K+-Induced Smooth Muscle Calcium Sensitization Requires RhoA Kinase (ROK) Translocation to Caveolae Which Is Inhibited in Non-Neuronal Cell Memory

KC1 causes smooth muscle contraction by elevating intracellular free calcium ([Ca2+]i), while receptor stimulation activates an additional mechanism termed Ca2+- sensitization that can involve activation of ROK and PKC. However, recent studies support the hypothesis that KC1 may also increase Ca2+-sensitivity (36). Our data showed that the PKC inhibitor, GF-109203X, did not, while the ROK inhibitor, Y-27632, did inhibit KCl-induced tonic (5’) force and myosin light chain (MLC) phosphorylation in rabbit artery. Y-27632 also inhibited Bay K-8644- and ionomycin-induced MLC phosphorylation and force, but did not inhibit KCl-induced calcium entry or peak (~15”) force. Moreover, KC1 and Bay K-8644 nearly doubled the amount o f ROK colocalized to caveolae at 30”, a time that preceded inhibition of force by Y-27632. Colocalization was not inhibited by Y-27632, but was abolished by nifedipine and the calmodulin blocker, trifluoperazine. Since, -30% of RhoA is colocalized with caveolin basally, these data suggest a novel model for Ca2+-activated Ca2+-sensitization, elicited by KC1 contraction, that involves Ca2+/cam dependent ROK translocation to caveolae and activation by RhoA

Direct Activation of TRPC3 Channels by the Antimalarial Agent Artemisinin

(1) Background: Members of the TRPC3/TRPC6/TRPC7 subfamily of canonical transient receptor potential (TRP) channels share an amino acid similarity of more than 80% and can form heteromeric channel complexes. They are directly gated by diacylglycerols in a protein kinase C-independent manner. To assess TRPC3 channel functions without concomitant protein kinase C activation, direct activators are highly desirable. (2) Methods: By screening 2000 bioactive compounds in a Ca2+ influx assay, we identified artemisinin as a TRPC3 activator. Validation and characterization of the hit was performed by applying fluorometric Ca2+ influx assays and electrophysiological patch-clamp experiments in heterologously or endogenously TRPC3-expressing cells. (3) Results: Artemisinin elicited Ca2+ entry through TRPC3 or heteromeric TRPC3:TRPC6 channels, but did not or only weakly activated TRPC6 and TRPC7. Electrophysiological recordings confirmed the reversible and repeatable TRPC3 activation by artemisinin that was inhibited by established TRPC3 channel blockers. Rectification properties and reversal potentials were similar to those observed after stimulation with a diacylglycerol mimic, indicating that artemisinin induces a similar active state as the physiological activator. In rat pheochromocytoma PC12 cells that endogenously express TRPC3, artemisinin induced a Ca2+ influx and TRPC3-like currents. (4) Conclusions: Our findings identify artemisinin as a new biologically active entity to activate recombinant or native TRPC3-bearing channel complexes in a membrane-confined fashion

The relaxed investor with partial information

We consider an investor in a financial market consisting of a riskless bond and several risky assets. The price processes of the risky assets are geometric Brownian motions where either the drifts are modelled as random variables assuming a constant volatility matrix or the volatility matrix is considered random and drifts are assumed to be constant. The investor is only able to observe the asset prices but not all the model parameters and hence information is only partial. A Bayesian approach is used with known prior distributions for the random model parameters. We assume that the investor can only trade at discrete time points which are multiples of h > 0 and investigate the loss in expected utility of terminal wealth which is due to the fact that the investor cannot trade and observe continuously. It turns out that in general a discretization gap appears, i.e., for h ! 0 the expected utility of the h-investor does not converge to the expected utility of the continuous investor. This is in contrast to results under full information in (Rogers, L.C.G. 2001. The relaxed investor and parameter uncertainty. Finance and Stochastics, 5(2), 131-154). We also present simple asymptotically optimal portfolio strategies for the discrete-time problem. Our results are illustrated by some numerical examples

Wearable Assistive Communication Device

The purpose of this project was to develop a portable and customizable device that encouraged communication through affordable technologies. The device was designed to fill a well-defined need for affordable technologies that enhance multifaceted therapeutic and assistive healthcare services. The device was created to operate without sound which increases the accessibility of assistive and rehabilitative technologies, specifically for deaf, hearing impaired, and sound-averse individuals, including many on the Autism spectrum. In the design process, we focused on the development of the devices fabric housing and touch areas utilizing smart textiles and conductive thread. Smart textiles, such as touch capacitive fabrics, are fabrics woven with materials that alter an electrical signal in a measurable way if the textile is touched, stretched, etc. For this particular communication device, the user touches a specific button made of touch capacitive fabric, and a particular word/phrase is displayed on the connected screen. The device has 8 tactile buttons going down the back all programmed to display different words and phrases. Throughout this process we were able to work with different kinds of touch capacitive fabrics, conductive thread, while working towards the end goal of a fully functioning device. The device facilitates non-auditory communication for hearing impaired or nonverbal individuals who are sound averse, while utilizing inclusive fabrics. It was also designed with removable electronic components from the fabric casing in order to allow for cleaning and customization for the patient

Material World: The Effects of Meditation Content on Materialistic Values

In the twenty-first century, Western cultures are highly materialistic and defined by consumeristic goals to garner as much “stuff” as possible (Berger, 2015). This constant pursuit has demonstrable adverse effects on personal and social well being (Bahl et al., 2016; Wang, et al., 2017), while overconsumption also has devastating impacts on the global environment. Previous studies found a negative relationship between levels of mindfulness and levels of materialism (Nagpaul & Pang, 2015; Watson, 2019), indicating the potential for mindfulness to combat otherwise materialistic behaviors. Furthermore, previous research demonstrated gratitude interventions led to lower scores on materialism (Chaplin, et al., 2018), indicating the significance of meditation content on one’s materialistic values. Following literature that meditation increased a person’s suggestibility (Gloede, et al., 2021), experiencing a ‘material abundance’ meditation may promote increased materialistic values. The purpose of this study was to explore the relationship between mindfulness meditation content and materialistic values through an experimental manipulation. We hypothesized participants who experienced a ‘material abundance’ meditation would show the highest materialistic values, followed by those who experienced a ‘body scan’ meditation, and lastly, those who experienced a ‘gratitude’ meditation would show the lowest materialistic values

Pharmacological inhibition of TRPV2 attenuates phagocytosis and lipopolysaccharide‐induced migration of primary macrophages

Background and Purpose: In macrophages, transient receptor potential vanilloid 2 (TRPV2) channel contributes to various cellular processes such as cytokine production, differentiation, phagocytosis and migration. Due to a lack of selective pharmacological tools, its function in immunological processes is not well understood and the identification of novel and selective TRPV2 modulators is highly desirable. Experimental Approach: Novel and selective TRPV2 modulators were identified by screening a compound library using Ca2+ influx assays with human embryonic kidney 293 (HEK293) cells heterologously expressing rat TRPV2. Hits were further characterized and validated with Ca2+ influx and electrophysiological assays. Phagocytosis and migration of macrophages were analysed and the contribution of TRPV2 to the generation of Ca2+ microdomains was studied by total internal reflection fluorescence microscopy (TIRFM). Key Results: The compound IV2-1, a dithiolane derivative (1,3-dithiolan-2-ylidene)-4-methyl-5-phenylpentan-2-one), is a potent inhibitor of heterologously expressed TRPV2 channels (IC50 = 6.3 ± 0.7 μM) but does not modify TRPV1, TRPV3 or TRPV4 channels. IV2-1 also inhibits TRPV2-mediated Ca2+ influx in macrophages. IV2-1 inhibits macrophage phagocytosis along with valdecoxib and after siRNA-mediated knockdown. Moreover, TRPV2 inhibition inhibits lipopolysaccharide-induced migration of macrophages whereas TRPV2 activation promotes migration. After activation, TRPV2 shapes Ca2+ microdomains predominantly at the margin of macrophages, which are important cellular regions to promote phagocytosis and migration. Conclusions and Implications: IV2-1 is a novel TRPV2-selective blocker and underline the role of TRPV2 in macrophage-mediated phagocytosis and migration. Furthermore, we provide evidence that TRPV2 activation generates Ca2+ microdomains, which may be involved in phagocytosis and migration of macrophages

Secondary BRCA1 Mutations in BRCA1-Mutated Ovarian carcinomas with platinum resistance.

Although ovarian carcinomas with mutated BRCA1 or BRCA2 are sensitive to platinum compounds, such carcinomas eventually develop platinum resistance. Previously, we showed that acquired resistance to cisplatin in BRCA2-mutated tumors can be mediated by secondary intragenic mutations in BRCA2 that restore the wild-type BRCA2 reading frame. Here, we show that secondary mutations of BRCA1 also occur in BRCA1-mutated ovarian cancer with platinum resistance. We evaluated nine recurrent BRCA1-mutated ovarian cancers previously treated with platinum compounds, including five with acquired platinum resistance, one with primary platinum resistance, and three with platinum sensitivity. Four of the six recurrent platinum-resistant tumors had developed secondary genetic changes in BRCA1 that restored the reading frame of the BRCA1 protein, whereas none of the three platinum-sensitive recurrent tumors developed BRCA1 sequence alterations. We immunohistochemically confirmed restored expression of BRCA1 protein in two cases with secondary mutations. Intriguingly, the case with primary platinum resistance showed back mutation of BRCA1 in the primary tumor and showed another secondary mutation in the recurrent tumor. Our results suggest that secondary mutations in BRCA1 can mediate resistance to platinum in BRCA1-mutated ovarian tumors