Cationic Peptide Exposure Enhances Pulsed-Electric-Field-Mediated Membrane Disruption

Background: The use of pulsed electric fields (PEFs) to irreversibly electroporate cells is a promising approach for destroying undesirable cells. This approach may gain enhanced applicability if the intensity of the PEF required to electrically disrupt cell membranes can be reduced via exposure to a molecular deliverable. This will be particularly impactful if that reduced PEF minimally influences cells that are not exposed to the deliverable. We hypothesized that the introduction of charged molecules to the cell surfaces would create regions of enhanced transmembrane electric potential in the vicinity of each charged molecule, thereby lowering the PEF intensity required to disrupt the plasma membranes. This study will therefore examine if exposure to cationic peptides can enhance a PEF’s ability to disrupt plasma membranes. Methodology/Principal Findings We exposed leukemia cells to 40 μs PEFs in media containing varying concentrations of a cationic peptide, polyarginine. We observed the internalization of a membrane integrity indicator, propidium iodide (PI), in real time. Based on an individual cell’s PI fluorescence versus time signature, we were able to determine the relative degree of membrane disruption. When using 1–2 kV/cm, exposure to >50 μg/ml of polyarginine resulted in immediate and high levels of PI uptake, indicating severe membrane disruption, whereas in the absence of peptide, cells predominantly exhibited signatures indicative of no membrane disruption. Additionally, PI entered cells through the anode-facing membrane when exposed to cationic peptide, which was theoretically expected. Conclusions/Significance: Exposure to cationic peptides reduced the PEF intensity required to induce rapid and irreversible membrane disruption. Critically, peptide exposure reduced the PEF intensities required to elicit irreversible membrane disruption at normally sub-electroporation intensities. We believe that these cationic peptides, when coupled with current advancements in cell targeting techniques will be useful tools in applications where targeted destruction of unwanted cell populations is desired

Interpersonal Arrogance and the Incentive Salience of Power <i>Versus</i> Affiliation Cues

The arrogance dimension of the circumplex contrasts people who seemingly value power over affiliation (high arrogance) versus those who do not (low arrogance). Following this line of thinking, and building on an incentive salience model of approach motivation, three studies (total N = 284) examined the differential processing of power versus affiliation stimuli in categorization, perception and approach–avoidance paradigms. All studies found interactions of the same type. In study 2, for example, people high in arrogance perceived power stimuli to be larger than affiliation stimuli, but this differential pattern was not evident at low arrogance levels. People high, but not low, in arrogance also approached power stimuli faster than affiliation stimuli in a motor movement task (study 3). The results contribute to a process–based understanding of how interpersonal arrogance functions while linking such differences to the manner in which power versus affiliation cues are perceived and reacted to. Copyright © 2014 European Association of Personality Psychology </jats:p

Reversing the Extraverted Leadership Advantage: The Role of Employee Proactivity

Extraversion predicts leadership emergence and effectiveness, but do groups perform more effectively under extraverted leadership? Drawing on dominance complementarity theory, we propose that although extraverted leadership enhances group performance when employees are passive, this effect reverses when employees are proactive, because extraverted leaders are less receptive to proactivity. In Study 1, pizza stores with leaders rated high (low) in extraversion achieved higher profits when employees were passive (proactive). Study 2 constructively replicates these findings in the laboratory: passive (proactive) groups achieved higher performance when leaders acted high (low) in extraversion. We discuss theoretical and practical implications for leadership and proactivity

Epigenetics and developmental programming of welfare and production traits in farm animals

The concept that postnatal health and development can be influenced by events that occur in utero originated from epidemiological studies in humans supported by numerous mechanistic (including epigenetic) studies in a variety of model species. Referred to as the ‘developmental origins of health and disease’ or ‘DOHaD’ hypothesis, the primary focus of large-animal studies until quite recently had been biomedical. Attention has since turned towards traits of commercial importance in farm animals. Herein we review the evidence that prenatal risk factors, including suboptimal parental nutrition, gestational stress, exposure to environmental chemicals and advanced breeding technologies, can determine traits such as postnatal growth, feed efficiency, milk yield, carcass composition, animal welfare and reproductive potential. We consider the role of epigenetic and cytoplasmic mechanisms of inheritance, and discuss implications for livestock production and future research endeavours. We conclude that although the concept is proven for several traits, issues relating to effect size, and hence commercial importance, remain. Studies have also invariably been conducted under controlled experimental conditions, frequently assessing single risk factors, thereby limiting their translational value for livestock production. We propose concerted international research efforts that consider multiple, concurrent stressors to better represent effects of contemporary animal production systems

HIV-1 capsid-cyclophilin interactions determine nuclear import pathway, integration targeting and replication efficiency.

Lentiviruses such as HIV-1 traverse nuclear pore complexes (NPC) and infect terminally differentiated non-dividing cells, but how they do this is unclear. The cytoplasmic NPC protein Nup358/RanBP2 was identified as an HIV-1 co-factor in previous studies. Here we report that HIV-1 capsid (CA) binds directly to the cyclophilin domain of Nup358/RanBP2. Fusion of the Nup358/RanBP2 cyclophilin (Cyp) domain to the tripartite motif of TRIM5 created a novel inhibitor of HIV-1 replication, consistent with an interaction in vivo. In contrast to CypA binding to HIV-1 CA, Nup358 binding is insensitive to inhibition with cyclosporine, allowing contributions from CypA and Nup358 to be distinguished. Inhibition of CypA reduced dependence on Nup358 and the nuclear basket protein Nup153, suggesting that CypA regulates the choice of the nuclear import machinery that is engaged by the virus. HIV-1 cyclophilin-binding mutants CA G89V and P90A favored integration in genomic regions with a higher density of transcription units and associated features than wild type virus. Integration preference of wild type virus in the presence of cyclosporine was similarly altered to regions of higher transcription density. In contrast, HIV-1 CA alterations in another patch on the capsid surface that render the virus less sensitive to Nup358 or TRN-SR2 depletion (CA N74D, N57A) resulted in integration in genomic regions sparse in transcription units. Both groups of CA mutants are impaired in replication in HeLa cells and human monocyte derived macrophages. Our findings link HIV-1 engagement of cyclophilins with both integration targeting and replication efficiency and provide insight into the conservation of viral cyclophilin recruitment

Let\u27s talk sooner rather than later: The strategic communication decisions of activist blockholders

When starting their campaigns, activist investors face the decision of when to begin communication with the management of the target firm. We document how the choice to start communication early with management, before the 13D disclosure, fits within the campaign\u27s overall strategy. Nearly a quarter of the activist campaigns in our sample begin with what we call open activism. More credible activists with lower costs of activism are more likely to engage with management early and this early engagement is related to their desire to see specific changes made at the target firm. Eventual actions taken by activists, such as a subsequent merger or proxy contest, as well as the long-run performance of the target, are also related to this initial communication decision. Together, our findings suggest that open activism is an important part of the activist\u27s underlying strategy and that market participants understand this link