Relative positioning of diazepam in the benzodiazepine-binding-pocket of GABA receptors

GABA(A) receptors are the major inhibitory neurotransmitter receptors in the brain. Some of them are targets of benzodiazepines that are widely used in clinical practice for their sedative/hypnotic, anxiolytic, muscle relaxant and anticonvulsant effects. In order to rationally separate these different drug actions, we need to understand the interaction of such compounds with the benzodiazepine-binding pocket. With this aim, we mutated residues located in the benzodiazepine-binding site individually to cysteine. These mutated receptors were combined with benzodiazepine site ligands carrying a cysteine reactive group in a defined position. Proximal apposition of reaction partners will lead to a covalent reaction. We describe here such proximity-accelerated chemical coupling reactions of alpha(1)S205C and alpha(1)T206C with a diazepam derivative modified at the C-3 position with a reactive isothiocyanate group (-NCS). We also provide new data that identify alpha(1)H101C and alpha(1)N102C as exclusive sites of the reaction of a diazepam derivative where the -Cl atom is replaced by a -NCS group. Based on these observations we propose a relative positioning of diazepam within the benzodiazepine-binding site of alpha(1)beta(2)gamma(2) receptors.

Carbamyl Analogs of Phosphatidylcholines Synthesis, Interaction With Phospholipases and Permeability Behavior of their Liposomes

A novel class of phospholipase-resisting phosphatidylcholine analogs, in which the C-2 ester group or both C-1 and C-2 ester groups have been replaced by carbamyloxy functions (-NH-C-O-), have been synthesized. These lipids were not degraded by phospholipase A2 while complete hydrolysis occurred with phospholipase C. Ultrasonic irradiation of the aqueous dispersions of the phospholipids in the presence as well as in the absence of cholesterol resulted in the formation of closed bilayer structures as evidenced by negative staining electron microscopy and also by their ability to entrap [14C]glucose. The leakage rates of glucose at 37°C from liposomes of these compounds have also been measured. Liposomes consisting of 1,2-dipentadecanylcarbamyloxy-sn-glycero- 3-phosphorylcholine were found to be more leaky (2.1 %/h) as compared to the liposomes of 1-palmitoyl-2-pentadecanylcarbamyloxy-sn -glycero-3-phosphoryl- choline (O.5%/h). Moreover, inclusion of cholesterol (33 mol%) into the bilayers of the former phospholipid had no effect on the leakage rate (2.4%/h) while it effectively reduced permeability of the latter (O.22%/h). These phosphatidylcholines are useful for studying the possible role of phospholipases in the capture and lysis of liposomes in vivo.

Molecular analysis of the human $\gamma$-chain T cell receptor genes

In our studies we have focused on the issue of variability and diversity of the $\gamma$ (or $\delta)$ chain T cell receptor (TCR) genes by studying cDNA transcripts in peripheral blood mononuclear cells or $\gamma\delta$ TCR+ T cell clones. The significance of these studies lies in the better understanding of the molecular biology of the $\gamma\delta$ T cell receptor as well as in answering the question whether certain molecular forms predominate in $\gamma\delta$ T cells exhibiting specific immunologic functions. We establish that certain $\gamma$-chain TCR genes exhibit particular patterns of rearrangements in cDNA transcripts in normal individuals. V$\gamma$I subgroup were shown to preferentially rearrange to J$\gamma$2C$\gamma$2 gene segments. These preferential VJC rearrangements, may have implications regarding the potential for diversity and polymorphism of the $\gamma$-chain TCR gene. In addition, the preferential association of V$\gamma$I genes with J$\gamma$2C$\gamma$2, which encode a non-disulfide-linked $\gamma\delta$ TCR, suggests that $\gamma$ chains utilizing V$\gamma$I are predominantly expressed as non-disulfide-linked $\gamma\delta$ TCR heterodimers. The implications of this type of expression remain to be determined. We identified two alternative splicing events of the $\gamma$-chain TCR genes occurring in high frequency in all the normal individuals examined. These events may suggest additional mechanisms of regulation and control as well as diversification of $\gamma\delta$ TCR gene expression. The question whether particular forms of $\gamma$ or $\delta$-chain TCR genes are involved in HLA Class I recognition by specific $\gamma\delta$ cytotoxic T cell clones was addressed. Our results indicated that the T cell clones expressed identical $\gamma$ but distinct $\delta$-chains suggesting that the specificity for recognition of HLA-A2 or HLA-A3 may be conferred by the $\delta$-chain TCR. The issue of the degree of diversity and polymorphism of the $\delta$-chain TCR genes in a patient with a primary immunodeficiency (Omenn's syndrome) was addressed. A limited pattern of rearrangements in peripheral blood transcripts was found, suggesting that a limited $\gamma\delta$ TCR repertoire may be expressed in this particular primary immunodeficiency syndrome. Overall, our findings suggest that $\delta$-chain TCR genes exhibit the potential for significant diversity and that there are certain preferential patterns of expression that may be associated with particular immunologic functions. ^

The mobility of Nb in rutile-saturated NaCl- and NaF-bearing aqueous fluids from 1-6.5 GPa and 300-800 °C

Rutile (TiO2) is an important host phase for high field strength elements (HFSE) such as Nb in metamorphic and subduction zone environments. The observed depletion of Nb in arc rocks is often explained by the hypothesis that rutile sequesters HFSE in the subducted slab and overlying sediment, and is chemically inert with respect to aqueous fluids evolved during prograde metamorphism in the forearc to subarc environment. However, field observations of exhumed terranes, and experimental studies, indicate that HFSE may be soluble in complex aqueous fluids at high pressure (i.e., >0.5 GPa) and moderate to high temperature (i.e., >300 degrees C). In this study, we investigated experimentally the mobility of Nb in NaCl- and NaF-bearing aqueous fluids in equilibrium with Nb-bearing rutile at pressure-temperature conditions applicable to fluid evolution in arc environments. Niobium concentrations in aqueous fluid at rutile saturation were measured directly by using a hydrothermal diamond-anvil cell (HDAC) and synchrotron X-ray fluorescence (SXRF) at 2.1 to 6.5 GPa and 300-500 degrees C, and indirectly by performing mass loss experiments in a piston-cylinder (PC) apparatus at similar to 1 GPa and 700-800 degrees C. The concentration of Nb in a 10 wt% NaCl aqueous fluid increases from 6 to 11 mu g/g as temperature increases from 300 to 500 degrees C, over a pressure range from 2.1 to 2.8 GPa, consistent with a positive temperature dependence. The concentration of Nb in a 20 wt% NaCl aqueous fluid varies from 55 to 150 mu g/g at 300 to 500 degrees C, over a pressure range from 1.8 to 6.4 GPa; however, there is no discernible temperature or pressure dependence. The Nb concentration in a 4 wt% NaF-bearing aqueous fluid increases from 180 to 910 mu g/g as temperature increases from 300 to 500 degrees C over the pressure range 2.1 to 6.5 GPa. The data for the F-bearing fluid indicate that the Nb content of the fluid exhibits a dependence on temperature between 300 and 500 degrees C at >= 2 GPa, but there is no observed dependence on pressure. Together, the data demonstrate that the hydrothermal mobility of Nb is strongly controlled by the composition of the fluid, consistent with published data for Ti. At all experimental conditions, however, the concentration of Nb in the fluid is always lower than coexisting rutile, consistent with a role for rutile in moderating the Nb budget of arc rocks.

Heterotrimeric G protein -mediated signal transduction in Neurospora crassa

Heterotrimeric G protein-mediated signal transduction is one of numerous means that cells utilize to respond to external stimuli. G proteins consist of α, β andγ subunits. Extracellular ligands bind to seven-transmembrane helix receptors, triggering conformational changes. This is followed by activation of coupled G proteins through the exchange of GDP for GTP on the Gα subunit. Once activated, Gα-GTP dissociates from the βγ dimer. Both of these two moieties can interact with downstream effectors, such as adenylyl cyclase, phospholipase C, phosphodiesterases, or ion channels, leading to a series of changes in cellular metabolism and physiology. ^ Neurospora crassa is a eukaryotic multicellular filamentous fungus, with asexual/vegetative and sexual phases to its life cycle. Three Gα (GNA-1, GNA-2, GNA-3) and one Gβ (GNB-1) proteins have been identified in this organism. This dissertation investigates GNA-1 and GNB-1 mediated signaling pathways in N. crassa. ^ GNA-1 was the first identified microbial Gα that belongs to a mammalian superfamily (Gαi). Deletion of GNA-1 leads to multiple defects in N. crassa. During the asexual cycle, Δgna-1 strains display a slower growth rate and delayed conidiation on solid medium. In the sexual cycle, the Δgna-1 mutant is male-fertile but female-sterile. Biochemical studies have shown that Δ gna-1 strains have lower adenosine 3′–5 ′ cyclic monophosphate (cAMP) levels than wild type under conditions where phenotypic defects are observed. In this thesis work, strains containing one of two GTPase-deficient gna-1 alleles (gna-1 R178C, gna-1Q204L) leading to constitutive activation of GNA-1 have been constructed and characterized. Activation of GNA-1 causes uncontrolled aerial hyphae proliferation, elevated sensitivity to heat and oxidative stresses, and lower carotenoid synthesis. To further study the function of GNA-1, constructs to enable expression of mammalian Gαi superfamily members were transformed into a Δ gna-1 strain, and complementation of Δgna-1 defects investigated. Gαs, which is not a member of Gα i superfamily was used as a control. These mammalian Gα genes were able to rescue the vegetative growth rate defect of the Δ gna-1 strain in the following order: Gαz > Gα o > Gαs > Gαt > Gαi. In contrast, only Gαo was able to complement the sexual defect of a Δgna-1 strain. With regard to the thermotolerance phenotype, none of the mammalian Gα genes restored the sensitivity to a wild type level. These results suggest that GNA-1 regulates two independent pathways during the vegetative and sexual cycles in N. crassa. ^ GNB-1, a G protein β subunit from N. crassa, was identified and its functions investigated in this thesis work. The sequence of the gnb-1 gene predicts a polypeptide of 358 residues with a molecular mass of 39.7 kDa. GNB-1 exhibits 91% identity to Cryphonectria parasitica CPGB-1, and also displays significant homology with human and Dictyostelium Gβ genes (∼66%). A Δ gnb-1 strain was constructed and shown to exhibit defects in asexual spore germination, vacuole number and size, mass accumulation and female fertility. A novel role for GNB-1 in regulation of GNA-1 and GNA-2 protein levels was also demonstrated. ^

Net primary productivity, POC export, Th234 and U238 activities and abundance of autotrophs during U.S.C.G.C. Healy cruises HLY0802 and HLY0803

Seasonal patterns in the partitioning of phytoplankton carbon during receding sea ice conditions in the eastern Bering Sea water column are presented using rates of 14C net primary productivity (NPP), phototrophic plankton carbon content, and POC export fluxes from shelf and slope waters in the spring (March 30-May 6) and summer (July 3-30) of 2008. At ice-covered and marginal ice zone (MIZ) stations on the inner and middle shelf in spring, NPP averaged 76 ± 93 mmol C/m**2/d, and in ice-free waters on the outer shelf NPP averaged 102 ± 137 mmol C/m**2/d. In summer, rates of NPP were more uniform across the entire shelf and averaged 43 ± 23 mmol C/m**2/d over the entire shelf. A concomitant shift was observed in the phototrophic pico-, nano-, and microplankton community in the chlorophyll maximum, from a diatom dominated system (80 ± 12% autotrophic C) in ice covered and MIZ waters in spring, to a microflagellate dominated system (71 ± 31% autotrophic C) in summer. Sediment trap POC fluxes near the 1% PAR depth in ice-free slope waters increased by 70% from spring to summer, from 10 ± 7 mmol C/m**2/d to 17 ± 5 mmol C/m**2/d, respectively. Over the shelf, under-ice trap fluxes at 20 m were higher, averaging 43 ± 17 mmol C/m**2/d POC export over the shelf and slope estimated from 234Th deficits averaged 11 ± 5 mmol C/m**2/d in spring and 10 ± 2 mmol C/m**2/d in summer. Average e-ratios calculated on a station-by-station basis decreased by ~ 30% from spring to summer, from 0.46 ± 0.48 in ice-covered and MIZ waters, to 0.33 ± 0.26 in summer, though the high uncertainty prevents a statistical differentiation of these data.

Tab. 1+2: Representative electron-microprobe analyses of minerals from Du Toit Nunataks

An example of cordierite-bearing gneiss that is part of a high-grade gneiss-migmatite sequence is described from the Hatch Plain in the Read Mountains of the Shackleton Range, Antarctica, for the first time. The cordierite-bearing rocks constitute the more melanosomic portions of the metatectic and migmatitic rocks that are associated with relict granulite facies rocks such as enderbitic granulite and enderbitic garnet granulite. The predominant mineral assemblage in the cordierite-bearing rocks is chemically homogeneous cordierite (XMg 0.61) and biotite (XMg 0.47), strongly zoned garnet (XMg 0.18-0.11), sillimanite, K-feldspar (Or81-94Ab5-18An0.6), plagioclase (An28), and quartz. Inclusions of sillimanite and biotite relics in both garnet and cordierite indicate that garnet and cordierite were produced by the coupled, discontinuous reaction biotite + sillimanite + quartz = cordierite + garnet + K-feldspar + H2O. Various garnet-biotite and garnet-cordierite geothermometers and sillimanite-quartz-plagioclase-garnet-cordierite geobarometers yield a continuous clockwise path in the P-T diagram. The P-T conditions for equilibrium between garnet core and cordierite and between garnet core and biotite during peak metamorphism and migmatization were estimated to be 690 °C at 5-6 kb. This was followed by cooling and unloading with continuously changing conditions down to 515 °C at 2-3 kb. This low-pressure re-equilibration correlates with the pressure conditions evaluated by SCHULZE (1989) for the widespread granitic gneisses of the Read Group in the Shackleton Range. The associated relict enderbitic granulites representing low-pressure type granulite (8 kb; 790 °C) are comparable to similar low-pressure granulites from the East Antarctic craton. They were either formed by under-accretion processes after collision (WELLS 1979, p. 217) or they are a product of remetamorphism at P-T conditions intermediate between granulite and amphibolite facies. A model of a multiple imbrication zone with crustal thickening (CUTHBERT et al. 1983) is discussed for the formation of the relict granulites of the central and eastern Read Mountains which show higher pressure conditions (8-12 kb, SCHULZE & OLESCH 1990), indicating a Proterozoic crustal thickness of at least 40 km.

(Table 2) Vertical fluxes of organic carbon and sediment matter from the photic zone in the Arctic Basin

On the basis of analysis of satellite and field data collected in Russian Arctic Seas maps of distribution of primary production for different months of the vegetation period were compiled. These maps were used to estimate annual primary production of organic carbon: 55 million tons in the Barents Sea; about 20 million tons in the Kara Sea; 10-15 million tons in the Laptev Sea and in the East Siberian Sea, 42 million tons in the Chukchi Sea. In the central and eastern parts of the Barents Sea during the vegetation period values of primary production decreased by factor >5 (from >500 to <100 mg C/m**2/day). By reviewing results of studies with sediment traps vertical fluxes of organic carbon in different regions of the Arctic Basin were estimated. Significant temporal variability of Corg fluxes with maxima during phytoplankton blooms (by 830 mg C/m**2/day) was noted. Typical summer fluxes of Corg are 10-40 mg C/m**2/day in the southern Barents Sea, 1-10 mg C/m**2/day in the northern Barents Sea and in the Kara Sea, and up to 370 mg C/m**2/day in the zone of marginal filters of the Ob and Yenisey rivers.

Characteristics of eggs and female adults of Calanus finmarchicus, C. glacialis and C. hyperboreus from Disko Bay, western Greenland

This is the first high temporal-resolution study in Disko Bay covering population dynamics, grazing, reproduction, and biochemical composition of 3 dominating copepod species (Calanus finmarchicus, C. glacialis and C. hyperboreus) from late winter to midsummer in 2008. C. finmarchicus and C. glacialis ascended to the surface layer at the onset of the spring phytoplankton bloom, followed by C. hyperboreus 2 wk later. C. finmarchicus spawning occurred during the bloom and postbloom period, partially fueled by wax esters. C. glacialis commenced spawning before the bloom, yet it was greatly stimulated when food became available. However, feeding and reproduction was terminated after the main bloom despite the presence of food. In terms of feeding, this was also the strategy for C. hyperboreus. Between pre-bloom and post-bloom, C. finmarchicus showed an increase in carbon, nitrogen, and phospholipid content but a decrease in total lipid content. This was likely the result of protein synthesis, oocyte maturation, and spawning fueled by wax esters and by feeding. C. glacialis showed a similar pattern, although with an increasing total lipid content from pre-bloom to post-bloom, and an increasing wax ester and decreasing phospholipid content after reproduction was terminated. C. hyperboreus showed greatly increased content of carbon, nitrogen, and all lipid classes between the pre- and post-bloom periods. Hence, C. finmarchicus commenced feeding and spawning at the onset of the bloom and continued throughout the remaining study period. Both C. glacialis and C. hyperboreus females refueled their storage lipids (wax esters) during the bloom and post-bloom period, suggesting that they may spawn in an additional year.

(Table 2) Production characteristics of phytoplankton and selected related factors at bottle sampling stations in the subtropical and tropical Atlantic Ocean

In October and November 2002, high and relatively high values of chlorophyll a concentration at the sea surface (Cchl) were observed in the English Channel (0.47 mg/m**3), in waters of the North Atlantic Current (0.25 mg/m**3 ), in the tropical and subtropical anticyclonic gyres (0.07-0.42 mg/m**3), and also in the southwestern region of the southern subtropical anticyclonic gyre (usually 0.11-0.23 mg/m**3). The central regions of the southern subtropical anticyclonic gyre (SATG) and the North Atlantic tropical gyre (NATR) were characterized by lower values of Cchl (0.02-0.08 mg/m**3 for the SATG and 0.07-0.14 mg/m**3 for the NATR). At most of the SATG stations, values of surface primary production (Cphs) varied from 2.5 to 5.5 mg C/m**3 per day and were mainly defined by fluctuations of Cchl (r = +0.78) rather than by those of the assimilation number (r = +0.54). Low assimilation activity of phytoplankton in these waters (1.3-4.6 mg chl a per hour) pointed to a lack of nutrients. Analysis of variability of their concentration and composition of photosynthetic pigments showed that, in waters north of 30°N, the growth of phytoplankton was mostly restricted by deficiency of nitrogen, while, in more southern areas, at the majority of stations (about 60%), phosphorus concentrations were minimal. At low concentrations of nitrates and nitrites, ammonium represented itself as a buffer that prevented planktonic algae from extreme degrees of nitric starvation. In tropical waters and in waters of the SATG, primary production throughout the water column varied from 240 to 380 mg C/m**2 30° per day. This level of productivity at stations with low values of C chl (<0.08 mg/m**3) was provided by a well-developed deep chlorophyll maximum and high transparency of water. Light curves of photosynthesis based on in situ measurements point to high efficiency of utilizing penetrating solar radiation by phytoplankton on cloudy days.

(Table 2) Production parameters of phytoplankton and some associated parameters in the area of the Titanic Polygon

Studies were carried out mostly in the area of RMS Titanic wreck site (41°44'N, 49°57'W) located above the continental slope and the south of the Grand Banks of Newfoundland. In a period from 18.06 to 24.09.2001 five surveys of production characteristics of surface phytoplankton were conducted over 5-9 days. Mean values of these characteristics obtained during the surveys were 9.2-11.7 mg C/m**3 per day for primary production (C_phs), 0.102-0.188 mg/m**3 for chlorophyll a (C_chls), and 4.44-7.42 mg C/mg chl. a per hour for assimilation number (AN). The main reason for low C_phs variability was a significant inverse relationship (R=-0.66) between AN and C_chls found over the research area. When cold shelf waters dominated in the area (27.07 to 19.08.2001), C_chls values for the slope region (0.125+/-0.031 µg/l) and for the outer shelf (0.130+/-0.040 µg/l) were similar. During strengthening of influence of warmer slope waters within area (from 29.08 to 13.09.2001), C_chls concentration within surface waters of the outer shelf was 0.152+/-0.039 µg/l and exceeded one for the slope region (0.094+/-0.004 µg/l) by factor 1.6. Against the background of low Cchls values, the High values of integral primary production in the water column (510-1010 mg C/m**2 per day) at low C_chls values measured within the area were determined both by high assimilation activity of phytoplankton and by the deep (30-40 m) maximum of primary production. Main reasons for formation of such a maximum were high chlorophyll concentration within the layer of the deep chlorophyll maximum (up to 0.5-2.5 µg/l) and in the relatively high solar irradiance within this layer varying from 1.4 to 8.6% of subsurface PAR.

Analysis of Manganese nodules from Sonne cruises SO06/1 and /2, "Hawaii-Tahiti-Transect", Teilprojekt ICIME

Manganese nodules research has focused on the area between the Clarion Fracture Zone to the North and the Clipperton Fracture Zone to the South where significant concentrations were found ni Ni-Cu. During the CCOP/SOPAC-IOC/IDOE International workshop on the "Geology Mineral Resources and Geophysics of the South Pacific" held in Fiji in September 1975, a working group on manganese nodules was formed by scientists from: CNEXO, Brest, the Institute of Oceanography, New Zealand, Imperial College, London and the Technical University of Aachen. A draft project was presented in July 1976 by J. Andrews, University of Hawaii and G. Pautot, Cnexo on a joint survey under the name of: "Hawaii-Tahiti Transect program". Further details were worked on in September 1976 during the International Geological Congress in Sydney with the participation of D. Cronan, Imperial College, Glasby, New Zealand Geological Survey and G. Friedrich, Aachen TU. The scientific final program was established in July 1977, planning on the participation of three research vessels: the Suroit (CNEXO), the Kana Keoki (U. of Hawaii) and the Sonne (Aachen TU). Several survey areas were selected across the Pacific Ocean (Areas A, B, C, D, E, F, G and H) with about the same crustal age (about 40 million years) and a similar water depths. Being near large fault zones, the ares would be adequate to study the influences of biological productivity, sedimentation rate and possibly volcanic activity on the formation and growth of manganese nodules. The influnece of volcanic activity study would particularly apply to area G being situated near the Marquesas Fracture Zone. The cruise from R/V Sonne started in August 1978 over areas C, D, F, G K. The R/V suroit conducted a similar expedition in 1979 over areas A, B, C, D, E, H and I. Others cruises were planned during the 1979-1980 for the R/V Kana Keoki. The present text relates the R/V Sonne Cruises SO-06/1 and SO-06/2 held within the frame work of this international cooperative project.

A “REVOLTA” DE JEÚ E A ESTELA DE DÃ: Um Estudo Em 2 Reis 10,28-36

A pesquisa tem por objetivo trabalhar o evento da Revolta de Jeú, em conjunto com a Estela de Dã, tendo como ponto de partida para tal, a exegese da perícope de 2 Reis 10-28,36. A história Deuteronomista apresenta o ato da Revolta de Jeú como sendo um feito demasiadamente importante, na restauração do culto a Javé em Israel, a partir de um contexto onde o culto a outras divindades, em Israel Norte, estava em pleno curso. No entanto, a partir da análise conjunta da Estela de Dã, que tem como provável autor o rei Hazael de Damasco, somos desafiados a ler esta história pelas entrelinhas não contempladas pelo texto, que apontam para uma participação ativa de Hazael, nos desfechos referentes a Revolta de Jeú, como sendo o responsável direto que proporcionou a subida de Jeú ao trono em Israel, clarificando desta forma este importante período na história Bíblica. Para tal análise, observar-se-á três distintos tópicos, ligados diretamente ao tema proposto: (1) A Revolta de Jeú e a Redação Deuteronomista, a partir do estudo exegético da perícope de 2 Reis 10,28-36, onde estão descritas informações pontuais sobre período em que Jeú reinou em Israel; (2) Jeú e a Estela de Dã, a partir da apresentação e análise do conteúdo da Estela de Dã, tratando diretamente dos desdobramentos da guerra em Ramote de Gileade, de onde se dá o ponto de partida à Revolta de Jeú; e por fim (3) O Império da Síria, onde a partir da continuidade da análise do conteúdo da Estela de Dã, demonstraremos a significância deste reino, além de apontamentos diretamente ligados ao reinado de Hazael, personagem mui relevante no evento da Revolta de Jeú.

Transient cardiac expression of constitutively active Gαq leads to hypertrophy and dilated cardiomyopathy by calcineurin-dependent and independent pathways

Cardiac hypertrophy and dilatation can result from stimulation of signal transduction pathways mediated by heterotrimeric G proteins, especially Gq, whose α subunit activates phospholipase Cβ (PLCβ). We now report that transient, modest expression of a hemagglutinin (HA) epitope-tagged, constitutively active mutant of the Gq α subunit (HAα*q) in hearts of transgenic mice is sufficient to induce cardiac hypertrophy and dilatation that continue to progress after the initiating stimulus becomes undetectable. At 2 weeks, HAα*q protein is expressed at less than 50% of endogenous αq/11, and the transgenic hearts are essentially normal morphologically. Although HAα*q protein declines at 4 weeks and is undetectable by 10 weeks, the animals develop cardiac hypertrophy and dilatation and die between 8 and 30 weeks in heart failure. As the pathology develops, endogenous αq/11 rises (2.9-fold in atria; 1.8-fold in ventricles). At 2 weeks, basal PLC activity is increased 9- to 10-fold in atria but not ventricles. By 10 weeks, it is elevated in both, presumably because of the rise in endogenous αq/11. We conclude that the pathological changes initiated by early, transient HAα*q expression are maintained in part by compensatory changes in signal transduction and other pathways. Cyclosporin A (CsA) prevents hypertrophy caused by activation of calcineurin [Molkentin, J. D., Lu, J.-R., Antos, C. L., Markham, B., Richardson, J., Robbins, J., Grant, S. R. & Olson, E. N. (1998) Cell 93, 215–228]. Because HAα*q acts upstream of calcineurin, we hypothesized that HAα*q might initiate additional pathways leading to hypertrophy and dilatation. Treating HAα*q mice with CsA diminished some, but not all, aspects of the hypertrophic phenotype, suggesting that multiple pathways are involved.