Structural basis of malaria transmission blockade by a monoclonal antibody to gamete fusogen HAP2

HAP2 is a transmembrane gamete fusogen found in multiple eukaryotic kingdoms and is structurally homologous to viral class II fusogens. Studies in Plasmodium have suggested that HAP2 is an attractive target for vaccines that block transmission of malaria. HAP2 has three extracellular domains, arranged in the order D2, D1, and D3. Here, we report monoclonal antibodies against the D3 fragment of Plasmodium berghei HAP2 and crystal structures of D3 in complex with Fab fragments of two of these antibodies, one of which blocks fertilization of Plasmodium berghei in vitro and transmission of malaria in mosquitoes. We also show how this Fab binds the complete HAP2 ectodomain with electron microscopy. The two antibodies cross-react with HAP2 among multiple plasmodial species. Our characterization of the Plasmodium D3 structure, HAP2 ectodomain architecture, and mechanism of inhibition provide insights for the development of a vaccine to block malaria transmission.

Reconfigurable Intelligent Surface-Based Space-Time Block Transmission on 6G

Reconfigurable intelligent surface (RIS) is considered to be a new technology with great potential and is being studied extensively and deeply. And the application extension of STBC in the RIS-aided scheme provides a new train of thought for the research of channel coding. In this paper, we propose we extend the scheme of using the RIS to adjust the phase and reconfigure the reflected signal and propose the design of the RIS-aided QO-STBC scheme and the RIS-aided QO-STBC scheme with interference cancellation. Particularly in the RIS-aided QO-STBC scheme with interference cancellation, the design can achieve the transmission of the full rate and full diversity using an auxiliary reflection group to eliminate the influence of interference term. Also, the advantages and disadvantages of the schemes are analyzed in the paper, and the decoding algorithms with different complexity used in the proposed schemes are described. The simulation results show that the performance of the RIS-aided QO-STBC scheme with interference cancellation is better than that of the RIS-aided QO-STBC scheme and the RIS-aided Alamouti scheme by about 5 dB and 7 dB at 1 0 − 3 BER because of diversity gain and coding gain.

Recombinant neutralizing secretory IgA antibodies for preventing mucosal carriage and transmission of SARS-CoV-2

Passive delivery of antibodies to mucosal sites might be a valuable adjunct to COVID-19 vaccination to prevent infection, treat viral carriage, or block transmission. However, monoclonal IgG antibody therapies, currently used for treatment of severe infections, are unlikely to prove useful in mucosal sites where SARS-CoV-2 resides and replicates in early infection. Here, we investigated the feasibility of producing neutralising monoclonal IgA antibodies against SARS-COV-2. We identified two class-switched mAbs that express well as monomeric and secretory IgA variants with retained antigen binding affinities and increased stability in mucosal secretions compared to their IgG counterparts. SIgAs had stronger virus neutralisation activities than IgG mAbs and were able to reduce SARS-CoV-2 infection in an in vivo murine model. Our findings provide a persuasive case for developing recombinant SIgAs for mucosal application as a new tool in the fight against COVID-19.

Prevention of Airborne Transmission of SARS-CoV-2 by UV-C Illumination of Airflow

SARS-CoV-2 is frequently transmitted by aerosol, and the sterilization of the virus in airflows has numerous potential applications. We evaluated a UV-C illuminator similar to what might be incorporated into tubing of a mechanical ventilator for its ability to block transmission of the airborne virus from infected to naïve hamsters. Hamsters protected by the UV system were consistently protected from infection, whereas non-protected hamsters uniformly became infected and displayed virus shedding and high burdens of virus in respiratory tissues. The efficiency and speed with which the virus in flowing air was inactivated using this system suggests several applications for mitigating transmission of this virus.

Structural basis of malaria transmission blockade by a monoclonal antibody to gamete fusogen HAP2

HAP2 is a transmembrane gamete fusogen found in multiple eukaryotic kingdoms and is structurally homologous to viral class II fusogens. Studies in Plasmodium have suggested that HAP2 is an attractive target for vaccines that block transmission of malaria. HAP2 has three extracellular domains, arranged in the order D2, D1, and D3. Here, we report monoclonal antibodies against the D3 fragment of Plasmodium berghei HAP2 and crystal structures of D3 in complex with Fab fragments of two of these antibodies, one of which blocks fertilization of Plasmodium berghei in vitro and transmission of malaria in mosquitos. We also show how this Fab binds the complete HAP2 ectodomain with electron microscopy. The two antibodies cross-react with HAP2 among multiple plasmodial species. Our characterization of the Plasmodium D3 structure, HAP2 ectodomain architecture, and mechanism of inhibition provide insights for the development of a vaccine to block malaria transmission.

Deep Reinforcement Learning-Based Network Routing Technology for Data Recovery in Exa-Scale Cloud Distributed Clustering Systems

Research has been conducted to efficiently transfer blocks and reduce network costs when decoding and recovering data from an erasure coding-based distributed file system. Technologies using software-defined network (SDN) controllers can collect and more efficiently manage network data. However, the bandwidth depends dynamically on the number of data transmitted on the network, and the data transfer time is inefficient owing to the longer latency of existing routing paths when nodes and switches fail. We propose deep Q-network erasure coding (DQN-EC) to solve routing problems by converging erasure coding with DQN to learn dynamically changing network elements. Using the SDN controller, DQN-EC collects the status, number, and block size of nodes possessing stored blocks during erasure coding. The fat-tree network topology used for experimental evaluation collects elements of typical network packets, the bandwidth of the nodes and switches, and other information. The data collected undergo deep reinforcement learning to avoid node and switch failures and provide optimized routing paths by selecting switches that efficiently conduct block transfers. DQN-EC achieves a 2.5-times-faster block transmission time and 0.4-times-higher network throughput than open shortest path first (OSPF) routing algorithms. The bottleneck bandwidth and transmission link cost can be reduced, improving the recovery time approximately twofold.

Bacterial evolution during human infection: Adapt and live or adapt and die

Microbes are constantly evolving. Laboratory studies of bacterial evolution increase our understanding of evolutionary dynamics, identify adaptive changes, and answer important questions that impact human health. During bacterial infections in humans, however, the evolutionary parameters acting on infecting populations are likely to be much more complex than those that can be tested in the laboratory. Nonetheless, human infections can be thought of as naturally occurring in vivo bacterial evolution experiments, which can teach us about antibiotic resistance, pathogenesis, and transmission. Here, we review recent advances in the study of within-host bacterial evolution during human infection and discuss practical considerations for conducting such studies. We focus on 2 possible outcomes for de novo adaptive mutations, which we have termed “adapt-and-live” and “adapt-and-die.” In the adapt-and-live scenario, a mutation is long lived, enabling its transmission on to other individuals, or the establishment of chronic infection. In the adapt-and-die scenario, a mutation is rapidly extinguished, either because it carries a substantial fitness cost, it arises within tissues that block transmission to new hosts, it is outcompeted by more fit clones, or the infection resolves. Adapt-and-die mutations can provide rich information about selection pressures in vivo, yet they can easily elude detection because they are short lived, may be more difficult to sample, or could be maladaptive in the long term. Understanding how bacteria adapt under each of these scenarios can reveal new insights about the basic biology of pathogenic microbes and could aid in the design of new translational approaches to combat bacterial infections.

Wolbachia strain wAu differs in cellular perturbation and virus inhibition profiles from previously characterised Wolbachia strains

Some strains of the inherited bacterium Wolbachia have been shown to be effective at reducing the transmission of dengue and other positive-sense RNA viruses by Aedes aegypti in both laboratory and field settings and are being deployed for dengue control. The degree of virus inhibition varies between Wolbachia strains density and tissue tropism can contribute to these differences but there are also indications that this is not the only factor involved: for example, strains wAu and wAlbA are maintained at similar densities but only wAu produces strong dengue inhibition. We previously reported perturbations in lipid transport dynamics, including sequestration of cholesterol in lipid droplets, with strains wMel/wMelPop in Ae.aegypti. Here we show that strain wAu does not produce the same cholesterol sequestration phenotype despite displaying strong virus inhibition and moreover, in contrast to wMel, wAu antiviral activity was not rescued by cyclodextrin treatment. To further investigate the cellular basis underlying these differences, proteomic analysis of midguts was carried out on Ae. aegypti lines and revealed that wAu-carrying midguts showed a distinct proteome when compared to Wolbachia-free, wMel- or wAlbA-carrying midguts, in particular with respect to lipid transport and metabolism. The data suggest a possible role for perturbed RNA processing pathways in wAu virus inhibition. Together these results indicate that wAu shows unique features in its inhibition of arboviruses compared to previously characterized Wolbachia strains.

Monoclonal antibodies block transmission of genetically diverse Plasmodium falciparum strains to mosquitoes

Malaria parasite transmission to mosquitoes relies on the uptake of sexual stage parasites during a blood meal and subsequent formation of oocysts on the mosquito midgut wall. Transmission-blocking vaccines (TBVs) and monoclonal antibodies (mAbs) target sexual stage antigens to interrupt human-to-mosquito transmission and may form important tools for malaria elimination. Although most epitopes of these antigens are considered highly conserved, little is known about the impact of natural genetic diversity on the functional activity of transmission-blocking antibodies. Here we measured the efficacy of three mAbs against leading TBV candidates (Pfs48/45, Pfs25 and Pfs230) in transmission assays with parasites from naturally infected donors compared to their efficacy against the strain they were raised against (NF54). Transmission-reducing activity (TRA) was measured as reduction in mean oocyst intensity. mAb 45.1 (α-Pfs48/45) and mAb 4B7 (α-Pfs25) reduced transmission of field parasites from almost all donors with IC80 values similar to NF54. Sequencing of oocysts that survived high mAb concentrations did not suggest enrichment of escape genotypes. mAb 2A2 (α-Pfs230) only reduced transmission of parasites from a minority of the donors, suggesting that it targets a non-conserved epitope. Using six laboratory-adapted strains, we revealed that mutations in one Pfs230 domain correlate with mAb gamete surface binding and functional TRA. Our findings demonstrate that, despite the conserved nature of sexual stage antigens, minor sequence variation can significantly impact the efficacy of transmission-blocking mAbs. Since mAb 45.1 shows high potency against genetically diverse strains, our findings support its further clinical development and may inform Pfs48/45 vaccine design.