Optimizing the placement of medical wastewater outlets in sewer systems to reduce chemical consumption at wastewater treatment plants.

The severely low influent chemical oxygen demand (COD) concentration at wastewater treatment plants (WWTPs) has become a critical issue. A key factor is the excessive biodegradation of organic matter by microbial communities within sewer systems. Intense disinfection commonly adopted for medical wastewater leads to abundant residual chlorine entering sewers, likely causing significant changes in microbial communities and sewage quality in sewers, yet our understanding is limited. Through long-term sewer simulation batch tests, this study revealed the response mechanism of microbial communities to residual chlorine and its impact on organic matter concentration in sewage. Under residual chlorine stress, microbial community structure rapidly changed, and more complex microbial interactions were observed. Besides, pathways related to stress response such as two-component system were significantly enriched; pathways related to energy metabolism (such as carbon fixation in prokaryotes and citrate cycle) in microbial communities were inhibited, and carbon metabolism shifted from the Embden-Meyerhof pathway to the pentose phosphate pathway to enhance cellular reducing power, reduce oxidative stress, and consequently decrease organic matter degradation. Therefore, compared to sewers with normal disinfection, concentrations of COD and dissolved organic carbon in sewage under chlorine stress increased by 12.6 % and 7.4 %, respectively. Besides, the decay and transformation of residual chlorine in sewers were explored. These findings suggest a new approach to medical wastewater discharge management: placing the medical wastewater outlet at the upstream in sewer systems, which ensures that residual chlorine consumption reaches maximum during long-distance transportation, mitigating its harmful effects on WWTPs, and increases the influent organic matter concentration, thereby reducing the need for additional carbon sources.

Activation of the HMGB1-TLR4 pathway impacts the functionality of bone marrow mesenchymal stem cells and disrupts macrophage polarization in immune thrombocytopenia.

Recent evidence suggests that immune thrombocytopenia (ITP), a common bleeding disorder, is linked to an imbalance in macrophage polarization and impaired bone marrow mesenchymal stem cells (BMSCs). However, the relationship between macrophage polarization imbalance and functional defects in BMSCs, as well as the involvement of associated molecules in BMSCs' defects, is not well understood. This study aimed to investigate the regulatory effects of high mobility group protein 1 (HMGB1) on the physiological functions of BMSCs, specifically in relation to macrophage polarization imbalance. Patients with ITP showed dysregulation in monocyte/macrophage polarization and impaired BMSCs function. HMGB1 was found to have a negative impact on the ability of BMSCs to regulate the imbalance in macrophage polarization, especially when inflammatory factors are present. The MyD88-dependent pathway downstream of BMSCs was found to be significantly enhanced with HMGB1 treatment. Furthermore, treatment with toll-like receptor 4 (TLR4) inhibitors successfully restored the regulatory capacity of BMSCs in ameliorating macrophage polarization imbalance and effectively inhibited the activation of the MyD88-dependent pathway. Meanwhile, infusion of si-TLR4-BMSCs reversed HMGB1-induced platelet dysfunction and reduced over-polarization to M1-like macrophages in the ITP mouse model. Consequently, targeting the HMGB1-TLR4 pathway could be a potential approach to restore the immunoregulatory function of BMSCs.

Optimizing anaerobic digestion: Benefits of mild temperature transition from thermophilic to mesophilic conditions.

Anaerobic digestion (AD) plays a significant role in renewable energy recovery. Upgrading AD from thermophilic (50-57 °C) to mesophilic (30-38 °C) conditions to enhance process stability and reduce energy input remains challenging due to the high sensitivity of thermophilic microbiomes to temperature fluctuations. Here we compare the effects of two decreasing-temperature modes from 55 to 35 °C on cell viability, microbial dynamics, and interspecies interactions. A sharp transition (ST) is a one-step transition by 20 °C d-1, while a mild transition (MT) is a stepwise transition by 1 °C d-1. We find a greater decrease in methane production with ST (88.8%) compared to MT (38.9%) during the transition period. ST mode overproduced reactive oxygen species by 1.6-fold, increased membrane permeability by 2.2-fold, and downregulated microbial energy metabolism by 25.1%, leading to increased apoptosis of anaerobes by 1.9-fold and release of intracellular substances by 2.9-fold, further constraining methanogenesis. The higher (1.6 vs. 1.1 copies per gyrA) metabolic activity of acetate-dependent methanogenesis implied more efficient methane production in a steady mesophilic, MT-mediated system. Metagenomic binning and network analyses indicated that ST induced dysbiosis in keystone species and greatly enhanced microbial functional redundancy, causing loss of microbial syntrophic interactions and redundant metabolic pathways. In contrast, the greater microbial interconnections (average degrees 44.9 vs. 22.1) in MT at a steady mesophilic state suggested that MT could better maintain necessary system functionality and stability through microbial syntrophy or specialized pathways. Adopting MT to transform thermophilic digesters into mesophilic digesters is feasible and could potentially enhance the further optimization and broader application of practical anaerobic engineering.

Neglected risks of enhanced antimicrobial resistance and pathogenicity in anaerobic digestion during transition from thermophilic to mesophilic.

Minimization of antibiotic resistance genes (ARGs) and potential pathogenic antibiotic-resistant bacteria (PARB) during anaerobic digestion (AD) is significantly impacted by temperature. However, knowledge on how ARGs and PARB respond to temperature transition from thermophilic to mesophilic is limited. Here, we combined metagenomic-based with culture-based approaches and revealed the risks of antimicrobial resistance and pathogenicity during transition from 55 °C to 35 °C for AD, with strategies of sharp (ST, one-step by 20 °C/d) and mild (MT, step-wise by 1 °C/d). Results indicated a lower decrease in methane production with MT (by 38.9%) than ST (by 88.8%). Phenotypic assays characterized a significant propagation of multi-resistant lactose-fermenting Enterobacteriaceae and indicator pathogens after both transitions, especially via ST. Further genomic evidence indicated a significant increase of ARGs (29.4-fold), virulence factor genes (1.8-fold) and PARB (65.3-fold) after ST, while slight enrichment via MT. Bacterial succession and enhanced horizontal transfer mediated by mobile genetic elements promoted ARG propagation in AD during transition, which was synchronously exacerbated through horizontal transfer mechanisms mediated by cellular physiological responses (oxidative stress, membrane permeability, bacterial conjugation and transformation) and co-selection mechanisms of biomethanation metabolic functions (acidogenesis and acetogenesis). This study reveals temperature-dependent resistome and pathogenicity development in AD, facilitating microbial risk control.

CCL22 Induces the Polarization of Immature Dendritic Cells into Tolerogenic Dendritic Cells in Radiation-Induced Lung Injury through the CCR4-Dectin2-PLC-γ2-NFATC2-Nr4a2-PD-L1 Signaling Pathway.

Recruitment of immune cells to the injury site plays a pivotal role in the pathology of radiation-associated diseases. In this study, we investigated the impact of the chemokine CCL22 released from alveolar type II epithelial (AT2) cells after irradiation on the recruitment and functional changes of dendritic cells (DCs) in the development of radiation-induced lung injury (RILI). By examining changes in CCL22 protein levels in lung tissue of C57BL/6N mice with RILI, we discovered that ionizing radiation increased CCL22 expression in irradiated alveolar AT2 cells, as did MLE-12 cells after irradiation. A transwell migration assay revealed that CCL22 promoted the migration of CCR4-positive DCs to the injury site, which explained the migration of pulmonary CCR4-positive DCs in RILI mice in vivo. Coculture experiments demonstrated that, consistent with the response of regulatory T cells in the lung tissue of RILI mice, exogenous CCL22-induced DCs promoted regulatory T cell proliferation. Mechanistically, we demonstrated that Dectin2 and Nr4a2 are key targets in the CCL22 signaling pathway, which was confirmed in pulmonary DCs of RILI mice. As a result, CCL22 upregulated the expression of PD-L1, IL-6, and IL-10 in DCs. Consequently, we identified a mechanism in which CCL22 induced DC tolerance through the CCR4-Dectin2-PLC-γ2-NFATC2-Nr4a2-PD-L1 pathway. Collectively, these findings demonstrated that ionizing radiation stimulates the expression of CCL22 in AT2 cells to recruit DCs to the injury site and further polarizes them into a tolerant subgroup of CCL22 DCs to regulate lung immunity, ultimately providing potential therapeutic targets for DC-mediated RILI.

Identification of urine biomarkers predictive of prolonged QTc interval in multidrug-resistant tuberculosis patients treated with bedaquiline.

The most frequent adverse event associated with bedaquiline (BDQ) is the QTc interval prolongation; however, there was no biomarkers that could be used to predict the occurrence of QTc prolongation in BDQ-treated patients. In this study, we employed the ultra-high performance liquid chromatography-MS/MS (UHPLC-MS/MS) to generate metabolic profiling for the discovery of potential predictive urine biomarkers of QTc prolongation in these patients. Untargeted metabolomic technique was used to concentrate the differential metabolic pathway, and targeted metabolomic technique was subsequently performed to identify predictive biomarkers for QTc prolongation. A total of 45 rifampicin-resistant TB (RR-TB) and multidrug-resistant TB (MDR-TB) patients were enrolled in our study, including 15 RR/MDR-TB patients with QTc interval prolongation (QIP) and 30 RR/MDR-TB patients with QTc interval un-prolongations (QIU). Untargeted technique revealed that the lipid metabolism was the most differential metabolic pathway between two groups. Further targeted technique identified four differential metabolites, including betaine, LPE (18:2), LPE (20:3), and LPE (20:4). The combined analysis of metabolisms revealed that the combined use of LPE (20:3) and LPE (20:4) had the best performance for predicting the occurrence of QTc prolongation in TB patients, yielding a sensitivity of 87.4% and a specificity of 78.5%. In addition, with the progression of BDQ treatment, the LPEs exhibited persistent difference in the BDQ-treated TB patients experiencing QTc interval prolongation. In conclusion, our data demonstrate that the combined use of LPE (20:3) and LPE (20:4) yields promising performance for predicting the occurrence of QTc interval prolongation in BDQ-treated patients.

PHGDH is Key to a Prognostic Multigene Signature and a Potential Therapeutic Target in Acute Myeloid Leukemia.

As a rate-limiting enzyme for the serine biosynthesis pathway (SSP) in the initial step, phosphoglycerate dehydrogenase (PHGDH) is overexpressed in many different tumors, and pharmacological or genetic inhibition of PHGDH promotes antitumor effects. In the present research, by analyzing several acute myeloid leukemia (AML) datasets in the Gene Expression Omnibus (GEO), we identified prognosis-related genes and constructed a multigene signature by univariate, multivariate Cox regression and LASSO regression. Subsequently, the multigene signature was confirmed through Cox, Kaplan-Meier, and ROC analyses in the validation cohort. Moreover, PHGDH acted as a risk factor and was correlated with inferior overall survival. We further analysed other datasets and found that PHGDH was overexpressed in AML. Importantly, the expression of PHGDH was higher in drug-resistant AML compared to drug-sensitive ones. In vitro experiments showed that inhibition of PHGDH induced apoptosis and reduced proliferation in AML cells, and these antitumor effects could be related to the Bcl-2/Bax signaling pathway by the noncanonical or nonmetabolic functions of PHGDH. In summary, we constructed a twenty-gene signature that could predicate prognosis of AML patients and found that PHGDH may be a potential target for AML treatment.

Preparation of functional geopolymers from municipal solid waste incineration fly ash: An approach combining experimental and computational simulation studies.

This study aims to evaluate the feasibility and safety of using municipal solid waste incineration fly ash (MSW-IFA) in the development of geopolymer-based solidification/stabilization (S/S) treatments. Geopolymers have garnered attention as a sustainable alternative to traditional cement, owing to their high strength, stability, and minimal CO2 emissions. In this study, a combination of experimental and simulation calculations was used to investigate the setting time, mechanical properties, environmental risks, hydration mechanisms and processes of municipal solid waste incineration fly ash-based polymeric functional cementitious materials (GFCM). The results demonstrate that the mechanical properties of GFCM are related to the changes in the mineral phases and the degree of compactness. Quantum chemical calculations indicate that the hydration products may be [Si(OH)4], [Al(OH)3(OH2)] and [Al(OH)4]-. It is possible that the heavy metals are embedded in the hydrated silica-aluminate by electrostatic interaction or chemisorption. Heavy metals may be embedded in hydrated silica-aluminate by electrostatic action or chemisorption. This study provides a feasible method for resource utilization and heavy metal stabilization mechanism of MSW-IFA.

Antigen-specific chemokine profiles as biomarkers for detecting Mycobacterium tuberculosis infection.

Background: Latent tuberculosis (TB) infection can progress to active TB, which perpetuates community transmission that undermines global TB control efforts. Clinically, interferon-γ release assays (IGRAs) are commonly used for active TB case detection. However, low IGRA sensitivity rates lead to false-negative results for a high proportion of active TB cases, thus highlighting IGRA ineffectiveness in differentiating MTB-infected individuals from healthy individuals. Methods: Participants enrolled at Beijing Chest Hospital from May 2020-April 2022 were assigned to healthy control (HC), LTBI, IGRA-positive TB, and IGRA-negative TB groups. Screening cohort MTB antigen-specific blood plasma chemokine concentrations were measured using Luminex xMAP assays then were verified via testing of validation cohort samples. Results: A total of 302 individuals meeting study inclusion criteria were assigned to screening and validation cohorts. Testing revealed significant differences in blood plasma levels of CXCL9, CXCL10, CXCL16, CXCL21, CCL1, CCL19, CCL27, TNF-α, and IL-4 between IGRA-negative TB and HC groups. Levels of CXCL9, CXCL10, IL-2, and CCL8 biomarkers were predictive for active TB, as reflected by AUC values of ≥0.9. CXCL9-based enzyme-linked immunosorbent assay sensitivity and specificity rates were 95.9% (95%CI: 91.7-98.3) and 100.0% (92.7-100.0), respectively. Statistically similar AUC values were obtained for CXCL9 and CXCL9-CXCL10 assays, thus demonstrating that combined analysis of CXCL10 and CXCL9 levels did not improve active TB diagnostic performance. Conclusion: The MTB antigen stimulation-based CXCL9 assay may compensate for low IGRA diagnostic accuracy when used to diagnose IGRA-negative active TB cases and thus is an accurate and sensitive alternative to IGRAs for detecting MTB infection.

Multiple exposures to low-dose ionizing radiation induced the initiation and progression of pro-atherosclerotic phenotypes in mice and vascular endothelial cell damage.

OBJECTIVE: This study aimed to investigate the effects of low-dose radiation on the abdominal aorta of mice and vascular endothelial cells. METHODS: Wild-type and tumor-bearing mice were exposed to 15 sessions of low-dose irradiation, resulting in cumulative radiation doses of 187.5, 375, and 750 mGy. The effect on the cardiovascular system was assessed. Immunohistochemistry analyzed protein expressions of PAPP-A, CD62, P65, and COX-2 in the abdominal aorta. Microarray technology, Gene Ontology analysis, and pathway enrichment analysis evaluated gene expression changes in endothelial cells exposed to 375 mGy X-ray. Cell viability was assessed using the Cell Counting Kit 8 assay. Immunofluorescence staining measured γ-H2AX levels, and real-time polymerase chain reaction quantified mRNA levels of interleukin-6 (IL-6), ICAM-1, and Cx43. RESULTS: Hematoxylin and eosin staining revealed thickening of the inner membranes and irregular arrangement of smooth muscle cells in the media membrane at 375 and 750 mGy. Inflammation was observed in the inner membranes at 750 mGy, with a clear inflammatory response in the hearts of tumor-bearing mice. Immunohistochemistry indicated increased levels of PAPP-A, P65, and COX-2 post-irradiation. Microarray analysis showed 425 up-regulated and 235 down-regulated genes, associated with processes like endothelial cell-cell adhesion, IL-6, and NF-κB signaling. Cell Counting Kit 8 assay results indicated inhibited viability at 750 mGy in EA.hy926 cells. Immunofluorescence staining demonstrated a dose-dependent increase in γ-H2AX foci. Reverse transcription quantitative PCR results showed increased expression of IL6, ICAM-1, and Cx43 in EA.hy926 cells post 750 mGy X-ray exposure. CONCLUSION: Repeated low-dose ionizing radiation exposures triggered the development of pro-atherosclerotic phenotypes in mice and damage to vascular endothelial cells.

Functional traits and health implications of the global household drinking-water microbiome retrieved using an integrative genome-centric approach.

The biological safety of drinking water plays a crucial role in public health protection. However, research on the drinking water microbiome remains in its infancy, especially little is known about the potentially pathogenic bacteria in and functional characteristics of the microbiome in household tap water that people are directly exposed to. In this study, we used a genomic-centric approach to construct a genetic catalogue of the drinking water microbiome by analysing 116 metagenomic datasets of household tap water worldwide, spanning nine countries/regions on five continents. We reconstructed 859 high-quality metagenome-assembled genomes (MAGs) spanning 27 bacterial and 2 archaeal phyla, and found that the core MAGs belonging to the phylum Proteobacteria encoded the highest metabolic functional diversity of the 33 key complete metabolic modules. In particular, we found that two core MAGs of Brevibacillus and Methylomona encoded genes for methane metabolism, which may support the growth of heterotrophic organisms observed in the oligotrophic ecosystem. Four MAGs of complete ammonia oxidation (comammox) Nitrospira were identified and functional metabolic analysis suggested these may enable mixotrophic growth and encode genes for reactive oxygen stress defence and arsenite reduction that could aid survival in the environment of oligotrophic drinking water systems. Four MAGs were annotated as potentially pathogenic bacteria (PPB) and thus represented a possible public health concern. They belonged to the genera Acinetobacter (n = 3) and Mycobacterium (n = 1), with a total relative abundance of 1.06 % in all samples. The genomes of PPB A. junii and A. ursingii were discovered to contain antibiotic resistance genes and mobile genetic elements that could contribute to antimicrobial dissemination in drinking water. Further network analysis suggested that symbiotic microbes which support the growth of pathogenic bacteria can be targets for future surveillance and removal.

Unraveling the link between childhood maltreatment and depression: Insights from the role of ventral striatum and middle cingulate cortex in hedonic experience and emotion regulation.

Childhood maltreatment is an established risk factor for psychopathology. However, it remains unclear how childhood traumatic events relate to mental health problems and how the brain is involved. This study examined the serial mediation effect of brain morphological alterations and emotion-/reward-related functions on linking the relationship from maltreatment to depression. We recruited 156 healthy adolescents and young adults and an additional sample of 31 adolescents with major depressive disorder for assessment of childhood maltreatment, depressive symptoms, cognitive reappraisal and anticipatory/consummatory pleasure. Structural MRI data were acquired to identify maltreatment-related cortical and subcortical morphological differences. The mediation models suggested that emotional maltreatment of abuse and neglect, was respectively associated with increased gray matter volume in the ventral striatum and greater thickness in the middle cingulate cortex. These structural alterations were further related to reduced anticipatory pleasure and disrupted cognitive reappraisal, which contributed to more severe depressive symptoms among healthy individuals. The above mediating effects were not replicated in our clinical group partly due to the small sample size. Preventative interventions can target emotional and reward systems to foster resilience and reduce the likelihood of future psychiatric disorders among individuals with a history of maltreatment.

The Notch1/Hes1 pathway regulates Neuregulin 1/ErbB4 and participates in microglial activation in rats with VPA-induced autism.

The core clinical characteristics of autism, which is a neurodevelopmental disease, involve repetitive behavior and impaired social interactions. Studies have shown that the Notch and Neuregulin1 (NRG1) signaling pathways are abnormally activated in autism, but the mechanism by which these two signaling pathways interact to contribute to the progression of autism has not been determined. Our results suggest that the levels of Notch1, Hes1, NRG1, and phosphorylated ErbB4 in the cerebellum (CB), hippocampus (HC), and prefrontal cortex (PFC) were increased in rats with valproic acid (VPA)-induced autism compared to those in the Con group. However, 3, 5-difluorophenyl-L-alanyl-L-2-phenylglycine tert-butyl (DAPT), which is a Notch pathway inhibitor, ameliorated autism-like behavioral abnormalities and decreased the protein levels of NRG1 and phosphorylated ErbB4 in rats with VPA-induced autism; these results demonstrated that the Notch1/Hes1 pathway could participate in the pathogenesis of autism by regulating the NRG1/ErbB4 signaling pathway. Studies have shown that the Notch pathway regulates microglial differentiation and activation during the onset of neurological disorders and that microglia affect autism-like behavior via synaptic pruning. Therefore, we hypothesized that the Notch1/Hes1 pathway could regulate the NRG1/ErbB4 pathway and thus participate in the development of autism by regulating microglial functions. The present study showed that AG1478, which is an ErbB4 inhibitor, ameliorated the autism-like behaviors in a VPA-induced autism rat model, reduced abnormal microglial activation, and decreased NRG1 and Iba-1 colocalization; however, AG1478 did not alter Notch1/Hes1 activity. These results demonstrated that Notch1/Hes1 may participate in the microglial activation in autism by regulating NRG1/ErbB4, revealing a new mechanism underlying the pathogenesis of autism.

Understanding the effects of A-site Ag-doping on LaCoO3 perovskite for NO oxidation: Structural and magnetic properties.

The partial substitution of A-site in perovskites is a major strategy to enhance the catalytic oxidation activity. This study explores the use of silver (Ag) to partially replace the lanthanum (La) ion at the A-site in LaCoO3 perovskite, investigating the role of Ag in the ABO3 perovskite structure, elucidating the nitric oxide (NO) oxidation mechanism over La1-xAgxCoO3 (x = 0.1-0.5) perovskites. La0.7Ag0.3CoO3 with an Ag-doping amount of 0.3, exhibited the highest NO oxidation activity of 88.5% at 275 °C. Characterization results indicated that Ag substitution enhanced the perovskite, maintaining its original phase structure, existing in the form of a mixture of Ag0 and Ag+ in the La1-xAgxCoO3 (x = 0.1-0.5) perovskites. Notably, Ag substitution improved the specific surface area, reduction performance, Co3+, and surface adsorption oxygen content. Additionally, the study investigated the relationship between magnetism and NO oxidation from a magnetism perspective. Ag-doping strengthened the magnetism of La-Ag perovskite, resulting in stronger adsorption of paramagnetic NO. This study elucidated the NO oxidation mechanism over La-Ag perovskite, considering structural and magnetic properties, providing valuable insights for the subsequent development and industrial application of high oxidation ability perovskite catalysts.

How does benign/malicious envy impact young women's subjective well-being in daily life? An investigation of intrapersonal and interpersonal pathway.

Although previous cross-sectional studies have investigated the between-person correlation between dispositional envy and subjective well-being, few longitudinal studies have explored the within-person relationships between state benign/malicious envy and subjective well-being, as well as the intrapersonal and interpersonal mechanisms involved. This study adopted a diary approach for 14 consecutive days from a sample of 167 young women to investigate the within-person associations among benign/malicious envy, self-esteem, perceived social support, and subjective well-being. The results revealed that benign and malicious envy had opposite effects on subjective well-being within individuals. Besides, the results indicated that self-esteem and perceived social support mediated the relationships between benign envy and two dimensions of subjective well-being (positive affect and life satisfaction) within individuals. Furthermore, self-esteem played a within-person mediating role in the relationships between malicious envy and three dimensions of subjective well-being, whereas perceived social support only served as a within-person mediator between malicious envy and positive affect. These findings shed light on the distinction between benign envy and malicious envy and help in comprehending the intrapersonal and interpersonal mechanisms through which the two types of envy impact subjective well-being in daily life.

Approaches for reducing chemo/radiation-induced cardiotoxicity by nanoparticles.

Nanoparticles are fascinating and encouraging carriers for cancer treatment due to their extraordinary properties and potential applications in targeted drug delivery, treatment, and diagnosis. Experimental studies including in vitro and in vivo examinations show that nanoparticles can cause a revolution in different aspects of cancer therapy. Normal tissue toxicity and early and late consequences are the major limitations of cancer therapy by radiotherapy and chemotherapy. However, the delivery of drugs into tumors or reducing the accumulation of drugs in normal tissues can permit a more satisfactory response of malignancies to therapy with more inferior side effects. Cardiac toxicity is one of the major problems for chemotherapy and radiotherapy. Therefore, several experimental studies have been performed to minimize the degenerative impacts of cancer treatment on the heart and also enhance the influences of radiotherapy and chemotherapy agents in cancers. This review article emphasizes the benefits of nanoparticle-based drug delivery techniques, including minimizing the exposure of the heart to anticancer drugs, enhancing the accumulation of drugs in cancers, and expanding the effectiveness of radiotherapy. The article also discusses the challenges and problems accompanied with nanoparticle-based drug delivery techniques such as toxicity, which need to be addressed through further research. Moreover, the article emphasizes the importance of developing safe and effective nanoparticle-based therapies that can be translated into clinical practice.

Mutual antagonism of mouse-adaptation mutations in HA and PA proteins on H9N2 virus replication.

Avian H9N2 viruses have wide host range among the influenza A viruses. However, knowledge of H9N2 mammalian adaptation is limited. To explore the molecular basis of the adaptation to mammals, we performed serial lung passaging of the H9N2 strain A/chicken/Hunan/8.27 YYGK3W3-OC/2018 (3W3) in mice and identified six mutations in the hemagglutinin (HA) and polymerase acidic (PA) proteins. Mutations L226Q, T511I, and A528V of HA were responsible for enhanced pathogenicity and viral replication in mice; notably, HA-L226Q was the key determinant. Mutations T97I, I545V, and S594G of PA contributed to enhanced polymerase activity in mammalian cells and increased viral replication levels in vitro and in vivo. PA-T97I increased viral polymerase activity by accelerating the viral polymerase complex assembly. Our findings revealed that the viral replication was affected by the presence of PA-97I and/or PA-545V in combination with a triple-point HA mutation. Furthermore, the double- and triple-point PA mutations demonstrated antagonistic effect on viral replication when combined with HA-226Q. Notably, any combination of PA mutations, along with double-point HA mutations, resulted in antagonistic effect on viral replication. We also observed antagonism in viral replication between PA-545V and PA-97I, as well as between HA-528V and PA-545V. Our findings demonstrated that several antagonistic mutations in HA and PA proteins affect viral replication, which may contribute to the H9N2 virus adaptation to mice and mammalian cells. These findings can potentially contribute to the monitoring of H9N2 field strains for assessing their potential risk in mammals.

Microbiome-functionality in anaerobic digesters: A critical review.

Microbially driven anaerobic digestion (AD) processes are of immense interest due to their role in the biovalorization of biowastes into renewable energy resources. The function-versatile microbiome, interspecies syntrophic interactions, and trophic-level metabolic pathways are important microbial components of AD. However, the lack of a comprehensive understanding of the process hampers efforts to improve AD efficiency. This study presents a holistic review of research on the microbial and metabolic "black box" of AD processes. Recent research on microbiology, functional traits, and metabolic pathways in AD, as well as the responses of functional microbiota and metabolic capabilities to optimization strategies are reviewed. The diverse ecophysiological traits and cooperation/competition interactions of the functional guilds and the biomanipulation of microbial ecology to generate valuable products other than methane during AD are outlined. The results show that AD communities prioritize cooperation to improve functional redundancy, and the dominance of specific microbes can be explained by thermodynamics, resource allocation models, and metabolic division of labor during cross-feeding. In addition, the multi-omics approaches used to decipher the ecological principles of AD consortia are summarized in detail. Lastly, future microbial research and engineering applications of AD are proposed. This review presents an in-depth understanding of microbiome-functionality mechanisms of AD and provides critical guidance for the directional and efficient bioconversion of biowastes into methane and other valuable products.

Tenecteplase versus alteplase in treatment of acute ST-segment elevation myocardial infarction: A randomized non-inferiority trial.

BACKGROUND: A phase II trial on recombinant human tenecteplase tissue-type plasminogen activator (rhTNK-tPA) has previously shown its preliminary efficacy in ST elevation myocardial infarction (STEMI) patients. This study was designed as a pivotal postmarketing trial to compare its efficacy and safety with rrecombinant human tissue-type plasminogen activator alteplase (rt-PA) in Chinese patients with STEMI. METHODS: In this multicenter, randomized, open-label, non-inferiority trial, patients with acute STEMI were randomly assigned (1:1) to receive an intravenous bolus of 16 mg rhTNK-tPA or an intravenous bolus of 8 mg rt-PA followed by an infusion of 42 mg in 90 min. The primary endpoint was recanalization defined by thrombolysis in myocardial infarction (TIMI) flow grade 2 or 3. The secondary endpoint was clinically justified recanalization. Other endpoints included 30-day major adverse cardiovascular and cerebrovascular events (MACCEs) and safety endpoints. RESULTS: From July 2016 to September 2019, 767 eligible patients were randomly assigned to receive rhTNK-tPA ( n = 384) or rt-PA ( n = 383). Among them, 369 patients had coronary angiography data on TIMI flow, and 711 patients had data on clinically justified recanalization. Both used a -15% difference as the non-inferiority efficacy margin. In comparison to rt-PA, both the proportion of patients with TIMI grade 2 or 3 flow (78.3% [148/189] vs. 81.7% [147/180]; differences: -3.4%; 95% confidence interval [CI]: -11.5%, 4.8%) and clinically justified recanalization (85.4% [305/357] vs. 85.9% [304/354]; difference: -0.5%; 95% CI: -5.6%, 4.7%) in the rhTNK-tPA group were non-inferior. The occurrence of 30-day MACCEs (10.2% [39/384] vs. 11.0% [42/383]; hazard ratio: 0.96; 95% CI: 0.61, 1.50) did not differ significantly between groups. No safety outcomes significantly differed between groups. CONCLUSION: rhTNK-tPA was non-inferior to rt-PA in the effect of improving recanalization of the infarct-related artery, a validated surrogate of clinical outcomes, among Chinese patients with acute STEMI. TRIAL REGISTRATION: www.ClinicalTrials.gov (No. NCT02835534).

Biodosimetry Based on Gamma-H2AX Quantification in Human Peripheral Blood Lymphocytes after Partial-body Irradiation.

ABSTRACT: Quantification of gamma-H2AX foci can estimate exposure to ionizing radiation. Most nuclear and radiation accidents are partial-body irradiation, and the doses estimated using the total-body irradiation dose estimation formula are often lower than the actual dose. To evaluate the dose-response relation of gamma-H2AX foci in human peripheral blood lymphocytes after partial-body irradiation and establish a simple and high throughput model to estimate partial-body irradiation dose, we collected human peripheral blood and irradiated with 0-, 0.5-, 1-, 2-, 3-, 4-, 5-, 6-, and 8-Gy gamma rays to simulate total-body irradiation in vitro. Gamma-H2AX foci were quantitated by flow cytometry at 1 h after irradiation, and a dose-response curve was established for total-body irradiation dose estimation. Then, a partial-body irradiation dose-response calibration curve was established by adding calibration coefficients based on the Dolphin method. To reflect the data distribution of all doses more realistically, the partial-body irradiation dose-response calibration curve was divided into two sections. In addition, partial-body irradiation was simulated in vitro, and the PBI data were substituted into curves to verify the accuracy of the two partial-body irradiation calibration curves. Results showed that the dose estimation variations were all less than 30% except the 25% partial-body irradiation group at 1 Gy, and the partial-body irradiation calibration dose-response curves were YF 1 = - 3.444 x 2 + 18.532 x + 3.109, R 2 = 0.92 (YF ≤ 27.95); YF 2 = - 2.704 x 2 + 37.97 x - 56.45, R 2 = 0.86 (YF > 27.95). Results also suggested that the partial-body irradiation dose-response calibration curve based on the gamma-H2AX foci quantification in human peripheral blood lymphocytes is a simple and high throughput model to assess partial-body irradiation dose.