Airborne bacteria have an important role in atmospheric processes and human health. However, there is still little information on the transmission and distribution of bacteria via the airborne route. ...To characterize the impact of foggy, haze, haze-fog (HF) and dust days on the concentration and viability of bacteria in atmospheric aerosols, size-segregated bioaerosol samples were collected in the Qingdao coastal region from March 2018 to February 2019. The total airborne microbes and viable/non-viable bacteria in the bioaerosol samples were measured using an epifluorescence microscope after staining with DAPI (4′, 6-diamidino-2-phenylindole) and a LIVE/DEAD® BacLight Bacterial Viability Kit. The average concentrations of total airborne microbes on haze and dust days were 6.75 × 105 and 1.03 × 106 cells/m3, respectively, which increased by a factor of 1.3 and 2.5 (on average), respectively, relative to those on sunny days. The concentrations of non-viable bacteria on haze and dust days increased by a factor of 1.2 and 3.6 (on average), respectively, relative to those on sunny days. In contrast, the concentrations of viable bacteria on foggy and HF days were 7.13 × 103 and 5.74 × 103 cells/m3, decreases of 38% and 50%, respectively, compared with those on sunny days. Foggy, haze, dust and HF days had a significant effect on the trend of the seasonal variation in the total airborne microbes and non-viable bacteria. Bacterial viability was 20.8% on sunny days and significantly higher than the 14.1% on foggy days, 11.2% on haze days, 8.6% during the HF phenomenon and 6.1% on dust days, indicating that special weather is harmful to some bacterial species. Correlation analysis showed that the factors that influenced the bacterial concentration and viability depended on different weather conditions. The main influential factors were temperature, NO2 and SO2 concentrations on haze days, and temperature, particulate matter (PM2.5) and NO2 concentrations on foggy days. The median size of particles containing viable bacteria was 1.94 μm on sunny days and decreased to 1.88 μm and 1.74 μm on foggy and haze days, respectively, but increased to 2.18 μm and 2.37 μm on dust and HF days, respectively.
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•The concentration of non-viable bacteria increased and viable bacteria decreased on foggy and haze-fog days.•Bacterial viability was higher on sunny days than on polluted days.•The median size of particles containing viable bacteria increased on haze-fog and dust days.•Temperature, PM2.5 and NO2 affected bacteria viability on polluted days.
Bacteria are important components of bioaerosols with the potential to influence human health and atmospheric dynamics. However, information on the concentrations and influencing factors of viable ...bacteria is poorly understood. In this study, size-segregated bioaerosol samples were collected from Aug. 2017 to Feb. 2018 in the coastal region of Qingdao, China. The total microbes and viable/non-viable bacteria in the samples were measured using an epifluorescence microscope after staining with the DAPI (4′, 6-diamidino-2-phenylindole) and LIVE/DEAD® BacLight™ Bacterial Viability Kit, respectively. The concentrations of non-viable bacteria increased when the air quality index (AQI) increased from <50 to 300, with the proportion of non-viable bacteria to total microbes increasing from (11.1 ± 12.0)% at an AQI of <50 to (18.4 ± 14.7)% at an AQI of >201. However, the concentrations of viable bacteria decreased from (2.12 ± 2.04) × 104 cells·m−3 to (9.00 ± 1.72) × 103 cells·m−3 when the AQI increased from <50 to 150. The ratio of viable bacteria to total bacteria (viability) decreased from (31.0 ± 14.7)% at 0 < AQI<50 to (8.6 ± 1.0)% at 101 < AQI<150 and then increased to (9.6 ± 5.3)% at an AQI of 201–300. The results indicated that the bacterial viability decreased when air pollution occurred and increased again when pollution became severe. The mean size distribution of non-viable bacteria exhibited a bimodal distribution pattern at an AQI<50 with two peaks at 2.1–3.3 μm and >7.0 μm, while the viable bacteria had two peaks at 1.1–2.1 μm and >7 μm. When the AQI increased from 101 to 300, the size distribution of viable/non-viable bacteria varied with an increased proportion of fine particles. The multiple linear regression analysis results verified that the AQI and PM10 had important effects on the concentrations of non-viable bacteria. These results highlight impacts of air pollution on viable/non-viable bacteria and the interactions between complex environmental factors and bacteria interactions, improving our understanding of bioaerosols under air pollution conditions.
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•The contribution of non-viable bacteria to total microbes increased with the AQI.•The bacterial viability decreased when air pollution occurred and increased slightly when pollution lasted and became severe.•The proportion of bacteria in fine particles increased greatly on pollution days.•The AQI and PM10 effect the concentrations of non-viable bacteria.
Microbial activities in the atmosphere can indicate the physiological processes of microorganisms and can indirectly affect cloud formation and environmental health. In this study, the microbial ...activity in bioaerosols collected in the Qingdao coastal region was investigated using the fluorescein diacetate (FDA) hydrolysis method to detect the enzyme activity of microorganisms. The results showed that the microbial activity ranged from 5.49 to 102 ng/m3 sodium fluorescein from March 2013 to February 2014; the average value was 34.4 ng/m3. Microbial activity has no statistical correlation with total microbial quantity. Multiple linear regression analysis showed that meteorological factors such as atmospheric temperature, relative humidity and wind speed accounted for approximately 35.7% of the variation of the microbial activity, although their individual impacts on microbial activity varied. According to the correlation analysis, atmospheric temperature and wind speed had a significant positive and negative influence on microbial activity, respectively, whereas relative humidity and wind direction had no significant influence. The seasonal distribution of microbial activity in bioaerosols was in the order of summer > autumn > winter > spring, with high fluctuations in the summer and autumn. Microbial activity in bioaerosols differed in different weather conditions such as the sunny, foggy, and hazy days of different seasons. Further in situ observations in different weather conditions at different times and places are needed to understand the seasonal distribution characteristics of microbial activity in bioaerosols and the influence factors of microbial activity.
•Microbial activity has no statistical correlation with total microbial quantity.•Temperature and wind speed had significant correlation with microbial activity.•Microbial activity showed a seasonal variation of summer > autumn > winter > spring.•Microbial activity was affected by foggy and hazy days.
Atmospheric bioaerosol particles were collected using a bioaerosol sampler from Oct. 2013 to Aug. 2014 in the coastal region of Qingdao. The total microbes were measured using an epifluorescence ...microscope after staining with DAPI (4′,6-diamidino-2-phenylindole). The concentration of total airborne microbes showed seasonal variation, with the highest value in winter and the lowest in summer. The mean concentration of total microbes was 6.55×105Cells/m3 on non-hazy days. The total microbe concentration increased to 7.09×105 and 9.00×105Cells/m3 on hazy and foggy days, respectively. The particle sizes of the total microbes presented a bimodal distribution on sunny days, with one peak at 1.1–2.1μm and another at 4.7–7.0μm. The size distribution of total microbes showed an increase in the fine fraction on hazy days and an increase in the coarse fraction on foggy days. However, the size distribution became unimodal during a heating period. Spearman correlation analysis showed that temperature and O3 had a significant negative correlation with the airborne microbe concentration, while PM2.5, SO2, NO2, CO and the air quality index (AQI) had significant positive correlations with the airborne microbe concentration during hazy days. The increased number of airborne microbes will affect the air quality on hazy days.
Concentration and size distribution of microbes in bioaerosols from Oct. 2013 to Aug. 2014 in the Qingdao coastal region under different weather conditions. Display omitted
•High concentration of the total microbe concentration on hazy and foggy days.•Microbial concentration was highest in the winter and lowest in the summer.•Microbes presented a bimodal size distribution on hazy and foggy days.•Microbes were correlated with some environmental parameters during hazy days.
Abstract
This study aimed to develop a physiologically-based pharmacokinetic (PBPK) model to predict the maximum plasma concentration (C
max
) and trough concentration (C
trough
) at steady-state of ...olaparib (OLA) in Caucasian, Japanese and Chinese. Furthermore, the PBPK model was combined with mean and 95% confidence interval to predict optimal dosing regimens of OLA when co-administered with CYP3A4 modulators and administered to patients with hepatic/renal impairment. The dosing regimens were determined based on safety and efficacy PK threshold C
max
(< 12,500 ng/mL) and C
trough
(772–2500 ng/mL). The population PBPK model for OLA was successfully developed and validated, demonstrating good consistency with clinically observed data. The ratios of predicted to observed values for C
max
and C
trough
fell within the range of 0.5 to 2.0. When OLA was co-administered with a strong or moderate CYP3A4 inhibitor, the recommended dosing regimens should be reduced to 100 mg BID and 150 mg BID, respectively. Additionally, the PBPK model also suggested that OLA could be not recommended with a strong or moderate CYP3A4 inducer. For patients with moderate hepatic and renal impairment, the dosing regimens of OLA were recommended to be reduced to 200 mg BID and 150 mg BID, respectively. In cases of severe hepatic and renal impairment, the PBPK model suggested a dosing regimen of 100 mg BID for OLA. Overall, this present PBPK model can determine the optimal dosing regimens for various clinical scenarios involving OLA.
Liver cancer remains difficult to treat, owing to a paucity of drugs that target critical dependencies
; broad-spectrum kinase inhibitors such as sorafenib provide only a modest benefit to patients ...with hepatocellular carcinoma
. The induction of senescence may represent a strategy for the treatment of cancer, especially when combined with a second drug that selectively eliminates senescent cancer cells (senolysis)
. Here, using a kinome-focused genetic screen, we show that pharmacological inhibition of the DNA-replication kinase CDC7 induces senescence selectively in liver cancer cells with mutations in TP53. A follow-up chemical screen identified the antidepressant sertraline as an agent that kills hepatocellular carcinoma cells that have been rendered senescent by inhibition of CDC7. Sertraline suppressed mTOR signalling, and selective drugs that target this pathway were highly effective in causing the apoptotic cell death of hepatocellular carcinoma cells treated with a CDC7 inhibitor. The feedback reactivation of mTOR signalling after its inhibition
is blocked in cells that have been treated with a CDC7 inhibitor, which leads to the sustained inhibition of mTOR and cell death. Using multiple in vivo mouse models of liver cancer, we show that treatment with combined inhibition of of CDC7 and mTOR results in a marked reduction of tumour growth. Our data indicate that exploiting an induced vulnerability could be an effective treatment for liver cancer.
The study aimed to investigate the state of human papillomavirus (HPV) infection in patients with cervical cancer in the Uyghur population in China and to identify miRNA as biomarker for cervical ...cancer and HPV infection. We also performed genotyping to determine the variation in the types of HPV. Using microRNA (miRNA) microarray technology, differential miRNA expression between HPV-infected cervical cancer and uninfected normal cervical tissues was determined; the microarray results were verified by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) using 20 samples of both the tissues. The infection rate of HPV in patients with cervical cancer was 96.7% (29 of 30), and the main subtype identified was HPV16 (29 of 29). HPV16 integration assay demonstrated that the majority of infectious cases were of the integrated form (26 of 29). Analysis of 140 miRNAs demonstrated greater than two-fold change in miRNA expression in HPV-infected cervical cancer tissue as compared to that in uninfected cervical tissue. The qRT-PCR analysis verified that the expression of miR-15a-5p, miR-17-5p, miR-20a-5p, miR-21-5p, miR-96, miR-106b-5p, and miR-3653 was higher, while the expression of miR-497-5p was lower in cancer tissues than in normal tissues. The results demonstrate significant changes in miRNA expression in cervical cancer tissues associated with HPV infection as compared to that in normal tissues. These molecular markers may be useful for an early diagnosis and prognosis of cervical cancer in specific human populations.
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•ERK2 inhibition was identified as an enhancer of the response to sorafenib in HCC.•Selumetinib increases the response of sorafenib in HCC cell lines with high p-ERK.•The synthetic ...lethal effect is derived from synergistic inhibition of ERK kinase.•The combination therapy is most likely to be effective in tumors with high p-ERK.
Treatment of liver cancer remains challenging because of a paucity of drugs that target critical dependencies. Sorafenib is a multikinase inhibitor that is approved as the standard therapy for patients with advanced hepatocellular carcinoma, but it only provides limited survival benefit. In this study we aimed to identify potential combination therapies to improve the clinical response to sorafenib.
To investigate the cause of the limited therapeutic effect of sorafenib, we performed a CRISPR-Cas9 based synthetic lethality screen to search for kinases whose knockout synergizes with sorafenib. Synergistic effects of sorafenib and selumetinib on cell apoptosis and phospho-ERK (p-ERK) were analyzed by caspase-3/7 apoptosis assay and western blot, respectively. p-ERK was measured by immunochemical analysis using a tissue microarray containing 78 liver cancer specimens. The in vivo effects of the combination were also measured in two xenograft models.
We found that suppression of ERK2 (MAPK1) sensitizes several liver cancer cell lines to sorafenib. Drugs inhibiting the MEK (MEK1/2 MAP2K1/2) or ERK (ERK1/2 MAPK1/3) kinases reverse unresponsiveness to sorafenib in vitro and in vivo in a subset of liver cancer cell lines characterized by high levels of active p-ERK, through synergistic inhibition of ERK kinase activity.
Our data provide a combination strategy for treating liver cancer and suggest that tumors with high basal p-ERK levels, which are seen in approximately 30% of liver cancers, are most likely to benefit from such combinatorial treatment.
Sorafenib is approved as the standard therapy for patients with advanced hepatocellular carcinoma, but only provides limited survival benefit. Herein, we found that inhibition of the kinase ERK2 increases the response to sorafenib in liver cancer. Our data indicate that a combination of sorafenib and a MEK inhibitor is most likely to be effective in tumors with high basal phospho-ERK levels.
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