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Sporozoite-based approaches currently represent the most effective vaccine strategies for induction of sterile protection against Plasmodium falciparum (Pf) malaria. Clinical development of subunit vaccines is almost exclusively centered on the circum-sporozoite protein (CSP), an abundantly expressed protein on the sporozoite membrane. Anti-CSP antibodies are able to block sporozoite invasion and development in human hepatocytes and subsequently prevent clinical malaria. Here, we have investigated whether sporozoite-induced human antibodies with specificities different from CSP can reduce Pf-liver stage development. IgG preparations were obtained from 12 volunteers inoculated with a protective immunization regime of whole sporozoites under chloroquine prophylaxis. These IgGs were depleted for CSP specificity by affinity chromatography. Recovered non-CSP antibodies were tested for sporozoite membrane binding and for functional inhibition of sporozoite invasion of a human hepatoma cell line and hepatocytes both in vitro and in vivo. Postimmunization IgGs depleted for CS specificity of 9 of 12 donors recognized sporozoite surface antigens. Samples from 5 of 12 donors functionally reduced parasite-liver cell invasion or development using the hepatoma cell line HC-04 and FRG-huHep mice containing human liver cells. The combined data provide clear evidence that non-CSP proteins, as yet undefined, do represent antibody targets for functional immunity against Pf parasites responsible for malaria.

We present a draft genome sequence of the platypus, Ornithorhynchus anatinus. This monotreme exhibits a fascinating combination of reptilian and mammalian characters. For example, platypuses have a coat of fur adapted to an aquatic lifestyle; platypus females lactate, yet lay eggs; and males are equipped with venom similar to that of reptiles. Analysis of the first monotreme genome aligned these features with genetic innovations. We find that reptile and platypus venom proteins have been co- opted independently from the same gene families; milk protein genes are conserved despite platypuses laying eggs; and immune gene family expansions are directly related to platypus biology. Expansions of protein, non- protein- coding RNA and microRNA families, as well as repeat elements, are identified. Sequencing of this genome now provides a valuable resource for deep mammalian comparative analyses, as well as for monotreme biology and conservation.

We present here a draft genome sequence of the red jungle fowl, Gallus gallus. Because the chicken is a modern descendant of the dinosaurs and the first non-mammalian amniote to have its genome sequenced, the draft sequence of its genome—composed of approximately one billion base pairs of sequence and an estimated 20,000–23,000 genes—provides a new perspective on vertebrate genome evolution, while also improving the annotation of mammalian genomes. For example, the evolutionary distance between chicken and human provides high specificity in detecting functional elements, both non-coding and coding. Notably, many conserved non-coding sequences are far from genes and cannot be assigned to defined functional classes. In coding regions the evolutionary dynamics of protein domains and orthologous groups illustrate processes that distinguish the lineages leading to birds and mammals. The distinctive properties of avian microchromosomes, together with the inferred patterns of conserved synteny, provide additional insights into vertebrate chromosome architecture.

Recent evidence suggests that certain vaccines, including Bacillus-Calmette Guérin (BCG), can induce changes in the innate immune system with non-specific memory characteristics, termed ‘trained immunity’. Here we present the results of a randomised, controlled phase 1 clinical trial in 20 healthy male and female volunteers to evaluate the induction of immunity and protective efficacy of the anti-tuberculosis BCG vaccine against a controlled human malaria infection. After malaria challenge infection, BCG vaccinated volunteers present with earlier and more severe clinical adverse events, and have significantly earlier expression of NK cell activation markers and a trend towards earlier phenotypic monocyte activation. Furthermore, parasitemia in BCG vaccinated volunteers is inversely correlated with increased phenotypic NK cell and monocyte activation. The combined data demonstrate that BCG vaccination alters the clinical and immunological response to malaria, and form an impetus to further explore its potential in strategies for clinical malaria vaccine development. Immune activation induces long-term alterations of setpoints, impacting responses to subsequent unrelated stimuli. Here the authors show that volunteers vaccinated with BCG respond to controlled human malaria infection with increased clinical symptoms and an inverse correlation between immune activation markers and parasitemia.

The miR156 and plant specific transcription factor SQUAMOSA PROMOTER BINDING PROTEIN-LIKE ( SPL ) are known for their function regulating plant growth and development. In this study, we identified 20 GmSPL s which are targeted by gma-miR156b via plant small RNA target and degradome analysis. And we found high transcript levels of gma-miR156b and its targeted GmSPL s in the flower of soybean cytoplasmic male sterility (CMS) line and its maintainer. The gma-miR156b direct cleavage of GmSPL2b and GmSPL9b , and have opposite expression levels during early flower buds development. We observed a high expression level of GUS protein in the anthers of the line with pgma-MIR156b::GUS reporter. Over-expression of the gma-miR156b precursor in Arabidopsis inhibited floral organ development, including reduced anther size and the amount of pollen grains per anther etc. Like miR156-targeted SPL genes, non-targeted GmSPL8 s were also down-regulated in early flower bud development of soybean CMS line compared with its maintainer line, which might act in concert with miR156-targeted SPL genes to participate in the floral organ development. Quantitative real time PCR (qRT-PCR) suggested that miR156/ SPL modulates floral organ development by regulating the expression of LATERAL ORGAN BOUNDARIES DOMAIN22 ( LBD22 ), LBD36 , AGAMOUS-LIKE30 ( AGL30 ) and AGL104 . Our findings will facilitate understanding of the biological functions of miR156/ SPL in floral organ development of soybean CMS.

Plasmodium falciparum ( Pf ) parasite development in liver represents the initial step of the life-cycle in the human host after a Pf- infected mosquito bite. While an attractive stage for life-cycle interruption, understanding of parasite-hepatocyte interaction is inadequate due to limitations of existing in vitro models. We explore the suitability of hepatocyte organoids (HepOrgs) for Pf -development and show that these cells permitted parasite invasion, differentiation and maturation of different Pf strains. Single-cell messenger RNA sequencing (scRNAseq) of Pf- infected HepOrg cells has identified 80 Pf- transcripts upregulated on day 5 post-infection. Transcriptional profile changes are found involving distinct metabolic pathways in hepatocytes with Scavenger Receptor B1 (SR-B1) transcripts highly upregulated. A novel functional involvement in schizont maturation is confirmed in fresh primary hepatocytes. Thus, HepOrgs provide a strong foundation for a versatile in vitro model for Pf liver-stages accommodating basic biological studies and accelerated clinical development of novel tools for malaria control. Suitable in vitro models allowing to assess Plasmodium liver stage development are still limited. Here, Yang et al. show that hepatocytes derived from human hepatocyte organoids (HepOrgs) can support P. falciparum development. This allowed for the identification and validation of the importance of the host factor, scavenger receptor B1 (SRB1), in parasite development.

After infection of the human host, the first stage of the Plasmodium falciparum (Pf) lifecycle takes place in the liver. Understanding of host-parasite interactions during liver stage development is compromised by the rapid loss of functionality and Pf permissiveness of cultured primary human hepatocytes (PHHs). Here, we substantially delay the loss of Pf permissiveness by using a medium containing serum-replacement and signal transduction inhibitors. We analyzed and integrated transcriptomic profiles of cultured PHHs with the phenotypic presentation of developing Pf liver stages, revealing a number of host signaling pathways that contributed to dedifferentiation of hepatocytes and influenced Pf liver stage development. In particular, inhibition of the Wnt pathway showed a significant positive impact on size and maturity of Pf liver stage schizonts, while retaining the metabolic activity and epithelial nature of PHHs. Therefore, our study provides insights into hepatocyte characteristics that are important for Pf permissiveness and an improved in vitro liver stage model. This should facilitate identification and development of novel therapeutic strategies for Pf liver stages.

With the energy consumption increasing, the coal supply in China has been becoming tight, which has made it difficult for thermal power generation in Yunnan Province. Making full use of local inferior coal and biomass resources in Yunnan can remedy the lack of fuel in power plants. In this paper, an oxygen-rich atmosphere thermogravimetric experiment was performed for a blended sample of Xiaolongtan lignite, Yiliang tobacco rod, and Fuyuan bituminous coal. The combustion characteristics of the mixed fuel under several key operating parameters (i.e., mass ratios, oxygen concentration, and heating rates) were studied. The response surface methodology was used to determine the optimal blending ratio of the three fuels. The results show that the ignition and burnout temperature of coal decrease and the combustion time diminishes with the enrichment of oxygen. The optimal oxygen concentration in the practical application is around 30%. The activation energy and preexponential factor increase with the enlargement of oxygen concentration. Such complex evaluation and optimization approach ensure the stable operation of thermal power plant production.

Background Sporozoite invasion of hepatocytes is an essential step in the Plasmodium life-cycle and has similarities, at the cellular level, to merozoite invasion of erythrocytes. In the case of the Plasmodium blood-stage, efforts to identify host–pathogen protein–protein interactions have yielded important insights including vaccine candidates. In the case of sporozoite-hepatocyte invasion, the host–pathogen protein–protein interactions involved are poorly understood. Methods To gain a better understanding of the protein–protein interaction between the sporozoite ligands and host receptors, a systematic screen was performed. The previous Plasmodium falciparum and human surface protein ectodomain libraries were substantially extended, resulting in the creation of new libraries comprising 88 P. falciparum sporozoite protein coding sequences and 182 sequences encoding human hepatocyte surface proteins. Having expressed recombinant proteins from these sequences, a plate-based assay was used, capable of detecting low affinity interactions between recombinant proteins, modified for enhanced throughput, to screen the proteins for interactions. The novel interactions identified in the screen were characterized biochemically, and their essential role in parasite invasion was further elucidated using antibodies and genetically manipulated Plasmodium parasites. Results A total of 7540 sporozoite-hepatocyte protein pairs were tested under conditions capable of detecting interactions of at least 1.2 µM K D . An interaction between the human fibroblast growth factor receptor 4 (FGFR4) and the P. falciparum protein Pf34 is identified and reported here, characterizing its affinity and demonstrating the blockade of the interaction by reagents, including a monoclonal antibody. Furthermore, further interactions between Pf34 and a second P. falciparum rhoptry neck protein, PfRON6, and between human low-density lipoprotein receptor (LDLR) and the P. falciparum protein PIESP15 are identified. Conditional genetic deletion confirmed the essentiality of PfRON6 in the blood-stage, consistent with the important role of this protein in parasite lifecycle. Pf34 was refractory to attempted genetic modification. Antibodies to Pf34 abrogated the interaction and had a modest effect upon sporozoite invasion into primary human hepatocytes. Conclusion Pf34 and PfRON6 may be members of a functionally important invasion complex which could be a target for future interventions. The modified interaction screening assay, protein expression libraries and P. falciparum mutant parasites reported here may be a useful tool for protein interaction discovery and antigen candidate screening which could be of wider value to the scientific community.

Summary The malaria sporozoite injected by a mosquito migrates to the liver by traversing host cells. The sporozoite also traverses hepatocytes before invading a terminal hepatocyte and developing into exoerythrocytic forms. Hepatocyte infection is critical for parasite development into merozoites that infect erythrocytes, and the sporozoite is thus an important target for antimalarial intervention. Here, we investigated two abundant sporozoite proteins of the most virulent malaria parasite Plasmodium falciparum and show that they play important roles during cell traversal and invasion of human hepatocytes. Incubation of P. falciparum sporozoites with R1 peptide, an inhibitor of apical merozoite antigen 1 (AMA1) that blocks merozoite invasion of erythrocytes, strongly reduced cell traversal activity. Consistent with its inhibitory effect on merozoites, R1 peptide also reduced sporozoite entry into human hepatocytes. The strong but incomplete inhibition prompted us to study the AMA‐like protein, merozoite apical erythrocyte‐binding ligand (MAEBL). MAEBL‐deficient P. falciparum sporozoites were severely attenuated for cell traversal activity and hepatocyte entry in vitro and for liver infection in humanized chimeric liver mice. This study shows that AMA1 and MAEBL are important for P. falciparum sporozoites to perform typical functions necessary for infection of human hepatocytes. These two proteins therefore have important roles during infection at distinct points in the life cycle, including the blood, mosquito, and liver stages.