Surb Grigor Lusaworichʻ pederimizin tevarihi : ve encamında bazı muhtasar ve elzem tefekkürler ilâve olunmuş dur.

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Allosteric Control of Gating Mechanisms Revisited: The Large Conductance Ca(2+)-Activated K(+) Channel

Large-conductance Ca(2+)-activated K(+) channels (BK) play a fundamental role in modulating membrane potential in many cell types. The gating of BK channels and its modulation by Ca(2+) and voltage has been the subject of intensive research over almost three decades, yielding several of the most complicated kinetic mechanisms ever proposed. A large number of open and closed states disposed, respectively, in two planes, named tiers, characterize these mechanisms. Transitions between states in the same plane are cooperative and modulated by Ca(2+). Transitions across planes are highly concerted and voltage-dependent. Here we reexamine the validity of the two-tiered hypothesis by restricting attention to the modulation by Ca(2+). Large single channel data sets at five Ca(2+) concentrations were simultaneously analyzed from a Bayesian perspective by using hidden Markov models and Markov-chain Monte Carlo stochastic integration techniques. Our results support a dramatic reduction in model complexity, favoring a simple mechanism derived from the Monod-Wyman-Changeux allosteric model for homotetramers, able to explain the Ca(2+) modulation of the gating process. This model differs from the standard Monod-Wyman-Changeux scheme in that one distinguishes when two Ca(2+) ions are bound to adjacent or diagonal subunits of the tetramer.

The L-Type Ca+ and KATP channels may contribute to pacing-induced protection against anoxia-reoxygenation in the embryonic heart model.

L-Type Ca(2+) and K(ATP) Channels in Pacing-Induced Cardioprotection. AIMS: The L-type Ca(2+) channel, the sarcolemmal (sarcK(ATP)), and mitochondrial K(ATP) (mitoK(ATP)) channels are involved in myocardial preconditioning. We aimed at determining to what extent these channels can also participate in pacing-induced cardioprotection. METHODS: Hearts of 4-day-old chick embryos were paced in ovo during 12 hour using asynchronous intermittent ventricular stimulation at 110% of the intrinsic rate. Sham operated and paced hearts were then submitted in vitro to anoxia (30 minutes) and reoxygenation (60 minutes). These hearts were exposed to L-type Ca(2+) channel agonist Bay-K-8644 (BAY-K) or blocker verapamil, nonselective K(ATP) channel antagonist glibenclamide (GLIB), mitoK(ATP) channel agonist diazoxide (DIAZO), or antagonist 5-hydroxydecanoate. Electrocardiogram, electromechanical delay (EMD) reflecting excitation-contraction (E-C) coupling, and contractility were determined. RESULTS: Under normoxia, heart rate, QT duration, conduction, EMD, and ventricular shortening were similar in sham and paced hearts. During reoxygenation, arrhythmias ceased earlier and ventricular EMD recovered faster in paced hearts than in sham hearts. In sham hearts, BAY-K (but not verapamil), DIAZO (but not 5-hydroxydecanoate) or GLIB accelerated recovery of ventricular EMD, reproducing the pacing-induced protection. By contrast, none of these agents further ameliorated recovery of the paced hearts. CONCLUSION: The protective effect of chronic asynchronous pacing at near physiological rate on ventricular E-C coupling appears to be associated with subtle activation of L-type Ca(2+) channel, inhibition of sarcK(ATP) channel, and/or opening of mitoK(ATP) channel.

An ultra-sensitive impedimetric immunosensor for detection of the serum oncomarker CA-125 in ovarian cancer patients.

Effective treatment of ovarian cancer depends upon the early detection of the malignancy. Here, we report on the development of a new nanostructured immunosensor for early detection of cancer antigen 125 (CA-125). A gold electrode was modified with mercaptopropionic acid (MPA), and then consecutively conjugated with silica coated gold nanoparticles (AuNP@SiO2), CdSe quantum dots (QDs) and anti-CA-125 monoclonal antibody (mAb). The engineered MPA|AuNP@SiO2|QD|mAb immunosensor was characterised using transmission electron microscopy (TEM), atomic force microscopy (AFM), cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS). Successive conjugation of AuNP@SiO2, CdSe QD and anti-CA-125 mAb onto the gold electrode resulted in sensitive detection of CA-125 with a limit of detection (LOD) of 0.0016 U mL(-1) and a linear detection range (LDR) of 0-0.1 U mL(-1). Based on the high sensitivity and specificity of the immunosensor, we propose this highly stable and reproducible biosensor for the early detection of CA-125.

CENTRAL NORTH ATLANTIC PALEOCEANOGRAPHY DURING THE MIDDLE PLEISTOCENE (ca. 726–603 ka): INSIGHTS FROM THE DINOFLAGELLATE CYST RECORD

Integrated Ocean Drilling Program (IODP) Site U1313, located at the northern boundary of the subtropical gyre in the central North Atlantic, lies within the southern part of the ice-rafted debris belt. Seventy-three palynological samples were studied from an uninterrupted interval ca. 726–603 ka (upper Marine Isotope Stage [MIS] 18 through lower MIS 15) to resolve conflicting paleoceanographic interpretations. Glacial stages were characterized by high productivity surface waters reflecting a southward shift of the Arctic Front. Sea surface salinities (SSSs) and sea surface temperatures (SSTs) were obtained by transfer functions using the Modern Analogue Technique. The lowest SSTs of 9ºC (±1.3) and 10ºC (±1.3) were recorded in glacial MIS 16 and MIS 18 respectively. However, these reconstructions are influenced by abundant heterotrophic taxa and may reflect elevated nutrient levels rather than lowered temperatures. Reworked palynomorphs uniquely indicate a Cretaceous as well as Paleozoic provenance for the first Heinrich-like events.

Computer simulation study of collective dynamics in the glass former Ca(NO3)(2)center dot 4H(2)O

Time correlation functions of current fluctuations were calculated by molecular dynamics (MD) simulations in order to investigate sound waves of high wavevectors in the glass-forming liquid Ca(NO3)(2)center dot 4H(2)O. Dispersion curves, omega(k), were obtained for longitudinal (LA) and transverse acoustic (TA) modes, and also for longitudinal optic (LO) modes. Spectra of LA modes calculated by MD simulations were modeled by a viscoelastic model within the memory function framework. The viscoelastic model is used to rationalize the change of slope taking place at k similar to 0.3 angstrom(-1) in the omega(k) curve of acoustic modes. For still larger wavevectors, mixing of acoustic and optic modes is observed. Partial time correlation functions of longitudinal mass currents were calculated separately for the ions and the water molecules. The wavevector dependence of excitation energies of the corresponding partial LA modes indicates the coexistence of a relatively stiff subsystem made of cations and anions, and a softer subsystem made of water molecules. (C) 2012 American Institute of Physics. [http://dx.doi.org/10.1063/1.4751548]

Ca(2+) release from the sarcoplasmic reticulum activated by the low affinity Ca(2+) chelator TPEN in ventricular myocytes

The Ca(2+) content of the sarcoplasmic reticulum (SR) of cardiac myocytes is thought to play a role in the regulation and termination of SR Ca(2+) release through the ryanodine receptors (RyRs). Experimentally altering the amount of Ca(2+) within the SR with the membrane-permeant low affinity Ca(2+) chelator TPEN could improve our understanding of the mechanism(s) by which SR Ca(2+) content and SR Ca(2+) depletion can influence Ca(2+) release sensitivity and termination. We applied laser-scanning confocal microscopy to examine SR Ca(2+) release in freshly isolated ventricular myocytes loaded with fluo-3, while simultaneously recording membrane currents using the whole-cell patch-clamp technique. Following application of TPEN, local spontaneous Ca(2+) releases increased in frequency and developed into cell-wide Ca(2+) waves. SR Ca(2+) load after TPEN application was found to be reduced to about 60% of control. Isolated cardiac RyRs reconstituted into lipid bilayers exhibited a two-fold increase of their open probability. At the low concentration used (20-40muM), TPEN did not significantly inhibit the SR-Ca(2+)-ATPase in SR vesicles. These results indicate that TPEN, traditionally used as a low affinity Ca(2+) chelator in intracellular Ca(2+) stores, may also act directly on the RyRs inducing an increase in their open probability. This in turn results in an increased Ca(2+) leak from the SR leading to its Ca(2+) depletion. Lowering of SR Ca(2+) content may be a mechanism underlying the recently reported cardioprotective and antiarrhythmic features of TPEN.

Role of the N- and C-lobes of calmodulin in the activation of Ca(2+)/calmodulin-dependent protein kinase II.

Understanding the principles of calmodulin (CaM) activation of target enzymes will help delineate how this seemingly simple molecule can play such a complex role in transducing Ca (2+)-signals to a variety of downstream pathways. In the work reported here, we use biochemical and biophysical tools and a panel of CaM constructs to examine the lobe specific interactions between CaM and CaMKII necessary for the activation and autophosphorylation of the enzyme. Interestingly, the N-terminal lobe of CaM by itself was able to partially activate and allow autophosphorylation of CaMKII while the C-terminal lobe was inactive. When used together, CaMN and CaMC produced maximal CaMKII activation and autophosphorylation. Moreover, CaMNN and CaMCC (chimeras of the two N- or C-terminal lobes) both activated the kinase but with greater K act than for wtCaM. Isothermal titration calorimetry experiments showed the same rank order of affinities of wtCaM > CaMNN > CaMCC as those determined in the activity assay and that the CaM to CaMKII subunit binding ratio was 1:1. Together, our results lead to a proposed sequential mechanism to describe the activation pathway of CaMKII led by binding of the N-lobe followed by the C-lobe. This mechanism contrasts the typical sequential binding mode of CaM with other CaM-dependent enzymes, where the C-lobe of CaM binds first. The consequence of such lobe specific binding mechanisms is discussed in relation to the differential rates of Ca (2+)-binding to each lobe of CaM during intracellular Ca (2+) oscillations.

Optical absorption and applications of the ABO4 (A=Ca, Pb and B= Mo, W) semiconductors

Ternary molybdates and tungstates ABO4 (A=Ca, Pb and B= Mo, W) are a group of materials that could be used for a variety of optoelectronic applications. We present a study of the optoelectronic properties based on first-principles using several orbitaldependent one-electron potentials applied to several orbital subspaces. The optical properties are split into chemical-species contributions in order to quantify the microscopic contributions. Furthermore, the effect of using several one-electron potentials and orbital subspaces is analyzed. From the results, the larger contribution to the optical absorption comes from the B-O transitions. The possible use as multi-gap solar cell absorbents is analyzed.

I. Calculation of the length of printed lines of all the volumes in the Harvard Library, ca. 1789

This series contains one small leaf with handwritten calculations related to the number of volumes in the Harvard College Library. The verso has the note: "No. of Vol: in Harvard College 11465 vol. making one line 15380 miles long. The document is in the hand of Loammi Baldwin Sr., and may have been created in 1789 while the Library was compiling a catalog of its holdings.

Plan of Cellar Stairs for the South Entry. A reversed set for the North Entry, ca. 1813

Detailed drawing of stairways to be built in University Hall. Includes dimensions for height, length, and width of stairs.

Instructions for printing the Hebrew Grammar, [ca. 1735]

A one-page handwritten list of instructions, in President Benjamin Wadsworth's hand, for printing, distributing, and collecting revenue on the Hebrew Grammar.

I. Calculation of the length of printed lines of all the volumes in the Harvard Library, ca. 1789

This series contains one small leaf with handwritten calculations related to the number of volumes in the Harvard College Library. The verso has the note: "No. of Vol: in Harvard College 11465 vol. making one line 15380 miles long. The document is in the hand of Loammi Baldwin Sr., and may have been created in 1789 while the Library was compiling a catalog of its holdings.

Records of the Geographical Society, ca. 1796

This small blue-covered paper notebook contains four leaves with the handwritten records of the Geographical Society, an undergraduate organization at Harvard in the late 1790s. The records consist of ten handwritten "Laws of the Geographical Society" and a short list of fines dispensed on October 7th. A list of six student surnames is written on a scrap of paper and attached with pins to the notebook's inside front cover. The surnames likely correspond to six members of the Harvard Class of 1798: John Abbot (1777-1854), Isaac Adams (d. 1807), Francis Brigham (d. November 14, 1796), Humphrey Devereux (1779-1867), Joseph Emerson (1777-1833), and Artemas Sawyer (d. 1826). The notebook is undated but was presumably kept in 1795 or 1796 around the time of Brigham's death on November 14, 1796. While Brigham's surname appears in the list of fines, it is crossed out on the inside front cover.

A collection of autograph letters and original documents relating to the Island of Barbados in the 18th century, ca. 1730-1778

A miscellaneous collection of letter and legal documents relating to Barbados, especially prize causes, inheritance and slaves.