Sexual Dimorphism and Estrogen Regulation of KCNE3 Expression Modulates the Functional Properties of KCNQ1 K+ Channels

The KCNQ1 potassium channel associates with various KCNE ancillary subunits that drastically affect channel gating and pharmacology. Co-assembly with KCNE3 produces a current with nearly instantaneous activation, some time-dependent activation at very positive potentials, a linear current voltage relationship and a 10-fold higher sensitivity to chromanol 293B. KCNQ1:KCNE3 channels are expressed in colonic crypts and mediate basolateral K+ recycling required for Cl- secretion. We have previously reported the female-specific anti-secretory effects of estrogen via KCNQ1:KCNE3 channel inhibition in colonic crypts. This study was designed to determine whether gender and estrogen regulate the expression and function of KCNQ1 and KCNE3 in rat distal colon. Colonic crypts were isolated from Sprague-Dawley rats and used for whole-cell patch-clamp and to extract total RNA and protein. Sheets of epithelium were used for short-circuit current recordings. KCNE1 and KCNE3 mRNA and protein abundance was significantly higher in male than female crypts. No expression of KCNE2 was found and no difference was observed in KCNQ1 expression between male and female (at estrous) colonic crypts. Male crypts showed a 2.2-fold higher level of association of KCNQ1 and KCNE3 compared to female cells. In female colonic crypts, KCNQ1 and KCNE3 protein expression fluctuated throughout the estrous cycle and 17-estradiol (E2 10 nM) produced a rapid (\u3c15\u3emin) dissociation of KCNQ1 and KCNE3 in female crypts only. Whole-cell K+ currents showed a linear current-voltage relationship in male crypts, while K+ currents in colonic crypts isolated from females displayed voltage-dependent outward rectification. Currents in isolated male crypts and epithelial sheets were 10-fold more sensitive to specific KCNQ1 inhibitors, such as chromanol 293B and HMR-1556, than in female. The effect of E2 on K+ currents mediated by KCNQ1 with or without different -subunits was assayed from current-voltage relations elicited in CHO cells transfected with KCNQ1 and KCNE3 or KCNE1 cDNA. E2 (100 nM) reduced the currents mediated by the KCNQ1:KCNE3 potassium channel and had no effect on currents via KCNQ1:KCNE1 or KCNQ1 alone. Currents mediated by the complex formed by KCNQ1 and the mutant KCNE3-S82A β-subunit showed rapid run-down and insensitivity to E2. Together, these data suggest that estrogen regulates the expression of the KCNE1 and KCNE3 and with it the gating and pharmacological properties of the K+ conductance required for Cl- secretion. The decreased association of the KCNQ1:KCNE3 channel complex promoted by estrogen exposure underlies the molecular mechanism for the sexual dimorphism and estrous cycle dependence of the anti-secretory actions of estrogen in the intestine

Emotional ratings and skin conductance response to visual, auditory and haptic stimuli

The human emotional reactions to stimuli delivered by different sensory modalities is a topic of interest for many disciplines, from Human-Computer-Interaction to cognitive sciences. Different databases of stimuli eliciting emotional reaction are available, tested on a high number of participants. Interestingly, stimuli within one database are always of the same type. In other words, to date, no data was obtained and compared from distinct types of emotion-eliciting stimuli from the same participant. This makes it difficult to use different databases within the same experiment, limiting the complexity of experiments investigating emotional reactions. Moreover, whereas the stimuli and the participants’ rating to the stimuli are available, physiological reactions of participants to the emotional stimuli are often recorded but not shared. Here, we test stimuli delivered either through a visual, auditory, or haptic modality in a within participant experimental design. We provide the results of our study in the form of a MATLAB structure including basic demographics on the participants, the participant’s self-assessment of his/her emotional state, and his/her physiological reactions (i.e., skin conductance)

Treatment of Hepatitis C as Prevention: A Modeling Case Study in Vietnam

Background: Treatment of hepatitis C (HCV) is very effective, achieving a cure in 50–90 % of patients. Besides its own good for individuals, this most likely translates in reduced transmission, but this phenomenon has yet to be fully explored. Methods and Findings: In this mathematical modeling study done in the context of Vietnam, we estimated the public health benefit that HCV therapy for injecting drug users (IDUs) may achieve. Treatment coverage of 25, 50 and 75 % of chronically HCV-infected IDUs (4 years into infection) is predicted to reduce the chronic HCV viremia prevalence respectively by 21, 37 and 50%, 11 years after full scale up to the intended coverage. At a constant 50 % coverage level, earlier treatment, 3, 2, and 1 year into infection is predicted to reduce the chronic HCV viremia prevalence by 46, 60 and 85%. In these later 3 scenarios, for every 100 treatment courses provided, a total of respectively 50, 61 and 94 new infections could be averted. These benefits were projected in the context of current low coverage of methadone maintenance therapy and needles/ syringes exchange programs, and these services expansion showed complementary preventive benefits to HCV therapy. The program treatment commitment associated with the various scenarios is deemed reasonable. Our model projections are robust under adjustment for uncertainty in the model parameter values. Conclusions: In this case study in Vietnam, we project that treatment of HCV for injecting drug users will have a preventative herd effect in addition to curing patients in need for therapy, achieving a substantial reduction in HCV transmission an

Profaning the sacred in leadership studies: A reading of Murakami's A Wild Sheep Chase

The leadership literature is full of stories of heroic self-sacrifice. Sacrificial leadership behaviour, some scholars conclude, is to be recommended. In this article we follow Keith Grint's conceptualization of leadership as necessarily pertaining to the sacred, but-drawing on Giorgio Agamben's notion of profanation-we highlight the need for organization scholars to profane the sacralizations embedded in leadership thinking. One example of this, which guides us throughout the article, is the novel A Wild Sheep Chase, by the Japanese author Haruki Murakami. By means of a thematic reading of the novel, we discuss how it contributes to profaning particular notions of sacrifice and the sacred in leadership thinking. In the novel, self-sacrifice does not function as a way of establishing a leadership position, but as a way to avoid the dangers associated with leadership, and possibly redeem humans from their current collective urge to become leaders. Inspired by Murakami's fictional example, we call organization scholars to engage in profanation of leadership studies and, in doing so, open new vistas for leadership theory and practice. © The Author(s) 2012