Calmodulin-Dependent Regulation of Overexpressed but Not Endogenous TMEM16A Expressed in Airway Epithelial Cells

Regulation of the Ca2+-activated Cl− channel TMEM16A by Ca2+/calmodulin (CAM) is discussed controversially. In the present study, we compared regulation of TMEM16A by Ca2+/calmodulin (holo-CAM), CAM-dependent kinase (CAMKII), and CAM-dependent phosphatase calcineurin in TMEM16A-overexpressing HEK293 cells and TMEM16A expressed endogenously in airway and colonic epithelial cells. The activator of the Ca2+/CAM-regulated K+ channel KCNN4, 1-EBIO, activated TMEM16A in overexpressing cells, but not in cells with endogenous expression of TMEM16A. Evidence is provided that CAM-interaction with TMEM16A modulates the Ca2+ sensitivity of the Cl− channel. Enhanced Ca2+ sensitivity of overexpressed TMEM16A explains its activity at basal (non-elevated) intracellular Ca2+ levels. The present results correspond well to a recent report that demonstrates a Ca2+-unbound form of CAM (apo-CAM) that is pre-associated with TMEM16A and mediates a Ca2+-dependent sensitization of activation (and inactivation). However, when using activators or inhibitors for holo-CAM, CAMKII, or calcineurin, we were unable to detect a significant impact of CAM, and limit evidence for regulation by CAM-dependent regulatory proteins on receptor-mediated activation of endogenous TMEM16A in airway or colonic epithelial cells. We propose that regulatory properties of TMEM16A and and other members of the TMEM16 family as detected in overexpression studies, should be validated for endogenous TMEM16A and physiological stimuli such as activation of phospholipase C (PLC)-coupled receptors.

Hydration breaking and chemical ordering in a levitated NaCl solution droplet beyond the metastable zone width limit: evidence for the early stage of two-step nucleation

This work provides evidence for two-step nucleation in highly supersaturated bulk NaCl solution, using electrostatic levitation combined with Raman/X-ray scatterings.

Belief in God by Intuitive knowledge

The epistemological approach of evidentialism maintains that a belief must have sufficient evidence in order to be rationally justified. The belief in God is no exception and, hence, it too must pass the litmus test of evidence as a measure of its rational justification. But what counts as evidence? Responding to this question and identifying the nature of the evidence that can be used to justify belief has become a point of contention between philosophers. While some evidentialists have denied the possibility of evidence for the belief in God, others have attacked the very basis of the evidentialist claim by promoting belief in God without evidence. The following paper briefly describes these two currents and culminates by discussing the notion of innate concepts and presential knowledge as proposed by Mulla Sadra. According to the authors, this type of presential knowledge can be included as “evidence” even from the evidentialist point of view which does not limit evidence to conceptual knowledge.

Postglacial emergence in the Canadian High Arctic: integrating glacioisostasy, eustasy, and late deglaciation

Throughout the last glaciation, the Innuitian Sea, rather than glaciers, occupied many fiords and channels of the Queen Elizabeth Islands. Two alternative hypotheses, which constitute end members, are presented to account for the transgression of the Innuitian Sea between 18 and 8.8 ka, at which time it reached marine limit. Hypothesis A proposes that the last ice load was fully established by 18 ka and that it remained stable while sea level rose eustatically from approximately 60 m asl to marine limit by 8.8 ka. Hypothesis B proposes an advance of glaciers from present-day positions after 14 ka, when increased precipitation allowed rapid glacial loading to accompany the eustatic sea-level rise. By the early Holocene (when glaciers stood at the last ice limit) evidence suggests maximum warming and a shift to a negative mass balance.It is now recognized that the stable relative sea level at marine limit must record the balance between the rate of eustatic rise and the rate of uplift due to glacial unloading (thinning) between 8.8 and 7.8 ka. The rate of glacial unloading during this interval was low, approximately 1 m/100 years. Although the sea first penetrated inside the last ice limit by 8 ka, the first observed emergence was delayed until after 7.8 ka. By 7.6 ka many of the largest outlet glaciers from the Agassiz Ice Cap had retreated to positions equivalent to, or upvalley from, present-day margins. Nonetheless, between 7.8 and 7.2 ka, emergence progressed slowly (2 m/100 years), indicating that the large outlet glaciers retreated by calving, causing little change in the ice load. After 7.2 ka emergence was rapid, indicating that the regional glacial unloading was also rapid.It is proposed that the late deglaciation (Holocene) of the High Arctic favoured substantial postglacial emergence because the countering effect of the eustatic rise was largely completed by this time. Isobases drawn on the limit of the Innuitian Sea (the 8 ka shoreline) show a plunging ridge aligned with the south shore of Greely Fiord. It parallels the structural trends, suggesting the possibility of a tectonic component to the postglacial uplift.It is apparent that the style of ice advance and retreat in the High Arctic was controlled by several factors in addition to climatic change. These factors include topography, glacier dynamics, fiord bathymetry, sea-ice stability, and eustatic sea level.