Merozoite surface protein 1 of Plasmodium vivax (PvMSP1), a glycosylphosphatidylinositol-anchored protein (GPI-AP), is a malaria vaccine candidate for P. vivax. The paralog of PvMSP1, named P. vivax merozoite surface protein 1 paralog (PvMSP1P; PlasmoDB PVX_099975), was recently identified and predicted as a GPI-AP. The similarities in genetic structural characteristics between PvMSP1 and PvMSP1P (e.g., size of open reading frames, two epidermal growth factor-like domains, and GPI anchor motif in the C terminus) led us to study this protein. In the present study, different regions of the PvMSP1P protein, demarcated based on the processed forms of PvMSP1, were expressed successfully as recombinant proteins [i.e., 83 (A, B, and C), 30, 38, 42, 33, and 19 fragments]. We studied the naturally acquired immune response against each fragment of recombinant PvMSP1P and the potential ability of each fragment to bind erythrocytes. The N-terminal fragment (83A) and two C-terminal fragments (33 and 19) reacted strongly with sera from P. vivax-infected patients, with 50 to 68% sensitivity and 95 to 96% specificity, respectively. Due to colocalization of PvMSP1P with PvMSP1, we supposed that PvMSP1P plays a similar role as PvMSP1 during erythrocyte invasion. An in vitro cytoadherence assay showed that PvMSP1P, especially the 19-kDa C-terminal region, could bind to erythrocytes. We also found that human sera from populations naturally exposed to vivax malaria and antisera obtained by immunization using the recombinant molecule PvMSP1P-19 inhibited in vitro binding of human erythrocytes to PvMSP1P-19. These results provide further evidence that the PvMSP1P might be an essential parasite adhesion molecule in the P. vivax merozoite and is a potential vaccine candidate against P. vivax.
Abstract The Plasmodium vivax merozoite surface protein 1 paralog (PvMSP1P), which has epidermal growth factor (EGF)-like domains, was identified as a novel erythrocyte adhesive molecule. This EGF-like domain (PvMSP1P-19) elicited high level of acquired immune response in patients. Antibodies against PvMSP1P significantly reduced erythrocyte adhesion activity to its unknown receptor. To determine PvMSP1P-19-specific antibody function and B-cell epitopes in vivax patients, five monoclonal antibodies (mAbs) and 18-mer peptides were generated. The mAb functions were determined by erythrocyte-binding inhibition assay and invasion inhibition assay with P. knowlesi . B-cell epitopes of PvMSP1P-19 domains were evaluated by peptide microarray. The pvmsp1p-19 sequences showed limited polymorphism in P. vivax worldwide isolates. The 1BH9-A10 showed erythrocyte binding inhibitory by interaction with the N-terminus of PvMSP1P-19, while this mAb failed to recognize PkMSP1P-19 suggesting the species-specific for P. vivax . Other mAbs showed cross-reactivity with PkMSP1P-19. Among them, the 2AF4-A2 and 2AF4-A6 mAb significantly reduced parasite invasion through C-terminal recognition. The linear B-cell epitope in naturally exposed P. vivax patient was identified at three linear epitopes. In this study, PvMSP1P-19 N-terminal-specific 1BH9-A10 and C-terminal-specific 2AF4 mAbs showed functional activity for epitope recognition suggesting that PvMSP1P may be useful for vaccine development strategy for specific single epitope to prevent P. vivax invasion.
Colorectal cancer (CRC) is one of the most lethal and prevalent malignancies. While the overexpression of pioneer factor GATA6 in CRC has been linked with metastasis, its role in genome-wide gene expression dysregulation remains unclear. Through studies of primary human CRC tissues and analysis of the TCGA data, we found that GATA6 preferentially binds at CRC-specific active enhancers, with enrichment at enhancer-promoter loop anchors. GATA6 protein also physically interacts with CTCF, suggesting its critical role in 3D genome organization. The ablation of GATA6 through AID and CRISPR systems severely impaired cancer cell clonogenicity and proliferation. Mechanistically, GATA6 knockout induced global loss of CRC-specific open chromatins and extensive alterations of critical enhancer-promoter interactions for CRC oncogenes. Last, we showed that GATA6 knockout greatly reduced tumor growth and improved survival in mice. Together, we revealed a previously unidentified mechanism by which GATA6 contributes to the pathogenesis of colorectal cancer.
In Plasmodium, the membrane of intracellular parasites is initially formed during invasion as an invagination of the red blood cell surface, which forms a barrier between the parasite and infected red blood cells in asexual blood stage parasites. The membrane proteins of intracellular parasites of Plasmodium species have been identified such as early-transcribed membrane proteins (ETRAMPs) and exported proteins (EXPs). However, there is little or no information regarding the intracellular parasite membrane in Plasmodium vivax. In the present study, recombinant PvETRAMP11.2 (PVX_003565) and PvEXP1 (PVX_091700) were expressed and evaluated antigenicity tests using sera from P. vivax-infected patients. A large proportion of infected individuals presented with IgG antibody responses against PvETRAMP11.2 (76.8%) and PvEXP1 (69.6%). Both of the recombinant proteins elicited high antibody titers capable of recognizing parasites of vivax malaria patients. PvETRAMP11.2 partially co-localized with PvEXP1 on the intracellular membranes of immature schizont. Moreover, they were also detected at the apical organelles of newly formed merozoites of mature schizont. We first proposed that these proteins might be synthesized in the preceding schizont stage, localized on the parasite membranes and apical organelles of infected erythrocytes, and induced high IgG antibody responses in patients.
Background: In December 2019, coronavirus disease 2019 (COVID-19) broke out in Wuhan, China and quickly spread to other areas and other countries worldwide. Since then, Wuhan implemented Fang Cang Shelter hospitals to stop the spread of SARS-CoV-2. This study aimed to evaluate the effects of Fang Cang Shelter hospitals on the trend of COVID-19 using an interrupted time series analysis to provide a reference for COVID-19 control in other countries. Methods: To evaluate whether Fang Cang Shelter hospitals change the epidemic trend of COVID-19 in Wuhan, China, an interrupted time series analysis was performed to compare the number of new confirmed cases of COVID-19 before (January 16, 2020–February 4, 2020) and after (February 5, 2020–March 16, 2020) the operation of Fang Cang Shelter hospitals. Our setting included Wuhan, China, where severe acute respiratory syndrome coronavirus 2 (SARSCoV-2) was identified firstly as the cause of coronavirus disease-2019 (COVID-19). The information obtained included numbers of confirmed COVID-19 cases in Wuhan. Findings: The initial number of confirmed cases increased significantly per day prior to February 4, 2020 by 68.54 cases ( P < 0.0001; CI, 36.42–100.67) in Wuhan. Compared with the number of cases noted 20 days before the use of Fang Cang Shelter hospitals , a sustained reduction in the number of confirmed (trend change, −125.57; P < 0.0001 ; CI, −160.44 to − 90.69) cases of COVID-19 in Wuhan was noted 41 days after the use of Fang Cang Shelter hospitals. Immediate-level changes were observed for confirmed cases in Wuhan (level change, 725.97; P = 0.025; CI, 93.34–1358.59). These changes led to an estimated 5148 fewer confirmed cases ( P < 0.0001; CI, −6578.04 to −3718.29 ). Furthermore, according to the mean confirmed cases of 395.71 per day before the intervention, we estimated that Wuhan had advanced the terminal phase of COVID-19 by 13 days. Interpretation: Interrupted time series analysis revealed that Fang Cang Shelter hospitals were likely to reverse the epidemic trend of COVID-19 while containment strategy was implemented in Wuhan. The results provide a valuable reference for health policy makers in countries to which the COVID-19 outbreak has also spread, including Italy, Iran, and Spain.Funding Statement: This work was supported by The National Natural Science Foundation of China (81871681), The National First-class Discipline Programme of Food Science and Technology (JUFSTR20180101), The Fundamental Research Funds for the Central Universities funded by the Ministry of Education of China (JUSRP51710A), and Project of Wuxi Science and Technology Supporting Plan (N2020X004). Declaration of Interests: We declare no competing interests.
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