Neural Mechanisms of the Rejection-Aggression Link

Social rejection is a painful event that often increases aggression. However, the neural mechanisms of this rejection–aggression link remain unclear. A potential clue may be that rejected people often recruit the ventrolateral prefrontal cortex’s (VLPFC) self-regulatory processes to manage the pain of rejection. Using functional MRI, we replicated previous links between rejection and activity in the brain’s mentalizing network, social pain network and VLPFC. VLPFC recruitment during rejection was associated with greater activity in the brain’s reward network (i.e. the ventral striatum) when individuals were given an opportunity to retaliate. This retaliation-related striatal response was associated with greater levels of retaliatory aggression. Dispositionally aggressive individuals exhibited less functional connectivity between the ventral striatum and the right VLPFC during aggression. This connectivity exerted a suppressing effect on dispositionally aggressive individuals’ greater aggressive responses to rejection. These results help explain how the pain of rejection and reward of revenge motivate rejected people to behave aggressively

Physical Aggressiveness and Gray Matter Deficits in Ventromedial Prefrontal Cortex

What causes individuals to hurt others? Since the famous case of Phineas Gage, lesions of the ventromedial prefrontal cortex (VMPFC) have been reliably linked to physically aggressive behavior. However, it is unclear whether naturally-occurring deficits in VMPFC, among normal individuals, might have widespread consequences for aggression. Using voxel based morphometry, we regressed gray matter density from the brains of 138 normal female and male adults onto their dispositional levels of physical aggression, verbal aggression, and sex, simultaneously. Physical, but not verbal, aggression was associated with reduced gray matter volume in the VMPFC and to a lesser extent, frontopolar cortex. Participants with less gray matter density in this VMPFC cluster were much more likely to engage in real-world violence. These findings suggest that even granular deficits in normal individuals’ VMPFC gray matter can promote physical aggression

Social Rejection Magnifies Impulsive Behavior Among Individuals with Greater Negative Urgency: An Experimental Test of Urgency Theory

Impulsivity is a multifaceted trait with substantial implications for human well-being. One facet of impulsivity is negative urgency, the tendency to act impulsively in response to negative affect. Correlational evidence suggests that negative affect magnifies impulsive behavior among individuals with greater negative urgency, yet causal evidence for this core pillar of urgency theory is lacking. To fill this gap in the literature, participants (N = 363) were randomly assigned to experience social rejection (a situation shown to induce negative affect) or acceptance. Participants then reported their subjective negative affect, completed a behavioral measure of impulsivity, and reported their negative urgency. Among individuals with relatively high and average negative urgency, social rejection increased their impulsive behavior through greater experiences of negative affect. These indirect effects were not observed among individuals relatively low in negative urgency. These findings suggest that negative urgency exists at the nexus of urgent dispositions and situations that elicit negative affect, which offers novel support for urgency theory

P. falciparum and P. vivax Epitope-Focused VLPs Elicit Sterile Immunity to Blood Stage Infections

In order to design P. falciparum preerythrocytic vaccine candidates, a library of circumsporozoite (CS) T and B cell epitopes displayed on the woodchuck hepatitis virus core antigen (WHcAg) VLP platform was produced. To test the protective efficacy of the WHcAg-CS VLPs, hybrid CS P. berghei/P. falciparum (Pb/Pf) sporozoites were used to challenge immunized mice. VLPs carrying 1 or 2 different CS repeat B cell epitopes and 3 VLPs carrying different CS non-repeat B cell epitopes elicited high levels of anti-insert antibodies (Abs). Whereas, VLPs carrying CS repeat B cell epitopes conferred 98% protection of the liver against a 10,000 Pb/Pf sporozoite challenge, VLPs carrying the CS non-repeat B cell eptiopes were minimally-to-non-protective. One-to-three CS-specific CD4/CD8 T cell sites were also fused to VLPs, which primed CS-specific as well as WHcAg-specific T cells. However, a VLP carrying only the 3 T cell domains failed to protect against a sporozoite challenge, indicating a requirement for anti-CS repeat Abs. A VLP carrying 2 CS repeat B cell epitopes and 3 CS T cell sites in alum adjuvant elicited high titer anti-CS Abs (endpoint dilution titer \u3e1x106) and provided 80–100% protection against blood stage malaria. Using a similar strategy, VLPs were constructed carrying P. vivax CS repeat B cell epitopes (WHc-Pv-78), which elicited high levels of anti-CS Abs and conferred 99% protection of the liver against a 10,000 Pb/Pv sporozoite challenge and elicited sterile immunity to blood stage infection. These results indicate that immunization with epitope-focused VLPs carrying selected B and T cell epitopes from the P.falciparum and P. vivax CS proteins can elicit sterile immunity against blood stage malaria. Hybrid WHcAg-CS VLPs could provide the basis for a bivalent P. falciparum/P. vivax malaria vaccine

A novel malaria vaccine candidate antigen expressed in Tetrahymena thermophila

Development of effective malaria vaccines is hampered by the problem of producing correctly folded Plasmodium proteins for use as vaccine components. We have investigated the use of a novel ciliate expression system, Tetrahymena thermophila, as a P. falciparum vaccine antigen platform. A synthetic vaccine antigen composed of N-terminal and C-terminal regions of merozoite surface protein-1 (MSP-1) was expressed in Tetrahymena thermophila. The recombinant antigen was secreted into the culture medium and purified by monoclonal antibody (mAb) affinity chromatography. The vaccine was immunogenic in MF1 mice, eliciting high antibody titers against both N- and C-terminal components. Sera from immunized animals reacted strongly with P. falciparum parasites from three antigenically different strains by immunofluorescence assays, confirming that the antibodies produced are able to recognize parasite antigens in their native form. Epitope mapping of serum reactivity with a peptide library derived from all three MSP-1 Block 2 serotypes confirmed that the MSP-1 Block 2 hybrid component of the vaccine had effectively targeted all three serotypes of this polymorphic region of MSP-1. This study has successfully demonstrated the use of Tetrahymena thermophila as a recombinant protein expression platform for the production of malaria vaccine antigens

Tandem fusion of hepatitis B core antigen allows assembly of virus-like particles in bacteria and plants with enhanced capacity to accommodate foreign proteins

The core protein of the hepatitis B virus, HBcAg, assembles into highly immunogenic viruslike particles (HBc VLPs) when expressed in a variety of heterologous systems. Specifically, the major insertion region (MIR) on the HBcAg protein allows the insertion of foreign sequences, which are then exposed on the tips of surface spike structures on the outside of the assembled particle. Here, we present a novel strategy which aids the display of whole proteins on the surface of HBc particles. This strategy, named tandem core, is based on the production of the HBcAg dimer as a single polypeptide chain by tandem fusion of two HBcAg open reading frames. This allows the insertion of large heterologous sequences in only one of the two MIRs in each spike, without compromising VLP formation. We present the use of tandem core technology in both plant and bacterial expression systems. The results show that tandem core particles can be produced with unmodified MIRs, or with one MIR in each tandem dimer modified to contain the entire sequence of GFP or of a camelid nanobody. Both inserted proteins are correctly folded and the nanobody fused to the surface of the tandem core particle (which we name tandibody) retains the ability to bind to its cognate antigen. This technology paves the way for the display of natively folded proteins on the surface of HBc particles either through direct fusion or through non-covalent attachment via a nanobody

Transgenic Technology and the Study of Hepatitis Viruses: A Review of What We Have Learned

Because of the absence of inbred animal models susceptible to infection by the hepatitis B (HBV), C (HCV) and delta (HDV) viruses, and the inability to culture these viruses, a number of investigators have produced transgenic (Tg) mice that express one or all the viral genes. This review attempts to catalogue and characterize the Tg mice produced to date. The topics addressed are HBV, HCV and HDV gene expression and regulation; HBV replication models and factors that inhibit replication; HBV pathogenesis models; HBV tolerance and persistence models; modulation of the immune response to HBV proteins in Tg mice; T cell receptor Tg mice; and models of hepatocellular carcinoma