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Abstract Background Streptococcus suis is an important zoonotic pathogen. Biofilm formation largely explains the difficulty in preventing and controlling S. suis. However, little is known about the molecular mechanism of S. suis biofilm formation. Results In this study, transcriptomic and metabolomic analyses of S. suis in biofilm and planktonic states were performed to identify key genes and metabolites involved in biofilm formation. A total of 789 differential genes and 365 differential metabolites were identified. By integrating transcriptomics and metabolomics, five main metabolic pathways were identified, including amino acid pathway, nucleotide metabolism pathway, carbon metabolism pathway, vitamin and cofactor metabolism pathway, and aminoacyl-tRNA biosynthesis metabolic pathway. Conclusions These results provide new insights for exploring the molecular mechanism of S. suis biofilm formation.

Abstract Rational provincial allocation of carbon quotas serves as the foundational premise for attaining China’s carbon peak. Yet, prevailing strategies often overlook the holistic integration of trade-induced carbon transfers and ecological carbon sequestration, resulting in equity and scientific robustness deficiencies. This study addresses these shortcomings by examining historical carbon sources and sinks across China’s provinces and proposing a novel provincial allocation scheme based on the ‘equal consumption-based cumulative per capita net emission’ principle. Our findings reveal significant disparities in the carbon quotas between provinces, ranging from ‒98 Mt in Shanghai to 1016 Mt in Sichuan, primarily influenced by factors such as population size, historical emissions, and carbon sinks. The proposed scheme, integrating considerations of carbon transfers and sinks, safeguards the interests of less developed provinces (e.g., Hebei and Inner Mongolia) and those with valuable ecosystems (e.g., Yunnan and Inner Mongolia). Furthermore, the impact of carbon transfers on provincial carbon allocation quotas is more pronounced than that of carbon sinks. For instance, the inclusion of carbon transfers has increased Inner Mongolia’s quotas by 238 Mt, compared to 125 Mt attributed to carbon sinks. Considering the disparities in emissions reduction pressure and capacity across different provinces, combining fair carbon quota allocation with a nationwide carbon market can achieve cost-effective emissions reduction while ensuring the attainment of carbon peak.

ObjectiveThis paper aims to explore the influence of a warhead's nose shape on penetrating homogeneous metallic plates. MethodsA series of armor-piercing penetration tests are performed by launching sharp and blunt-nosed projectiles from a 92 mm smoothbore gun to impact Q345B and 921A steel target plates. By recording the initial and residual velocity measurements of the warhead before and after penetrating into the target plates using a target net and high-speed video camera, the failure modes and damage modes related to the plates and projectile after the penetration test are analyzed, and an improved estimation method is established for calculating the residual velocity of the penetration of armor-piercing projectiles with different nose shapes. ResultsThe results indicate that the warhead's nose shape has a significant impact on both the damage mode of the pierced plate and the conversion between various types of steel plate for the purpose of obtaining equivalent ballistic performance. In terms of damage characteristics, the petal failure of the target plate is the dominant mode after penetration by a sharp-nosed projectile, while a blunt-nosed projectile mainly contributes to the punching shear failure of the plate. In contrast with the K.A. Belkin formula for calculating the residual velocity of armor-piercing projectiles penetrating into plates, the proposed improved Thompson's formula in this paper is in better agreement with the test results. ConclusionThe results show that the proposed method is adaptable to the similar estimation of armor-piercing projectile performance, thereby providing a basis for further research on the penetration of large-mass warheads into metallic plates.

Endothelial cells (ECs) rely on glycolysis for energy production to maintain vascular homeostasis and the normalization of hyperglycolysis in tumor vessels has recently gained attention as a therapeutic target. We analyzed the TCGA database and found reduced Foxp1 expression in lung carcinoma. Immunostaining demonstrated reduced expression more restricted at tumor vascular ECs. Therefore, we investigated the function and mechanisms of Foxp1 in EC metabolism for tumor angiogenesis required for tumor growth. EC-Foxp1 deletion mice exhibited a significant increase of tumor and retinal developmental angiogenesis and Hif1α was identified as Foxp1 target gene, and Hk2 as Hif1α target gene. The Foxp1-Hif1α-Hk2 pathway in ECs is important in the regulation of glycolytic metabolism to govern tumor angiogenesis. Finally, we used genetic deletion of EC-Hif1α and RGD-peptide nanoparticles EC target delivery of Hif1α/Hk2-siRNAs to knockdown gene expression which reduced the tumor EC hyperglycolysis state and restricted angiogenesis for tumor growth. This study advances our understanding of EC metabolism for tumor angiogenesis, and meanwhile provides evidence for future therapeutic intervention of hyperglycolysis in tumor ECs for suppression of tumor growth.

Background: Rujin Jiedu decoction (RJJDD) is a classical prescription of Traditional Chinese Medicine that has long been applied to treat pneumonia caused by external infection, but whether and how it benefits influenza virus therapy remains largely unclear. The aim of this study was to investigate the anti-inflammatory effect of RJJDD on the mouse model of influenza and to explore its potential mechanism. Methods: The mice were mock-infected with PBS or infected with PR8 virus followed by treatment with RJJDD or antiviral oseltamivir. The weight loss and morbidity of mice were monitored daily. Network pharmacology is used to explore the potential pathways that RJJDD may modulate. qRT-PCR and ELISA were performed to assess the expression of inflammatory cytokines in the lung tissue and macrophages. The intestinal feces were collected for 16S rDNA sequencing to assess the changes in gut microbiota. Results: We demonstrate that RJJDD protects against IAV-induced pneumonia. Comprehensive network pharmacology analyses of the Mass Spec-identified components of RJJDD suggest that RJJDD may act through down-regulating key signaling pathways producing inflammatory cytokines, which was experimentally confirmed by cytokine expression analysis in IAV-infected mouse lung tissues and IAV single-strand RNA mimic R837-induced macrophages. Furthermore, gut microbiota analysis indicates that RJJDD prevented IAV-induced dysbiosis of host intestinal flora, thereby offering a mechanistic explanation for RJJDD's efficacy in influenza pneumonia. Conclusion: This study defines a previously uncharacterized role for RJJDD in protecting against influenza likely by maintaining homeostasis of gut microbiota, and provides a new therapeutic option for severe influenza.

Samples of agilawood (agarwood), which were studied in this work, were produced in Zhongshan City, Guangdong Province, China. To enhance incense production, a specific concentration of plant hormone is employed for induction. The extraction technology of agilawood essential oil was explored using supercritical carbon dioxide fluid, which exhibited a more pronounced induction effect. The pressure, temperature, and flow rate, respectively, were 8, 16, and 24 MPa; 35, 45, and 55 °C; and 20, 30, and 40 L/h. A Box-Behnken analysis was adopted for experimental data, which involved 33 experiments. The data were fitted with the equation Y = 2.18 + 0.1312X1 - 0.025X2 + 0.1236X3 - 0.0025X1X2 - 0.0125X2X3 + 0.0175X12 + 0.035X22 - 0.1275X32. Hence, the optimal process parameters in the supercritical extraction of agarwood essential oil were as follows: the pressure, temperature, and flow rate of 24 MPa, 35 °C, and 33 L/h, respectively. An analysis was conducted with the statistical analysis software Design-Expert 11, which indicated that the extraction yield of agarwood essential oil by supercritical carbon dioxide was mainly affected by the pressure and flow rate. The yield was proportional to the pressure and flow, and inversely proportional to the temperature.

Abstract The Mulibrey (Muscle–liver–brain–eye) nanism caused by loss-of-function variants in TRIM37 gene is an autosomal recessive disorder characterized by severe growth failure and constrictive pericarditis. These patients also suffer from severe respiratory infections, co-incident with an increased mortality rate. Here, we revealed that TRIM37 variants were associated with recurrent infection. Trim37 FIN major (a representative variant of Mulibrey nanism patients) and Trim37 knockout mice were susceptible to influenza virus infection. These mice showed defects in follicular helper T (TFH) cell development and antibody production. The effects of Trim37 on TFH cell differentiation relied on its E3 ligase activity catalyzing the K27/29-linked polyubiquitination of Bcl6 and its MATH domain-mediated interactions with Bcl6, thereby protecting Bcl6 from proteasome-mediated degradation. Collectively, these findings highlight the importance of the Trim37-Bcl6 axis in controlling the development of TFH cells and the production of high-affinity antibodies, and further unveil the immunologic mechanism underlying recurrent respiratory infection in Mulibrey nanism.

Abstract Background The goal of this study is to develop a fully automated segmentation and morphometric parameter estimation system for assessing abnormal corneal endothelial cells (CECs) from LASER in vivo confocal microscopy (IVCM) images. Methods First, we developed a fully automated deep learning system for assessing abnormal CECs using a previous development set composed of normal images and a newly constructed development set composed of abnormal images. Second, two testing sets, one with 169 normal images and the other with 211 abnormal images, were used to evaluate the clinical validity and effectiveness of the proposed system on LASER IVCM images with different corneal endothelial conditions, particularly on abnormal images. Third, the automatically calculated endothelial cell density (ECD) and the manually calculated ECD were compared using both the previous and proposed systems. Results The automated morphometric parameter estimations of the average number of cells, ECD, coefficient of variation in cell area and percentage of hexagonal cells were 257 cells, 2648 ± 511 cells/mm2, 32.18 ± 6.70% and 56.23 ± 8.69% for the normal CEC testing set and 83 cells, 1450 ± 656 cells/mm2, 34.87 ± 10.53% and 42.55 ± 20.64% for the abnormal CEC testing set. Furthermore, for the abnormal CEC testing set, Pearson’s correlation coefficient between the automatically and manually calculated ECDs was 0.9447; the 95% limits of agreement between the manually and automatically calculated ECDs were between 329.0 and − 579.5 (concordance correlation coefficient = 0.93). Conclusions This is the first report to count and analyze the morphology of abnormal CECs in LASER IVCM images using deep learning. Deep learning produces highly objective evaluation indicators for LASER IVCM corneal endothelium images and greatly expands the range of applications for LASER IVCM.

Bordetella bronchiseptica is a significant contributor to respiratory disease in pigs, leading to substantial economic losses in the swine industry worldwide. We isolated 52 B. bronchiseptica strains from 542 samples collected from pigs with atrophic rhinitis and bronchopneumonia in central China. Multi-locus sequence typing identified two prevalent sequence types: ST6 (69.23%) and ST7 (30.77%). PCR-based detection of seven virulence genes (fhaB, prn, cyaA, dnt, bteA, fla, and bfrZ) revealed that six of these genes were present in over 90% of the isolates, with bfrZ being the exception at 59.62%. Antimicrobial susceptibility testing, performed using the K-B method, demonstrated high sensitivity to enrofloxacin, polymyxin, and doxycycline but a notable resistance to tylosin, trimethoprim, tobramycin, ciprofloxacin, and amikacin. Remarkably, 86.54% of the isolates exhibited a multidrug-resistant phenotype. Notably, we successfully screened a strain of B. bronchiseptica with a heteroresistance phenotype to gentamicin using population analysis profiling, which is a rare case. Biofilm-formation assays indicated that 96.15% of the isolates possessed biofilm-forming capabilities. These findings provide crucial insights into the prevalence of B. bronchiseptica in central China, facilitating the development of effective preventive measures to safeguard both animal and human health.

Fleet electrification is one of the most promising strategies to mitigate carbon emissions and improve air quality. This study provides a comprehensive analysis of the currently unclear CO2 mitigation and human health benefits from electric vehicle (EV) adoption and energy decarbonization in the Yangtze River Delta (YRD) region by integrating fleet modeling, emission projection, air quality modeling and health risk assessment. Based on future socioeconomic trajectories, we project that the total vehicle stock in the YRD region will peak at 107–117 million around 2045–2050. The transition to EVs combined with largely renewable energy in the YRD region can potentially reduce CO2 emissions by 870 Tg in 2060 and brings along substantial health co-benefits with ∼360 avoided premature deaths per million from reduced PM2.5 and O3 concentrations. This study further explores the NO2-attributable burden from road transportation and reveals that fleet electrification could yield greater NO2-attributable health benefits than those from reduced PM2.5 and O3, especially in traffic-dense urban areas. Those findings indicate that China’s near-term energy development plans (35% renewable energy) have created the conditions for large-scale EV adoption. Our results imply that the benefits of EVs exhibit substantial spatial heterogeneity, underscoring the importance of region-specific EV incentive policies, and hint that policymakers should prioritize densely populated megacities to maximize the potential for public health gains.

The emergence of multiple severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern threatens the efficacy of currently approved vaccines and authorized therapeutic monoclonal antibodies (MAbs). It is hence important to continue searching for SARS-CoV-2 broadly neutralizing MAbs and defining their epitopes. Here, we isolate 9 neutralizing mouse MAbs raised against the spike protein of a SARS-CoV-2 prototype strain and evaluate their neutralizing potency towards a panel of variants, including B.1.1.7, B.1.351, B.1.617.1, and B.1.617.2. By using a combination of biochemical, virological, and cryo-EM structural analyses, we identify three types of cross-variant neutralizing MAbs, represented by S5D2, S5G2, and S3H3, respectively, and further define their epitopes. S5D2 binds the top lateral edge of the receptor-binding motif within the receptor-binding domain (RBD) with a binding footprint centred around the loop477–489, and efficiently neutralizes all variant pseudoviruses, but the potency against B.1.617.2 was observed to decrease significantly. S5G2 targets the highly conserved RBD core region and exhibits comparable neutralization towards the variant panel. S3H3 binds a previously unreported epitope located within the evolutionarily stable SD1 region and is able to near equally neutralize all of the variants tested. Our work thus defines three distinct cross-variant neutralizing sites on the SARS-CoV-2 spike protein, providing guidance for design and development of broadly effective vaccines and MAb-based therapies.

HIV-1 latency posts a major obstacle for HIV-1 eradication. Currently, no desirable latency reversing agents (LRAs) have been implicated in the “Shock and Kill” strategy to mobilize the latently infected cells to be susceptible for clearance by immune responses. Identification of key cellular pathways that modulate HIV-1 latency helps to develop efficient LRAs. In this study, we demonstrate that the Wnt downstream β-catenin/TCF1 pathway is a crucial modulator for HIV-1 latency. The pharmacological activation of the β-catenin/TCF1 pathway with glycogen synthase kinase-3 (GSK3) inhibitors promoted transcription of HIV-1 proviral DNA and reactivated latency in CD4+ T cells; the GSK3 kinase inhibitor 6-bromoindirubin-3′-oxime (6-BIO)-induced HIV-1 reactivation was subsequently confirmed in resting CD4+ T cells from cART-suppressed patients and SIV-infected rhesus macaques. These findings advance our understanding of the mechanisms responsible for viral latency, and provide the potent LRA that can be further used in conjunction of immunotherapies to eradicate viral reservoirs.

Abstract The United States of America (USA) was afflicted by extreme heat in the summer of 2021 and some states experienced a record‐hot or top‐10 hottest summer. Meanwhile, the United States was also one of the countries impacted most by the coronavirus disease 2019 (COVID‐19) pandemic. Growing numbers of studies have revealed that meteorological factors such as temperature may influence the number of confirmed COVID‐19 cases and deaths. However, the associations between temperature and COVID‐19 severity differ in various study areas and periods, especially in periods of high temperatures. Here we choose 119 US counties with large counts of COVID‐19 deaths during the summer of 2021 to examine the relationship between COVID‐19 deaths and temperature by applying a two‐stage epidemiological analytical approach. We also calculate the years of life lost (YLL) owing to COVID‐19 and the corresponding values attributable to high temperature exposure. The daily mean temperature is approximately positively correlated with COVID‐19 deaths nationwide, with a relative risk of 1.108 (95% confidence interval: 1.046, 1.173) in the 90th percentile of the mean temperature distribution compared with the median temperature. In addition, 0.02 YLL per COVID‐19 death attributable to high temperature are estimated at the national level, and distinct spatial variability from −0.10 to 0.08 years is observed in different states. Our results provide new evidence on the relationship between high temperature and COVID‐19 deaths, which might help us to understand the underlying modulation of the COVID‐19 pandemic by meteorological variables and to develop epidemic policy response strategies.

Abstract Background To investigate the sensitivity and specificity of corneal confocal microscopy (CCM) in the diagnosis of immune-related motor neuron disease syndrome and evaluation of the response to immunosuppressive therapy. Methods Seventy-two patients with clinical manifestations of motor neuron disease (MND) were analysed. According to whether they had concomitant rheumatic immune disease or rheumatic immune antibody abnormalities, they were divided into an MND group (33 patients) and an immune-related MND syndrome group (39 patients). Another 10 healthy adults were selected as the control group. All individuals were examined by CCM. Results For Langerhans cell(LC) density, the area under the receiver operating characteristic(ROC)curve was 0.8, the best cut-off was 67.7 cells/mm2, the sensitivity was 79.5%, and the specificity was 72.7%. For inferior whorl length (IWL), the area under the ROC curve was 0.674, the best cut-off was 17.41 mm/mm2, the sensitivity was 69.2%, and the specificity was 66.7%. After immunosuppressive therapy in 5 patients with immune-related MND syndrome, the LCD was significantly reduced (P 0.05). Conclusion The LC density and IWL are ideal for distinguishing MND from immune-related MND syndrome. The LC density reflects the immunotherapy response sensitively.

Understanding benefits of carbon mitigation is an important impetus for governments to adopt more ambitious climate targets. Here, the authors show positive air quality and health co-benefits are possible if China’s CO2 emissions peak before 2030.

Abstract Background Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with progressive motor system impairment, and recent evidence has identified the extra-motor involvement. Small fiber neuropathy reflecting by sensory and autonomic disturbances in ALS has been reported to accompany the motor damage. However, non-invasive assessment of this impairment and its application in disease evaluation of ALS is scarce. We aim to evaluate the use of corneal confocal microscopy (CCM) to non-invasively quantify the corneal small fiber neuropathy in ALS and explore its clinical value in assessing disease severity of ALS. Methods Sixty-six patients with ALS and 64 healthy controls were included in this cross-sectional study. Participants underwent detailed clinical assessments and corneal imaging with in vivo CCM. Using ImageJ, the following parameters were quantified: corneal nerve length (IWL) and dendritic cell density (IWDC) in the inferior whorl region and corneal nerve fiber length (CNFL), nerve fiber density (CNFD), nerve branch density (CNBD), and dendritic cell density (CDC) in the peripheral region. Disease severity was evaluated using recognized scales. Results Corneal nerve lengths (IWL and CNFL) were lower while dendritic cell densities (IWDC and CDC) were higher in patients with ALS than controls in peripheral and inferior whorl regions (p

ABSTRACT Streptococcus suis is a zoonotic pathogen that continuously threatens animal husbandry and public health worldwide. Studies have shown that S. suis can cause persistent infection by forming biofilms. In this study, a model of S. suis biofilm-related infection was successfully constructed for the first time by simulating the natural infection of S. suis, and biofilm of S. suis in vivo was successfully observed in the lung tissue of infected pigs by a variety of detection methods. Subsequently, selective capture of transcribed sequences (SCOTS) was used to identify genes expressed by S. suis in vivo biofilms. Sixty-nine genes were captured in in vivo biofilms formed by S. suis for the first time by SCOTS; they were mainly involved in metabolism, cell replication, and division, transport, signal transduction, cell wall, etc. Genes related to S. suis in vitro biofilm formation were also identified by SCOTS and RNA sequencing. Approximately half of the genes captured by SCOTS in the in vivo and in vitro biofilms were found to be different. In summary, our study provides powerful clues for future exploration of the mechanisms of S. suis biofilm formation. IMPORTANCE Streptococcus suis is considered an important zoonotic pathogen, and persistent infection caused by biofilm is currently considered to be the reason why S. suis is difficult to control in swine. However, to date, a model of the biofilm of S. suis in vivo has not been successfully constructed. Here, we successfully detected biofilms of S. suis in vivo in lung tissues of piglets infected with S. suis. Selective capture of transcribed sequences and the transcriptome were used to obtain gene profiles of S. suis in vivo and in vitro biofilms, and the results showed large differences between them. Such data are of importance for future experimental studies exploring the mechanism of biofilm formation by S. suis in vivo.

Summary: Artisanal and small-scale gold mining (ASGM) is the leading source of mercury (Hg), a global neurotoxin. Past research has focused on the health impacts on miners and nearby residents; here, we estimate the risk for global general populations by employing a comprehensive atmosphere-land-ocean-ecosystem and exposure-risk-valuation model framework. Our results suggest that ASGM sources contribute 12%, 10%, and 0.63% to the atmospheric Hg deposition, plankton methylmercury concentrations, and soil total Hg concentrations at present day, respectively, and cause 5.8×105 points of intelligence quotient decrements and 1,430 deaths for global general populations per year. The monetized global health impact of ASGM ($154 billion) is 1.5 times its local impact and accounts for half of the total revenue of ASGM ($319 billion). A major spatial decoupling between the health impact and economic gains is also revealed, suggesting that intervention measures such as awareness-raising, capacity-building, and technology transfer funded by the Global North are cost-effective.

Abstract Massive production of efficacious SARS-CoV-2 vaccines is essential for controlling the ongoing COVID-19 pandemic. We report here the preclinical development of yeast-produced receptor-binding domain (RBD)-based recombinant protein SARS-CoV-2 vaccines. We found that monomeric RBD of SARS-CoV-2 could be efficiently produced as a secreted protein from transformed Pichia pastoris (P. pastoris) yeast. Yeast-derived RBD-monomer possessed functional conformation and was able to elicit protective level of neutralizing antibodies in mice. We further designed and expressed a genetically linked dimeric RBD protein in yeast. The engineered dimeric RBD was more potent than the monomeric RBD in inducing long-lasting neutralizing antibodies. Mice immunized with either monomeric RBD or dimeric RBD were effectively protected from live SARS-CoV-2 virus challenge even at 18 weeks after the last vaccine dose. Importantly, we found that the antisera raised against the RBD of a single SARS-CoV-2 prototype strain could effectively neutralize the two predominant circulating variants B.1.1.7 and B.1.351, implying broad-spectrum protective potential of the RBD-based vaccines. Our data demonstrate that yeast-derived RBD-based recombinant SARS-CoV-2 vaccines are feasible and efficacious, opening up a new avenue for rapid and cost-effective production of SARS-CoV-2 vaccines to achieve global immunization.

Abstract This randomized controlled study used corneal confocal microscopy (CCM) to compare the efficacy of Mecobalamin intramuscular injections vs oral tablets in treating mild to moderate diabetic peripheral neuropathy (DPN) by detecting early nerve fiber repair. Enrolled patients were randomized approximately 1:1 to receive Mecobalamin intramuscular injections (0.5 mg/day, 3 times/week) or Mecobalamin oral tablets (1.5 mg/day) for 8 weeks. Primary outcome was change of inferior whorl length (IWL) from baseline. Secondary outcomes included changes of corneal nerve fibre length (CNFL), corneal nerve fibre density (CNFD), corneal nerve branch density (CNBD) and the Survey of Autonomic Symptoms (SAS). 15 (93.75%) patients in the injection group and 17 (89.47%) patients in the tablet group completed the study. The injection treatment significantly improved patients’ IWL from baseline (21.64 ± 3.00 mm/mm2 vs 17.64 ± 4.83 mm/mm2, P

Human Treg cells are central to immune tolerance, yet their heterogeneity and differentiation remain incompletely understood. Here the authors perform single-cell RNA and T cell receptor sequencing to resolve Treg cells from healthy individuals and patients with or without acute graft-versus-host disease revealing Treg complexity in health and disease.

Privacy concerns can effectively predict behavioral intention between users and short-form video platforms, but existing studies lack of multidimensional scales to measure privacy concerns towards short-form video platforms. To this end, this study took privacy concerns theory as the theoretical foundation to develop and validate a multidimensional privacy concerns scale in short-form video platforms by referring to the development of Smith, Milberg and Burke' multidimensional scale of concerns for information privacy (CFIP), Sheehan and Hoy's multidimensional scale of privacy concerns, Malhotra, Kim and Agarwal's Internet users' information privacy concerns (IUIPC) scale, and Hong and Thong's Internet privacy concerns (IPC) multidimensional scale. In this research, three representative short-form video platforms, TikTok, Kuaishou and Xigua, were selected as research samples. The multidimensional privacy concerns scale was refined by qualitative interviews and open-ended questionnaires et al. and tested by item analysis, exploratory factor analysis, confirmatory factor analysis, and discriminant validity et al. The results show that the privacy concerns scale towards short-form video platforms consists of three dimensions: collection concerns, awareness concerns, and usage concerns. And the multidimensional scale developed in this study has good reliability, convergent validity, and content validity, which can help guide short-form video platforms to take targeted measures to manage privacy concerns in business practices and provide a basis for future empirical studies on privacy concerns.

Respiratory infections seriously affect the swine industry worldwide. Co-infections of two vital pathogenic bacteria Streptococcus suis (S. suis) and Actinobacillus pleuropneumoniae (A. pleuropneumoniae), colonizing the respiratory tract often occurs in veterinary clinical practice. Moreover, our previous research found that S. suis and A. pleuropneumoniae can form biofilm in vitro. The formation of a mixed biofilm not only causes persistent infections, but also increases the multiple drug resistance of bacteria, which brings difficulties to disease prevention and control. However, the methods for detecting S. suis and A. pleuropneumoniae in co-infection and biofilm are immature. Therefore, in this study, primers and probes were designed based on the conservative sequence of S. suis gdh gene and A. pleuropneumoniae apxIVA gene. Then, a TaqMan duplex real-time PCR method for simultaneous detection of S. suis and A. pleuropneumoniae was successfully established via optimizing the reaction system and conditions. The specificity analysis results showed that this TaqMan real-time PCR method had strong specificity and high reliability. The sensitivity test results showed that the minimum detection concentration of S. suis and A. pleuropneumoniae recombinant plasmid was 10 copies/μL, which is 100 times more sensitive than conventional PCR methods. The amplification efficiencies of S. suis and A. pleuropneumoniae were 95.9% and 104.4% with R2 value greater than 0.995, respectively. The slopes of the calibration curves of absolute cell abundance of S. suis and A. pleuropneumoniae were 1.02 and 1.09, respectively. The assays were applied to cultivated mixed biofilms and approximately 108 CFUs per biofilm were quantified when 108 CFUs planktonic bacteria of either S. suis or A. pleuropneumoniae were added to biofilms. In summary, this study developed a TaqMan real-time PCR assay for specific, accurate quantification of S. suis or A. pleuropneumoniae in mixed biofilms, which may help for the detection, prevention and control of diseases caused by a bacterial mixed infection involving S. suis and A. pleuropneumoniae.

The newly emerged Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) contains more than 30 mutations on the spike protein, 15 of which are located within the receptor binding domain (RBD). Consequently, Omicron is able to extensively escape existing neutralizing antibodies and may therefore compromise the efficacy of current vaccines based on the original strain, highlighting the importance and urgency of developing effective vaccines against Omicron. Here we report the rapid generation and evaluation of an mRNA vaccine candidate specific to Omicron, and explore the feasibility of heterologous immunization with WT and Omicron RBD vaccines. This mRNA vaccine encodes the RBD of Omicron (designated as RBD-O) and is formulated with lipid nanoparticle. Two doses of the RBD-O mRNA vaccine efficiently induce neutralizing antibodies in mice; however, the antisera are effective only on the Omicron variant but not on the wildtype and Delta strains, indicating a narrow neutralization spectrum. It is noted that the neutralization profile of the RBD-O mRNA vaccine is opposite to that observed for the mRNA vaccine expressing the wildtype RBD (RBD-WT). Importantly, booster with RBD-O mRNA vaccine after two doses of RBD-WT mRNA vaccine can significantly increase neutralization titers against Omicron. Additionally, an obvious increase in IFN-γ, IL-2, and TNF-α-expressing RBD-specific CD4+ T cell responses was observed after immunization with the RBD-WT and/or RBD-O mRNA vaccine. Together, our work demonstrates the feasibility and potency of an RBD-based mRNA vaccine specific to Omicron, providing important information for further development of heterologous immunization program or bivalent/multivalent SARS-CoV-2 vaccines with broad-spectrum efficacy.

Although enterovirus D68 poses a major global threat to children, neither vaccines nor therapeutics are currently available. Using Cryo-EM, Zhang et al. show that two murine-derived monoclonal antibodies with therapeutic efficacy neutralize virions via binding to the canyon region, creating steric hindrance for sialic acid receptor binding.

Here, the authors identify and characterize two mouse-derived monoclonal antibodies against SARS-CoV-2 spike protein that target different epitopes in RBD and block the interaction S/ACE2 and show that a formulated humanized version cocktail exhibits prophylaxis and therapeutic antiviral effects in an hACE2-adenovector expressed mouse model.

Online shopping deliveries are booming, but the environmental cost is not always accounted. Here, the authors examine the impact of delivery services in China from 2007 to 2018 and find that Greenhouse gas emissions surged from 0.3 Mt in 2007 to 13.7 Mt of CO2-equivalent in 2018, they predict that emissions could reach 75 MtCO2e by 2035 if no mitigation measures are adopted.

As the two largest developing countries globally, China and India have become the top 1 and 3 carbon emitters, respectively. Quantitating their CO2 emissions in terms of the characteristics and driving factors is highly significant to mitigating global climate change. This study compiled the CO2 emission inventories from 1990 to 2017 in China and India. The Tapio model and index decomposition analysis were used to analyze the impact of socio-economic factors on CO2 emissions. We found that 1) CO2 emissions of China and India reached 9526 and 2242 Mt, respectively, in 2017. CO2 emissions increased during 1990–2017 with an average annual growth rate of 5% in both countries. 2) In China, the economic development has remained weakly decoupling from emissions since 2012, reaching a strong decoupling (-0.2) in 2017. In contrast, the contribution of India’s economy to emissions continued to increase, and the decoupling status showed continuous fluctuations. 3) Economic development and population explosion were the dominant factors driving CO2 emissions in the countries. The effect of energy intensity inhibited India’s emissions growth after 2008 with an impact degree lower than China. Overall, our findings on the impact of the economy and emission development may provide references for other developing countries at different stages to achieve low-carbon development.

Imaging methods, such as CT or MRI, cannot provide accurate diagnosis between malignant thymomas and other thymic abnormalities. Here the authors show that the levels of IL-8 in circulating naive T cells are elevated in patients with thymoma compared with other thymic masses, proposing IL-8 as a candidate biomarker for thymoma diagnosis and recurrence surveillance.

PurposeLess was known about globular cells which were a type of dendritic cells (DCs) in cornea. We aimed to investigate the morphological and distribution characteristics of globular cells in corneal vortex and their clinical correlations with ocular surface.MethodsCase records of patients who underwent in vivo confocal microscopy (IVCM) were evaluated retrospectively. The morphology and distribution features of globular cells in cornea nerve vortex and their co-existence status with Langerhans cells (LCs) were analyzed. Data of ocular surface symptoms and signs were collected and their correlations with globular cells distribution patterns and dendritic forms were performed. Dry eye patients without LCs were treated with preservative-free artificial tears, while patients with LCs were treated with artificial tears and fluoromethalone until the activated LCs disappeared.ResultsA total of 836 eyes from 451 individuals were included. Three distribution patterns of globular cells in vortex were investigated, type 1 scattered globular cells (57.66%), type 2 large amounts of globular cells (≥50 cells) gathering in vortex and along some fixed vortex direction horizontally (13.52%) and type 3 no globular cells (28.83%). Their location and cell count altered slightly in the follow-ups but would not disappear. LCs could co-exist with globular cells and could fade after treatment. The type 2 distribution pattern was associated with older age (p = 0.000) and higher upper eyelid Meiboscore (p = 0.006). Dendritic globular cells had higher Meiboscore than Non-dendritic forms.ConclusionsGlobular cells had characteristic distribution patterns and biological features different from LCs. They were associated with long-term irritation of the meibomian gland dysfunction.

In this study, a latest reanalysis dataset of atmospheric composition, the Global Exposure Mortality Model and a log-linear exposure-response function were employed to estimate the national deaths attributable to fine particulate matter (PM _2.5 ) and ozone (O _3 ) pollution in China for the period 2016–2020, including the lockdown due to COVID-19 pandemic in 2020. The national mortality attributable to long-term PM _2.5 exposure decreased year by year from 2.18 million (95% confidence interval (1.83, 2.51), the same hereinafter) in 2016 to 1.99 million (1.66, 2.30) in 2020. In particular, the number in 2020 was 133.16 thousand less than 2019 owing to the reduced emissions during the pandemic, and the mortality attributable to short-term PM _2.5 exposure dropped from 46.86 thousand in 2019 to 36.56 thousand in 2020. However, because O _3 concentrations have kept increasing during the period, the national mortality attributable to long-term O _3 exposure increased from 132.79 thousand (128.58, 137.00) in 2016 to 197.00 thousand (190.98, 203.03) in 2020. In addition, compared to before the pandemic, the national mortality attributable to short-term O _3 exposure showed an increase in February, April and May of 2020, and the sharpest year-on-year increase of 162% occurred in April. The different trends of mortality after anthropogenic emissions were reduced pose a challenge for policy-makers and researchers.

RIPK1 integrates signals that drive both NF-κB activation and cell death pathways. Here Zhang et al. generate RIPK1 knock-in mice lacking a major ubiquitination site and demonstrate that this modification is important to suppress cell death during embryogenesis and inflammation postnatally.

Here, the authors show that Zika virus (ZIKV) infection induces Th1-like Tfh cells that depend on T-bet for their development and are essential for class switching of ZIKV-specific IgG2c antibodies and maintenance of long-term neutralizing antibody responses.

Emissions from power plants in China and India contain a myriad of fine particulate matter (PM2.5, PM ≤ 2.5 μm in diameter) precursors, posing significant health risks among large, densely settled populations. Studies isolating the contributions of various source classes and geographic regions are limited in China and India, but such information could be helpful for policy makers attempting to identify efficient mitigation strategies. We quantified the impact of power generation emissions on annual mean PM2.5 concentrations using the state-of-the-art atmospheric chemistry model WRF-Chem (Weather Research Forecasting model coupled with Chemistry) in China and India. Evaluations using nationwide surface measurements show the model performs reasonably well. We calculated province-specific annual changes in mortality and life expectancy due to power generation emissions generated PM2.5 using the Integrated Exposure Response (IER) model, recently updated IER parameters from Global Burden of Disease (GBD) 2015, population data, and the World Health Organization (WHO) life tables for China and India. We estimate that 15 million (95% Confidence Interval (CI): 10 to 21 million) years of life lost can be avoided in China each year and 11 million (95% CI: 7 to 15 million) in India by eliminating power generation emissions. Priorities in upgrading existing power generating technologies should be given to Shandong, Henan, and Sichuan provinces in China, and Uttar Pradesh state in India due to their dominant contributions to the current health risks. Keywords: Air quality modeling, Power generation, China, India, WRF-Chem

Holding the largest recoverable reserves over the world, China makes an ambitious plan to increase shale gas production. Here we use an integrated approach to quantify its impact on indoor and outdoor air quality and greenhouse gas emissions. This approach includes emission estimation, three-dimensional atmospheric chemistry modeling, and human health assessment. Although the production of shale gas generates PM2.5, this risk is outweighed by the benefits of the decreased PM2.5 resulted from coal combustion when shale gas replaces coal as a fuel source. The total avoided premature deaths are 14,000 (10,650–17,160 as 95% confidence interval) and 13,400 (10,350–17,100) in 2017, resulted from the outdoor and indoor pathways, respectively. Future scenario analysis suggests deploying shale gas in the residential sector, but the greenhouse gas emission reductions are minimal if replacing biomass fuel. In production regions, a net deterioration of air quality is predicted if deploying shale gas in the power and industrial sectors, but a net benefit is calculated if deploying in the residential sector. Our study calls for more stringent emission control during upstream processes, and comprehensive consideration of the cost and benefits in both the production and consumption regions.

The purpose of automatic speech recognition (ASR) is to make the machine to be able to “understand” the human speech and transform it to readable text information.ASR is one of the key technologies of human machine interaction and also a hot research domain for a long time.In recent years,due to the application of deep neural networks,the use of big data and the popularity of cloud computing,ASR has made great progress and break through the threshold of application in many industries.More and more products with ASR have entered people’s daily life,such as Apple’s Siri,Amazon’s Alexa,IFLYTEK speech input method and Dingdong intelligent speaker and so on.The development status and key breakthrough technologies in recent years were introduced.Also,a forecast of ASR technologies’ trend of development was given.

The ongoing coronavirus disease 2019 (COVID-19) pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Most of the currently approved SARS-CoV-2 vaccines use the prototype strain-derived spike (S) protein or its receptor-binding domain (RBD) as the vaccine antigen. The emergence of several novel SARS-CoV-2 variants has raised concerns about potential immune escape. In this study, we performed an immunogenicity comparison of prototype strain-derived RBD, S1, and S ectodomain trimer (S-trimer) antigens and evaluated their induction of neutralizing antibodies against three circulating SARS-CoV-2 variants, including B.1.1.7, B.1.351, and B.1.617.1. We found that, at the same antigen dose, the RBD and S-trimer vaccines were more potent than the S1 vaccine in eliciting long-lasting, high-titer broadly neutralizing antibodies in mice. The RBD immune sera remained highly effective against the B.1.1.7, B.1.351, and B.1.617.1 variants despite the corresponding neutralizing titers decreasing by 1.2-, 2.8-, and 3.5-fold relative to that against the wild-type strain. Significantly, the S-trimer immune sera exhibited comparable neutralization potency (less than twofold variation in neutralizing GMTs) towards the prototype strain and all three variants tested. These findings provide valuable information for further development of recombinant protein-based SARS-CoV-2 vaccines and support the continued use of currently approved SARS-CoV-2 vaccines in the regions/countries where variant viruses circulate.

International and domestic interprovincial trade of China are entangled, but their health impacts have been treated separately in earlier studies. Here Wang. quantify the complex impacts of trade on public health across China within an integrative framework.

Dendritic cells (DCs) play pivotal roles in T-cell homeostasis and activation, and metabolic programing has been recently linked to DC development and function. However, the metabolic underpinnings corresponding to distinct DC functions remain largely unresolved. Here, we demonstrate a special metabolic-epigenetic coupling mechanism orchestrated by tuberous sclerosis complex subunit 1 (TSC1)-mechanistic target of rapamycin (mTOR) for homeostatic DC function. Specific ablation of Tsc1 in the DC compartment (Tsc1DC-KO) largely preserved DC development but led to pronounced reduction in naïve and memory-phenotype cluster of differentiation (CD)8+ T cells, a defect fully rescued by concomitant ablation of mTor or regulatory associated protein of MTOR, complex 1 (Rptor) in DCs. Moreover, Tsc1DC-KO mice were unable to launch efficient antigen-specific CD8+ T effector responses required for containing Listeria monocytogenes and B16 melanomas. Mechanistically, our data suggest that the steady-state DCs tend to tune down de novo fatty acid synthesis and divert acetyl-coenzyme A (acetyl-CoA) for histone acetylation, a process critically controlled by TSC1-mTOR. Correspondingly, TSC1 deficiency elevated acetyl-CoA carboxylase 1 (ACC1) expression and fatty acid synthesis, leading to impaired epigenetic imprinting on selective genes such as major histocompatibility complex (MHC)-I and interleukin (IL)-7. Remarkably, tempering ACC1 activity was able to divert cytosolic acetyl-CoA for histone acetylation and restore the gene expression program compromised by TSC1 deficiency. Taken together, our results uncover a crucial role for TSC1-mTOR in metabolic programing of the homeostatic DCs for T-cell homeostasis and implicate metabolic-coupled epigenetic imprinting as a paradigm for DC specification.

Regulatory T (Treg) cells play central roles in maintaining immune homeostasis and self-tolerance. However, the molecular mechanisms underlying Treg cell homeostasis and suppressive function are still not fully understood. Here, we report that the deletion of another P subfamily members of the forkhead box (Foxp) subfamily member Foxp1 in Treg cells led to increased numbers of activated Treg (aTreg) cells at the expense of quiescent Treg cells, and also resulted in impaired Treg suppressive function. Mice with Foxp1-deficient Treg cells developed spontaneous inflammatory disease with age; they also had more severe inflammatory disease in colitis and experimental autoimmune encephalomyelitis (EAE) models. Mechanistically, we found that Foxp1 bound to the conserved noncoding sequence 2 (CNS2) element of the Foxp3 locus and helped maintain Treg suppressive function by stabilizing the Foxp3 expression. Furthermore, we found that Foxp1 and Foxp3 coordinated the regulation of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) expression levels. Taken together, our study demonstrates that Foxp1 plays critical roles in both maintaining Treg cell quiescence during homeostasis and regulating Treg suppressive function.

The immunosuppressive role of regulatory T (Treg) cells largely depends on their virtue of expressing the transcription factor FOXP3. Here the authors show that the E3 deubiquitinase USP21 stabilizes FOXP3 by mediating its deubiquitination and helps to maintain the expression of Treg signature genes and Treg lineage stability in mice.

As the carbon monoxide (CO) total column over Asia is among the highest in the world, it is important to characterize its variations in space and time. Using Measurements of Pollution in the Troposphere (MOPITT) and Atmospheric InfraRed Sounder (AIRS) satellite data, the variations and trends in CO total column over Asia and its seven subregions during 2003−2017 are investigated in this study. The CO total column in Asia is higher in spring and winter than in summer and autumn. The seasonal maximum and minimum are in spring and summer respectively in the regional mean over Asia, varying between land and oceans, as well as among the subregions. The CO total column in Asia shows strong interannual variation, with a regional mean coefficient of variation of 5.8% in MOPITT data. From 2003 to 2017, the annual mean of CO total column over Asia decreased significantly at a rate of (0.58 ± 0.15)% per year (or −(0.11 ± 0.03) × 1017 molecules cm−2 per year) in MOPITT data, resulting from significant CO decreases in winter, summer, and spring. In most of the subregions, significant decreasing trends in CO total column are also observed, more obviously over areas with high CO total column, including eastern regions of China and the Sichuan Basin. The regional decreasing trends in these areas are over 1% per year. Over the entire Asia, and in fire-prone subregions including South Siberia, Indo-China Peninsula, and Indonesia, we found significant correlations between the MOPITT CO total column and the fire counts from the Moderate Resolution Imaging Spectroradiometer (MODIS). The variations in MODIS fire counts may explain 58%, 60%, 36%, and 71% of the interannual variation in CO total column in Asia and these three subregions, respectively. Over different land cover types, the variations in biomass burning may explain 62%, 52%, and 31% of the interannual variation in CO total column, respectively, over the forest, grassland, and shrubland in Asia. Extremes in CO total column in Asia can be largely explained by the extreme fire events, such as the fires over Siberia in 2003 and 2012 and over Indonesia in 2006 and 2015. The significant decreasing trends in MODIS fire counts inside and outside Asia suggest that global biomass burning may be a driver for the decreasing trend in CO total column in Asia, especially in spring. In general, the variations and trends in CO total column over Asia detected by AIRS are similar to but smaller than those by MOPITT. The two datasets show similar spatial and temporal variations in CO total column over Asia, with correlation coefficients of 0.86−0.98 in the annual means. This study shows that the interannual variation in atmospheric CO in Asia is sensitive to biomass burning, while the decreasing trend in atmospheric CO over Asia coincides with the decreasing trend in MODIS fire counts from 2003 to 2017.

Forest vegetation plays a crucial role in improving the ecological environment and maintaining the regional ecological balance. However, most studies pay little attention to the factors that can impact forest biomass carbon storage (FBCS). This research estimated the FBCS by combining relevant forest inventory data and models of continuous functions for biomass expansion factor. A modeling equation was then established and applied to examine the impact of socioeconomic factors on FBCS in Jiangsu, a coastal province in Eastern China, as a case study. The results showed that Jiangsu’s FBCS increased by 20.28 Tg from 2005 to 2010, showing a prominent carbon sink effect but with spatial imbalance among the changes in carbon storage. Jiangsu’s FBCS is significantly affected by land use factors (e.g., forest area and cultivated area), population factors (e.g., population density and urbanization), and economic development factors (e.g., GDP). Relatively speaking, the forest area and GDP had positive effects on FBCS, while cultivated area, population density, and urbanization had significant negative effects.

Aim. To study the correlation between intestinal flora and ulcerative colitis by analyzing the abundance of Bacteroides, Fusobacterium, Clostridium, Bifidobacterium spp., and Faecalibacterium prausnitzii in the intestinal of ulcerative colitis (UC) patients and healthy controls with Uygur and Han ethnic. Methods. Bacterial genomic DNA was extracted from fecal samples and analyzed with real-time fluorescence quantitative polymerase chain reaction (PCR) to identify the abundance of Bacteroides, Fusobacterium, Clostridium, Bifidobacterium spp., and Faecalibacterium prausnitzii. Results. The samples from UC patients, Uygur and Han ethnic combined, had higher abundance of Bacteroides (P=0.026) but lower Clostridium (P=0.004), Bifidobacterium spp. (P=0.009), and Faecalibacterium prausnitzii (P=0.008) than those from healthy controls. Among UC patients, Bacteroides population was raised in acute UC patients (P≤0.05), while the abundance of Clostridium, Bifidobacterium spp., Fusobacterium, and Faecalibacterium prausnitzii decreased (P≤0.05) compared with the remission. In both UC patients group and control group, no difference was observed in the abundance of these 5 bacteria between the Han and the Uygur group. Conclusions. Variations in the abundance of these five bacterial strains in intestines may be associated with the occurrence of UC in Uygur and Han populations; however, these variations were not associated with ethnic difference.

Background TAM receptors (Tyro3, Axl and Mer) are expressed in hematopoietic tissues. The roles of the three receptors in hematopoiesis are, however, largely unknown. We investigated the role of TAM receptors in regulating erythropoiesis.Design and Methods Single and double mutant mice for Axl and Mer were used in the study. Cellularity of bone marrow and spleen, hematologic parameters, flow cytometry analysis of erythroid cell maturation, erythropoietic response to acute hemolytic anemia, bone marrow transplantation and the expression of erythropoisis were analyzed to evaluate the function of Axl and Mer in erythropoiesis.Results Axl and Mer, but not Tyro3, were constitutively expressed in developing erythroid cells. Mice lacking Axl and Mer (Axl−/−Me−/−) had impaired erythropoiesis in bone marrow and expanded splenic erythropoiesis. We found an inhibition of differentiation at the transition from erythroid progenitors to proerythroblasts in Axl−/−Mer−/− mice. These mice exhibited a low rate of erythropoietic response to acute anemia induced by phenylhydrazine. Bone marrow transplantation studies showed that the impaired erythropoiesis in Axl−/−Mer−/− mice is erythroid cell-autonomous. TAM receptors may influence erythropoiesis through the regulation of GATA-1 erythropoietin receptor and EpoR expression in erythroid progenitors. Notably, mice lacking single Axl or Mer exhibited normal erythropoiesis in steady-state conditions.Conclusions Axl and Mer play an important role in regulating erythropoiesis. This finding provides a novel insight into the mechanism of erythropoiesis.

Background and Objectives The molecular mechanisms regulating megakaryocytopoiesis and hemostasis remain largely unknown. The Tyro 3 subfamily of receptor tyrosine kinases (RTK), which is composed of three members (Tyro 3, Axl and Mer), plays important roles in various tissues, such as those in the nervous, immune and reproductive systems. Here, we investigate the roles of the Tyro 3 RTK subfamily in regulating megakaryocytopoiesis and hemostasis.Design and Methods Single, double, and triple knock-out mice for the three Tyro 3 RTK were used in the study. Bleeding time, platelet count, megakaryocyte count, megakaryocyte ploidy, rate of proplatelet formation, platelet aggregation and ATP release were used as criteria to evaluate hemostasis, megakaryocytopoiesis and platelet function.Results Mice lacking all three receptors had impaired hemostasis and mild thrombocytopenia, which may be due to platelet dysfunction and defective megakaryocytopoiesis. Mice lacking different combinations of two receptors of the Tyro 3 RTK subfamily had normal platelet counts in peripheral blood, but exhibited impaired hemostasis and platelet function. Although knock-out mice for any single receptor had normal hemostasis and megakaryocytopoiesis, they exhibited a mild platelet dysfunction.Interpretation and Conclusions The Tyro 3 RTK subfamily plays important roles in regulating hemostasis, megakaryocytopoiesis and platelet function.