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Objective Multidrug-resistant Klebsiella pneumoniae (MDR KP) bloodstream infections are a serious problem. The objective of this study was to investigate the effects of appropriate combination therapies on MDR KP bloodstream infections. Methods MDR KP strains isolated from clinical samples were assessed for antibiotic susceptibility using the broth microdilution method. Twenty consecutive MDR KP clinical isolates from patients with bloodstream infections were examined in this study. The experiments were conducted at the Bacterial Laboratory of Tongde Hospital from March to August 2021. Antibiotic combination tests were performed using the minimum inhibitory concentration (MIC) test, and the sum of the fractional inhibitory concentration was used to assess synergy. Results Following treatment with a combination of two antibiotic agents, the MIC50 and MIC90 values decreased compared with that before treatment. MIC50 decreased by at least 50%, with one value reduced to 6.25% of the pretreatment value. None of the antibiotic combinations were antagonistic. Combination of polymyxin B with rifampicin or tigecycline had a synergistic effect on 70% and 65% of the strains, respectively. Conclusions In vitro combination therapies with two active drug agents (polymyxin B plus rifampicin or tigecycline) had a better effect on MDR KP infections compared with that in other regimens.

Introduction Traditional Chinese medicinal plant, safflower, shows effective for treating pulmonary arterial hypertension (PAH), yet the underlying mechanisms remain largely unexplored. This study is aimed at exploring the potential molecular mechanisms of safflower in the treatment of PAH. Methods Network pharmacology approach and molecular docking were applied to identify the core active compounds, therapeutic targets, and potential signaling pathways of safflower against PAH. Meanwhile, high‐performance liquid chromatography (HPLC) assay was performed to determine the core compounds from safflower. Further, the mechanism of action of safflower on PAH was verified by in vivo and in vitro experiments. Results A total of 15 active compounds and 177 targets were screened from safflower against PAH. Enrichment analysis indicated that these therapeutic targets were mainly involved in multiple key pathways, such as TNF signaling pathway and Th17 cell differentiation. Notably, molecular docking revealed that quercetin (core compound in safflower) displayed highest binding capacity with NLRP3. In vivo, safflower exerted therapeutic effects on PAH by inhibiting right ventricular hypertrophy, inflammatory factor release, and pulmonary vascular remodeling. Mechanistically, it significantly reduced the expression of proangiogenesis‐related factors (MMP‐2, MMP‐9, Collagen 1, and Collagen 3) and NLRP3 inflammasome components (NLRP3, ASC, and Caspase‐1) in PAH model. Similarly, these results were observed in vitro. Besides, we further confirmed that NLRP3 inhibitor had the same therapeutic effect as safflower in vitro. Conclusion Our findings suggest that safflower mitigates PAH primarily by inhibiting NLRP3 inflammasome activation. This provides novel insights into the potential use of safflower as an alternative therapeutic approach for PAH. Integrating network pharmacology, molecular docking, and experimental validation to identify the effects of safflower against pulmonary arterial hypertension.

Infection with pathogenic Leptospira species causes serious systemic inflammation in patients. Although a few leptospiral proinflammatory molecules have been identified, Leptospira likely encodes other unidentified strong inflammation stimulators. The pathogenic L. interrogans genome encodes numerous putative hemolysin genes. Since hemolysins from other bacteria can cause inflammatory reactions, we hypothesized that leptospiral hemolysins may function as proinflammatory stimulators that contribute to the strong inflammation associated with Leptospira infection. We first used cytokine protein microarrays for systematic analysis of serum cytokine profiles in leptospirosis patients and leptospire-infected mice. We found that IL-1β, IL-6 and TNF-α were the main proinflammatory cytokines in the sera of both the patients and the mice. We then analyzed eight putative hemolysins in L. interrogans strain Lai. The results showed that five of them, Sph1, Sph2, Sph3, HlpA and TlyA were secreted and had hemolytic activity. More importantly, these five hemolysins induced the strong production of IL-1β, IL-6 and TNF-α in human and mouse macrophages (although a bit lower in the latter). Furthermore, blockade of TLR2 or TLR4 with either antibodies or inhibitors of the NF-κB or JNK signaling pathways significantly reduced the production of hemolysin-induced IL-1β, IL-6 and TNF-α. Macrophages isolated from TLR2-, TLR4-or double TLR2-and 4-deficient mice also confirmed that the leptospiral hemolysins that induce proinflammatory cytokines are both TLR2-and TLR4-dependent. Our findings demonstrate that L. interrogans secretes many hemolysins that function as powerful inducers of proinflammatory cytokines through both TLR2-and TLR4-dependent JNK and NF-κB pathways.

Background Gram-positive bacteria are dangerous and challenging agents of infection due to their increasing resistance to antibiotics. We aim to analyse the epidemiology and risk factors of methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) in Zhejiang China. Methods Gram-positive bacteria (including S. aureus , Enterococcus faecalis and Enterococcus faecium ) were collected from eighty-six hospitals of eleven cities in Zhejiang China from 2015 to 2017. The detection rates of MRSA and VRE infection were calculated for the non-duplicated isolate according to year, region, hospital level, patient age, specimen type and patient category. Meanwhile, the detected resistances of MRSA, E. faecalis and E. faecium to different antibiotics from 2015 to 2017 were compared. The risk factors and the differences in MRSA and VRE detection rates were compared using odds ratio (OR) with 95% confidence interval (95% CI) and Chi-square test respectively. Results From 2015 to 2017, the detection rates of MRSA and VRE decreased gradually. The cities with the highest MRSA and VRE detection rates tended to be adjacent; for example, the neighbouring cities Hangzhou and Quzhou had simultaneously high rates of MRSA and VRE infection. Patients from IIIA hospital who were older than 75 years and in the intensive care unit (ICU) were most at risk. No vancomycin-resistant isolate was found in MRSA. Resistance of E. faecalis and E. faecium to vancomycin and linezolid decreased slightly and then maintained a low level. Conclusions The detection rates of MRSA and VRE stayed at moderate and low levels during the three year period of this study, while local dissemination was found in MRSA and VRE isolates. Sustained surveillance is necessary to prevent the spread or clonal dissemination of drug-resistant strains in Zhejiang China.

Objective Multidrug-resistant Klebsiella pneumoniae (MDR KP) bloodstream infections are a serious problem. The objective of this study was to investigate the effects of appropriate combination therapies on MDR KP bloodstream infections. Methods MDR KP strains isolated from clinical samples were assessed for antibiotic susceptibility using the broth microdilution method. Twenty consecutive MDR KP clinical isolates from patients with bloodstream infections were examined in this study. The experiments were conducted at the Bacterial Laboratory of Tongde Hospital from March to August 2021. Antibiotic combination tests were performed using the minimum inhibitory concentration (MIC) test, and the sum of the fractional inhibitory concentration was used to assess synergy. Results Following treatment with a combination of two antibiotic agents, the MIC50 and MIC90 values decreased compared with that before treatment. MIC50 decreased by at least 50%, with one value reduced to 6.25% of the pretreatment value. None of the antibiotic combinations were antagonistic. Combination of polymyxin B with rifampicin or tigecycline had a synergistic effect on 70% and 65% of the strains, respectively. Conclusions In vitro combination therapies with two active drug agents (polymyxin B plus rifampicin or tigecycline) had a better effect on MDR KP infections compared with that in other regimens.

Infection with pathogenic Leptospira species causes serious systemic inflammation in patients. Although a few leptospiral proinflammatory molecules have been identified, Leptospira likely encodes other unidentified strong inflammation stimulators. The pathogenic L. interrogans genome encodes numerous putative hemolysin genes. Since hemolysins from other bacteria can cause inflammatory reactions, we hypothesized that leptospiral hemolysins may function as proinflammatory stimulators that contribute to the strong inflammation associated with Leptospira infection. We first used cytokine protein microarrays for systematic analysis of serum cytokine profiles in leptospirosis patients and leptospire-infected mice. We found that IL-1[beta], IL-6 and TNF-[alpha] were the main proinflammatory cytokines in the sera of both the patients and the mice. We then analyzed eight putative hemolysins in L. interrogans strain Lai. The results showed that five of them, Sph1, Sph2, Sph3, HlpA and TlyA were secreted and had hemolytic activity. More importantly, these five hemolysins induced the strong production of IL-1[beta], IL-6 and TNF-[alpha] in human and mouse macrophages (although a bit lower in the latter). Furthermore, blockade of TLR2 or TLR4 with either antibodies or inhibitors of the NF-[kappa]B or JNK signaling pathways significantly reduced the production of hemolysin-induced IL-1[beta], IL-6 and TNF-[alpha]. Macrophages isolated from TLR2-, TLR4-or double TLR2-and 4-deficient mice also confirmed that the leptospiral hemolysins that induce proinflammatory cytokines are both TLR2-and TLR4-dependent. Our findings demonstrate that L. interrogans secretes many hemolysins that function as powerful inducers of proinflammatory cytokines through both TLR2-and TLR4-dependent JNK and NF-[kappa]B pathways.

Impressive methods for object detection tasks have been proposed based on convolutional neural networks (CNNs), however, they usually use very computation expensive deep networks to obtain such significant performance. Knowledge distillation has attracted much attention in the task of image classification lately since it can use compact models that reduce computations while preserving performance. Moreover, the best performing deep neural networks often assemble the outputs of multiple networks in an average way. However, the memory required to store these networks, and the time required to execute them in inference, which prohibits these methods used in real-time applications. In this paper, we present a knowledge distillation method for one-stage object detection, which can assemble a variety of large, complex trained networks into a lightweight network. In order to transfer diverse knowledge from various trained one-stage object detection networks, an adversarial-based learning strategy is employed as supervision to guide and optimize the lightweight student network to recover the knowledge of teacher networks, and to enable the discriminator module to distinguish the feature of teacher and student simultaneously. The proposed method exhibits two predominant advantages: (1) The lightweight student model can learn the knowledge of the teacher, which contains richer discriminative information than the model trained from scratch. (2) Faster inference speed than traditional ensemble methods from multiple networks is realized. A large number of experiments are carried out on PASCAL VOC and MS COCO datasets to verify the effectiveness of the proposed method for one-stage object detection, which obtains 3.43%, 2.48%, and 5.78% mAP promotions for vgg11-ssd, mobilenetv1-ssd-lite and mobilenetv2-ssd-lite student network on the PASCAL VOC 2007 dataset, respectively. Furthermore, with multi-teacher ensemble method, vgg11-ssd gains 7.10% improvement, which is remarkable.

Ongoing fiscal support is a crucial assurance for achieving green development, while the increasingly prominent fiscal expenditure stress has been subjected to a great challenge in achieving green transformation. Based on China’s education authority reform as a quasi-natural experiment, this study uses green total factor productivity to represent urban green development, which has been widely used in the literature, and reveals how local government fiscal expenditure stress affects green total factor productivity. It is found that local fiscal stress significantly decreases the green total factor productivity of cities. This effect is particularly pronounced for resource-based cities, cities with laxer environmental regulations, and cities under greater pressure to promote and develop their economies. Moreover, it is confirmed that it is not the revenue-raising effect but rather the expenditure reduction effect that is at play. Specifically, local governments have reduced environmental protection expenditures and green subsidies, leading to a decline in the green innovation capacity of cities and corporations. Finally, based on the above findings, policy implications are provided to reduce the risk of green transformation from the perspective of policymakers.

Landslides have had a huge effect on human life, the environment and local economic development, and therefore they need to be well understood. In this study, we presented an approach for the analysis and modeling of landslide data using rare events logistic regression and applied the approach to an area in Lianyungang, China. Digital orthophotomaps, digital elevation models of the region, geological maps and different GIS layers including settlement, road net and rivers were collected and applied in the analysis. Landslides were identified by monoscopic manual interpretation and validated during the field investigation. To validate the quality of mapping, the data from the study area were divided into a training set and validation set. The result map showed that 4.26% of the study area was identified as having very high susceptibility to landslides, whereas the others were classified as having very low susceptibility (47.2%), low susceptibility (22.21%), medium susceptibility (14.39%) and high susceptibility (11.93%). The quality of the landslide-susceptibility map produced in this paper was validated, and it can be used for planning protective and mitigation measures. The landslide-susceptibility map is a fundamental part of the Lianyungang city landslide risk assessment.

Endothelial inflammation is a crucial event in the initiation of atherosclerosis. Here, we identify Ataxin-10 protein as a novel negative modulator of endothelial activation by suppressing IRF-1 transcription activity. The protein level of Ataxin-10 is relatively higher in human vascular endothelial cells, which can be significantly suppressed by TNF-α in both HUVECs and HLMECs. Overexpression of Ataxin-10 markedly inhibited the mRNA expressions of VCAM-1 and several cytokines including MCP-1, CXCL-1, CCL-5, and TNF-α; thus, it can also suppress monocyte adhesion to endothelial cells. Accordingly, Ataxin-10 silencing promoted endothelial inflammation. However, Ataxin-10 did not affect the MAPK/NF-κB signaling pathway stimulated by TNF-α in HUVECs. Using the yeast two-hybrid assay, we found that Ataxin-10 can directly bind to interferon regulatory factor-1 (IRF-1). Upon TNF-α stimulation, Ataxin-10 promoted the cytoplasmic localization of IRF-1, which inhibited the transcription of VCAM-1. Moreover, knockdown of IRF-1 can eliminate the effect of Ataxin-10 on the expression of VCAM-1 in HUVECs induced by TNF-α. Taken together, these results indicate that Ataxin-10 inhibits endothelial cell activation and may serve as a promising therapeutic target for some vascular inflammatory-related diseases such as atherosclerosis.