Do You See What I Mean? Corticospinal Excitability During Observation of Culture-Specific Gestures

People all over the world use their hands to communicate expressively. Autonomous gestures, also known as emblems, are highly social in nature, and convey conventionalized meaning without accompanying speech. To study the neural bases of cross-cultural social communication, we used single pulse transcranial magnetic stimulation (TMS) to measure corticospinal excitability (CSE) during observation of culture-specific emblems. Foreign Nicaraguan and familiar American emblems as well as meaningless control gestures were performed by both a Euro-American and a Nicaraguan actor. Euro-American participants demonstrated higher CSE during observation of the American compared to the Nicaraguan actor. This motor resonance phenomenon may reflect ethnic and cultural ingroup familiarity effects. However, participants also demonstrated a nearly significant (p = 0.053) actor by emblem interaction whereby both Nicaraguan and American emblems performed by the American actor elicited similar CSE, whereas Nicaraguan emblems performed by the Nicaraguan actor yielded higher CSE than American emblems. The latter result cannot be interpreted simply as an effect of ethnic ingroup familiarity. Thus, a likely explanation of these findings is that motor resonance is modulated by interacting biological and cultural factors

NSC23925, Identified in a High-Throughput Cell-Based Screen, Reverses Multidrug Resistance

Multidrug resistance (MDR) is a major factor which contributes to the failure of cancer chemotherapy, and numerous efforts have been attempted to overcome MDR. To date, none of these attempts have yielded a tolerable and effective therapy to reverse MDR; thus, identification of new agents would be useful both clinically and scientifically.To identify small molecule compounds that can reverse chemoresistance, we developed a 96-well plate high-throughput cell-based screening assay in a paclitaxel resistant ovarian cancer cell line. Coincubating cells with a sublethal concentration of paclitaxel in combination with each of 2,000 small molecule compounds from the National Cancer Institute Diversity Set Library, we identified a previously uncharacterized molecule, NSC23925, that inhibits Pgp1 and reverses MDR1 (Pgp1) but does not inhibit MRP or BCRP-mediated MDR. The cytotoxic activity of NSC23925 was further evaluated using a panel of cancer cell lines expressing Pgp1, MRP, and BCRP. We found that at a concentration of >10 microM NSC23925 moderately inhibits the proliferation of both sensitive and resistant cell lines with almost equal activity, but its inhibitory effect was not altered by co-incubation with the Pgp1 inhibitor, verapamil, suggesting that NSC23925 itself is not a substrate of Pgp1. Additionally, NSC23925 increases the intracellular accumulation of Pgp1 substrates: calcein AM, Rhodamine-123, paclitaxel, mitoxantrone, and doxorubicin. Interestingly, we further observed that, although NSC23925 directly inhibits the function of Pgp1 in a dose-dependent manner without altering the total expression level of Pgp1, NSC23925 actually stimulates ATPase activity of Pgp, a phenomenon seen in other Pgp inhibitors.The ability of NSC23925 to restore sensitivity to the cytotoxic effects of chemotherapy or to prevent resistance could significantly benefit cancer patients

Adherence with isoniazid for prevention of tuberculosis among HIV-infected adults in South Africa

BACKGROUND: Tuberculosis (TB) is the most common opportunistic infection in HIV-infected adults in developing countries. Isoniazid (INH) is recommended for treatment of latent TB infection, however non-adherence is common. The purpose of this study was to apply in-house prepared isoniazid (INH) urine test strips in a clinical setting, and identify predictors of positive test results in an adherence questionnaire in HIV-infected adults taking INH for prevention of TB. METHODS: Cross-sectional study of adherence using a questionnaire and urine test strips for detection of INH metabolites at two hospitals in Pietermaritzburg, South Africa. Participants were aged at least 18 years, HIV positive, and receiving INH for prevention of tuberculosis disease. Univariate and multivariate analyses are used to identify factors relevant to adherence. RESULTS: 301 consecutive patients were recruited. 28% of participants had negative urine tests. 32 (37.2%, 95% CI25.4, 45.0) of the 86 patients who received INH from peripheral pharmacies said the pharmacy had run out of INH at some time, compared with central hospital pharmacies (p = 0.0001). In univariate analysis, a negative test was associated with self-reported missed INH doses (p = 0.043). Each 12-hour increment since last reported dose increased the likelihood of a negative test by 34% (p = 0.0007). Belief in INH safety was associated with a positive test (p = 0.021). In multivariate analysis, patients who believed INH is important for prevention of TB disease were more likely to be negative (p = 0.0086). CONCLUSION: Adequate drug availability at peripheral pharmacies remains an important intervention for TB prevention. Key questions may identify potentially non-adherent patients. In-house prepared urine tests strips are an effective and cheap method of objectively assessing INH adherence, and could be used an important tool in TB control programs

Resistance to chemotherapy: new treatments and novel insights into an old problem

Resistance to cancer chemotherapeutic treatment is a common phenomenon, especially in progressive disease. The generation of cellular models of drug resistance has been pivotal in unravelling the main effectors of resistance to traditional chemotherapy at the molecular level (i.e. intracellular drug inactivation, detoxifying systems, defects in DNA repair, apoptosis evasion, membrane transporters and cell adhesion). The development of targeted therapies has also been followed by resistance, reminiscent of an evolutionary arms race, as exemplified by imatinib and other BCR-ABL inhibitors for the treatment of chronic myelogenous leukaemia. Although traditionally associated with the last stages of the disease, recent findings with minimally transformed pretumorigenic primary human cells indicate that the ability to generate drug resistance arises early during the tumorigenic process, before the full transformation. Novel technologies, such as genome profiling, have in certain cases predicted the outcome of chemotherapy and undoubtedly have tremendous potential for the future. In addition, the novel cancer stem cell paradigm raises the prospect of cell-targeted therapies instead of treatment directed against the whole tumour

Imidazoacridinone-dependent lysosomal photodestruction: a pharmacological Trojan horse approach to eradicate multidrug-resistant cancers

Multidrug resistance (MDR) remains a primary hindrance to curative cancer therapy. Thus, introduction of novel strategies to overcome MDR is of paramount therapeutic significance. Sequestration of chemotherapeutics in lysosomes is an established mechanism of drug resistance. Here, we show that MDR cells display a marked increase in lysosome number. We further demonstrate that imidazoacridinones (IAs), which are cytotoxic fluorochromes, undergo a dramatic compartmentalization in lysosomes because of their hydrophobic weak base nature. We hence developed a novel photoactivation-based pharmacological Trojan horse approach to target and eradicate MDR cancer cells based on photo-rupture of IA-loaded lysosomes and tumor cell lysis via formation of reactive oxygen species. Illumination of IA-loaded cells resulted in lysosomal photodestruction and restoration of parental cell drug sensitivity. Lysosomal photodestruction of MDR cells overexpressing the key MDR efflux transporters ABCG2, ABCB1 or ABCC1 resulted in 10- to 52-fold lower IC(50) values of various IAs, thereby restoring parental cell sensitivity. Finally, in vivo application of this photodynamic therapy strategy after i.v. injection of IAs in human ovarian tumor xenografts in the chorioallantoic membrane model revealed selective destruction of tumors and their associated vasculature. These findings identify lysosomal sequestration of IAs as an Achilles heel of MDR cells that can be harnessed to eradicate MDR tumor cells via lysosomal photodestruction

Empathy Manipulation Impacts Music-Induced Emotions: A Psychophysiological Study on Opera

This study investigated the effects of voluntarily empathizing with a musical performer (i.e., cognitive empathy) on music-induced emotions and their underlying physiological activity. N = 56 participants watched video-clips of two operatic compositions performed in concerts, with low or high empathy instructions. Heart rate and heart rate variability, skin conductance level (SCL), and respiration rate (RR) were measured during music listening, and music-induced emotions were quantified using the Geneva Emotional Music Scale immediately after music listening. Listening to the aria with sad content in a high empathy condition facilitated the emotion of nostalgia and decreased SCL, in comparison to the low empathy condition. Listening to the song with happy content in a high empathy condition also facilitated the emotion of power and increased RR, in comparison to the low empathy condition. To our knowledge, this study offers the first experimental evidence that cognitive empathy influences emotion psychophysiology during music listening

Continuous Quinacrine Treatment Results in the Formation of Drug-Resistant Prions

Quinacrine is a potent antiprion compound in cell culture models of prion disease but has failed to show efficacy in animal bioassays and human clinical trials. Previous studies demonstrated that quinacrine inefficiently penetrates the blood-brain barrier (BBB), which could contribute to its lack of efficacy in vivo. As quinacrine is known to be a substrate for P-glycoprotein multi-drug resistance (MDR) transporters, we circumvented its poor BBB permeability by utilizing MDR0/0 mice that are deficient in mdr1a and mdr1b genes. Mice treated with 40 mg/kg/day of quinacrine accumulated up to 100 µM of quinacrine in their brains without acute toxicity. PrPSc levels in the brains of prion-inoculated MDR0/0 mice diminished upon the initiation of quinacrine treatment. However, this reduction was transient and PrPSc levels recovered despite the continuous administration of quinacrine. Treatment with quinacrine did not prolong the survival times of prion-inoculated, wild-type or MDR0/0 mice compared to untreated mice. A similar phenomenon was observed in cultured differentiated prion-infected neuroblastoma cells: PrPSc levels initially decreased after quinacrine treatment then rapidly recovered after 3 d of continuous treatment. Biochemical characterization of PrPSc that persisted in the brains of quinacrine-treated mice had a lower conformational stability and different immunoaffinities compared to that found in the brains of untreated controls. These physical properties were not maintained upon passage in MDR0/0 mice. From these data, we propose that quinacrine eliminates a specific subset of PrPSc conformers, resulting in the survival of drug-resistant prion conformations. Transient accumulation of this drug-resistant prion population provides a possible explanation for the lack of in vivo efficacy of quinacrine and other antiprion drugs

Follow My Eyes: The Gaze of Politicians Reflexively Captures the Gaze of Ingroup Voters

Studies in human and non-human primates indicate that basic socio-cognitive operations are inherently linked to the power of gaze in capturing reflexively the attention of an observer. Although monkey studies indicate that the automatic tendency to follow the gaze of a conspecific is modulated by the leader-follower social status, evidence for such effects in humans is meager. Here, we used a gaze following paradigm where the directional gaze of right- or left-wing Italian political characters could influence the oculomotor behavior of ingroup or outgroup voters. We show that the gaze of Berlusconi, the right-wing leader currently dominating the Italian political landscape, potentiates and inhibits gaze following behavior in ingroup and outgroup voters, respectively. Importantly, the higher the perceived similarity in personality traits between voters and Berlusconi, the stronger the gaze interference effect. Thus, higher-order social variables such as political leadership and affiliation prepotently affect reflexive shifts of attention