Metacognitive Performance, the Tip-of-Tongue Experience, Is Not Disrupted in Parkinsonian Patients

The present study investigated whether a form of metamemory, the tip-of-tongue phenomenon (TOT), was affected in patients with Parkinson's disease (PD). The PD patient (n = 22), age-matched elderly control (n = 22), and college student control (n = 46) groups were compared on a motor timing task and TOT measures. Motor timing was assessed using a cued hand-clapping task, whereas TOT was assessed using general knowledge questions. The results indicated that motor timing was significantly impaired in the PD group relative to both control groups. However, all of the TOT metacognitive measures: frequency, strength, and accuracy were statistically equivalent between the PD patients and elderly control groups, both of whom showed significantly better memory performance than college controls. These findings demonstrate that TOT metamemory is not compromised in PD patients, and that further insight into TOT mechanisms in PD may prove helpful in developing novel intervention strategies to enhance memory and general cognitive functions in these patients

Development of selective blockers for Ca2+-activated Cl- channel using Xenopus laevis oocytes with an improved drug screening strategy

<p>Abstract</p> <p>Background</p> <p>Ca²⁺-activated Cl^-channels (CaCCs) participate in many important physiological processes. However, the lack of effective and selective blockers has hindered the study of these channels, mostly due to the lack of good assay system. Here, we have developed a reliable drug screening method for better blockers of CaCCs, using the endogeneous CaCCs in <it>Xenopus laevis </it>oocytes and two-electrode voltage-clamp (TEVC) technique.</p> <p>Results</p> <p>Oocytes were prepared with a treatment of Ca²⁺ionophore, which was followed by a treatment of thapsigargin which depletes Ca²⁺stores to eliminate any contribution of Ca²⁺release. TEVC was performed with micropipette containing chelerythrine to prevent PKC dependent run-up or run-down. Under these conditions, Ca²⁺-activated Cl^-currents induced by bath application of Ca²⁺to oocytes showed stable peak amplitude when repetitively activated, allowing us to test several concentrations of a test compound from one oocyte. Inhibitory activities of commercially available blockers and synthesized anthranilic acid derivatives were tested using this method. As a result, newly synthesized <it>N</it>-(4-trifluoromethylphenyl)anthranilic acid with trifluoromethyl group (-CF₃) at <it>para </it>position on the benzene ring showed the lowest IC₅₀.</p> <p>Conclusion</p> <p>Our results provide an optimal drug screening strategy suitable for high throughput screening, and propose <it>N</it>-(4-trifluoromethylphenyl)anthranilic acid as an improved CaCC blocker.</p

Isolation and Expression Profile of the Ca2+-Activated Chloride Channel-like Membrane Protein 6 Gene in Xenopus laevis

To clone the first anion channel from Xenopus laevis (X. laevis), we isolated a calcium-activated chloride channel (CLCA)-like membrane protein 6 gene (CMP6) in X. laevis. As a first step in gene isolation, an expressed sequence tags database was screened to find the partial cDNA fragment. A putative partial cDNA sequence was obtained by comparison with rat CLCAs identified in our laboratory. First stranded cDNA was synthesized by reverse transcription polymerase-chain reaction (RT-PCR) using a specific primer designed for the target cDNA. Repeating the 5' and 3' rapid amplification of cDNA ends, full-length cDNA was constructed from the cDNA pool. The full-length CMP6 cDNA completed via 5'- and 3'-RACE was 2,940 bp long and had an open reading frame (ORF) of 940 amino acids. The predicted 940 polypeptides have four major transmembrane domains and showed about 50% identity with that of rat brain CLCAs in our previously published data. Semi-quantification analysis revealed that CMP6 was most abundantly expressed in small intestine, colon and liver. However, all tissues except small intestine, colon and liver had undetectable levels. This result became more credible after we did real-time PCR quantification for the target gene. In view of all CLCA studies focused on human or murine channels, this finding suggests a hypothetical protein as an ion channel, an X. laevis CLCA

Direct activation of Transient Receptor Potential Vanilloid 1(TRPV1) by Diacylglycerol (DAG)

The capsaicin receptor, known as transient receptor potential channel vanilloid subtype 1 (TRPV1), is activated by a wide range of noxious stimulants and putative ligands such as capsaicin, heat, pH, anandamide, and phosphorylation by protein kinase C (PKC). However, the identity of endogenous activators for TRPV1 under physiological condition is still debated. Here, we report that diacylglycerol (DAG) directly activates TRPV1 channel in a membrane-delimited manner in rat dorsal root ganglion (DRG) neurons. 1-oleoyl-2-acetyl-sn-glycerol (OAG), a membrane-permeable DAG analog, elicited intracellular Ca2+ transients, cationic currents and cobalt uptake that were blocked by TRPV1-selective antagonists, but not by inhibitors of PKC and DAG lipase in rat DRG neurons or HEK 293 cells heterologously expressing TRPV1. OAG induced responses were about one fifth of capsaicin induced signals, suggesting that OAG displays partial agonism. We also found that endogenously produced DAG can activate rat TRPV1 channels. Mutagenesis of rat TRPV1 revealed that DAG-binding site is at Y511, the same site for capsaicin binding, and PtdIns(4,5)P2binding site may not be critical for the activation of rat TRPV1 by DAG in heterologous system. We propose that DAG serves as an endogenous ligand for rat TRPV1, acting as an integrator of Gq/11-coupled receptors and receptor tyrosine kinases that are linked to phospholipase C

The Relationship between the Level of Fatness and Fitness during Adolescence and the Risk Factors of Metabolic Disorders in Adulthood

BACKGROUND: The purpose of the current study was to investigate the association between the level of obesity and physical fitness (PF) during adolescence and the risk factors of metabolic disorders during adulthood. METHODS: In the current analysis, 3,993 Korean adults (mean age, 38.70 +/- 1.69 years) were recruited. The level of body index (BI) and PF were examined during adolescence through high school record, and their health examination data, including systolic blood pressure (SBP), diastolic blood pressure (DBP), fasting glucose (FG), total cholesterol (TC), and current body mass index (BMI) were obtained from National Health Insurance Corporation Data. Gender-specific analyses were administered to compare health exam data across the level of BI, the level of PF, and a mixed level of BI and PF. RESULTS: Most obese males during high school had statistically higher SBP, DBP, FG, and BMI in adulthood, and most obese females had higher BMI, as compared to most lean males or females. Least fit males during high school had statistically higher BMI in adulthood, and least fit females had statistically higher SBP, DBP, FG, TC, and BMI, as compared to most fit males or females. There was a significant relationship between the mixed level of BI and PF and SBP, DBP, TC and current BMI in both genders. CONCLUSION: Maintaining a healthy level of body weight and PF during adolescence is recommended to prevent the development of metabolic diseases in adulthood.ope

Experimental compressive phase space tomography

Phase space tomography estimates correlation functions entirely from snapshots in the evolution of the wave function along a time or space variable. In contrast, traditional interferometric methods require measurement of multiple two-point correlations. However, as in every tomographic formulation, undersampling poses a severe limitation. Here we present the first, to our knowledge, experimental demonstration of compressive reconstruction of the classical optical correlation function, i.e. the mutual intensity function. Our compressive algorithm makes explicit use of the physically justifiable assumption of a low-entropy source (or state.) Since the source was directly accessible in our classical experiment, we were able to compare the compressive estimate of the mutual intensity to an independent ground-truth estimate from the van Cittert-Zernike theorem and verify substantial quantitative improvements in the reconstruction

Model-observation and reanalyses comparison at key locations for heat transport to the Arctic: Assessment of key lower latitude influences on the Arctic and their simulation

Blue-Action Work Package 2 (WP2) focuses on lower latitude drivers of Arctic change, with a focus on the influence of the Atlantic Ocean and atmosphere on the Arctic. In particular, warm water travels from the Atlantic, across the Greenland-Scotland ridge, through the Norwegian Sea towards the Arctic. A large proportion of the heat transported northwards by the ocean is released to the atmosphere and carried eastward towards Europe by the prevailing westerly winds. This is an important contribution to northwestern Europe's mild climate. The remaining heat travels north into the Arctic. Variations in the amount of heat transported into the Arctic will influence the long term climate of the Northern Hemisphere. Here we assess how well the state of the art coupled climate models estimate this northwards transport of heat in the ocean, and how the atmospheric heat transport varies with changes in the ocean heat transport. We seek to improve the ocean monitoring systems that are in place by introducing measurements from ocean gliders, Argo floats and satellites. These state of the art computer simulations are evaluated by comparison with key trans-Atlantic observations. In addition to the coupled models ‘ocean-only’ evaluations are made. In general the coupled model simulations have too much heat going into the Arctic region and the transports have too much variability. The models generally reproduce the variability of the Atlantic Meridional Ocean Circulation (AMOC) well. All models in this study have a too strong southwards transport of freshwater at 26°N in the North Atlantic, but the divergence between 26°N and Bering Straits is generally reproduced really well in all the models. Altimetry from satellites have been used to reconstruct the ocean circulation 26°N in the Atlantic, over the Greenland Scotland Ridge and alongside ship based observations along the GO-SHIP OVIDE Section. Although it is still a challenge to estimate the ocean circulation at 26°N without using the RAPID 26°N array, satellites can be used to reconstruct the longer term ocean signal. The OSNAP project measures the oceanic transport of heat across a section which stretches from Canada to the UK, via Greenland. The project has used ocean gliders to great success to measure the transport on the eastern side of the array. Every 10 days up to 4000 Argo floats measure temperature and salinity in the top 2000m of the ocean, away from ocean boundaries, and report back the measurements via satellite. These data are employed at 26°N in the Atlantic to enable the calculation of the heat and freshwater transports. As explained above, both ocean and atmosphere carry vast amounts of heat poleward in the Atlantic. In the long term average the Atlantic ocean releases large amounts of heat to the atmosphere between the subtropical and subpolar regions, heat which is then carried by the atmosphere to western Europe and the Arctic. On shorter timescales, interannual to decadal, the amounts of heat carried by ocean and atmosphere vary considerably. An important question is whether the total amount of heat transported, atmosphere plus ocean, remains roughly constant, whether significant amounts of heat are gained or lost from space and how the relative amount transported by the atmosphere and ocean change with time. This is an important distinction because the same amount of anomalous heat transport will have very different effects depending on whether it is transported by ocean or the atmosphere. For example the effects on Arctic sea ice will depend very much on whether the surface of the ice experiences anomalous warming by the atmosphere versus the base of the ice experiencing anomalous warming from the ocean. In Blue-Action we investigated the relationship between atmospheric and oceanic heat transports at key locations corresponding to the positions of observational arrays (RAPID at 26°N, OSNAP at ~55N, and the Denmark Strait, Iceland-Scotland Ridge and Davis Strait at ~67N) in a number of cutting edge high resolution coupled ocean-atmosphere simulations. We split the analysis into two different timescales, interannual to decadal (1-10 years) and multidecadal (greater than 10 years). In the 1-10 year case, the relationship between ocean and atmosphere transports is complex, but a robust result is that although there is little local correlation between oceanic and atmospheric heat transports, Correlations do occur at different latitudes. Thus increased oceanic heat transport at 26°N is accompanied by reduced heat transport at ~50N and a longitudinal shift in the location of atmospheric flow of heat into the Arctic. Conversely, on longer timescales, there appears to be a much stronger local compensation between oceanic and atmospheric heat transport i.e. Bjerknes compensation

A MicroRNA Linking Human Positive Selection and Metabolic Disorders

Postponed access: the file will be accessible after 2021-10-14Positive selection in Europeans at the 2q21.3 locus harboring the lactase gene has been attributed to selection for the ability of adults to digest milk to survive famine in ancient times. However, the 2q21.3 locus is also associated with obesity and type 2 diabetes in humans, raising the possibility that additional genetic elements in the locus may have contributed to evolutionary adaptation to famine by promoting energy storage, but which now confer susceptibility to metabolic diseases. We show here that the miR-128-1 microRNA, located at the center of the positively selected locus, represents a crucial metabolic regulator in mammals. Antisense targeting and genetic ablation of miR-128-1 in mouse metabolic disease models result in increased energy expenditure and amelioration of high-fat-diet-induced obesity and markedly improved glucose tolerance. A thrifty phenotype connected to miR-128-1-dependent energy storage may link ancient adaptation to famine and modern metabolic maladaptation associated with nutritional overabundance.acceptedVersio

Microneedles: A New Frontier in Nanomedicine Delivery

This review aims to concisely chart the development of two individual research fields, namely nanomedicines, with specific emphasis on nanoparticles (NP) and microparticles (MP), and microneedle (MN) technologies, which have, in the recent past, been exploited in combinatorial approaches for the efficient delivery of a variety of medicinal agents across the skin. This is an emerging and exciting area of pharmaceutical sciences research within the remit of transdermal drug delivery and as such will undoubtedly continue to grow with the emergence of new formulation and fabrication methodologies for particles and MN. Firstly, the fundamental aspects of skin architecture and structure are outlined, with particular reference to their influence on NP and MP penetration. Following on from this, a variety of different particles are described, as are the diverse range of MN modalities currently under development. The review concludes by highlighting some of the novel delivery systems which have been described in the literature exploiting these two approaches and directs the reader towards emerging uses for nanomedicines in combination with MN