Bryostatin Modulates Latent HIV-1 Infection via PKC and AMPK Signaling but Inhibits Acute Infection in a Receptor Independent Manner

HIV's ability to establish long-lived latent infection is mainly due to transcriptional silencing in resting memory T lymphocytes and other non dividing cells including monocytes. Despite an undetectable viral load in patients treated with potent antiretrovirals, current therapy is unable to purge the virus from these latent reservoirs. In order to broaden the inhibitory range and effectiveness of current antiretrovirals, the potential of bryostatin was investigated as an HIV inhibitor and latent activator. Bryostatin revealed antiviral activity against R5- and X4-tropic viruses in receptor independent and partly via transient decrease in CD4/CXCR4 expression. Further, bryostatin at low nanomolar concentrations robustly reactivated latent viral infection in monocytic and lymphocytic cells via activation of Protein Kinase C (PKC) -α and -δ, because PKC inhibitors rottlerin and GF109203X abrogated the bryostatin effect. Bryostatin specifically modulated novel PKC (nPKC) involving stress induced AMP Kinase (AMPK) inasmuch as an inhibitor of AMPK, compound C partially ablated the viral reactivation effect. Above all, bryostatin was non-toxic in vitro and was unable to provoke T-cell activation. The dual role of bryostatin on HIV life cycle may be a beneficial adjunct to the treatment of HIV especially by purging latent virus from different cellular reservoirs such as brain and lymphoid organs

An early history of T cell-mediated cytotoxicity.

After 60 years of intense fundamental research into T cell-mediated cytotoxicity, we have gained a detailed knowledge of the cells involved, specific recognition mechanisms and post-recognition perforin-granzyme-based and FAS-based molecular mechanisms. What could not be anticipated at the outset was how discovery of the mechanisms regulating the activation and function of cytotoxic T cells would lead to new developments in cancer immunotherapy. Given the profound recent interest in therapeutic manipulation of cytotoxic T cell responses, it is an opportune time to look back on the early history of the field. This Timeline describes how the early findings occurred and eventually led to current therapeutic applications

Cross-Cultural Sexism and the Effectiveness of Gender (Non)Traditional Advertising: A Comparison of Purchase Intentions in Poland, South Africa, and the United Kingdom.

Findings regarding the effectiveness of (non)traditionally gendered advertisements are mixed and largely emanate from the United States. We tested the stereotype content model and ambivalent sexism theory cross-nationally in an advertising context and predicted that paternalistic (vs. envious) female stereotypes will trigger higher purchase intent (PI) irrespective of country (Hypothesis 1), viewers’ benevolent sexism will positively predict PI for paternalistic housewife advertisements (Hypothesis 2a), viewers’ hostile sexism will negatively predict PI for envious businesswoman advertisements (Hypothesis 2b), and these relationships with sexism will be confined to less gender egalitarian countries (i.e., Poland and South Africa) (Hypothesis 3). Statistical analyses of data from 468 Polish, South African, and British university students supported Hypothesis 1 and partially supported Hypotheses 2 and 3. The predicted patterns held for South Africa, but in Poland, viewers’ benevolence positively predicted PI for both advertisement types, with the exception of highly hostile women. British viewers’ hostility positively predicted PI for the housewife advertisement. Our findings support the cross-cultural applicability of the stereotype content model to advertising and suggest that the predictive role of sexism changes depending on its type, advertisement type, country, and gender. We recommend that advertisers should adopt a nuanced approach in predicting the effectiveness of gendered advertisements

Rewarding effects of opiates are absent in mice lacking the receptor for substance P

Modulation of substance P activity offers a radical new approach to the management of depression, anxiety and stress(1-3). The substance P receptor is highly expressed in areas of the brain that are implicated in these behaviours, but also in other areas such as the nucleus accumbens which mediate the motivational properties of both natural rewards such as food and of drugs of abuse such as opiates(4-7). Here we show a loss of the rewarding properties of morphine in mice with a genetic disruption of the substance P receptor. The loss was specific to morphine, as both groups of mice responded when cocaine or food were used as rewards. The physical response to opiate withdrawal was also reduced in substance P receptor knockout mice. We conclude that substance P has an important and specific role in mediating the motivational aspects of opiates and may represent a new pharmacological route for the control of drug abuse