Voltage-gated potassium channel dependent mechanisms of cardiovascular adaptation to chronic exercise.

Exercise increases cardiac workload, escalating the demand for oxygen. The myocardial vasculature responds to the greater demand for oxygen by increasing blood flow to match the needs of the heart during augmented work. Increasing blood flow requires the coronary arteries dilate (a.k.a. vasodilation); this is mediated predominantly by vascular smooth muscle cell relaxation. Vasodilation is driven through inhibition of calcium influx into vascular smooth muscle cells. The prevention of calcium influx is largely mediated by efflux of potassium via potassium channels causing membrane hyperpolarization, which in turn closes voltage-dependent (or gated) calcium channels (VDCC). Changes in vascular smooth muscle cell membrane potential are influenced by the movement of potassium ions through K+ channels such as the voltage gated potassium (Kv) channels. Kv channels form heteromeric octomeric complexes consisting of four membrane bound α-subunits that comprise the voltage-sensitive pore complex, and associate with four intracellular auxiliary β-subunits (Κvβ). The auxiliary β-subunits are members of the aldo-keto reductase (AKR) super family, enzymes that catalytically react with carbonyl substrates. These β-subunits sense changes in oxygen availability, metabolic signal transducer ratios (e.g., NADH:NAD+) and metabolites (e.g., H2O2). In this study I investigated the role of Kv channels and their auxiliary Kvβ2 subunits in vasodilation response to conditions of altered metabolism, physiological cardiac adaptation, and myocardial blood flow in response to 4 weeks of exercise. I found that Kvβ2 is necessary to induce Kv driven vasodilation under hypoxic conditions. Loss of Kvβ2 significantly impaired exercise capacity in both naïve and 4-week exercised (exe) mice, relative to sedentary and wildtype controls. Chronic exercise also enhanced myocardial perfusion in WT mice but not Kvβ2-/- male mice. Additionally, 4-weeks of exercise significantly increased Kv1 associated Kvβ2, in proximity ligation assay experiments. In isolated arteries from SM22α-rtTA single transgenic mice, the perfusion of external 10 mM L-lactate in the presence of 10-5 M H2O2 induced significantly greater vasodilation. Interestingly, this effect was not seen in arteries from SM22α-rtTA:TRE β1 double transgenic mice. Administration of NADH and H2O2 induced significant increases in Kv channel open probability (nPo). Additionally, in vascular smooth muscle cells, isolated from SM22α-rtTA mice, externally perfused with 1 mM NADH plus of 10-5 M H2O2 we observed a significant increase in Kv nPo. Hence, we conclude that loss of Kvβ2 impairs vasodilatory capacity in response to conditions that reflect increased work. Also, exercise capacity and myocardial perfusion are impaired in the absence of Kvβ2. Additionally, the increased presence of Kvβ1 relative to Kvβ2 in the Kv channel complex opposes the vasodilatory response to metabolites and signal transducers of increased work (e.g., NADH and H2O2). In conclusion, the presence of the Kvβ2 protein in arterial myocytes is crucial for adaptation following chronic exercise training

Effects of Cobalt on DNA Double Strand Break Repair-Deficient Cells

Epidemiology studies of human workers exposed to particulate cobalt have found increased incidence of lung cancer. A hallmark of lung cancer, chromosome instability(CIN) manifests as either numerical or structural abnormalities, which are thought to result from unrepaired or miss-repaired DNA double strand breaks, homologous recombination (HR) and non homologous end joining (NHEJ). Previous studies have shown that HR protects cells against metal induced CIN while NHEJ does not. We investigated whether this outcome occurs for cobalt

No Child Left Behind and the Highly Qualified Teacher : Perceptions of Teachers and Parents

The No Child Left Behind Act of 2001 (NCLB) was signed into law on January 8th, 2002. It appears that in an effort to comply with No Child Left Behind, my school district displaced me from my former secondary teaching position, where I taught students with autism, to an elementary, Emotionally/Behaviorally Disordered (E/BD) position. As an educator and parent, I was not properly informed about the educational act, so I took it upon myself to find out more. This paper will look into NCLB and ask fellow cooperating teachers and parents of students in my program what they know about NCLB. Using the qualitative research method, teachers and parents were asked to share what they knew about NCLB and the highly qualified teacher through interviews and sureys. These perceptions, explanations, and experiences will be documented and analyzed throughout this action research paper

Role of KVβ2 subunits in regulation of resistance arterial tone.

Voltage-gated potassium (Kv) channels control vascular resistance and facilitate the augmentation of myocardial blood flow in response to increases in cardiac workload (i.e., metabolic hyperemia). Native sarcolemmal Kv1 channels in arterial myocytes associate with a heteromeric auxiliary complex consisting of intracellular Kvβ1 and Kvβ2 proteins. The Kvβ proteins differentially regulate the function of heterologously expressed Kv channels, as well as native Kv1 channels in excitable cells of the cardiovascular and nervous systems. The physiological importance of vascular Kvβ proteins in mediating vasodilation remains unknown. In this study, I tested the hypothesis that Kvβ proteins functionally regulate vascular tone in response to an altered pyridine nucleotide redox state. I evaluated ex vivo vasoreactivity of small diameter mesenteric arteries isolated from wild type (WT), mutant mice in which either Kv channel subfamily a member regulatory beta subunits 1 or 2 (Kcnab1 or Kcnab2, respectively) was deleted (i.e., Kvβ1.1-/- and Kvβ2-/-, respectively), transgenic mice in which kcnab1.1 overexpression was induced by addition of doxycycline to the water (SM22α-rtTA: TRE β1) and point mutant mice in which the Kvβ2 subunit was catalytically inactive (Kvβ2Y90F). Loss of Kvβ1.1 or Kvβ2 did not significantly impact vasoconstriction in response to elevated extracellular K+ (60 mM), vi U46619 (thromboxane A2 analogue), or increases in intravascular pressure. Whereas vasodilation in response to application of adenosine (10-6 – 10-4 M) was similar between Kvβ-null and WT groups, vasodilation in response to external L-lactate (5-20 mM), which modifies cellular pyridine nucleotide redox state , was sensitive to inhibition by the Kv1-selective inhibitor psora-4 (500 nM) and was abolished in arteries from Kvβ2-/- mice but not in arteries from Kvβ1-/- mice. Interestingly, arteries from mice in which overexpression of the Kvβ1 subunit (SM22α-rtTA: TRE β1) and point-mutated inactivation of Kvβ2 (Kvβ2Y90F) enzymatic function, similarly abolished vasodilation in response to external L-lactate (5-20 mM). Our results indicate that vascular tone is differentially regulated by Kv1-associated Kvβ proteins, whereby Kvβ2 promotes and Kvβ1.1 opposes lactate induced vasodilation. Additionally, our data signify the importance of the Kvβ-subunit complex composition and enzymatic function in promoting vasodilation in response to an altered pyridine nucleotide redox state

Session 1-2-F: Rationality and Risk Intelligence in Binary Betting

We analyze 1.6 million binary bets on financial markets totaling $600 million in stakes, placed by 21,000 bettors at a large Internet betting site. The data set is unusually large and complete, plus has one additional important advantage: we can obtain objective independent estimates of the ex ante probability of winning each bet, using data from financial markets. This allows us to distinguish bettor profit due to superior prediction of financial events from bettor profit due to exploiting ex ante favorable odds situations. We focus on the degree or type of skill possessed by bettors (if any), and the amount of rationality and risk intelligence demonstrated in exploiting that skill

Shanghai as an International Financial Center - Aspiration, Reality and Implication

China’s rapid economic development, especially in the financial sector, has ignited the discussion of the re-emergence of Shanghai as a leading international financial center (IFC). Much still remains to be done for Shanghai to catch up with established centers such as New York and London, including deepening its capital markets and opening itself up to cross-border capital flows. While Shanghai’s current financial development has been made possible largely by China’s past economic conditions and policies, recent reforms are also likely to guarantee Shanghai the position as a world-class onshore IFC in the near future. The rise of Shanghai will likely benefit China’s economic structure, as well as that of Asia-Pacific region and the whole world

B802: Base-Age Invariant Polymorphic Site Index Curves for Even-Aged Spruce-Fir Stands in Maine

The spruce-fir forest cover type, occupying nearly 8 million acres in Maine, accounts for approximately 50 percent of the growing stock volume in the State. A similar portion of Maine\u27s commercial forest land is owned and managed by forest industry, with spruce and fir being the mainstay of the industry. Analyses in recent years of Maine\u27s timber supply have shown softwood removals to exceed growth. The dramatic effects of the spruce budworm (Choristoneura.fumiferana (Clemens)) on the spruce-fir forest of Maine has heightened concern over the timber supply. A greater emphasis on management is necessary if timber growth is to keep pace with demand. With increasing demand for timber, and the increasing value of timber products, intensive management is becoming economically feasible. High labor costs have led to an increase in mechanized harvesting. Consequently, the stage has been set for a greater emphasis on even-aged management of the spruce-fir forest type in Maine~ As red spruce (Picea rubens Sarg.), black spruce (Picea mariana (Mill.) B.S.P.), white spruce (Picea glauca (Moench) Voss), and balsam fir (Abies balsamea (L.) Mill.) are the backbone of Maine\u27s forest industry, it is desirable to identify those sites best suited to the growth of these species. An easily attained and sufficiently accurate method of estimating the relative quality of a particular site is essential to sound forest management. Site index, defined as being the height attained by the dominant stand at an arbitrarily chosen age, commonly 50 years in the northeastern United States, has been the most widely used measure of site quality. In addition to being an easily measured indicator of relative site quality, site index provides a crucial parameter in the estimation of the ultimate capability of forest land to produce wood volume.https://digitalcommons.library.umaine.edu/aes_bulletin/1100/thumbnail.jp

Associations between neighbourhood deprivation, ethnicity and maternal health outcomes in England: a nationwide cohort study using routinely collected healthcare data

Background: In the United Kingdom, pregnant women who live in the most deprived areas have two times the risk of dying than those who live in the least deprived areas. There are even greater disparities between women from different ethnic groups. The aim of this study was to investigate the role of area-based deprivation and ethnicity in the increased risk of severe maternal morbidity (SMM), in primiparous women in England. Methods: A retrospective nationwide population study was conducted using English National Hospital Episode Statistics Admitted Patient Care database. All primiparous women were included if they gave birth in an National Healthcare Service (NHS) hospital in England between 1 January 2016 and 31 December 2021. Logistic regression was used to examine the relative odds of SMM by Index of Multiple Deprivation and ethnicity, adjusting for age and health behaviours, medical and psychological factors. Results: The study population comprised 1 178 756 primiparous women. Neighbourhood deprivation increased the risk of SMM at the time of childbirth. In the fully adjusted model, there was a linear trend (p=0.001) between deprivation quintile and the odds of SMM. Being from a minoritised ethnic group also independently increased the risk of SMM, with black or black British African women having the highest risk, adjusted OR 1.84 (95% CI 1.70 to 2.00) compared with white women. There was no interaction between deprivation and ethnicity (p=0.49). Conclusion: This study has highlighted that neighbourhood deprivation and ethnicity are important, independently associated risk factors for SMM

Maldegem - Krommewege, Archeologisch vooronderzoek - november 2016

Aerial view of the Electric Manufacturing Company, a division of Amerace Corportation, from the the west end