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Sea-land breezes (SLBs 1 1 SLB, sea-land breeze; GBA, Greater Bay Area) are mesoscale circulation phenomena that significantly affect weather and air quality in coastal regions. The Guangdong–Hong Kong–Macau Greater Bay Area (GBA), one of the most densely populated and economically developed regions in China, experiences frequent SLB intrusion. In this study, we examined the SLB features in the GBA from 2013 to 2022 based on observations, focusing particularly on the influence of synoptic conditions on SLB behaviour and their interplay. The annual average daily sea and land wind speeds ranged from 2.8 to 3.2 m/s and 1.9 to 2.2 m/s, and from 1.8 to 2.2 m/s and 1.6 to 1.9 m/s in the eastern and western GBA, respectively. The start time of sea (land) winds first appeared at 0000 (1100) UTC and finally occurred at 0900 (2000) UTC. Climatologically, SLBs were observed more frequently when southerly synoptic winds prevailed in the GBA. SLBs were stronger under synoptic northerly winds, but weaker when synoptic southerly winds prevailed. The diurnal evolution amplitude of SLB strength was much more significant under the control of synoptic northerly winds. In addition, SLBs modified synoptic winds, leading to the distortion of the observed diurnal wind patterns. A southerly increment in synoptic winds was observed from noon to early night on SLB days, whereas a northerly increment was observed from midnight to morning. Northerly synoptic winds weakened or even transformed into southerly winds in the afternoon, whereas southerly synoptic winds were found to decrease or even turn northerly at night. Our study provides an integrated understanding of SLBs in the GBA, especially regarding the behaviour of SLBs under various synoptic conditions and their modification on synoptic winds that reshape the observed wind patterns. These results provide useful information for weather simulations in coastal areas. • A comprehensive study of SLBs in the GBA was conducted for the 2013–2022 period. • SLB behaviour differed under various synoptic situations. • SLB modulation under synoptic winds reshaped the observed wind patterns. [ABSTRACT FROM AUTHOR]

This study sets out to investigate the effects of traffic composition on freeway crash frequency by injury severity. A crash dataset collected from Kaiyang Freeway, China, is adopted for the empirical analysis, where vehicles are divided into five categories and crashes are classified into no injury and injury levels. In consideration of correlated spatial effects between adjacent segments, a Bayesian multivariate conditional autoregressive model is proposed to link no-injury and injury crash frequencies to the risk factors, including the percentages of different vehicle categories, daily vehicle kilometers traveled (DVKT), and roadway geometry. The model estimation results show that, compared to Category 5 vehicles (e.g., heavy truck), larger percentages of Categories 1 (e.g., passenger car) and 3 (e.g., medium truck) vehicles would lead to less no-injury crashes and more injury crashes. DVKT, horizontal curvature, and vertical grade are also found to be associated with no-injury and/or injury crash frequencies. The significant heterogeneous and spatial effects for no-injury and injury crashes justify the applicability of the proposed model. The findings are helpful to understand the relationship between traffic composition and freeway safety and to provide suggestions for designing strategies of vehicle safety improvement. [ABSTRACT FROM AUTHOR]

In this paper, we examine the direct effects of sulphate and black carbon (BC) aerosols in China on East Asia monsoons and its precipitation processes by using the Community Atmosphere Model (CAM) 3.0 model. It is demonstrated that sulphate and BC aerosols in China both have the effects to weaken East Asia monsoons in both summer and winter seasons. However, they certainly differ from each other in affecting vertical structures of temperature and atmospheric circulations. Their differences are expected because of their distinct optical properties, that is, scattering versus absorbing. Even for a single type of aerosol, its effects on temperature structures and atmospheric circulations are largely season-dependent. Applications of T-test on our results indicate that forcing from BC aerosols over China is relatively weak and limited. It is also evident from our results that the effects of synthetic aerosols (sulphate and BC together) on monsoons are not simply a linear summation between these two types of aerosols. Instead, they are determined by their integrated optical properties. Synthetic aerosols to a large degree resemble effects of sulphate aerosols. This implies a likely scattering property for the integration of BC and sulphate aerosols in China. [ABSTRACT FROM AUTHOR]

The induction of anergy, or T cell unresponsiveness to antigen, is preceded by T cell activation and cell division in response to fed antigens. These events parallel the activation observed in T cells following sensitization with antigen and adjuvant. The events that distinguish eventual sensitization versus tolerance remain unclear. Using a T lymphocyte transfer model specific to OVA, we demonstrated previously that oral encounter with antigen leads to functional anergy. Antigen-specific CD4+ T cells nevertheless become activated and cycle briefly after encounter with antigen. In this study, we measured the extent of cell cycling of antigen-specific T cells after oral encounter with their antigen. Whereas T cells cycle on the average of eight times in 4 days after conventional immunization, an abortive proliferation was observed in the draining LN T cells after oral encounter with antigen; OVA-specific T cells divided fewer times after exposure to fed OVA, compared to T cells in mice immunized with OVA. This abortive proliferation is antigen specific and not due to bystander suppression, as coadministration of an unrelated antigen that was previously used as a tolerogen does not alter the degree of abortive proliferation. Measurement of BrdU incorporation in mice that were previously fed ovalbumin indicates that up to 3 days following feeding, OVA-specific cells are actively cycling in vivo. However, by day 4, they have stopped cycling while identical T cells in OVA-sensitized mice continue to cycle. Our results indicate either that tolerance is a default pathway and a secondary stimulus is required at day 3 to progress to sensitization, or that elements that limit cell cycle progression are provided for tolerance induction. [Copyright &y& Elsevier]

Anergy, or T cell unresponsiveness to antigen, is one mechanism of T cell tolerance. However, the signaling events that lead to immune tolerance are not well understood. A common assumption is that soluble antigens, such as food antigens, are poor immunogens and induce tolerance because they fail to upregulate co-stimulatory molecules on the professional APC. Engagement of CD40 through a stimulatory antibody causes the upregulation of these costimulatory molecules. Using a CD4+ T cell adoptive transfer model specific to ovalbumin (OVA), we show that after upregulation of CD86 on APC through CD40 stimulation in vivo, T cells from OVA-fed mice remain refractory to proliferation, interleukin (IL)-2 and interferon (IFN)-γ production. We conclude that upregulation of CD86 alone does not inhibit oral tolerance induction of CD4+ T cells, indicating that additional signals are involved in the decision process for CD4+ T cells to commit to tolerance versus sensitization. Our data challenge the belief that reconstitution of a costimulatory signal in the presence of soluble antigen is sufficient to override T cell tolerance and anergy. [Copyright &y& Elsevier]

Scrub typhus is an acute febrile disease due to Orientia tsutsugamushi (Ot) infection and can be life-threatening with organ failure, hemorrhage, and fatality. Yet, little is known as to how the host reacts to Ot bacteria at early stages of infection; no reports have addressed the functional roles of type I versus type II interferon (IFN) responses in scrub typhus. In this study, we used comprehensive intradermal (i.d.) inoculation models and two clinically predominant Ot strains (Karp and Gilliam) to uncover early immune events. Karp infection induced sequential expression of Ifnb and Ifng in inflamed skin and draining lymph nodes at days 1 and 3 post-infection. Using double Ifnar1-/-Ifngr1-/- and Stat1-/- mice, we found that deficiency in IFN/STAT1 signaling resulted in lethal infection with profound pathology and skin eschar lesions, which resembled to human scrub typhus. Further analyses demonstrated that deficiency in IFN-γ, but not IFN-I, resulted in impaired NK cell and macrophage activation and uncontrolled bacterial growth and dissemination, leading to metabolic dysregulation, excessive inflammatory cell infiltration, and exacerbated tissue damage. NK cells were found to be the major cellular source of innate IFN-γ, contributing to the initial Ot control in the draining lymph nodes. In vitro studies with dendritic cell cultures revealed a superior antibacterial effect offered by IFN-γ than IFN-β. Comparative in vivo studies with Karp- and Gilliam-infection revealed a crucial role of IFN-γ signaling in protection against progression of eschar lesions and Ot infection lethality. Additionally, our i.d. mouse models of lethal infection with eschar lesions are promising tools for immunological study and vaccine development for scrub typhus. Author summary: Scrub typhus can lead to severe complications and even fatality if not treated properly; however, the early host immune responses to Ot bacterium infection remain unclear. This study focused on the functional roles of IFNs in i.d. inoculation mouse models of scrub typhus. We found that mice lacking IFN receptors were highly susceptible to Ot infection, which resulted in severe pathology and skin eschar lesions that resembled to human scrub typhus. Further investigation revealed that the lack of IFN-γ, but not IFN-I, resulted in dysregulated innate immune responses, leading to uncontrolled bacterial burdens and tissue damage. Using IFN-γ reporter mice and neutralizing antibody treatment, we confirmed that NK cells were the major source of early IFN-γ, and thus contributed to the bacterial control in the draining lymph nodes. Moreover, our comparative studies with two Ot strains revealed bacterium strain- and dose-dependent eschar formation and disease severity. In conclusion, our study highlights the crucial role of IFN-γ signaling in ensuring host protection against Ot infection. Our mouse models resemble skin eschar lesions and lethal infections observed in human disease, offering potential for future immunological studies on scrub typhus. [ABSTRACT FROM AUTHOR]

Scrub typhus is a leading cause of febrile illness in endemic countries due to infection with Orientia tsutsugamushi (Ot), a seriously understudied intracellular bacterium. Pulmonary involvement associated with vascular parasitism in patients is common and can develop into life threatening interstitial pneumonia. The diverse antigenicity of Ot genotypes and inter-strain differences in genome content are connected to varied virulence and clinical outcomes; however, detailed studies of strain-related pulmonary immune responses in human patients or small animal models of infection are lacking. In this study, we have used two clinically prevalent bacterial strains (Karp and Gilliam) to reveal cellular immune responses in inflamed lungs and potential biomarkers of disease severity. The results demonstrate that outbred CD-1 mice are highly susceptible to both Karp and Gilliam strains; however, C57BL/6 (B6) mice were susceptible to Karp, but resistant to Gilliam (with self-limiting infection), corresponding to their tissue bacterial burdens and lung pathological changes. Multicolor flow cytometric analyses of perfused B6 mouse lungs revealed robust and sustained influx and activation of innate immune cells (macrophages, neutrophils, and NK cells), followed by CD4+ and CD8+ T cells, during Karp infection, but such responses were greatly attenuated during Gilliam infection. The robust cellular responses in Karp-infected B6 mice positively correlated with significantly early and high levels of serum cytokine/chemokine protein levels (CXCL1, CCL2/3/5, and G-CSF), as well as pulmonary gene expression (Cxcl1/2, Ccl2/3/4, and Ifng). In vitro infection of B6 mouse-derived primary macrophages also revealed bacterial strain-dependent immune gene expression profiles. This study provided the lines of evidence that highlighted differential tissue cellular responses against Karp vs. Gilliam infection, offering a framework for future investigation of Ot strain-related mechanisms of disease pathogenesis vs. infection control. Author summary: Orientia tsutsugamushi (Ot) infection-induced scrub typhus is a leading cause of febrile illness in endemic countries. Research on Ot strain-related disease outcomes or immune signatures in tissue and blood samples is very limited. Using two clinically prevalent strains (Karp and Gilliam), we examined host susceptibility in inbred and outbred mouse models. Application of these small animal models of infection provided new evidence for the activation of pulmonary immune cell subsets during the acute stages of infection. While Gilliam-infected C57BL/6 (B6) mice developed self-limiting infection, mild cellular responses, and tissue injury, Karp infection led to a strong and sustained activation of innate immune cells, followed by extensive influx of activated T cells, which correlated to increased levels of inflammatory cytokines/chemokines in serum samples. We also provided in vitro evidence for Ot strain-dependent immune gene profiles, indicating differential macrophage responses to Karp versus Gilliam bacteria. This is the first comparison of different scrub typhus mouse models with in-depth analyses of cellular responses in inflamed lungs, offering novel insights into potential mechanisms of disease progression versus infection control related to Ot strains and laying the foundation for future investigations. [ABSTRACT FROM AUTHOR]

PM 2.5 and O 3 pollution are of concern for the Yangtze River Delta (YRD) region due to their adverse impact on human health. In conjunction with a complex distribution of emission sources, the synoptic circulation conditions control the temporal and spatial variability of air pollution levels and hence the pollution-related health burdens. In this study, a long-term synoptic circulation catalogue is developed by applying the automated Lamb weather type method to the ECMWF mean sea level pressure reanalysis for the YRD region during 2013–2016. Ten typical circulation types are examined in relation to the transport pathways and diffusion conditions, and then multi-site surface observations of PM 2.5 and O 3 are composited for different circulation conditions. The results show that each circulation type is characterized with distinct air mass origin, diffusion condition and air quality level. The anticyclonic type (Type A) corresponds to the highest regional PM 2.5 concentration (68.5 μg/m 3 ) due to the subsidence flow and long-range transport, while the westerly types (Types SW, W and NW) correspond to the higher regional maximum daily 8-h running average O 3 (MDA8 O 3 ) concentration (> 100 μg/m 3 ) due to favorable local meteorological conditions. Regional transport causes an east-high and west-low PM 2.5 distribution in westerly types but a west-high and east-low PM 2.5 distribution in easterly types (Types SE, E and NE). In contrast, nearly all the types show an east-high and west-low O 3 distribution, suggesting the predominated impacts of precursor emissions. By using established exposure-response functions, the health impact assessment (HIA) shows that Type W poses the greatest public health risk with mean daily excess mortality of 77.3 (95% CI: 61.9, 92.6) deaths and O 3 pollution accounts for approximately 70% of this health burden. [ABSTRACT FROM AUTHOR]

Scrub typhus is a poorly studied but life-threatening disease caused by the intracellular bacterium Orientia tsutsugamushi (Ot). Cellular and humoral immunity in Ot-infected patients is not long-lasting, waning as early as one-year post-infection; however, its underlying mechanisms remain unclear. To date, no studies have examined germinal center (GC) or B cell responses in Ot-infected humans or experimental animals. This study was aimed at evaluating humoral immune responses at acute stages of severe Ot infection and possible mechanisms underlying B cell dysfunction. Following inoculation with Ot Karp, a clinically dominant strain known to cause lethal infection in C57BL/6 mice, we measured antigen-specific antibody titers, revealing IgG2c as the dominant isotype induced by infection. Splenic GC responses were evaluated by immunohistology, co-staining for B cells (B220), T cells (CD3), and GCs (GL-7). Organized GCs were evident at day 4 post-infection (D4), but they were nearly absent at D8, accompanied by scattered T cells throughout splenic tissues. Flow cytometry revealed comparable numbers of GC B cells and T follicular helper (Tfh) cells at D4 and D8, indicating that GC collapse was not due to excessive death of these cell subtypes at D8. B cell RNAseq analysis revealed significant differences in expression of genes associated with B cell adhesion and co-stimulation at D8 versus D4. The significant downregulation of S1PR2 (a GC-specific adhesion gene) was most evident at D8, correlating with disrupted GC formation. Signaling pathway analysis uncovered downregulation of 71% of B cell activation genes at D8, suggesting attenuation of B cell activation during severe infection. This is the first study showing the disruption of B/T cell microenvironment and dysregulation of B cell responses during Ot infection, which may help understand the transient immunity associated with scrub typhus. Author summary: Scrub typhus is an understudied disease caused by the intracellular bacterium O. tsutsugamushi. A hallmark of scrub typhus is the unexplained, non-durable immunity after infection. While cellular immune responses are known to be important for controlling this infection, our understanding of B cell and GC responses remains limited. In this study, we examined B cell activation and GC responses using our recently established murine model of severe scrub typhus. We measured bacterial antigen-specific antibody titers and identified IgG2c, an IFN-γ-driven isotype, as the major IgG subtype. We also found that O. tsutsugamushi infection disrupted spleen morphology, exemplified by randomly dispersed T cells and lost GC structures. Transcriptomic analysis of purified splenic B cells demonstrated reduced expression of genes encoding critical adhesion and co-stimulation molecules, including GC-adhesion gene S1PR2, at severe stages of infection. Several humoral immune response pathways relevant to B cell receptor signaling, B cell activation and differentiation were significantly downregulated during infection. This study is the first report describing humoral immunity in a scrub typhus mouse model and provides detailed evidence that B cell and GC responses are impaired during acute infection. [ABSTRACT FROM AUTHOR]

It is generally accepted that the appropriate boost of early immune response will control viral replications and limit the immune-mediated pathology in viral hepatitis. However, poor immunity results in viral persistence, chronic inflammation and finally liver cirrhosis and carcinoma. As a peripheral non-lymphoid organ of immune surveillance, the liver continually encounters hundreds of molecules from the blood, including nutrients, toxins and pathogens. In this way, the liver maintains immune tolerance under healthy conditions, but responds quickly to the hepatotropic pathogens during the early stages of an infection. Although our knowledge of liver cell compositions and functions has been improved significantly in recent years, the intrahepatic immune regulation of antiviral T cells at the initial stage is complex and not well elucidated. Here, we summarize the role of liver cell subpopulations in regulating antiviral T cell response at the initial stages of viral infection. A better understanding of early hepatic immune regulation will pave the way for the development of novel therapies and vaccine design for human viral hepatitis. [ABSTRACT FROM AUTHOR]

Standing at the interface of innate and adaptive immune, γδ T cells play important pathophysiologic roles in infection, autoimmunity, and tumorigenesis. Recent studies indicate that γδ T cells could be categorized into IFN-γ + and IL-17 + subsets, both of which possess select TCR usages, bear unique surface markers and require different cytokine signaling to maintain the homeostasis. In addition, as the major innate IL-17 producers, γδ T cells are increasingly appreciated for their involvement in various acute infections and injuries. This review will summarize the characteristics of IFN-γ + (γδ T-IFN-γ) and IL-17 + γδ T cells (γδT17) and discuss their distinct pathogenic functions in different disease models. [ABSTRACT FROM AUTHOR]

In recent years, Chinese cities have faced persistent O 3 pollution challenges. O 3 concentrations at urban mountain sites, serving as proxies for urban background O 3 levels, can help address data gaps in O 3 research in China. This study, for the first time, analyzed O 3 data from ten urban mountain sites during 2015–2022 using statistical methods like the Mann-Kendall test, Theil-Sen slope estimation, and Pearson correlation analysis to reveal characteristics and trends in urban background O 3 and proposed a metric for assessing mountain sites as urban background stations. Results indicate that O 3 at mountain sites were generally higher than at plain sites, regardless of mean, 10th percentile, or 90th percentile the average maximum daily 8-h average (MDA8) O 3. Although mountain sites exhibited similar annual and diurnal variations as plain sites, their amplitudes were significantly lower. Significant upward trends (P < 0.05) in MDA8 O 3 were observed mainly at plain sites, whereas trends at mountain sites were insignificant (P > 0.05) during 2015–2022. The increase in urban ground-level O 3 was largely due to changes in VOCs and NO x emission structures, which reduce nighttime titration effects while enhancing daytime O 3 production. The insignificant trends observed at mountain sites suggest that these mountain sites may be in NO x -limited or transitional regimes rather than VOCs-limited regimes, which is also associated with their lower NO x concentrations compared to plain sites. These findings suggest that if China continues to prioritize the reduction of NO x emissions, urban ground-level O 3 could further increase and approach the O 3 at mountain sites. Finally, this study proposes that the correlation in nighttime O 3 concentrations between mountain and plain stations can serve as a valuable indicator for evaluating the suitability of mountain stations as regional background stations in urban areas. It recommends mountain sites in cities such as Changji, Nanping for urban background O 3 monitoring stations. • O 3 levels at mountain sites were generally higher than at plain sites, with similar annual and diurnal patterns but lower variation amplitudes. • The significant upward trends in the average maximum daily 8-h average (MDA8) O 3 from 2015 to 2022 were mainly concentrated at plain sites. • The nighttime O 3 correlation between mountain and plain stations can assess the suitability of mountain sites as urban background stations. [ABSTRACT FROM AUTHOR]

An extreme explosive extratropical cyclone over the northwestern Pacific Ocean (NPO) that formed in winter 2004 and went through two distinct rapid deepening periods was successfully simulated by a non-hydrostatic mesoscale model (MM5). Based on the simulation, the cyclone's rapid deepening was investigated in detail using the piecewise potential vorticity (PV) inversion method which successfully captured the characteristics of the cyclone and its associated background circulations. Results indicated that explosive development of the cyclone was dominated by forcings in the extended surface layer (ESL), which were closely related to baroclinity (temperature advection) and boundary layer processes (sensible heat exchange). In the interior layer (IL), direct effects of condensation were mainly conducive to the cyclone's development, whereas indirect effects (interactions with other layers) mainly acted conversely. Processes associated with latent heat release (LHR) were characterised by nonlinearity. Features of the precipitation, including intensity, duration, range and relative configuration to the cyclone determined the influences of condensation on the cyclone. In the upper layer (UL), tropopause-folding processes and horizontal PV advection were main influencing factors to the evolution of the cyclone. Upper-level forcings firstly exerted slight effects on the cyclone's development, since upper-level positive PV anomalies were far from the cyclone; then, as the influencing short-wave trough and the cyclone both moved northeastward, upper-level positive PV anomalies merged, enhanced and entered key areas of the cyclone, and thus both direct and indirect effects associated with the upper-level forcings strengthened significantly around the cyclone, and this dominated the cyclone's transition from a moderate explosive cyclone to an extreme one. [ABSTRACT FROM AUTHOR]

Interleukin (IL)‐33, a member in the IL‐1 family, plays a central role in innate and adaptive immunity; however, how IL‐33 mediates cytotoxic T‐cell regulation and the downstream signals remain elusive. In this study, we found increased mouse IL‐33 expression in CD8+ T cells following cell activation via anti‐CD3/CD28 stimulation in vitro or lymphocytic choriomeningitis virus (LCMV) infection in vivo. Our cell adoptive transfer experiment demonstrated that extracellular, but not nuclear, IL‐33 contributed to the activation and proliferation of CD8+, but not CD4+ T effector cells in LCMV infection. Importantly, IL‐33 induced mTORC1 activation in CD8+ T cells as evidenced by increased phosphorylated S6 ribosomal protein (p‐S6) levels both in vitro and in vivo. Meanwhile, this IL‐33‐induced CD8+ T‐cell activation was suppressed by mTORC1 inhibitors. Furthermore, IL‐33 elevated glucose uptake and lactate production in CD8+ T cells in both dose‐ and time‐dependent manners. The results of glycolytic rate assay demonstrated the increased glycolytic capacity of IL‐33‐treated CD8+ T cells compared with that of control cells. Our mechanistic study further revealed the capacity of IL‐33 in promoting the expression of glucose transporter 1 (Glut1) and glycolytic enzymes via mTORC1, leading to accelerated aerobic glucose metabolism Warburg effect and increased effector T‐cell activation. Together, our data provide new insights into IL‐33‐mediated regulation of CD8+ T cells, which might be beneficial for therapeutic strategies of inflammatory and infectious diseases in the future. [ABSTRACT FROM AUTHOR]

The present work investigates leading modes of winter fog days over eastern China and possible association with sea surface temperature (SST) variability. Based on the Empirical Orthogonal Function (EOF) analysis, two dominant interannual modes of winter fog days are identified: a monopole mode and a meridional dipole mode. The monopole mode displays a significantly positive relationship with El Niño-Southern Oscillation (ENSO). The meridional dipole mode is closely linked to North Atlantic tripole (NAT) SST anomalies. A quasi-barotropic Rossby wave train can be excited by the NAT SST anomalies and propagates eastwards to East Asia. During winters with the positive phase of the NAT SST anomalies, there appear cyclonic and anticyclonic circulation anomalies over northern and southern China, favoring less and more winter fog frequency, respectively. These observed impacts from the ENSO and NAT SST anomalies can be further reproduced by atmospheric general circulation model (AGCM) experiments. Consideration of the NAT SST anomalies can apparently improve the explained variance of winter fog days over eastern China on the basis of the common-used ENSO signal. When ENSO and NAT occur as in-phase combinations and out-of-phase combinations, winter fog days anomalies appear over southern and northern China, respectively. These results have important implications on the seasonal-to-interannual predictability of the winter fog frequency over eastern China. [ABSTRACT FROM AUTHOR]

Based on a 16-warm-season statistical study on the mesoscale convective systems (MCSs) that were generated over the Tibetan Plateau (TP), 11 long-lived eastward propagating MCSs of the same type were selected for a composite semi-idealized simulation and a corresponding no-latent-heating sensitivity run by using the Weather Research and Forecasting (WRF) model. Common evolutionary features and associated mechanisms of this type of long-lived eastward propagating MCS were investigated. Main results are as follows: (i) This type of MCS was generated in a favorable background environment which was characterized by a notable upper-tropospheric divergence south of an upper-level jet, a strong warm advection around a middle-level shortwave trough's central area, and an instable convective stratification below the trough. Development of the MCS featured rapid increase of cyclonic vorticity in the middle and lower troposphere. The convergence-related vertical stretching and tilting were key factors for the cyclonic-vorticity's production, and convection-related upward cyclonic-vorticity transport contributed to the upward extending of the MCS. (ii) During the vacating stage of the MCS, it first coupled with a quasi-stationary Tibetan Plateau vortex (TPV) over the TP's eastern section, and then decoupled from the vortex. In the former stage, the MCS contributed to maintaining ascending motions and convergence associated with the TPV, which favored its persistence; whereas, in the latter stage, decoupling weakened the TPV-associated convection significantly. This reduced the upward transport of cyclonic vorticity notably, which, together with the negative tilting effect, finally led to the vortex's dissipation. (iii) After vacating TP, the MCS first weakened due to the disappearance of strong direct sensible heating from the TP on its bottom, and then, under the favorable conditions associated with the shortwave trough over the eastern section of the TP, the MCS redeveloped rapidly. Convergence-related cyclonic-vorticity production in the middle and lower troposphere and upward transport of cyclonic vorticity due to convection governed the MCS's redevelopment. (iv) Sensitivity simulation shows that latent heating was a necessary condition for the formation and development of the long-lived eastward propagating MCS. On the one hand, this MCS affected the TP's eastern section and downstream regions directly by inducing precipitation; and on the other hand, it exerted effects on the precipitation over a wider range in the downstream regions by modulating large-scale circulations over and around the TP. [ABSTRACT FROM AUTHOR]

Orientia tsutsugamushi infection can cause acute lung injury and high mortality in humans; however, the underlying mechanisms are unclear. Here, we tested a hypothesis that dysregulated pulmonary inflammation and Tie2-mediated endothelial malfunction contribute to lung damage. Using a murine model of lethal O. tsutsugamushi infection, we demonstrated pathological characteristics of vascular activation and tissue damage: 1) a significant increase of ICAM-1 and angiopoietin-2 (Ang2) proteins in inflamed tissues and lung-derived endothelial cells (EC), 2) a progressive loss of endothelial quiescent and junction proteins (Ang1, VE-cadherin/CD144, occuludin), and 3) a profound impairment of Tie2 receptor at the transcriptional and functional levels. In vitro infection of primary human EC cultures and serum Ang2 proteins in scrub typhus patients support our animal studies, implying endothelial dysfunction in severe scrub typhus. Flow cytometric analyses of lung-recovered cells further revealed that pulmonary macrophages (MΦ) were polarized toward an M1-like phenotype (CD80+CD64+CD11b+Ly6G-) during the onset of disease and prior to host death, which correlated with the significant loss of CD31+CD45- ECs and M2-like (CD206+CD64+CD11b+Ly6G-) cells. In vitro studies indicated extensive bacterial replication in M2-type, but not M1-type, MΦs, implying the protective and pathogenic roles of M1-skewed responses. This is the first detailed investigation of lung cellular immune responses during acute O. tsutsugamushi infection. It uncovers specific biomarkers for vascular dysfunction and M1-skewed inflammatory responses, highlighting future therapeutic research for the control of this neglected tropical disease. Author summary: Scrub typhus is a life-threatening disease, infecting an estimated one million people yearly. Acute lung injury is a dangerous clinical development in severe cases; however, its pathogenic biomarkers and mechanisms of progression remain unknown. Here, we used a lethal infection mouse model that parallels certain aspects of severe scrub typhus, primary human endothelial cell cultures, and patient sera to define pathogenic biomarkers following Orientia tsutsugamushi infections. We found a significant increase in the levels of endothelial activation/stress markers (angiopoietins and ICAM-1) in infected mouse lungs and patient sera, but a progressive loss of endothelium-specific Tie2 receptor and junction proteins (VE-cadherin), at severe stages of disease. These signs of vasculature disruption positively correlated with the timing and magnitude of recruitment/activation of proinflammatory MΦ subsets in infected lungs. Bacterial growth in vitro was favored in M2-like, but not in M1-like, MΦs. This study, for the first time, reveals endothelial malfunction and dysregulated inflammatory responses, suggesting potential therapeutic targets to ameliorate tissue damage and pathogenesis. [ABSTRACT FROM AUTHOR]

The winter fog frequency over eastern China displays remarkable interannual variability, which has a linear relationship with El Niño-Southern Oscillation (ENSO). Eastern China usually experiences more (less) frequent fog during El Niño (La Niña) winters. During El Niño winters, an anomalous anticyclone tends to appear over the western North Pacific (WNP), which can weaken the climatological winter northerly winds and enhance water vapor supply from oceans, conducive to the formation of foggy weather. Roughly opposite anomalies of fog frequency are displayed during La Niña winters. However, this linear relationship is mainly contributed by the La Niña and partial El Niño events, since the El Niño events exhibit diversity in impacts on the winter fog frequency due to their different types. Increased winter fog frequency can be significantly detected during eastern-Pacific (EP) El Niño, while this signal is not observed during central-Pacific (CP) El Niño. It is found that the winter fog frequency during the CP El Niño seems to be dependent on its zonal locations, associated with different WNP atmospheric circulation and local difference between air temperature and dew point temperature (T − Td) anomalies. The further eastward CP El Niño largely coincides with more frequent fog weather similar to the EP El Niño, while the further westward CP El Niño is usually accompanied with less frequent fog weather. This relationship has important implications for seasonal prediction of winter fog frequency and places a high requirement on consideration of zonal location of the CP El Niño. [ABSTRACT FROM AUTHOR]

Trichloroethene (TCE) exposure is associated with the development of various autoimmune diseases (ADs), including autoimmune hepatitis (AIH) and systemic lupus erythematosus (SLE), potentially through the generation of excessive reactive oxygen and nitrogen species (RONS; oxidative stress). However, the mechanisms by which oxidative stress contributes to these TCE-mediated ADs are not fully understood, and are the focus of current investigation. Female MRL+/+ mice were treated with TCE along with or without antioxidant N-acetylcysteine (NAC) for 6 weeks (TCE, 10 mmol/kg, i. p., every 4th day; NAC, 250 mg/kg/day via drinking water). TCE-treated mice had elevated antinuclear antibodies (ANA) and 4-hydroxynonenal (HNE)-specific circulating immune complexes, suggesting the association of TCE-induced oxidative stress with autoimmune response. In addition, TCE exposure led to prominent lobular inflammation with sinusoid dilation, increased sinusoidal cellularity and increased staining for proliferating cell nuclear antigen (PCNA), confirming inflammatory and hepatocellular cell proliferation. Importantly, TCE exposure resulted in the activation of hepatic inflammasome (NLRP3 and caspase-1) and up-regulation of pro-inflammatory cytokine IL-1β, and these changes were attenuated by NAC supplementation. TCE treatment also led to dysregulation of hepatic immune response as evident from markedly increased hepatic lymphocyte infiltration (especially B cells) and imbalance between Tregs (decreased) and Th17 cells (increased). Interestingly, TCE-mediated dysregulation of various hepatic and splenic immune cells was also effectively attenuated by NAC. Taken together, our findings provide evidence for TCE-mediated inflammasome activation, infiltration of various immune cells, and skewed balance of Treg and Th17 cells in the liver. The attenuation of TCE-mediated hepatic inflammasome activation and immune responses by NAC further supports a critical role of oxidative stress in TCE-mediated inflammation and autoimmunity. These novel findings could help in designing therapeutic strategies for such ADs. • TCE exposure led to oxidative stress and hepatic inflammasome NLRP3 activation. • TCE induced hepatic CD8+ T cells, NK cells, dendritic cells, and B cell activation. • TCE exposure was associated with skewed Treg/Th17 ratio in the liver. • NAC attenuated TCE-induced inflammasome activation and autoimmune response. [ABSTRACT FROM AUTHOR]

Abstract Carbonaceous aerosols in high emission areas attract worldwide attention of the scientific community and the public due to their adverse impacts on the environment, human health and climate. However, long-term continuous hourly measurements are scarce on the regional scale. In this study, a one-year hourly measurement (from December 1, 2016 to November 30, 2017) of organic carbon (OC) and elemental carbon (EC) in airborne fine particles was performed using semi-continuous OC/EC analyzers in Beijing, Tianjin, Shijiazhuang and Tangshan in the Beijing-Tianjin-Hebei (BTH) region in China, which is one of high emission areas in China, even in the world. Marked spatiotemporal variations were observed. The highest concentrations of OC (22.8 ± 30.6 μg/m3) and EC (5.4 ± 6.5 μg/m3) occurred in Shijiangzhuang while the lowest concentrations of OC (11.0 ± 10.7 μg/m3) and EC (3.1 ± 3.6 μg/m3) were obtained in Beijing and Tianjin, respectively. Pronounced monthly, seasonal and diurnal variations of OC and EC were recorded. Compared to published data from the past two decades for the BTH region, our OC and EC levels were lower, implying some effect of recent measures for improving the air quality. Significant correlations of OC versus EC (p < 0.001) were found throughout the study period with high slopes and correlation coefficients in winter, but low slopes and correlation coefficients in summer. The estimated secondary OC (SOC), based on the minimum R squared (MRS) method, represented 29%, 47%, 38% and 48% of the OC for Beijing, Tianjin, Shijiazhuang and Tangshan, respectively. These percentages are larger than previous ones obtained for the BTH region in the past decade. There were obvious differences in the potential source regions of OC and EC among the four cities. Obvious prominent potential source areas of OC and EC were observed for Beijing, which were mainly located in the central and western areas of Inner Mongolia and even extended to the Mongolian regions, which is different from the findings in previous studies. For all sites, adjacent areas of the main provinces in northern China were found to be important potential source areas. Highlights • A one-year hourly measurement of OC and EC in PM2.5 aerosol was performed in Beijing, Tianjin, Shijiazhuang and Tangshan. • There were marked spatiotemporal variations, with highest levels in Shijiangzhuang and lowest ones in Beijing and Tianjin. • Pronounced monthly, seasonal and diurnal variations of OC and EC were observed. • Secondary OC (SOC) was estimated based on the minimum R squared (MRS) method. • There were obvious differences in the potential source regions of OC and EC among the four cities. [ABSTRACT FROM AUTHOR]

Nitrate has become the most important hydrophilic chemical component in PM 2.5 during serious air pollution periods in urban areas of the Pearl River Delta (PRD) region of south China, but there is a lack of fully understanding of its formation mechanisms and controlling factors, especially during daytime nitrate episodes. To fill the knowledge gap, water-soluble inorganic ions in PM 2.5 and trace gases including SO 2 , HNO 3 , NH 3 , NOx and O 3 , particle size distribution, vertical profile of aerosol backscatter density, and ground-level and vertical profiles of key meteorological variables were simultaneously measured at high time resolution in urban Guangzhou of the PRD. The remarkably enhanced nitrate mass concentrations observed at the surface-level during daytime were identified to be caused by strong boundary-layer turbulent mixing of residual aerosols produced from evaporation of low-level shallow stratocumulus clouds. This finding may have important implications on the sources of secondary inorganic aerosols in this and other similar cloudy regions. [ABSTRACT FROM AUTHOR]

• ZIKV infects human microglia in a dose- and time-dependent manner. • Metformin inhibits ZIKV replication and restrains inflammatory responses in human microglia. • Metformin upregulates type I and III interferons in ZIKV-infected microglia. The re-emergence of Zika virus (ZIKV) remains a major public health threat that has raised worldwide attention. Accumulating evidence suggests that ZIKV can cause serious pathological changes to the human nervous system, including microcephaly in newborns. Recent studies suggest that metformin, an established treatment for diabetes may play a role in viral infection; however, little is known about the interactions between ZIKV infection and metformin administration. Using fluorescent ZIKV by flow cytometry and immunofluorescence imaging, we found that ZIKV can infect microglia in a dose-dependent manner. Metformin diminished ZIKV replication without the alteration of viral entry and phagocytosis. Our study demonstrated that metformin downregulated ZIKV-induced inflammatory response in microglia in a time- and dose-dependent manner. Our RNA-Seq and qRT-PCR analysis found that type I and III interferons (IFN), such as IFNα2, IFNβ1 and IFNλ3 were upregulated in ZIKV-infected cells by metformin treatment, accompanied with the downregulation of GBP4, OAS1, MX1 and ISG15. Together, our results suggest that metformin-mediated modulation in multiple pathways may attribute to restraining ZIKV infection in microglia, which may provide a potential tool to consider for use in unique clinical circumstances. [ABSTRACT FROM AUTHOR]

Background: Scrub typhus is a life-threatening disease, due to infection with O. tsutsugamushi, a Gram-negative bacterium that preferentially replicates in endothelial cells and professional phagocytes. Meningoencephalitis has been reported in scrub typhus patients and experimentally-infected animals; however, the neurological manifestation and its underlying mechanisms remain poorly understood. To address this issue, we focused on Orientia tsutsugamushi Karp strain (OtK), and examined host responses in the brain during lethal versus self-healing scrub typhus disease in our newly established murine models. Principle findings: Following inoculation with a lethal dose of OtK, mice had a significant increase in brain transcripts related to pathogen-pattern recognition receptors (TLR2, TLR4, TLR9), type-1 responses (IFN-γ, TNF-α, CXCL9, CXCR3), and endothelial stress/damage such as angiopoietins, but a rapid down-regulation of Tie2. Sublethal infection displayed similar trends, implying the development of type 1-skewed proinflammatory responses in infected brains, independent of time and disease outcomes. Focal hemorrhagic lesions and meningitis were evident in both infection groups, but pathological changes were more diffuse and frequent in lethal infection. At 6–10 days of lethal infection, the cortex and cerebellum sections had increased ICAM-1-positive staining in vascular cells, as well as increased detection of CD45+ leukocytes, CD3+ T cells, IBA1+ phagocytes, and GFAP+ astrocytes, but a marked loss of occludin-positive tight junction staining, implying progressive endothelial activation/damage and cellular recruitment in inflamed brains. Orientia were sparse in the brains, but readily detectable within lectin+ vascular and IBA-1+ phagocytic cells. These CNS alterations were consistent with type 1-skewed, IL-13-suppressed responses in lethally-infected mouse lungs. Significance: This is the first report of type 1-skewed neuroinflammation and cellular activation, accompanied with vascular activation/damage, during OtK infection in C57BL/6 mice. This study not only enhances our understanding of the pathophysiological mechanisms of scrub typhus, but also correlates the impact of immune and vascular dysfunction on disease pathogenesis. [ABSTRACT FROM AUTHOR]

Understanding the formation of tropospheric ozone (O 3 ) and secondary particulates is essential for controlling secondary pollution in megacities. Intensive observations were conducted to investigate the evolution of O 3 , nitrate (NO 3 − ), sulfate (SO 4 2 − ) and oxygenated organic aerosols ((OOAs), a proxy for secondary organic aerosols) and the interactions between O 3 , NO x oxidation products (NO z ) and OOA in urban Beijing in August 2012. The O 3 concentrations exhibited similar variations at both the urban and urban background sites in Beijing. Regarding the O 3 profile, the O 3 concentrations increased with increasing altitude. The peaks in O 3 on the days exceeding the 1 h or 8 h O 3 standards (polluted days) were substantially wider than those on normal days. Significant increases in the NO z mixing ratio (i.e., NO y - NO x ) were observed between the morning and early afternoon, which were consistent with the increasing oxidant level. A discernable NO 3 − peak was also observed in the morning on the polluted days, and this peak was attributed to vertical mixing and strong photochemical production. In addition, a SO 4 2 − peak at 18:00 was likely caused by a combination of local generation and regional transport. The OOA concentration cycle exhibited two peaks at approximately 10:00 and 19:00. The OOA concentrations were correlated well with SO 4 2 − ([OOA] = 0.55 × [SO 4 2 − ] + 2.1, r 2 = 0.69) because they both originated from secondary transformations that were dependent on the ambient oxidization level and relative humidity. However, the slope between OOA and SO 4 2 − was only 0.35, which was smaller than the slope observed for all of the OOA and SO 4 2 − data, when the RH ranged from 40 to 50%. In addition, a photochemical episode was selected for analysis. The results showed that regional transport played an important role in the evolution of the investigated secondary pollutants. The measured OOA and O x concentrations were well correlated at the daily scale, whereas the hourly OOA and O x concentrations were insignificantly correlated in urban Beijing. The synoptic situation and the differences in the VOC oxidation contributing to O 3 and SOAs may have resulted in the differences among the correlations between OOA and O x at different time scale. We calculated OOA production rates using the photochemical age (defined as –log 10 (NO x /NO y )) in urban plumes. The CO-normalized OOA concentration increased with increasing photochemical age, with production rates ranging from 1.1 to 8.5 μg m − 3 ppm − 1 h − 1 for the plume from the NCP. [ABSTRACT FROM AUTHOR]

Myasthenia gravis (MG) is a debilitating autoimmune disease characterized by muscle fatigue and weakness caused by autoantibody- and complement-mediated damage to the neuromuscular junction. This study sought to compare the efficacy of unique sets of monoclonal antibody–siRNA conjugates, individually (mono) or in combination (duo), against the crucial receptors predominantly or solely expressed on two subsets of B cells—plasma B cells and their precursor (transitional mature B) cells in a mouse model of MG. At the optimized doses, the conjugates, likely due to the combined activities of mAb and siRNA, substantially decreased the expression levels of CD268 (B cell-activating factor receptor) in mature B cells and CD269 (B-cell maturation antigen) in plasma cells concomitantly with reducing the levels of acetylcholine receptor (AChR)-specific autoantibodies. PEGylation, but not pretreatment with an antibody against type 1 interferon receptor, further improved duoconjugate-induced reduction in the autoantibody levels. Our results show that the duoconjugate treatment significantly improved the clinical symptoms of MG, consistent with the preservation of bungarotoxin-bound functional AChRs. In the future, developing similar target-specific combination molecules can potentially turn into a new and effective therapeutic approach for MG. • B cell-targeting monoclonal antibody and siRNA conjugates were tested for therapeutic potential in a mouse model of myasthenia gravis (MG). • Both mono and duo conjugates substantially reduced critical receptors of B cells. • B cell targeting mAb-siRNA conjugates reduced AChR-specific autoantibody levels. • PEGylation further influenced conjugate induced target receptor suppression and autoantibody reduction. • Improvement of clinical symptoms were moderately affected by the duoconjugate treatment. [ABSTRACT FROM AUTHOR]

The quantile regression (QR) method has been increasingly introduced to atmospheric environmental studies to explore the non-linear relationship between local meteorological conditions and ozone mixing ratios. In this study, we applied QR for the first time, together with multiple linear regression (MLR), to analyze the dominant meteorological parameters influencing the mean, 10th percentile, 90th percentile and 99th percentile of maximum daily 8-h average (MDA8) ozone concentrations in 2000–2015 in Hong Kong. The dominance analysis (DA) was used to assess the relative importance of meteorological variables in the regression models. Results showed that the MLR models worked better at suburban and rural sites than at urban sites, and worked better in winter than in summer. QR models performed better in summer for 99th and 90th percentiles and performed better in autumn and winter for 10th percentile. And QR models also performed better in suburban and rural areas for 10th percentile. The top 3 dominant variables associated with MDA8 ozone concentrations, changing with seasons and regions, were frequently associated with the six meteorological parameters: boundary layer height, humidity, wind direction, surface solar radiation, total cloud cover and sea level pressure. Temperature rarely became a significant variable in any season, which could partly explain the peak of monthly average ozone concentrations in October in Hong Kong. And we found the effect of solar radiation would be enhanced during extremely ozone pollution episodes ( i.e., the 99th percentile). Finally, meteorological effects on MDA8 ozone had no significant changes before and after the 2010 Asian Games. [ABSTRACT FROM AUTHOR]

Loss of immune control over opportunistic infections can occur at different stages of HIV-1 (HIV) disease, among which mucosal candidiasis caused by the fungal pathogen Candida albicans (C. albicans) is one of the early and common manifestations in HIV-infected human subjects. The underlying immunological basis is not well defined. We have previously shown that compared to cytomegalovirus (CMV)-specific CD4 cells, C. albicans-specific CD4 T cells are highly permissive to HIV in vitro. Here, based on an antiretroviral treatment (ART) naïve HIV infection cohort (RV21), we investigated longitudinally the impact of HIV on C. albicans- and CMV-specific CD4 T-cell immunity in vivo. We found a sequential dysfunction and preferential depletion for C. albicans-specific CD4 T cell response during progressive HIV infection. Compared to Th1 (IFN-γ, MIP-1β) functional subsets, the Th17 functional subsets (IL-17, IL-22) of C. albicans-specific CD4 T cells were more permissive to HIV in vitro and impaired earlier in HIV-infected subjects. Infection history analysis showed that C. albicans-specific CD4 T cells were more susceptible to HIV in vivo, harboring modestly but significantly higher levels of HIV DNA, than CMV-specific CD4 T cells. Longitudinal analysis of HIV-infected individuals with ongoing CD4 depletion demonstrated that C. albicans-specific CD4 T-cell response was preferentially and progressively depleted. Taken together, these data suggest a potential mechanism for earlier loss of immune control over mucosal candidiasis in HIV-infected patients and provide new insights into pathogen-specific immune failure in AIDS pathogenesis. [ABSTRACT FROM AUTHOR]

Endothelial cells (EC) are the main target for Orientia tsutsugamushi infection and EC dysfunction is a hallmark of severe scrub typhus in patients. However, the molecular basis of EC dysfunction and its impact on infection outcome are poorly understood. We found that C57BL/6 mice that received a lethal dose of O. tsutsugamushi Karp strain had a significant increase in the expression of IL-33 and its receptor ST2L in the kidneys and liver, but a rapid reduction of IL-33 in the lungs. We also found exacerbated EC stress and activation in the kidneys of infected mice, as evidenced by elevated angiopoietin (Ang) 2/Ang1 ratio, increased endothelin 1 (ET-1) and endothelial nitric oxide synthase (eNOS) expression. Such responses were significantly attenuated in the IL-33-/- mice. Importantly, IL-33-/- mice also had markedly attenuated disease due to reduced EC stress and cellular apoptosis. To confirm the biological role of IL-33, we challenged wild-type (WT) mice with a sub-lethal dose of O. tsutsugamushi and gave mice recombinant IL-33 (rIL-33) every 2 days for 10 days. Exogenous IL-33 significantly increased disease severity and lethality, which correlated with increased EC stress and activation, increased CXCL1 and CXCL2 chemokines, but decreased anti-apoptotic gene BCL-2 in the kidneys. To further examine the role of EC stress, we infected human umbilical vein endothelial cells (HUVEC) in vitro. We found an infection dose-dependent increase in the expression of IL-33, ST2L soluble ST2 (sST2), and the Ang2/Ang1 ratio at 24 and 48 hours post-infection. This study indicates a pathogenic role of alarmin IL-33 in a murine model of scrub typhus and highlights infection-triggered EC damage and IL-33-mediated pathological changes during the course of Orientia infection. [ABSTRACT FROM AUTHOR]

Scrub typhus is a neglected, but important, tropical disease, which puts one-third of the world's population at risk. The disease is caused by Orientia tsutsugamushi, an obligately intracellular Gram-negative bacterium. Dysregulation in immune responses is known to contribute to disease pathogenesis; however, the nature and molecular basis of immune alterations are poorly defined. This study made use of a newly developed murine model of severe scrub typhus and focused on innate regulators and vascular growth factors in O. tsutsugamushi-infected liver, lungs and spleen. We found no activation or even reduction in base-line expression for multiple molecules (IL-7, IL-4, IL-13, GATA3, ROR-γt, and CXCL12) at 2, 6 and 10 days post-infection. This selective impairment in type 2-related immune responses correlated with a significant activation of the genes for IL-1β, IL-6, IL-10, TNF-α, IFN-γ, as well as CXCR3- and CXCR1-related chemokines in inflamed tissues. The elevated angiopoietin (Ang)-2 expression and Ang-2/Ang-1 ratios suggested excessive inflammation and the loss of endothelial integrity. These alterations, together with extensive recruitment of myeloperoxidase (MPO)-expressing neutrophils and the influx of CD3+ T cells, contributed to acute tissue damage and animal death. This is the first report of selective alterations in a panel of immune regulators during early O. tsutsugamushi infection in intravenously inoculated C57BL/6 mice. Our findings shed new light on the pathogenic mechanisms associated with severe scrub typhus and suggest potential targets for therapeutic investigation. Author Summary: Scrub typhus is a life-threatening disease, often displayed as severe acute febrile illness. It is caused by infection with O. tsutsugamushi, a Gram-negative intracellular bacterium. Every year, approximately one million people are infected globally, especially in the Asia-Pacific region. Mechanistic studies of host immune responses are limited, partially due to the limited availability of suitable animal models and research facilities. We demonstrated here selective suppression in innate immune regulators, but activation of inflammatory cytokines, during the first few days of O. tsutsugamushi infection in mice. Importantly, these immune alterations correlated with acute tissue damage, disease progression, and animal death. As the first report describing dysregulation in innate immune responses in a murine model of severe scrub typhus, this study improves our understanding of disease mechanisms and opens new avenues for the exploration of treatment options. [ABSTRACT FROM AUTHOR]

Scrub typhus is a neglected, but important, tropical disease, which puts one-third of the world's population at risk. The disease is caused by Orientia tsutsugamushi, an obligately intracellular Gram-negative bacterium. Dysregulation in immune responses is known to contribute to disease pathogenesis; however, the nature and molecular basis of immune alterations are poorly defined. This study made use of a newly developed murine model of severe scrub typhus and focused on innate regulators and vascular growth factors in O. tsutsugamushi-infected liver, lungs and spleen. We found no activation or even reduction in base-line expression for multiple molecules (IL-7, IL-4, IL-13, GATA3, ROR-γt, and CXCL12) at 2, 6 and 10 days post-infection. This selective impairment in type 2-related immune responses correlated with a significant activation of the genes for IL-1β, IL-6, IL-10, TNF-α, IFN-γ, as well as CXCR3- and CXCR1-related chemokines in inflamed tissues. The elevated angiopoietin (Ang)-2 expression and Ang-2/Ang-1 ratios suggested excessive inflammation and the loss of endothelial integrity. These alterations, together with extensive recruitment of myeloperoxidase (MPO)-expressing neutrophils and the influx of CD3+ T cells, contributed to acute tissue damage and animal death. This is the first report of selective alterations in a panel of immune regulators during early O. tsutsugamushi infection in intravenously inoculated C57BL/6 mice. Our findings shed new light on the pathogenic mechanisms associated with severe scrub typhus and suggest potential targets for therapeutic investigation. [ABSTRACT FROM AUTHOR]

Background and Aim Hepatocyte growth factor ( HGF) is a pleiotropic cytokine related with cell proliferation and survival; however, its role in viral hepatitis is not elucidated. In this study, we studied HGF immune role in viral hepatitis. Methods Mice received hydrodynamically delivered HGF plasmid or control plasmid and then infected with adenovirus, and parameters of immune-mediated liver damage were evaluated. We studied dendritic cell ( DC) activation in the presence of HGF. T cells collected from infected mice were restimulated with virally infected DC to measure cytokine production in vitro. Results HGF ameliorated the liver inflammation during viral hepatitis as alanine transferase, intrahepatic lymphocytes, and splenocyte counts were diminished by HGF. Lower histological scores of liver pathology were observed in the HGF group. DC from the HGF group expressed reduced C D40. The hepatic expression and serum concentration of IL-12p40 were diminished in HGF-transfected mice. In vitro experiments with DC confirmed that HGF diminished CD40 expression and IL-12p40 production. The expression and serum levels of IFN-γ, IL-6 and CXCL9 were significantly decreased in the HGF group. HGF overexpression diminished the expression and concentration of IL-10 and TGF-β. The frequency of PD-1+ Tim-3+ in CD8 T cells was decreased by HGF overexpression. Moreover, T cells in the HGF group at day 14 secreted more IFN-γ and TNF-α than those in the control group when restimulated with virally infected DC. Conclusion HGF modulated DC activation and T cell priming, thereby limiting the immune-mediated damage in the liver. However, viral clearance was not compromised by HGF. [ABSTRACT FROM AUTHOR]

Abstract: Studies on atmospheric mercury in the Pearl River Delta (PRD) region are important because of the economic relevance of this region to China, because of its economic developmental pattern and because it is a highly industrialised area influenced by the strong seasonal monsoons. Total gaseous mercury (TGM), meteorological parameters and criteria pollutant concentrations were measured at Mt. Dinghu (DH, a regional monitoring site) and Guangzhou (GZ, an urban monitoring site) in the PRD region from October 2009 to April 2010 and from November 2010 to November 2011, respectively. The ranges of daily average TGM concentrations at the DH and GZ sites were 1.87–29.9 ng m−3 (5.07 ± 2.89 ng m−3) and 2.66–11.1 ng m−3 (4.60 ± 1.36 ng m−3), respectively, which were far more significant than the background values in the Northern Hemisphere (1.5–1.7 ng m−3), suggesting that the atmosphere in the PRD has suffered from mercury pollution. Similar TGM seasonal distributions at the two sites were observed, with a descending order of spring, winter, autumn and summer. The different seasonal monsoons were the dominant factor controlling the seasonal variability of the TGM, with variations in the boundary layer and oxidation also possibly partially contributing. Different diurnal patterns of the TGM at two sites were observed. TGM levels during the daytime were higher than those during the nighttime and were predominantly influenced by mountain and valley winds at the DH site, whereas the opposite trend was evident at the GZ site, which was primarily influenced by the boundary-layer height and O3 concentration. During the monitoring period, the correlations between the daily TGM levels and the SO2 and NO2 levels at the DH site were significant (r = 0.36, p < 0.001; r = 0.29, p < 0.001), suggesting that coal-fired emission is an important source of mercury for this regional monitoring site. At the GZ site, the correlations between the daily TGM level and the NO, NO2, CO levels were significant (r = 0.501, p < 0.001; r = 0.579, p < 0.001; r = 0.358, p < 0.001). However, TGM was partially correlated with SO2, suggesting that the combined vehicle emissions and coal combustion were the dominant mercury sources for this urban monitoring site. The TGM distribution figure, which related to the wind-rose pattern and the distribution figure of emission sources, indicated significant contributions from anthropogenic emission sources. [Copyright &y& Elsevier]

Abstract: Total mercury (THg) and methylmercury (MeHg) were measured in large number of soil samples collected from areas with different types of land use, different depth in the Pearl River Delta (PRD) of South China. THg and MeHg concentrations ranged from 16.7 to 3320ngg−1 and 0.01 to 1.34ngg−1, respectively. THg levels are highest in the top 0–20cm soil layer, and decrease from the surface to bottom layer soil. Spatial variation was observed with different types of land use. Urban parks had the highest concentrations and the other areas tended to decrease in the order of residential areas, industrial areas, vegetable fields, cereal fields, and woodlands. Temporal variation was also noted, and two relatively high THg contamination zones located in the northwestern part of the PRD have significantly expanded over the last two decades. Both THg and MeHg concentrations were correlated significantly with soil organic matter (OM), but not with soil pH. THg pollution status was evaluated using two assessment methods. [Copyright &y& Elsevier]

Abstract: Hepatocyte apoptosis is an important feature of liver injury in hepatitis C virus (HCV) infection. However, the mechanism of apoptosis and consequences on disease progression in vivo have not been investigated fully in part due to the lack of adequate small animal models. In this study, transgenic (tg) mice were produced that express conditionally HCV structural proteins (core, E1, E2 and p7) in the liver following Cre-mediated DNA recombination. Using a novel Cre-estrogen receptor fusion protein (Cre-ER) induction strategy, tamoxifen was injected intraperitoneally (i.p.), which induced Cre nuclear translocation, transgene recombination and HCV protein expression in the liver. Hepatic expression of HCV core and envelope proteins resulted in increased hepatocyte apoptosis, detected by the TUNEL assay, between 7 and 33 days after induction. These results were confirmed by the presence of increased levels of apoptosis-associated cytokeratin 18 (CK-18) in the sera of the same animals. The presence of cleaved caspase-3 and elevated levels of CHOP/GADD153 in the liver suggests an endoplasmic reticulum (ER) stress-associated apoptosis mechanism. This study suggests an in vivo correlation between HCV structural protein expression, ER stress and hepatocyte apoptosis, implicating a potentially important mechanism of HCV pathogenesis. [Copyright &y& Elsevier]

Hepatitis C infection causes a state of chronic oxidative stress, which may contribute to fibrosis and carcinogenesis in the liver. Previous studies have shown that expression of the HCV core protein in hepatoma cells depolarized mitochondria and increased reactive oxygen species (ROS) production, but the mechanisms of these effects are unknown. In this study we examined the properties of liver mitochondria from transgenic mice expressing HCV core protein, and from normal liver mitochondria incubated with recombinant core protein. Liver mitochondria from transgenic mice expressing the HCV proteins core, E1 and E2 demonstrated oxidation of the glutathione pool and a decrease in NADPH content. In addition, there was reduced activity of electron transport complex I, and increased ROS production from complex I substrates. There were no abnormalities observed in complex II or complex III function. Incubation of control mitochondria in vitro with recombinant core protein also caused glutathione oxidation, selective complex I inhibition, and increased ROS production. Proteinase K digestion of either transgenic mitochondria or control mitochondria incubated with core protein showed that core protein associates strongly with mitochondria, remains associated with the outer membrane, and is not taken up across the outer membrane. Core protein also increased Ca2+ uptake into isolated mitochondria. These results suggest that interaction of core protein with mitochondria and subsequent oxidation of the glutathione pool and complex I inhibition may he an important cause of the oxidative stress seen in chronic hepatitis C. [ABSTRACT FROM AUTHOR]

Architectural decoration is one of the most important sources of anthropogenic volatile organic compound (VOC) emissions in China, as well as one of the major sources of indoor air pollution, which negatively affects the comfort, health, and productivity of residents. In this study, a VOC emission inventory of architectural coatings and adhesives for new buildings in China in 2017 was developed based on building area, using a new database established through a bottom-up activity level investigation and analysis of large number of samples. Our results show that the investigated coating ratio of exterior walls distinctly differed from the empirical value. The comprehensive VOC emission factors and total emissions for architectural coatings and adhesives in China in 2017 were 214.5 kg km−2 and 614 kt, respectively, with floor coatings (41.1%) and solvent-based adhesives (18.2%) being the highest contributors to emissions. Shandong, Jiangsu, Zhejiang, Sichuan, and Guangdong were the five largest emission contributors, accounting for 39.1% of VOC emissions from architectural coatings and adhesives for new buildings. Market access and supervision of architectural materials should be strengthened maximally, and gradual phasing out of solvent-based coatings and adhesives is advised in the future in China. • A VOC emission inventory for architectural decorations in 2017 in China was developed based on building area. • A new database of corresponding emission factors and activity data was established. • Floor coatings and solvent-based adhesives were key VOCs sources for architectural decorations. • Emission contributor was subdivided into provincial level. [ABSTRACT FROM AUTHOR]

Background: The Zika virus (ZIKV) outbreak that occurred in multiple countries was linked to increased risk of nervous system injuries and congenital defects. However, host immunity- and immune-mediated pathogenesis in ZIKV infection are not well understood. Interleukin-22 (IL-22) is a crucial cytokine for regulating host immunity in infectious diseases. Whether IL-22 plays, a role in ZIKV infection is unknown.Methods: The cellular source of IL-22 was identified in IFNAR-/- mice and wild-type (WT) neonatal mice during ZIKV infection. To determine the role of IL-22, we challenged 1-day-old WT and IL-22-/- mice with ZIKV and monitored clinical manifestations. Glial cell activation in the brain was assessed by confocal imaging. ZIKV-specific CD8+ T cell responses in both the spleen and brain were analyzed by flow cytometry. In addition, glial cells were cultured in vitro and infected with ZIKV in the presence of IL-22, followed by the evaluation of cell proliferation, cytokine expression, and viral loads.Results: We found that γδ T cells were the main source of IL-22 during ZIKV infection in both the spleen and brain. WT mice began to exhibit weight loss, staggered steps, bilateral hind limb paralysis, and weakness at 10 days post-infection (dpi) and ultimately succumbed to infection at 16-19 dpi. IL-22 deficiency lessened weight loss, moderated the systemic inflammatory response, and greatly improved clinical signs of neurological disease and mortality. ZIKV infection also induced the activation of microglia and astrocytes in vitro. Additional analysis demonstrated that the absence of IL-22 resulted in reduced activation of microglia and astrocytes in the cortex. Although IL-22 displayed a negligible effect on glial cells in vitro, IL-22-/- mice mounted more vigorous ZIKV-specific CD8+ T cell responses, which led to a more effective control of ZIKV in the brain.Conclusions: Our data revealed a pathogenic role of IL-22 in ZIKV encephalitis. [ABSTRACT FROM AUTHOR]