High thermostability improves neutralizing antibody responses induced by native-like HIV-1 envelope trimers

Soluble HIV-1 envelope glycoprotein (Env) immunogens are a prime constituent of candidate vaccines designed to induce broadly neutralizing antibodies. Several lines of evidence suggest that enhancing Env immunogen thermostability can improve neutralizing antibody (NAb) responses. Here, we generated BG505 SOSIP.v9 trimers, which displayed virtually no reactivity with non-neutralizing antibodies and showed increased global and epitope thermostability, compared to previous BG505 SOSIP versions. Chemical crosslinking of BG505 SOSIP.v9 further increased the melting temperature to 91.3 °C, which is almost 25 °C higher than that of the prototype SOSIP.664 trimer. Next, we compared the immunogenicity of a palette of BG505-based SOSIP trimers with a gradient of thermostabilities in rabbits. We also included SOSIP.v9 proteins in which a strain-specific immunodominant epitope was masked by glycans to redirect the NAb response to other subdominant epitopes. We found that increased trimer thermostability correlated with increased potency and consistency of the autologous NAb response. Furthermore, glycan masking steered the NAb response to subdominant epitopes without decreasing the potency of the autologous NAb response. In summary, SOSIP.v9 trimers and their glycan masked versions represent an improved platform for HIV-1 Env based vaccination strategies

Structural basis of glycan276-dependent recognition by HIV-1 broadly neutralizing antibodies

Recognition of N-linked glycan at residue N276 (glycan276) at the periphery of the CD4-binding site (CD4bs) on the HIV-envelope trimer is a formidable challenge for many CD4bs-directed antibodies. To understand how this glycan can be recognized, here we isolate two lineages of glycan276-dependent CD4bs antibodies. Antibody CH540-VRC40.01 (named for donor-lineage.clone) neutralizes 81% of a panel of 208 diverse strains, while antibody CH314-VRC33.01 neutralizes 45%. Cryo-electron microscopy (cryo-EM) structures of these two antibodies and 179NC75, a previously identified glycan276-dependent CD4bs antibody, in complex with HIV-envelope trimer reveal substantially different modes of glycan276 recognition. Despite these differences, binding of glycan276-dependent antibodies maintains a glycan276 conformation similar to that observed in the absence of glycan276-binding antibodies. By contrast, glycan276-independent CD4bs antibodies, such as VRC01, displace glycan276 upon binding. These results provide a foundation for understanding antibody recognition of glycan276 and suggest its presence may be crucial for priming immunogens seeking to initiate broad CD4bs recognition

Geographical and temporal distribution of SARS-CoV-2 clades in the WHO European Region, January to June 2020

We show the distribution of SARS-CoV-2 genetic clades over time and between countries and outline potential genomic surveillance objectives. We applied three available genomic nomenclature systems for SARS-CoV-2 to all sequence data from the WHO European Region available during the COVID-19 pandemic until 10 July 2020. We highlight the importance of real-time sequencing and data dissemination in a pandemic situation. We provide a comparison of the nomenclatures and lay a foundation for future European genomic surveillance of SARS-CoV-2.Peer reviewe

ATROPOS: a versatile data acquisition and analysis system

Versatile, portable, rugged, and compact test and control modules for use in the development and testing of detection equipment for high-energy physics experiments are frequently needed at SLAC. The basic system developed is based on an LSI-11 microcomputer with 24K RAM, 4K ROM, 2 serial interfaces (one to the console terminal, the other to the large SLAC IBM computer complex (the TRIPLEX)), a programable clock, and a CAMAC crate controller. Data logging support is provided for magnetic tape, floppy disk, and an interactive program (ACQUIRE) which runs on the TRIPLEX under the timesharing system ORVYL. Data are read from various CAMAC modules, collected, buffered, and optionally logged. At a lower priority, the data read are sampled and analyzed in real-time on the LSI-11 to produce various histograms and tables. Concurrently, a more extensive analysis can be performed by the TRIPLEX program on the data which are logged to it. Interactive facilities provided by the microcomputer operating system enable the user to change CAMAC module addresses and the function codes used with them, specify various data cuts and transformations that are to be performed on the sample data, and specify new histogram limits and titles. Results of the real-time analysis, by both the microcomputer and the TRIPLEX program (if it is attached), may be displayed in graphical or tabular form on the console terminal. The basic system hardware cost (exclusive of the magnetic tape drive and floppy disk drive) is around $7000. The software is written in a modular fashion so that the user can supply his own data reading and analysis routines. This system has been in use for two years by various groups on several LSI-11s at SLAC. 3 figures

Observed, executed, and imagined action representations can be decoded from ventral and dorsal areas

Previous functional magnetic resonance imaging (fMRI) research on action observation has emphasized the role of putative mirror neuron areas such as Broca's area, ventral premotor cortex, and the inferior parietal lobule. However, recent evidence suggests action observation involves many distributed cortical regions, including dorsal premotor and superior parietal cortex. How these different regions relate to traditional mirror neuron areas, and whether traditional mirror neuron areas play a special role in action representation, is unclear. Here we use multi-voxel pattern analysis (MVPA) to show that action representations, including observation, imagery, and execution of reaching movements: (1) are distributed across both dorsal (superior) and ventral (inferior) premotor and parietal areas; (2) can be decoded from areas that are jointly activated by observation, execution, and imagery of reaching movements, even in cases of equal-amplitude blood oxygen level-dependent (BOLD) responses; and (3) can be equally accurately classified from either posterior parietal or frontal (premotor and inferior frontal) regions. These results challenge the presumed dominance of traditional mirror neuron areas such as Broca's area in action observation and action representation more generally. Unlike traditional univariate fMRI analyses, MVPA was able to discriminate between imagined and observed movements from previously indistinguishable BOLD activations in commonly activated regions, suggesting finer-grained distributed patterns of activation

The World Is a Scary Place: Individual Differences in Belief in a Dangerous World Predict Specific Intergroup Prejudices

Research suggests that people chronically concerned with safety, as measured by the Belief in a Dangerous World (BDW) Scale, are prone to intergroup prejudice and likely to endorse negative stereotypes under conditions eliciting concern for safety. Using a sociofunctional, threat-based approach to prejudice, the current research tested whether people with high BDW report increased prejudice specifically toward groups stereotypically associated with safety-related threats compared to groups associated with unrelated threats. Studies 1 and 2 found that higher BDW predicts increased negativity, safety-related concern, and fear toward groups stereotypically associated with threats to safety (e.g., illegal immigrants and Muslims) compared to groups thought to pose unrelated threats (e.g., gay men and obese people). Study 3 activated concern for safety using a news story detailing increased crime (vs. a control story), finding an interaction between safety concern activation, target group, and BDW, such that situational threat concern elicited greater prejudice toward Mexican Americans, but not toward Asian Americans, from those participants with higher BDW. These studies suggest that individual differences in concern for safety predict specific prejudices (e.g., fear and social distancing) toward distinct groups rather than general outgroup negativity. © 2016, © The Author(s) 2016