Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Vertical S(1)-S(0) electronic transitions of the highly solvent-sensitive fluorescence label 2-propionyl-6-dimethylamino naphthalene (PRODAN) are modeled by semiempirical CISD AM1 and TD DFT calculations in a large number of solvents of different polarity and hydrogen donating ability. Calculations correctly reproduce the observed solvent induced shifts of the emission maxima. The fluorescence Frank-Condon transition energies in solvent can be predicted quantitatively at the AM1 SM5.42 OPEN(2,2) C.I.=5 CISD level. For the planar PRODAN emitting state at the latter level we obtain a regression with practically unit slope and zero intercept for aprotic solvents. The respective relationship for the O-twisted S(1) state has a slope of 0.59 and intercept of 9100 cm(-1). These results support the concept that no geometry twist in the S(1) state of PRODAN is necessary to explain the observed solvent effects on fluorescence.
Spectrochim Acta A Mol Biomol Spectrosc 2009 Feb
PMID:Solvent induced shifts of electronic spectra IV. Computational study on PRODAN fluorescence and implications to the excited state structure. 1901 Jul 22

The mechanisms underlying the Frank-Starling Law of the heart are elusive and the prevalent notion suggests that it is afterload independent. However, isolated fiber studies reveal that the afterload determines cardiac function through cross-bridge dependent mechanisms. The study explores the roles of the afterload, in situ. The LV was exposed by left-thoracotomy in adult sheep (72.6+/-8.2 kg, n=8). Pressure transducers were inserted into the LV and aorta, a flowmeter was placed around the aortic root, and the LV volume was assessed by sonocrystals. Occluders around the aorta and the inferior vena cava enabled control of the afterload and preload. Different afterloads were imposed by partial aortic occlusions. Transient inferior vena cava occlusions (IVCOs) were preformed whenever the afterload was steady. A highly linear relationship was found between the external work (EW) and pressure time integral (PTI) (R(2)=0.98+/-0.01) during each transient IVCO (n=48). The slope of the EW-PTI relationship (WPTiR) was preload independent since, for any given afterload, the EW and PTI lay on a straight line. Interestingly, the slope of the WPTiR was afterload dependant: The slope was 33.3+/-4.1 mJ/mmHg.s at baselines and decreased by 1.0+/-0.50 mJ/mmHg.s with every 1 mmHg.min/L increase in the peripheral resistance. A unique WPTiR was obtained during both the occlusion and release phases of each IVCO, while two distinct EW-preload or PTI-preload relationships were observed. The novel WPTiR ties the Frank (pressure development) and Starling (EW production) phenomena together. The dependence of the WPTiR on the afterload highlights the adaptive control of the Frank-Starling mechanisms to changes in the afterload.
J Mol Cell Cardiol 2009 Oct
PMID:The external work-pressure time integral relationships and the afterload dependence of Frank-Starling mechanism. 1946 30

Latitudinal comparisons of the Southern Ocean limpet, Nacella concinna, and clam, Laternula elliptica, acclimated to 0.0 degrees C, were used to assess differences in thermal response to two regimes, 0.0, 5.1 to 10.0 degrees C and 2.5, 7.5 to 12.5 degrees C, raised at 5.0 degrees C per week. At each temperature, tissue energy status was measured through a combination of O(2) consumption, intracellular pH, cCO(2), citrate synthase (CS) activity, organic acids (succinate, acetate, propionate), adenylates (ATP, ADP, AMP, ITP, PLA (phospho-L-arginine)) and heart rate. L. elliptica from Signy (60 degrees S) and Rothera (67 degrees S), which experience a similar thermal regime (-2 to +1 degrees C) had the same lethal (7.5-10.0 degrees C), critical (5.1-7.5 degrees C) and pejus (<5.1 degrees C;=getting worse) limits with only small differences in biochemical response. N. concinna, which experiences a wider thermal regime (-2 to +15.8 degrees C), had higher lethal limits (10.0-12.5 degrees C). However, at their Northern geographic limit N. concinna, which live in a warmer environment (South Georgia, 54 degrees S), had a lower critical limit (5.1-10.0 degrees C; O(2), PLA and organic acids) than Rothera and Signy N. concinna (10.0-12.5 degrees C). This lower limit indicates that South Georgia N. concinna have different biochemical responses to temperatures close to their thermal limit, which may make them more vulnerable to future warming trends.
Comp Biochem Physiol A Mol Integr Physiol 2009 Jun
PMID:Geographical variation in thermal tolerance within Southern Ocean marine ectotherms. 1953 33

Sanitization of the cellular nucleotide pools from mutagenic base analogues is necessary for the accuracy of transcription and replication of genetic material and plays a substantial role in cancer prevention. The undesirable mutagenic, recombinogenic, and toxic incorporation of purine base analogues [i.e., ITP, dITP, XTP, dXTP, or 6-hydroxylaminopurine (HAP) deoxynucleoside triphosphate] into nucleic acids is prevented by inosine triphosphate pyrophosphatase (ITPA). The ITPA gene is a highly conserved, moderately expressed gene. Defects in ITPA orthologs in model organisms cause severe sensitivity to HAP and chromosome fragmentation. A human polymorphic allele, 94C-->A, encodes for the enzyme with a P32T amino acid change and leads to accumulation of non-hydrolyzed ITP. ITPase activity is not detected in erythrocytes of these patients. The P32T polymorphism has also been associated with adverse sensitivity to purine base analogue drugs. We have found that the ITPA-P32T mutant is a dimer in solution, as is wild-type ITPA, and has normal ITPA activity in vitro, but the melting point of ITPA-P32T is 5 degrees C lower than that of wild-type. ITPA-P32T is also fully functional in vivo in model organisms as determined by a HAP mutagenesis assay and its complementation of a bacterial ITPA defect. The amount of ITPA protein detected by Western blot is severely diminished in a human fibroblast cell line with the 94C-->A change. We propose that the P32T mutation exerts its effect in certain human tissues by cumulative effects of destabilization of transcripts, protein stability, and availability.
J Mol Biol 2009 Sep 25
PMID:Functional study of the P32T ITPA variant associated with drug sensitivity in humans. 1963 56

Ion transport peptide (ITP) and ITP-like (ITPL) are highly conserved neuropeptides in insects and crustaceans. We investigated the alternatively spliced variants of ITP/ITPL in Tribolium castaneum to understand their functions. We identified three alternatively spliced transcripts named itp, itpl-1, and itpl-2. Expression patterns of the splice variants investigated by exon-specific in situ hybridization were somewhat different from those previously reported in other insect species. Most importantly, we found for the first time that itpl-1 transcripts are abundantly expressed in the midgut at the late larval stage, showing an expression pattern similar to that of the crustacean hyperglycemic hormone (CHH) in the crab Carcinus maenas. CHH was shown to function by increasing the body volume through fluid absorption, resulting in breakage of the outer shell at the time of molt. Exon-specific RNA interference (RNAi) was designed to distinguish between itp and itpl-1, but we were unable to design a dsRNA uniquely targeting or uniquely excluding itpl-2; therefore, RNAi targeting was limited to either itp/itpl-2 or itpl-1/itpl-2. For dsRNA injections in the larval stages, either RNAi led to gradually increasing mortality in the larval and pupal stages, with 100% cumulative mortality at the time of eclosion or shortly afterward. Developmental deficiencies in the adult tarsal segments were observed after RNAi suppressing either itp/itpl-2 or itpl-1/itpl-2. After dsRNA injections at the pupal stage, the most striking observation was a significant reduction in egg numbers (8% of control) and reduced survival of the offspring (5%) in RNAi targeting itpl-1/itpl-2, while a milder degree of the same phenotype was observed in that targeting itp/itpl-2.
Insect Biochem Mol Biol 2009 Oct
PMID:Functions of ion transport peptide and ion transport peptide-like in the red flour beetle Tribolium castaneum. 1971 61

Titin is the largest protein in mammals; it forms an elastic filament along the myofibril of cardiac and skeletal muscles. Novel studies employing the recently available varied technologies have revealed the molecular mechanisms by which titin generates passive force in the sarcomere in response to external stretch. Changes in titin stiffness occur during heart disease via a shift in the expression ratio of the two main titin isoforms, called N2B (stiff type) and N2BA (compliant type) titins. Protein kinase (PK)A, PKG and PKC phosphorylate the cardiac specific I-band titin segment, resulting in an acute decrease (by PKA and PKG) or increase (by PKC) in passive force. It has also been discovered that titin performs roles that go beyond passive force generation, by enhancing or terminating active force production, thereby adjusting the Frank-Starling mechanism of the heart. Therefore, titin is a self-adjustable and multi-functional spring that is indispensable for proper heart functions. Here, we discuss how titin regulates the passive and active properties of cardiac muscle in normal physiological conditions as well as in chronic heart disease.
J Mol Cell Cardiol 2010 May
PMID:Titin-based regulations of diastolic and systolic functions of mammalian cardiac muscle. 1996 82

The Frank-Starling law of the heart describes the interrelationship between end-diastolic volume and cardiac ejection volume, a regulatory system that operates on a beat-to-beat basis. The main cellular mechanism that underlies this phenomenon is an increase in the responsiveness of cardiac myofilaments to activating Ca(2+) ions at a longer sarcomere length, commonly referred to as myofilament length-dependent activation. This review focuses on what molecular mechanisms may underlie myofilament length dependency. Specifically, the roles of inter-filament spacing, thick and thin filament based regulation, as well as sarcomeric regulatory proteins are discussed. Although the "Frank-Starling law of the heart" constitutes a fundamental cardiac property that has been appreciated for well over a century, it is still not known in muscle how the contractile apparatus transduces the information concerning sarcomere length to modulate ventricular pressure development.
J Mol Cell Cardiol 2010 May
PMID:Myofilament length dependent activation. 2062 95

The mechanisms of regulation of respiration and energy fluxes in the cells are analyzed based on the concepts of systems biology, non-equilibrium steady state kinetics and applications of Wiener's cybernetic principles of feedback regulation. Under physiological conditions cardiac function is governed by the Frank-Starling law and the main metabolic characteristic of cardiac muscle cells is metabolic homeostasis, when both workload and respiration rate can be changed manifold at constant intracellular level of phosphocreatine and ATP in the cells. This is not observed in skeletal muscles. Controversies in theoretical explanations of these observations are analyzed. Experimental studies of permeabilized fibers from human skeletal muscle vastus lateralis and adult rat cardiomyocytes showed that the respiration rate is always an apparent hyperbolic but not a sigmoid function of ADP concentration. It is our conclusion that realistic explanations of regulation of energy fluxes in muscle cells require systemic approaches including application of the feedback theory of Wiener's cybernetics in combination with detailed experimental research. Such an analysis reveals the importance of limited permeability of mitochondrial outer membrane for ADP due to interactions of mitochondria with cytoskeleton resulting in quasi-linear dependence of respiration rate on amplitude of cyclic changes in cytoplasmic ADP concentrations. The system of compartmentalized creatine kinase (CK) isoenzymes functionally coupled to ANT and ATPases, and mitochondrial-cytoskeletal interactions separate energy fluxes (mass and energy transfer) from signalling (information transfer) within dissipative metabolic structures - intracellular energetic units (ICEU). Due to the non-equilibrium state of CK reactions, intracellular ATP utilization and mitochondrial ATP regeneration are interconnected by the PCr flux from mitochondria. The feedback regulation of respiration occurring via cyclic fluctuations of cytosolic ADP, Pi and Cr/PCr ensures metabolic stability necessary for normal function of cardiac cells.
Int J Mol Sci 2010 Mar 08
PMID:Application of the principles of systems biology and Wiener's cybernetics for analysis of regulation of energy fluxes in muscle cells in vivo. 2047 96

Previous work suggests that titin-based passive tension is a factor in the Frank-Starling mechanism of the heart, by increasing length-dependent activation (LDA) through an increase in calcium sensitivity at long sarcomere length. We tested this hypothesis in a mouse model (N2B KO model) in which titin-based passive tension is elevated as a result of the excision of the N2B element, one of cardiac titin's spring elements. LDA was assessed by measuring the active tension-pCa (-log[Ca(2+)]) relationship at sarcomere length (SLs) of 1.95, 2.10, and 2.30 microm in WT and N2B KO skinned myocardium. LDA was positively correlated with titin-based passive tension due to an increase in calcium sensitivity at the longer SLs in the KO. For example, at pCa 6.0, the KO:WT tension ratio was 1.28+/-0.07 and 1.42+/-0.04 at SLs of 2.1 and 2.3 microm, respectively. There was no difference in protein expression or total phosphorylation of sarcomeric proteins. We also measured the calcium sensitivity after PKA treating the skinned muscle and found that titin-based passive tension was also now correlated with LDA, with a slope that was significantly increased compared to no PKA treatment. Finally, we performed isolated heart experiments and measured the Frank-Starling relation (slope of developed wall stress-LV volume relation) as well as diastolic stiffness (slope of diastolic wall stress-volume relation). The FSM was more pronounced in the N2B KO hearts and the slope of the FSM correlated with diastolic stiffness. These findings support that titin-based passive tension triggers an increase in calcium sensitivity at long sarcomere length, thereby playing an important role in the Frank-Starling mechanism of the heart.
J Mol Cell Cardiol 2010 Sep
PMID:Calcium sensitivity and the Frank-Starling mechanism of the heart are increased in titin N2B region-deficient mice. 2050 34

Currently under codevelopment by Symphogen and Swedish Orphan Biovitrum, rozrolimupab is the first in a new class of recombinant polyclonal antibodies, known as symphobodies, produced using a proprietary technology from Symphogen. Rozrolimupab is being investigated for the prevention of hemolytic disease of the fetus and newborn (HDFN) and for the treatment of idiopathic thrombocytopenic purpura (ITP). Rozrolimupab comprises 25 genetically unique IgG1 antibodies, all of which are specific for the rhesus D (RhD) erythrocyte protein. In preclinical studies, rozrolimupab demonstrated binding to erythrocytes that was comparable with that of two plasma-derived anti-D Ig preparations. In a phase I clinical trial in healthy male volunteers, treatment with rozrolimupab was not associated with serious adverse events. In a phase II clinical trial of rozrolimupab in healthy, male, RhD-negative volunteers, rozrolimupab dose-dependently cleared RhD-positive erythrocytes from the circulation. Phase II clinical trials in ITP and HDFN are currently ongoing. Phase III clinical trials are necessary to establish the efficacy and safety profile of rozrolimupab compared with standard plasma-derived anti-D Ig preparations.
Curr Opin Mol Ther 2010 Dec
PMID:Rozrolimupab, symphobodies against rhesus D, for the potential prevention of hemolytic disease of the newborn and the treatment of idiopathic thrombocytopenic purpura. 2115 65


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