Phage therapy combats pandrug-resistant Acinetobacter baumannii infection safely and efficiently.

Phage therapy offers a promising approach to combat the growing threat of antimicrobial resistance. Yet, key questions remain regarding dosage, administration routes, combination therapy, and the causes of therapeutic failure. In this study, we focused on a novel lytic phage, ФAb4B, which specifically targeted the A. baumannii strains with KL160 CPS, including the pan-drug resistant A. baumannii YQ4. ФAb4B exhibited the ability to effectively inhibit biofilm formation and eradicate mature biofilms independently of dosage. Additionally, it demonstrated a wide spectrum of antibiotic-phage synergy and did not show any cytotoxic or hemolytic effects. Continuous phage injections, both intraperitoneally and intravenously over 7 days, showed no acute toxicity in vivo. Importantly, phage therapy significantly improved neutrophil counts, outperforming ciprofloxacin (CIP). However, excessive phage injections suppressed neutrophil levels. The combinatorial treatment of phage-CIP rescued 91% of the mice, a superior outcome compared to phage alone (67%). The efficacy of the combinatorial treatment was independent of phage dosage. Notably, prophylactic administration of the combinatorial regimen provided no protection, but even when combined with a delayed therapeutic regimen, it saved all the mice. Bacterial resistance to the phage was not a contributing factor to treatment failure. Our preclinical study systematically describes the lytic phage's effectiveness in both in vitro and in vivo settings, filling in crucial details about phage treatment against bacteriemia caused by A. baumannii, which will provide a robust foundation for the future of phage therapy.

A microbial knowledge graph-based deep learning model for predicting candidate microbes for target hosts.

Predicting interactions between microbes and hosts plays critical roles in microbiome population genetics and microbial ecology and evolution. How to systematically characterize the sophisticated mechanisms and signal interplay between microbes and hosts is a significant challenge for global health risks. Identifying microbe-host interactions (MHIs) can not only provide helpful insights into their fundamental regulatory mechanisms, but also facilitate the development of targeted therapies for microbial infections. In recent years, computational methods have become an appealing alternative due to the high risk and cost of wet-lab experiments. Therefore, in this study, we utilized rich microbial metagenomic information to construct a novel heterogeneous microbial network (HMN)-based model named KGVHI to predict candidate microbes for target hosts. Specifically, KGVHI first built a HMN by integrating human proteins, viruses and pathogenic bacteria with their biological attributes. Then KGVHI adopted a knowledge graph embedding strategy to capture the global topological structure information of the whole network. A natural language processing algorithm is used to extract the local biological attribute information from the nodes in HMN. Finally, we combined the local and global information and fed it into a blended deep neural network (DNN) for training and prediction. Compared to state-of-the-art methods, the comprehensive experimental results show that our model can obtain excellent results on the corresponding three MHI datasets. Furthermore, we also conducted two pathogenic bacteria case studies to further indicate that KGVHI has excellent predictive capabilities for potential MHI pairs.

Advance on Engineering of Bacteriophages by Synthetic Biology.

Since bacteriophages (phages) were firstly reported at the beginning of the 20th century, the study on them experiences booming-fading-emerging with discovery and overuse of antibiotics. Although they are the hotspots for therapy of antibiotic-resistant strains nowadays, natural phage applications encounter some challenges such as limited host range and bacterial resistance to phages. Synthetic biology, one of the most dramatic directions in the recent 20-years study of microbiology, has generated numerous methods and tools and has contributed a lot to understanding phage evolution, engineering modification, and controlling phage-bacteria interactions. In order to better modify and apply phages by using synthetic biology techniques in the future, in this review, we comprehensively introduce various strategies on engineering or modification of phage genome and rebooting of recombinant phages, summarize the recent researches and potential directions of phage synthetic biology, and outline the current application of engineered phages in practice.

ApoE Mimetic Peptide COG1410 Exhibits Strong Additive Interaction with Antibiotics Against Mycobacterium smegmatis.

Background: Drug-resistant tuberculosis (TB) is an emerging threat to public health worldwide. Antimicrobial peptide (AMP) is a promising solution to solve the antimicrobial resistance crisis. The apolipoprotein E mimetic peptide COG1410 has been confirmed to simultaneously have neuroprotective, anti-inflammatory, and antibacterial activity. However, whether it is effective to inhibit growth of mycobacteria has not been investigated yet. Methods: The peptide COG1410 was synthesized with conventional solid-phase peptide synthesis and qualified by HPLC and mass spectrometry. Micro-dilution method was used to determine the minimal inhibitory concentration. A time-kill assay was used to determine the bactericidal dynamics of antimicrobial peptide and relative antibiotics. Static biofilm formation was conducted in 24-well plate and the biofilm was separated from planktonic cells and collected. The mechanism of action of COG1410 was explored by TEM observation and ATP leak assay. The localization of COG1410 was observed by confocal laser scan microscopy. The drug-drug interaction was determined by a checkerboard assay. Results: COG1410 was a potent bactericidal agent against M. smegmatis in vitro and within the macrophages with MIC 16 µg/mL, but invalid against M. abscess and M. tuberculosis. A time-kill assay showed that COG1410 killed M. smegmatis as potent as clarithromycin, but faster than LL-37, another short synthetic cationic peptide. 1× MIC COG1410 almost reduced 90% biofilm formation of M. smegmatis. Additionally, COG1410 was able to penetrate the cell membrane of macrophage and inhibit intracellular M. smegmatis growth. TEM observation and ATP leak assay found that COG1410 disrupted cell membrane and caused release of cell contents. Confocal fluorescence microscopy showed that FITC-COG1410 aggregated around cell membrane instead of entering the cytoplasm. Although COG1410 had relative high cytotoxicity, it exhibited strong additive interaction with regular anti-TB antibiotics, which reduced the working concentration of COG1410 and expanding safety window. After 30 passages, there was no induced drug resistance for COG1410. Conclusion: COG1410 was a novel and potent AMP against M. smegmatis by disrupting the integrity of cell membrane.

Urgency of controlling agricultural nitrogen sources to alleviate summertime air pollution in the North China Plain.

Agricultural nitrogen sources (ANS) have played an increasingly important role in the air quality since ANS emission controls are much weaker than those for fossil fuel combustion sources due to the increasing food demand. However, ANS emissions are highly uncertain due to stochastic agricultural management activities and limited field measurements, and impacts of ANS on the air quality remain elusive. In the study, the WRF-Chem model has been used to investigate ANS shares in near surface air pollutant concentrations during a growing season in the North China Plain (NCP), with ANS emissions constrained by satellite retrievals. Soil NOX and agricultural NH3 emissions are about 36% and 92% of their total emissions during the growing season. Sensitivity studies demonstrate that ANS count 16.9 µg m-3 (9.9%) of the mean maximum daily average 8-h ozone concentrations (MDA8 [O3]) and 8.9 µg m-3 (31.7%) of fine particulate matter concentrations ([PM2.5]) on average in the NCP. Additionally, the contributions of ANS to MDA8 [O3] and [PM2.5] increase with the deterioration of air pollution in cities. A 50% emission reduction in ANS decreases MDA8 [O3] ([PM2.5]) from 4.2% to 8.4% (from 19.7% to 31.9%) when the air quality changes from being lightly to heavily polluted in terms of MDA8 [O3] (hourly [PM2.5]). Without fossil fuel combustion emissions, the simulated average MDA8 [O3] and [PM2.5] are 111.7 and 8.2 µg m-3 in cities of the NCP, respectively, exceeding the new standards from the World Health Organization. Our study highlights important contributions of ANS to air quality and the urgency of ANS emission abatement for air pollution alleviation during summertime in the NCP.

The predictive performance of the lactate clearance rate combined with the APACHE II score in the prediction of sepsis-associated acute kidney injury in 7 days.

Background: The purpose of this study was to evaluate the accuracy of the lactate clearance rate (LCR) combined with the Acute Physiology and Chronic Health Evaluation II (APACHE II) score in the prediction of sepsis-associated acute kidney injury (SAKI). Methods: Sepsis patients were divided into the SAKI group and non-SAKI group. Arterial blood lactate was collected at 0 h (before treatment), 2 h, 4 h, 6 h, and 8 h (after treatment), and the LCR was calculated. The physiological parameters and laboratory test results were used to calculate the APACHE II score and the Sequential Organ Failure Assessment (SOFA) score. The receiver operating characteristic (ROC) curves of LCR, APACHE II score and SOFA score for predicting patients with SAKI were drawn. Two single indicators with high areas under the curves (AUCs) were selected to calculate the joint probability through regression analysis, and the prediction efficiency corresponding to each curve was analyzed. Results: There were significant differences in LCR between different groups and time periods (Fgroup=17.44, Pgroup ≤0.0001, Ftime =11.71, Ptime =0.0014). After 8 h of treatment, there was a significant difference in the overall compliance rate between the 2 groups (P<0.0001). In addition, after 24 h of treatment, the APACHE II score in the SAKI group was significantly higher than that in the non-SAKI group (P=0.0007), and SOFA score was also significantly higher than that in the non-SAKI group (P=0.0001). ROC curve showed that the 0-8 h LCR and APACHE II scores had a high predictive performance for the acute kidney injury (AKI) occurrence in sepsis patients, and AUCs were 0.7637 and 0.7517, respectively, while the combined AUC of the 2 indicators was 0.7975. Conclusions: The 0-8 h LCR combined with APACHE II score can improve the early predictive value of SAKI, reduce the risk of AKI in patients with sepsis/septic shock, and reduce the social and family burden, which is worthy of clinical application.

The Effect of Worktime Control on Overtime Employees' Mental Health and Work-Family Conflict: The Mediating Role of Voluntary Overtime.

Overtime has become a widespread phenomenon in the current information age that creates a high speed working pace and fierce competition in the high technology global economy. Based on the time-regulation mechanism and effort-recovery model, we examined the effect of worktime control (WTC) on mental health and work-family conflict (WFC) among overtime employees, and whether voluntary overtime mediated the relationships. We also examined two separate dimensions of WTC (control over time-off and control over daily hours). The results showed that control over time-off was related to decreased depression, anxiety, stress and WFC, while control over daily hours was related to decreased stress and WFC. Generally, control over time-off was beneficial to females and employees with dependents. Furthermore, mediation results showed that voluntary overtime was a complete mediator of relationships between WTC and depression and anxiety as well as a partial mediator of the relationship between WTC and stress. However, this study did not find a mediating effect of voluntary overtime on the WTC-WFC relationship. Limitations and practical implications are discussed.

Effects of hydroperoxy radical heterogeneous loss on the summertime ozone formation in the North China Plain.

Hydroperoxy radical (HO2) is a crucial oxidant participating in the oxidation of nitrogen oxide to nitrogen dioxide which constitutes one of the most important pathways for the ozone (O3) photochemical formation in the troposphere. Laboratory experiments and field observations have revealed efficient HO2 heterogeneous uptake on wet aerosols, but its impact on the O3 formation remains controversial. A severe and persistent O3 pollution episode has been simulated using the WRF-Chem model to evaluate the impacts of the HO2 heterogeneous loss on the O3 formation in the North China Plain (NCP) during the summertime of 2018. Comparisons between experimental simulations with the HO2 effective uptake coefficient of 0.2 and 0.0 shows that the HO2 heterogeneous loss decreases the daytime HO2 and maximum daily average 8-hour (MDA8) O3 concentrations by about 5% and 1% in the NCP, respectively. Emission mitigation from 2013 to 2018 is found to contribute a 2.1 µg m-3 (5%) increase in the MDA8 O3 concentration due to decreased aerosol sink for the HO2 heterogeneous loss in the NCP. Our results reveal that decreased HO2 heterogeneous uptake does not constitute an important factor driving the O3 trend since 2013 in the NCP.

Cropland nitrogen dioxide emissions and effects on the ozone pollution in the North China plain.

Soil nitrogen dioxide (NOX = NO2 + NO) emissions have been measured and estimated to be the second most significant contributor to the NOX burden following the fossil fuel combustion source globally. NOX emissions from croplands are subject to being underestimated or overlooked in air pollution simulations of regional atmospheric chemistry models. With constraints of ground and space observations of NO2, the WRF-Chem model is used to investigate the cropland NOX emission and its contribution to the near-surface ozone (O3) pollution in North China Plain (NCP) during a growing season as a case study. Model simulations have revealed that the cropland NOX emissions are underestimated by around 80% without constraints of satellite measured NO2 column densities. The biogenic NOX source is estimated to account for half of the anthropogenic NOX emissions in the NCP during the growing season. Additionally, the cropland NOX source contributes around 5.0% of the maximum daily average 8h O3 concentration and 27.7% of NO2 concentration in the NCP. Our results suggest the agriculture NOX emission exerts non-negligible impacts on the summertime air quality and needs to be considered when designing emission abatement strategies.

Where is the limit for overtime? Impacts of overtime on employees' mental health and potential solutions: A qualitative study in China.

Although Labor Law of the People's Republic of China stipulates the overtime system, overtime is still widespread in the IT industry. Through qualitative interviews, we explored the impact of overtime on employees' mental health and life. The current study identified four main themes, namely overtime reasons, outcomes of overtime, influential factors and solutions to overtime challenges. Besides work-related reasons and cultural influence, it was found that employees may work overtime due to personal reasons, such as capability and personal qualities; the most frequent impacts reported were fatigue, depression, stress and interference with life; three predominant influential factors were timing of overtime, control and rewards; and overtime conditions could be improved in practical and emotional ways. The study's findings highlight the importance of the design of flexible working time arrangements for avoiding fatigue and improving employees' work-life balance, enhancement of schedule arrangement for avoiding daily work interruption and last-minute tasks, and optimization of rewarding systems for avoiding complaints and facilitating voluntary overtime. Results suggest that mental health and work-life balance can be promoted by organizational initiatives focusing on minimizing excessive job demands, increasing psychosocial resources, supporting boundary management, and enhancing perceived flexibility.

Homozygous spinocerebellar ataxia type 3 in China: a case report.

Spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disease caused by a heterozygous CAG repeat expansion in the ataxin 3 gene (ATXN3). However, patients with homozygous SCA3 carrying expanded CAG repeats in both alleles of ATXN3 are extremely rare. Herein, we present a case of a 50-year-old female who had homozygous SCA3 with expansion of 62/62 repeats. Segregation analysis of the patient's family showed both a contraction pattern of CAG repeat length and stable transmission. The present case demonstrated an earlier onset and more severe clinical phenotype than that seen in heterozygous individuals, suggesting that the gene dosage enhances disease severity.

Seasonal fluctuations in symbiotic bacteria and their role in environmental adaptation of the scleractinian coral Acropora pruinosa in high-latitude coral reef area of the South China Sea.

Coral-associated bacterial communities are paramount for coral ecosystems and holobiont health. However, the role of symbiotic bacteria in the adaptation of high-latitude corals to seasonal fluctuations remains underexplored. Therefore, we used 16S rRNA-based high-throughput sequencing to analyze the symbiotic bacterial diversity, composition, and core bacterial community in high-latitude coral and explored the seasonal fluctuation characteristics of symbiotic bacterial communities. We found that bacterial richness and α-diversity changed significantly across different seasons. Additionally, the community structure recombined seasonally, with different dominant bacterial phyla and genera in different seasons. However, the symbiotic bacterial community structures of Acropora pruinosa in winter and spring were similar. Proteobacteria were the dominant bacteria in spring, autumn, and winter. In summer, the dominant bacterial taxa were Bacteroidota and Proteobacteria. Ralstonia was the dominant bacterial genus in spring and winter, whereas in autumn, BD1-7_clade was dominant. Linear discriminant analysis effect size identified 20 abundant genera between the different groups. Core microbiome analysis revealed that 12 core bacterial operational taxonomic units were associated with A. pruinosa in all seasons, seven of which varied with the seasons, changing between dominant and rare. Distance-based redundancy and variation partitioning analyses revealed that sea surface temperature was the major contributor of variation in the microbial community structure. We hypothesized that the high diversity and abundance of symbiotic bacteria and the increase in Prosthecochloris abundance in coral in summer can help A. pruinosa maintain its physiological functions, ameliorating the negative physiological effects of the decrease in Symbiodiniaceae density under high-temperature stress. Thus, the rapid reorganization of the symbiotic bacterial community structure and core microflora in different seasons may allow the corals to adapt to large seasonal environmental fluctuations. In conclusion, seasonal variation of bacteria plays an important role in coral adaptation to large environmental fluctuations.

MiR-106a aggravates sepsis-induced acute kidney injury by targeting THBS2 in mice model.

PURPOSE: To investigate the role and related mechanisms of miR-106a in sepsis-induced AKI. METHODS: Serum from sepsis and healthy patients was collected, sepsis mouse model was established by cecal ligation and puncture (CLP). TCMK-1 cells were treated with lipopolysaccharide (LPS) and transfected with THBS2-small interfering RNA (siTHBS2), miR-106a inhibitor, miR-106a mimics and their negative controls (NCs). The expression of miR-106a, thrombospondin 2 (THBS2), Bax, cleaved caspase-3 and Bcl-2, cell viability, relative caspase-3 activity and TNF-α, IL-1ß, IL-6 content were respectively detected by quantitative real-time polymerase chain reaction (qRT-PCR), western blotting, Cell Counting Kit-8 (CCK-8) and enzyme linked immunosorbent assay (ELISA). The relationship between miR-106a and THBS2 was confirmed by dual luciferase reporter assay. RESULTS: MiR-106a was up-regulated in serum of sepsis patients, CLP-induced mice models and LPS-induced TCMK-1 cells. LPS reduced cell viability and Bcl-2 expression, and increased caspase-3 activity, Bax expression, the content of TNF-α, IL-1ß, IL-6. THBS2 was a target of miR-106a. The decreases of caspase-3 activity, TNF-α, IL-1ß, IL-6, Bax expression and the increases of cell viability, Bcl-2 expression caused by miR-106a knockdown were reversed when THBS2 silencing in LPS-stimulated TCMK-1 cells. CONCLUSION: MiR-106a aggravated LPS-induced inflammation and apoptosis of TCMK-1 cells via regulating THBS2 expression.

MiR-106a aggravates sepsis-induced acute kidney injury by targeting THBS2 in mice model

Abstract Purpose To investigate the role and related mechanisms of miR-106a in sepsis-induced AKI. Methods Serum from sepsis and healthy patients was collected, sepsis mouse model was established by cecal ligation and puncture (CLP). TCMK-1 cells were treated with lipopolysaccharide (LPS) and transfected with THBS2-small interfering RNA (siTHBS2), miR-106a inhibitor, miR-106a mimics and their negative controls (NCs). The expression of miR-106a, thrombospondin 2 (THBS2), Bax, cleaved caspase-3 and Bcl-2, cell viability, relative caspase-3 activity and TNF-α, IL-1β, IL-6 content were respectively detected by quantitative real-time polymerase chain reaction (qRT-PCR), western blotting, Cell Counting Kit-8 (CCK-8) and enzyme linked immunosorbent assay (ELISA). The relationship between miR-106a and THBS2 was confirmed by dual luciferase reporter assay. Results MiR-106a was up-regulated in serum of sepsis patients, CLP-induced mice models and LPS-induced TCMK-1 cells. LPS reduced cell viability and Bcl-2 expression, and increased caspase-3 activity, Bax expression, the content of TNF-α, IL-1β, IL-6. THBS2 was a target of miR-106a. The decreases of caspase-3 activity, TNF-α, IL-1β, IL-6, Bax expression and the increases of cell viability, Bcl-2 expression caused by miR-106a knockdown were reversed when THBS2 silencing in LPS-stimulated TCMK-1 cells. Conclusion MiR-106a aggravated LPS-induced inflammation and apoptosis of TCMK-1 cells via regulating THBS2 expression.