configurational analysis using fsQCA. Three paths with high coupling coordination and one path with non-high coupling coordination are identified, and the reasons for each path are analyzed. The results indicate that: 1) there are significant regional disparities in China regarding economic development, logistics development, and the degree of their coupling and coordination, with the eastern regions exhibiting higher levels and the western regions and other remote areas exhibiting lower levels. 2) The three paths with high coupling coordination are: "Infrastructure Investment-Technological Innovation", "Technological Innovation-Industrial Structure-Human Capital", and "Infrastructure Investment-Fundamental Innovation-Industrial Structure". These three types facilitate the well-coordinated progress of regional logistics and the economy. The article concludes by highlighting policy suggestions that underscore the significance of fortifying the bond between the logistics industry and the economy, alongside earnest efforts to enhance regional logistics standards. This will foster a mutually reinforcing and co-developing situation, further promoting coordinated development among regions, achieving high-quality regional development, and reducing the imbalances in logistics and economic development among different regions.

Multi-Stage Transcriptome Analysis Revealed the Growth Mechanism of Feathers and Hair Follicles during Induction Molting by Fasting in the Late Stage of Egg Laying.

Induced molting is a common method to obtain a new life in laying hens, in which periodic changes in feathers are the prominent feature. Nevertheless, its precise molecular mechanism remains unclear. In this study, feather and hair follicle samples were collected during fasting-induced physiological remodeling for hematoxylin-eosin staining, hormone changes and follicle traits, and transcriptome sequencing. Feather shedding was observed in F13 to R25, while newborns were observed in R3 to R32. Triiodothyronine and tetraiodothyronine were significantly elevated during feather shedding. The calcium content was significantly higher, and the ash content was significantly lower after the changeover. The determination of hair follicle traits revealed an increasing trend in pore density and a decrease in pore diameter after the resumption of feeding. According to RNA-seq results, several core genes were identified, including DSP, CDH1, PKP1, and PPCKB, which may have an impact on hair follicle growth. The focus was to discover that starvation may trigger changes in thyroid hormones, which in turn regulate feather molting through thyroid hormone synthesis, calcium signaling, and thyroid hormone signaling pathways. These data provide a valuable resource for the analysis of the molecular mechanisms underlying the cyclical growth of hair follicles in the skin during induced molting.

Acinetobacter baumannii up-regulates LncRNA-GAS5 and promotes the degradation of STX17 by blocking the activation of YY1.

Acinetobacter baumanniitriggers autophagy, affects the degradation of autophagy, and causes severe inflammatory injury. LncRNA growth arrest-specific transcript 5 (LncRNA-GAS5) and Yin and Yang 1 (YY1) are known to play an important role in the regulation of autophagy, however, the precise role of LncRNA-GAS5 and YY1 in the damage to autophagy caused by Acinetobacter baumanniiremains unclear. The aim of this study was to investigate the role of LncRNA-GAS5 and YY1 in the regulation of autophagy induced by Acinetobacter baumannii. We found that LncRNA-GAS5 was up-regulated following infection with Acinetobacter baumannii, thus resulting in the degradation of STX17, autophagy disorders, and the aggravated replication of Acinetobacter baumannii. We also analyzed the mechanism of interaction between LncRNA-GAS5 and YY1 and found that YY1 regulated its expression in a negative manner by binding to the promoter of LncRNA-GAS5. LncRNA-GAS5 and YY1 had opposite effects on the expression of STX17, this process maintained the stable expression of STX17. Following Acinetobacter baumannii infection, YY1 was down regulated and then separated from the binding region of LncRNA-GAS5, thus resulting in the activation of LncRNA-GAS5 transcription and reduction in STX17 protein expression. Finally, we infected LncRNA-GAS5 knockdown mice with Acinetobacter baumannii, the expression levels of IFN-ß in the lungs increased significantly, this alleviated lung injury. In conclusion, our work demonstrated the mechanism by which Acinetobacter baumannii infection can cause the degradation of STX17. We also demonstrated that LncRNA-GAS5 may be a potential therapeutic target for the treatment of lung injury induced by Acinetobacter baumannii.

1-Formyl-ß-carboline Derivatives Block Newcastle Disease Virus Proliferation through Suppressing Viral Adsorption and Entry Processes.

Newcastle disease virus (NDV) is one of the highly contagious pathogens causing devastating economic effects on the global poultry industry. In the present study, three 1-formyl-ß-carboline derivatives (compounds 6, 7, and 9) were found to be potent inhibitors of different genotypes of NDV with IC50 values within 10 µM, which are similar to ribavirin. The virus titers were decreased by the presence of 1-formyl-ß-carboline derivatives in a dose-dependent manner, and the inhibition rate was found to exceed 90% at the concentration of 20 µM. These compounds mainly suppressed the adsorption and entry processes of NDV lifecycle. Through DARTS, CETSA, and RBC binding assay, these compounds were identified as novel HN inhibitors, which could directly interact with the NDV HN protein to affect the adsorption of NDV. Furthermore, they could inhibit the entry of NDV through suppressing the PI3K/Akt pathway rather than the ERK pathway. The PI3K/Akt pathway was proved to be involved in NDV entry. Our findings reveal a unique mechanism through which 1-formyl-ß-carboline derivatives restrain NDV infection. Moreover, these compounds represent suitable scaffolds for designing novel HN inhibitors.

Acinetobacter baumannii outer membrane protein 34 elicits NLRP3 inflammasome activation via mitochondria-derived reactive oxygen species in RAW264.7 macrophages.

Acinetobacter baumannii (A. baumannii) is a Gram-negative bacterium, which acts as an opportunistic pathogen and causes hospital-acquired pneumonia and bacteremia by infecting the alveoli of epithelial cells and macrophages. Evidence reveals that A. baumannii outer membrane protein 34 (Omp34) elicits cellular immune responses and inflammation. The innate immunity NOD-like receptor 3 (NLRP3) inflammasome exerts critical function against pneumonia caused by A. baumannii infection, however, the role of Omp34 in the activation of the NLRP3 inflammasome and its corresponding regulatory mechanism are not clearly elucidated. The present study aimed to investigate whether Omp34 elicited NLRP3 inflammasome activation through the mitochondria-derived reactive oxygen species (ROS). Our results showed that Omp34 triggered cell pyroptosis by up-regulating the expression of NLRP3 inflammasome-associated proteins and IL-1ß release in a time- and dose-dependent manner. Omp34 induced the expression of caspase-1-p10 and IL-1ß, which was significantly attenuated by NLRP3 gene silencing in RAW264.7 mouse macrophage cells. Additionally, Omp34 stimulated RAW264.7 mitochondria to generate ROS, while the ROS scavenger Mito-TEMPO inhibited the Omp34-triggered expression of NLRP3 inflammasome-associated proteins and IL-1ß synthesis. The above findings indicate that mitochondria-derived ROS play an important role in the process of NLRP3 inflammasome activation. In summary, our study demonstrates that the A. baumannii pathogen pattern recognition receptor Omp34 activates NLRP3 inflammasome via mitochondria-derived ROS in RAW264.7 cells. Accordingly, down-regulating the mitochondria-derived ROS prevents the severe infection consequences caused by A. baumannii-induced NLRP3 inflammasome hyper-activation.

[Abnormalities of microsatellite in transitional cell carcinoma of urinary bladder related with aromatic amine exposure].

OBJECTIVE: To study the microsatellite abnormalities of the aromatic amine exposure-associated transitional cell carcinoma (TCC) and sporadic TCC of urinary bladder, and to evaluate the potential of microsatellite analysis on detection of this diseases. METHODS: Based on our previous investigations, 5 microsatellite markers (D17S695, D9S162, D3S1295, DBH and D3S1234) that had high frequencies of loss of heterozygosity (LOH) in sporadic TCC, were selected for analysis with the bladder lesions derived from 16 patients with aromatic amine exposure history. The microsatellite analysis with urine sediments from the post-operated patients was also carried out. RESULTS: There was at least one informative marker out of the 5 microsatellite foci showed polymorphism in the DNA derived from 16 patients examined. Within 87.50% (14/16) patients, LOH was detected in the bladder lesions at least with one microsatellite marker. The LOH frequency of D3S1295 was higher in occupational TCC patients than that in sporadic TCC patients. The diagnostic accordance rate of patients showed LOH in at least one microsatellite marker with patients diagnosed by pathology was 81.25% (13/16). In the urine sediments from 8 TCC post-operated patients, LOH was found at least with one microsatellite marker. CONCLUSION: There could be a different LOH pattern in aromatic amine exposure-associated TCC, and genes near D3S1295 might play a role in the occupational exposure-associated TCC.

Coagulation and fibrinolytic indices during the first trimester of pregnancy in women with polycystic ovary syndrome: a preliminary study.

OBJECTIVE: To evaluate the levels of coagulation and fibrinolytic markers during the first trimester of pregnancy in women with polycystic ovary syndrome (PCOS) and determine the effects of PCOS and obesity on the levels of these hemostatic markers. METHODS: A cross-sectional study was conducted in Beijing, China, on women with PCOS (n = 50), healthy women (n = 50), pregnant women with PCOS (n = 50), and healthy pregnant women (n = 50) at 12 weeks of pregnancy. Coagulation and fibrinolytic parameters were measured. RESULTS: The interaction between PCOS and pregnancy appears to exert effects on the activities of coagulation factors VIII and X. The interaction between PCOS and obesity also seems to affect the level of von Willebrand factor. CONCLUSIONS: Pregnant women with PCOS, especially women who are obese, are observed to be in a more prohemostatic state during the first trimester.