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ABSTRACT Helicobacter pylori is a microaerophilic Gram-negative bacterium that resides in the human stomach and is classified as a class I carcinogen for gastric cancer. Numerous studies have demonstrated that H. pylori infection plays a role in regulating the function of host cells, thereby contributing to the malignant transformation of these cells. However, H. pylori infection is a chronic process, and short-term cellular experiments may not provide a comprehensive understanding of the in vivo situation, especially when considering the lower oxygen levels in the human stomach. In this study, we aimed to investigate the mechanisms underlying gastric cell dysfunction after prolonged exposure to H. pylori under hypoxic conditions. We conducted a co-culture experiment using the gastric cell line GES-1 and H. pylori for 30 generations under intermittent hypoxic conditions. By closely monitoring cell proliferation, migration, invasion, autophagy, and apoptosis, we revealed that sustained H. pylori stimulation under hypoxic conditions significantly influences the function of GES-1 cells. This stimulation induces epithelial-mesenchymal transition and contributes to the propensity for malignant transformation of gastric cells. To confirm the in vitro results, we conducted an experiment involving Mongolian gerbils infected with H. pylori for 85 weeks. All the results strongly suggest that the Nod1 receptor signaling pathway plays a crucial role in H. pylori-related apoptosis and autophagy. In summary, continuous stimulation by H. pylori affects the functioning of gastric cells through the Nod1 receptor signaling pathway, increasing the likelihood of cell carcinogenesis. The presence of hypoxic conditions further exacerbates this process.IMPORTANCEDeciphering the collaborative effects of Helicobacter pylori infection on gastric epithelial cell function is key to unraveling the development mechanisms of gastric cancer. Prior research has solely examined the outcomes of short-term H. pylori stimulation on gastric epithelial cells under aerobic conditions, neglecting the bacterium’s nature as a microaerophilic organism that leads to cancer following prolonged stomach colonization. This study mimics a more genuine in vivo infection scenario by repeatedly exposing gastric epithelial cells to H. pylori under hypoxic conditions for up to 30 generations. The results show that chronic exposure to H. pylori in hypoxia substantially increases cell migration, invasion, and epithelial-mesenchymal transition, while suppressing autophagy and apoptosis. This highlights the significance of hypoxic conditions in intensifying the carcinogenic impact of H. pylori infection. By accurately replicating the in vivo gastric environment, this study enhances our comprehension of H. pylori’s pathogenic mechanisms in gastric cancer.

The Yarlung Zangbo Grand Canyon region （referred to as the YGC）， located in the southeast Qinghai-Xizang Plateau， is the main channel of the warm and humid air transported from the India Ocean to the Qinghai-Xizang Plateau （referred to as the QXP）， and it plays an important role in the water and energy cycle of the QXP.In order to explore the influences of the different horizontal water vapor transport on the water & heat exchanges flux， the water vapor intensity over the YGC from May 20， to July 9， 2013， was divided into three levels： strong， weak， and very weak based on the ECMWF Re-Analyses version5 data.And the fifth-generation public land model （Community Land Model version 5.0， CLM5.0） was deployed to simulate the impact of the horizontal water vapor transport on the YGC-atmospheric water and heat exchanges.The results show that the south （east） boundary of the YGC is the main input （output） boundary of water vapor， and the YGC valley over the south of the YGC is a strong water vapor transport belt.The YGC-atmospheric water & heat exchanges fluxes simulated by CLM5.0 has large errors compared to the actual measurements， the CLM5.0 simulated near-surface water & heat exchanges fluxes over the YGC have a high accuracy by optimizing the thermal roughness length （Z0h） parameterization schemes replacing the default soil attribute data-set.Compared with the simulations by using the CLM5.0 default parameterization scheme， the one developed by Zeng and Dickinson （1998）.（Z98 scheme for short） has the lowest errors， the root mean square error of the near-surface sensible heat flux at the wheat station and the grassland station decreased by 18.2% and 10.9%， respectively.The results of regional simulation show that the general distribution of the near-surface latent heat flux （LE） over the YGC is high in the southeast and low in the northwest， while the near-surface sensible heat flux （H） is the opposite.As the water vapor transport intensity decreasing， the area with high near-surface latent heat flux extends to the northwest， while the near-surface sensible heat flux （H） is the opposite.The H in the high-altitude ice and snow-covered area maintains a low value， while the LE is the opposite.During the entire experimental period， the precipitation was as high as 59% over the YGC， which is abundant precipitation.The near-surface effective energy is mainly transported to the atmosphere in a form of latent heat under different horizontal water vapor transport conditions.The near-surface sensible heat transport is the weakest in the strong water vapor transport belt under the condition of strong horizontal water vapor transport.The regional daily average value of the H is only -1.80 W∙m-2 by using the Z98 scheme， while the LE is greater than 70.0 W∙m-2.When the water vapor maintains a high-value range over the Grand Canyon area， the near-surface net radiation decreases， but the near-surface net radiation is still mainly consumed by the latent heat.The warming effect of the water vapor on the local atmosphere resulted in the difference of ground-atmospheric temperature decreases， and the near-surface sensible heat is significantly inhibited.The results of this study have a certain reference value for understanding the land surface process over the YGC and its response to horizontal water vapor transport.

Highly contagious respiratory illnesses like influenza and COVID-19 pose serious risks to public health. A two-in-one vaccine would be ideal to avoid multiple vaccinations for these diseases. Here, we generated a chimeric receptor binding domain of the spike protein (S-RBD) and hemagglutinin (HA)-stalk-based vaccine for both SARS-CoV-2 and influenza viruses. The S-RBD from SARS-CoV-2 Delta was fused to the headless HA from H1N1 (H1Delta), creating a chimera that forms trimers in solution. The cryo-electron microscopy structure of the chimeric protein complexed with the RBD-targeting CB6 and the HA-stalk-targeting CR9114 antibodies shows that the trimeric protein is stable and accessible for neutralizing antibody binding. Immunization with the vaccine elicited high and long-lasting neutralizing antibodies and effectively protected mice against the challenges of lethal H1N1 or heterosubtypic H5N8, as well as the SARS-CoV-2 Delta or Omicron BA.2 variants. Overall, this study offers a two-in-one universal vaccine design to combat infections caused by both SARS-CoV-2 variants of concern and influenza viruses.

The characteristics of local surface wind are closely related to the assessment of wind power resources and the oscillation period of offshore wind turbines. In this research, we analyzed near-surface wind observation data from the southern coast of Sri Lanka, comparing the surface wind variation characteristics across different seasons. Through spectral analysis, we discuss the wind stability and oscillation period, aiming to provide information for the management strategies and oscillation issues of offshore wind turbines in the North Equatorial Indian Ocean to ensure their stable operation. Our findings showed that the Indian summer monsoon dominated the seasonal surface wind variation in the southern coast of Sri Lanka. The local monsoon period began in mid-May and ended in mid-October, during which stable southwest winds prevailed with an average maximum 10 m wind speed exceeding 6.0 m/s. In contrast, surface wind was unstable and weaker during autumn and winter. The surface wind speed exhibited a clear diurnal oscillation throughout the year. The wind speed power spectral density exhibited clear peaks at periods of 24 h, 12 h, and 6 h.

The seasonal characteristics of water and heat exchange in the alpine grasslands are significant， and the freezing‐thawing process has an important impact on the land‐atmospheric water and heat exchange.Based on the observation data of the land surface process in the Tangchama small watershed in the source area of the Yellow River from May 2014 to May 2015， this research divides the soil freezing‐thawing process into thawed stage （TT）， frozen stage （FF）， thawing to freezing （T-F） and freezing to thawing （F-T）， and the changes in the different states and period of the net radiation， sensible heat flux， latent heat flux and surface heat flux of the underlying surface of the alpine grassland are analyzed to explore the characteristics of water and heat exchange between the land‐atmosphere in the soil freezing‐thawing process.The results are as follows： （1） The average value of the net radiation flux in the thawed stage is generally greater than that of the other three stages， and the maximum value reaches 203.7 W·m-2.The frozen soil melts in the freezing‐thawing stage， and the soil moisture content gradually increases.The radiation ratio increased significantly during the frozen stage， the net radiation diurnal variation was the largest in the thawed stage， reaching 717.6 W·m-2， and the frozen stage was the smallest， followed by the freezing‐thawing stage.（2） The proportion of sensible heat flux and latent heat flux is different in the thawed and frozen stages.When completely thawed， due to precipitation and soil moisture content， the net radiation is mainly converted into latent heat flux.The maximum diurnal variation of latent heat flux is 193.7 W·m-2， while the sensible heat flux is only about 80.0 W·m-2.The diurnal average of sensible heat and latent heat in the thawing‐freezing phase， the freezing‐thawing period and the frozen period is not much different.The mean latent heat in the three period is 21.9 W·m-2， and the sensible heat is 20.3 W·m-2； The diurnal variation is greater than the latent heat in the three period， the soil suffers a freezing‐thawing cycle， the soil temperature difference is small， and the water content changes， and the net radiation is mainly converted into sensible heat during this period； the diurnal variation of sensible heat was greater than that of latent heat in the three stages.The freezing-thawing cycle occurred in the soil， the difference between ground and air temperature was small， and the moisture content changed.During this period， the net radiation was mainly converted to sensible heat.（3） The soil heat flux is positive （negative） in thawed （frozen） state， indicating that the surface soil absorbs （releases） heat from the atmosphere， and its daily variation range is large （small）.The above results show that the state and process of soil freezing and thawing have different characteristics for the water and heat exchange process between the land and atmosphere.

The freeze-thaw process is one of the most prominent features of the land surface process on the Qinghai-Xizang Plateau， and quantifying the variation of the key variables that denote the soil freeze-thaw process has scientific significance for understanding the climate change， hydrological processes and ecosystems of the Qinghai-Tibetan Plateau.By using the ECMWF/ERA5 （European Centre for Medium-Range Weather Forecasts/ERA5） reanalyzed soil temperature， volumetric soil water and air temperature data， the temporal and spatial trends of the start date of soil freezing， the start date of soil thawing and the duration of the soil freezing and their relationships with the air temperature and altitude were investigated by using linear regression， Mann-Kendall test， moving t test and correlation analysis.These results demonstrated that the spatial distribution of soil freeze-thaw process in the Qinghai-Xizang Plateau is characterized by a trend of delaying freeze， advancing thaw and shortening freeze from the northwest to the southeast.The soil freeze-thaw process varied significantly on the Qinghai-Xizang Plateau from 1979 to 2018.The start date of soil freezing was delayed by 14.0 days with a rate of 0.17 d·a-1， and the start date of soil thawing was advanced by 11.0 days with a rate of 0.07 d·a-1， and the duration of the soil freeze was shortened by 25.0 days with a rate of 0.23 d·a-1 over the past 40 years.The overall trend of soil freeze-thaw process is the same in the Qinghai-Xizang Plateau， while the local rate is different.Throughout the period of study， the duration of the soil freeze in the southern and the northern Changtang Plateau is shortened by 47.2 days and 32.9 days.The first date of the soil freeze， the first date of the soil thaw and the duration of the soil freeze are significantly correlated with temperature and altitude.If the air temperature rises by 1.0 ℃， the first date of the soil freeze will be delayed by 5.2 days， and the first date of the soil thaw will be advanced by 4.5 days， so that the duration of the soil freeze will be shortened by 9.8 days.In the high cold Tibetan climatological zone， the first date of the soil freeze will be advanced by 9.1 days， and the first date of the soil thaw will be delayed by 4.9 days， while the duration of the soil freeze will be increased by 13.9 days as the altitude increases by 1000.0 m.

The near-surface energy budget closure has always been a scientific hot topic in the land-surface processes research， especially over the underlying surface of heterogeneous wetlands.In this investigation， the horizontal thermal advection caused by thermal inhomogeneity of the underlying surface over the wetland is calculated based on the data of the Flower-lake observation field in the Zoige alpine wetland.With considering the horizontal thermal advection， its contribution to the near-surface energy closure is analyzed.The results show that the mean horizontal thermal advection of the Zoige wetland is 22.9 W·m-2， and the maximum value can reach 58.7 W·m-2 in the daytime of summer 2017.After introducing the horizontal thermal advection and soil heat storage into the near-surface energy balance equation， the near-surface energy closure ratio increased from 41.8% to 67.9% in summer.The contribution of horizontal thermal advection was 5.8%， that of soil thermal storage was 20.1%， and that of plant photosynthetic thermal storage was 1.0%.The diurnal variation of the near-surface horizontal thermal advective is equivalent to the sensible heat flux in Zoige wetland， and the maximum diurnal variation is about one third of the thermal storage of the wetland soil.

Near-surface energy budget closure has been a trending topic in land surface processes research, especially on the underlying surfaces of heterogeneous wetlands. In this investigation, the horizontal thermal advection caused by thermal inhomogeneity over the alpine wetland is calculated based on the eddy covariance data observed at the Flower Lake observation field and WRF modelling data over the Zoige alpine wetland, China. The contribution of horizontal thermal advection to the near-surface energy closure is analysed. The results show that the mean horizontal heat advection of the Zoige wetland is 20.2 W·m−2, and the maximum value reached 55.0 W·m−2 in the summer of 2017. After introducing thermal advection into the near-surface energy balance equation, the near-surface energy closure ratio increased from 72.3% to 81.0%.

Zika virus (ZIKV)-specific T cells are activated by different peptides derived from virus structural and nonstructural proteins, and contributed to the viral clearance or protective immunity. Herein, we have depicted the profile of CD8+ and CD4+ T cell immunogenicity of ZIKV proteins in C57BL/6 (H-2b) and BALB/c (H-2d) mice, and found that featured cellular immunity antigens were variant among different murine alleles. In H-2b mice, the proteins E, NS2, NS3 and NS5 are recognized as immunodominant antigens by CD8+ T cells, while NS4 is dominantly recognized by CD4+ T cells. In contrast, in H-2d mice, NS1 and NS4 are the dominant CD8+ T cell antigen and NS4 as the dominant CD4+ T cell antigen, respectively. Among the synthesized 364 overlapping polypeptides spanning the whole proteome of ZIKV, we mapped 91 and 39 polypeptides which can induce ZIKV-specific T cell responses in H-2b and H-2d mice, respectively. Through the identification of CD8+ T cell epitopes, we found that immunodominant regions E294-302 and NS42351-2360 are hotspots epitopes with a distinct immunodominance hierarchy present in H-2b and H-2d mice, respectively. Our data characterized an overall landscape of the immunogenic spectrum of the ZIKV polyprotein, and provide useful insight into the vaccine development.

Helicobacter pylori is designated as a class I carcinogen of human gastric cancer following long-term infection. During this process, H. pylori bacteria persist in proliferation and death, and release bacterial components that come into contact with gastric epithelial cells and regulate host cell function. However, the impact of long-term exposure to H. pylori lysate on the pathological changes of gastric cells is not clear. In this study, we aimed to investigate the regulation and mechanisms involved in gastric cell dysfunction following continuous exposure to H. pylori lysate. We co-cultured gastric cell lines GES-1 and MKN-45 with H. pylori lysate for 30 generations, and we found that sustained exposure to H. pylori lysate inhibited GES-1 cell invasion, migration, autophagy, and apoptosis, while it did not inhibit MKN-45 cell invasion or migration. Furthermore, Mongolian gerbils infected with H. pylori ATCC 43504 strains for 90 weeks confirmed the in vitro results. The clinical and in vitro data indicated that sustained exposure to H. pylori lysate inhibited cell apoptosis and autophagy through the Nod1-NF-κB/MAPK-ERK/FOXO4 signaling pathway. In conclusion, sustained exposure to H. pylori lysate promoted proliferation of gastric epithelial cells and inhibited autophagy and apoptosis via Nod1-NF-κB/MAPK-ERK/FOXO4 signaling pathway. In the process of H. pylori-induced gastric lesions, H. pylori lysate plays as an “accomplice” to carcinogenesis.

Zika virus (ZIKV) is a unique flavivirus with high tropism to the testes. ZIKV can persist in human semen for months and can cause testicular damage in male mice. However, the mechanisms through which ZIKV enters the testes remain unclear. In this study, we revealed that matrix metalloproteinase 9 (MMP9) was upregulated by ZIKV infection in cell culture and in A129 mice. Furthermore, using an in vitro Sertoli cell barrier model and MMP9-/- mice, we found that ZIKV infection directly affected the permeability of the blood-testis barrier (BTB), and knockout or inhibition of MMP9 reduced the effects of ZIKV on the Sertoli cell BTB, highlighting its role in ZIKV-induced disruption of the BTB. Interestingly, the protein levels of MMP9 were elevated by ZIKV nonstructural protein 1 (NS1) in primary mouse Sertoli cells (mSCs) and other cell lines. Moreover, the interaction between NS1 and MMP9 induced the K63-linked polyubiquitination of MMP9, which enhanced the stability of MMP9. The upregulated MMP9 level led to the degradation of essential proteins involved in the maintenance of the BTB, such as tight junction proteins (TJPs) and type Ⅳ collagens. Collectively, we concluded that ZIKV infection promoted the expression of MMP9 which was further stabilized by NS1 induced K63-linked polyubiquitination to affect the TJPs/ type Ⅳ collagen network, thereby disrupting the BTB and facilitating ZIKV entry into the testes.

Abstract The association between Zika virus (ZIKV) infection and congenital malformations such as microcephaly in infants is a public health emergency. Although various in vivo and in vitro models are used for ZIKV research, few animal models are available for resolving the effects of maternal ZIKV infection on neonatal development. Here, we established an immunocompetent mouse model via intrauterine inoculation. Our results confirmed that ZIKV, but not dengue virus, infection caused spontaneous abortions, brain malformations, ocular abnormalities, spinal cord defects and paralysis in mouse offspring. Aside from microcephaly and hippocampal dysplasia, eye abnormalities, including microphthalmia, thinner optic nerves, damaged retinae, and deficient visual projection, were also observed following ZIKV infection. Moreover, ZIKV-infected offspring showed a loss of alpha motor neurons in the spinal cord and cerebellar malformation, which may cause paralysis. ZIKV also impaired adult neurogenesis in neonatal mice. Due to its intact immunity, our rodent model can be used to systematically evaluate the impact of ZIKV on embryonic and neonatal development and to explore potential therapies.

MraW is a 16S rRNA methyltransferase and plays a role in the fine-tuning of the ribosomal decoding center. It was recently found to contribute to the virulence of Staphylococcus aureus. In this study, we examined the function of MraW in Escherichia coli O157:H7 and found that the deletion of mraW led to decreased motility, flagellar production and DNA methylation. Whole-genome bisulfite sequencing showed a genome wide decrease of methylation of 336 genes and 219 promoters in the mraW mutant including flagellar genes. The methylation level of flagellar genes was confirmed by bisulfite PCR sequencing. Quantitative reverse transcription PCR results indicated that the transcription of these genes was also affected. MraW was furtherly observed to directly bind to the four flagellar gene sequences by electrophoretic mobility shift assay (EMSA). A common flexible motif in differentially methylated regions (DMRs) of promoters and coding regions of the four flagellar genes was identified. Reduced methylation was correlated with altered expression of 21 of the 24 genes tested. DNA methylation activity of MraW was confirmed by DNA methyltransferase activity assay in vitro and repressed by DNA methylation inhibitor 5-aza-2′-deoxycytidine (5-aza). In addition, the mraW mutant colonized poorer than wild type in mice. We also found that the expression of mraZ in the mraW mutant was increased confirming the antagonistic effect of mraW on mraZ. In conclusion, mraW was found to be a DNA methylase and have a wide-ranging effect on E. coli O157:H7 including motility and virulence in vivo via genome wide methylation and mraZ antagonism.

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease with a high fatality rate of up to 30% caused by SFTS virus (SFTSV). However, no specific vaccine or antiviral therapy has been approved for clinical use. To develop an effective treatment, we isolated a panel of human monoclonal antibodies (mAbs). SF5 and SF83 are two neutralizing mAbs that recognize two viral glycoproteins (Gn and Gc), respectively. We found that their epitopes are closely located, and we then engineered them as several bispecific antibodies (bsAbs). Neutralization and animal experiments indicated that bsAbs display more potent protective effects than the parental mAbs, and the cryoelectron microscopy structure of a bsAb3 Fab-Gn-Gc complex elucidated the mechanism of protection. In vivo virus passage in the presence of antibodies indicated that two bsAbs resulted in less selective pressure and could efficiently bind to all single parental mAb-escape mutants. Furthermore, epitope analysis of the protective mAbs against SFTSV and RVFV indicated that they are all located on the Gn subdomain I, where may be the hot spots in the phleboviruses. Collectively, these data provide potential therapeutic agents and molecular basis for the rational design of vaccines against SFTSV infection. [ABSTRACT FROM AUTHOR]

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can result in more severe syndromes and poorer outcomes in patients with diabetes and obesity. However, the precise mechanisms responsible for the combined impact of coronavirus disease 2019 (COVID-19) and diabetes have not yet been elucidated, and effective treatment options for SARS-CoV-2-infected diabetic patients remain limited. To investigate the disease pathogenesis, K18-hACE2 transgenic (hACE2Tg) mice with a leptin receptor deficiency (hACE2-Lepr-/-) and high-fat diet (hACE2-HFD) background were generated. The two mouse models were intranasally infected with a 5×105 median tissue culture infectious dose (TCID50) of SARS-CoV-2, with serum and lung tissue samples collected at 3 days post-infection. The hACE2-Lepr-/- mice were then administered a combination of low-molecular-weight heparin (LMWH) (1 mg/kg or 5 mg/kg) and insulin via subcutaneous injection prior to intranasal infection with 1×104 TCID50 of SARS-CoV-2. Daily drug administration continued until the euthanasia of the mice. Analyses of viral RNA loads, histopathological changes in lung tissue, and inflammation factors were conducted. Results demonstrated similar SARS-CoV-2 susceptibility in hACE2Tg mice under both lean (chow diet) and obese (HFD) conditions. However, compared to the hACE2-Lepr+/+ mice, hACE2-Lepr-/- mice exhibited more severe lung injury, enhanced expression of inflammatory cytokines and hypoxia-inducible factor-1α (HIF-1α), and increased apoptosis. Moreover, combined LMWH and insulin treatment effectively reduced disease progression and severity, attenuated lung pathological changes, and mitigated inflammatory responses. In conclusion, pre-existing diabetes can lead to more severe lung damage upon SARS-CoV-2 infection, and LMWH may be a valuable therapeutic approach for managing COVID-19 patients with diabetes. [ABSTRACT FROM AUTHOR]

The recent outbreak of Zika virus (ZIKV) has emerged as a global health concern. ZIKV can persist in human semen and be transmitted by sexual contact, as well as by mosquitoes, as seen for classical arboviruses. We along with others have previously demonstrated that ZIKV infection leads to testis damage and infertility in mouse models. So far, no prophylactics or therapeutics are available; therefore, vaccine development is urgently demanded. Recombinant chimpanzee adenovirus has been explored as the preferred vaccine vector for many pathogens due to the low preexisting immunity against the vector among the human population. Here, we developed a ZIKV vaccine based on recombinant chimpanzee adenovirus type 7 (AdC7) expressing ZIKV M/E glycoproteins. A single vaccination of AdC7-M/E was sufficient to elicit potent neutralizing antibodies and protective immunity against ZIKV in both immunocompetent and immunodeficient mice. Moreover, vaccinated mice rapidly developed neutralizing antibody with high titers within 1 week postvaccination, and the elicited antiserum could crossneutralize heterologous ZIKV strains. Additionally, ZIKV M- and E-specific T cell responses were robustly induced by AdC7-M/E. Moreover, one-dose inoculation of AdC7-M/E conferred mouse sterilizing immunity to eliminate viremia and viral burden in tissues against ZIKV challenge. Further investigations showed that vaccination with AdC7-M/E completely protected against ZIKV-induced testicular damage. These data demonstrate that AdC7-M/E is highly effective and represents a promising vaccine candidate for ZIKV control. [ABSTRACT FROM AUTHOR]