Dephasing and relaxational polarized sub-Ohmic baths acting on a two-level system.

We study a quantum two-level system under the influence of two independent baths, i.e., a sub-Ohmic pure dephasing bath and an Ohmic or sub-Ohmic relaxational bath. We show that cooling such a system invariably polarizes one of the two baths. A polarized relaxational bath creates an effective asymmetry. This asymmetry can be suppressed by additional dephasing noise. This being less effective, the more dominant low frequencies are in the dephasing noise. A polarized dephasing bath generates a large shift in the coherent oscillation frequency of the two-level system. This frequency shift is little affected by additional relaxational noise nor by the frequency distribution of the dephasing noise itself. As our model reflects a typical situation for superconducting phase qubits, our findings can help optimize cooling protocols for future quantum electronic devices.

Quasi-adiabatic path integral approach for quantum systems under the influence of multiple non-commuting fluctuations.

Quantum systems are typically subject to various environmental noise sources. Treating these environmental disturbances with a system-bath approach beyond weak coupling, one must refer to numerical methods as, for example, the numerically exact quasi-adiabatic path integral approach. This approach, however, cannot treat baths which couple to the system via operators, which do not commute. We extend the quasi-adiabatic path integral approach by determining the time discrete influence functional for such non-commuting fluctuations and by modifying the propagation scheme accordingly. We test the extended quasi-adiabatic path integral approach by determining the time evolution of a quantum two-level system coupled to two independent baths via non-commuting operators. We show that the convergent results can be obtained and agreement with the analytical weak coupling results is achieved in the respective limits.

Environmental rocking ratchet: Environmental rectification by a harmonically driven avoided crossing.

We propose a rocking ratchet designed as a symmetric quantum two-state system driven by a single periodic harmonic force and influenced symmetrically by thermal fluctuations. We show that the necessary broken symmetry can dynamically be achieved by a thermal environment that couples to the energy difference between the two states and the tunnel coupling between them. The quantum two-state system is driven by the harmonic periodic drive through its avoided crossing. The correspondingly driven dissipative quantum dynamics results on average in a finite population difference between both states. This then causes directed particle transport.

TRIM32-dependent transcription in adult neural progenitor cells regulates neuronal differentiation.

In the adult mammalian brain, neural stem cells in the subventricular zone continuously generate new neurons for the olfactory bulb. Cell fate commitment in these adult neural stem cells is regulated by cell fate-determining proteins. Here, we show that the cell fate-determinant TRIM32 is upregulated during differentiation of adult neural stem cells into olfactory bulb neurons. We further demonstrate that TRIM32 is necessary for the correct induction of neuronal differentiation in these cells. In the absence of TRIM32, neuroblasts differentiate slower and show gene expression profiles that are characteristic of immature cells. Interestingly, TRIM32 deficiency induces more neural progenitor cell proliferation and less cell death. Both effects accumulate in an overproduction of adult-generated olfactory bulb neurons of TRIM32 knockout mice. These results highlight the function of the cell fate-determinant TRIM32 for a balanced activity of the adult neurogenesis process.

Need and sequence of large joint replacements in rheumatoid arthritis. A 25-year follow-up study.

OBJECTIVE: The aim of the present study was to evaluate the number and sequence of large joint replacements (LJR) performed in long-term rheumatoid arthritis (RA) from an inception cohort of 103 patients with rheumatoid factor (RF)-positive RA followed over 25 years. METHODS: A total of 83 patients attended the 15-year and 68 patients the 20-year follow-up. Patient documents and radiographs were evaluated in the beginning of 2001 and a complementary interview was arranged to assess the number and sequence (timing) of LJRs performed. RESULTS: The cumulative number of LJRs performed for 22 patients (19 women) during the 25 years of follow-up was 41. Seventeen total hip joint replacements (THR) (42% of the total number of 41 LURs) were performed on 13 patients, median time from the diagnosis to the operation being 14 years; 14 total knee replacements (TKR) (34%) on 11 patients (after a median time of 17 years); 3 total shoulder replacements (TSR) (7%) on 3 patients (median time of 18 years); and 7 total elbow replacements (TER) (17%) on 4 patients (median time of 21 years), respectively. Six patients had undergone three or more LJRs during the follow-up period. CONCLUSION: During our 25 years of follow-up, in 27% of RA patients LUR was needed, and 41% of them needed more than one replacement.

Disease-causing mutations in cardiac troponin T: identification of a critical tropomyosin-binding region.

Fifteen percent of the mutations causing familial hypertrophic cardiomyopathy are in the troponin T gene. Most mutations are clustered between residues 79 and 179, a region known to bind to tropomyosin at the C-terminus near the complex between the N- and C-termini. Nine mutations were introduced into a troponin T fragment, Gly-hcTnT(70-170), that is soluble, alpha-helical, binds to tropomyosin, promotes the binding of tropomyosin to actin, and stabilizes an overlap complex of N-terminal and C-terminal tropomyosin peptides. Mutations between residues 92 and 110 (Arg92Leu, Arg92Gln, Arg92Trp, Arg94Leu, Ala104Val, and Phe110Ile) impair tropomyosin-dependent functions of troponin T. Except for Ala104Val, these mutants bound less strongly to a tropomyosin affinity column and were less able to stabilize the TM overlap complex, effects that were correlated with increased stability of the troponin T, measured using circular dichroism. All were less effective in promoting the binding of tropomyosin to actin. Mutations within residues 92-110 may cause disease because of altered interaction with tropomyosin at the overlap region, critical for cooperative actin binding and regulatory function. A model for a five-chained coiled-coil for troponin T in the tropomyosin overlap complex is presented. Mutations outside the region (Ile79Asn, Delta 160Glu, and Glu163Lys) functioned normally and must cause disease by another mechanism.

Solution NMR structure and folding dynamics of the N terminus of a rat non-muscle alpha-tropomyosin in an engineered chimeric protein.

Tropomyosin is an alpha-helical coiled-coil protein that aligns head-to-tail along the length of the actin filament and regulates its function. The solution structure of the functionally important N terminus of a short 247-residue non-muscle tropomyosin was determined in an engineered chimeric protein, GlyTM1bZip, consisting of the first 19 residues of rat short alpha-tropomyosin and the last 18 residues of the GCN4 leucine zipper. A gene encoding GlyTM1bZip was synthesized, cloned and expressed in Escherichia coli. Triple resonance NMR spectra were analyzed with the program AutoAssign to assign its backbone resonances. Multidimensional nuclear Overhauser effect spectra, X-filtered spectra and (3)J(H(N)-H(alpha)) scalar coupling were analyzed using AutoStructure. This is the first application of this new program to determine the three-dimensional structure of a symmetric homodimer and a structure not previously reported. Residues 7-35 in GlyTM1bZip form a coiled coil, but neither end is helical. Heteronuclear (15)N-(1)H nuclear Overhauser effect data showed that the non-helical N-terminal residues are flexible. The (13)C' chemical shifts of the coiled-coil backbone carbonyl groups in GlyTM1bZip showed a previously unreported periodicity, where resonances arising from residues at the coiled-coil interface in a and d positions of the heptad repeat were displaced relatively upfield and those arising from residues in c positions were displaced relatively downfield. Heteronuclear single quantum coherence spectra, collected as a function of temperature, showed that cross-peaks arising from the alpha-helical backbone and side-chains at the coiled-coil interface broadened or shifted with T(M) values approximately 20 degrees C lower than the loss of alpha-helix measured by circular dichroism, suggesting the presence of a folding intermediate. The side-chain of Ile14, a residue essential for binding interactions, exhibited multiple conformations. The conformational flexibility of the N termini of short tropomyosins may be important for their binding specificity.

Nucleotide-binding sites in the functional unit of sarcoplasmic reticulum Ca2+-ATPase as studied by photoaffinity spin-labeled 2-N3-SL-ATP.

2-N3-SL-ATP [2-azido-2',3'-O-(1-oxyl-2,2,5,5-tetramethyl-3-carbonyl-pyrroline) adenosine triphosphate], a photoaffinity spin-labeled derivative of ATP with a nitroxide moiety attached to the ribose ring and an azido group attached to C2 of the adenine ring, was used to study the nucleotide-binding site stoichiometry of sarcoplasmic reticulum (SR) Ca2+-ATPase. The label was shown to bind at the catalytic site of the enzyme, even though the rate of hydrolysis was poor. A maximal binding ratio of 1 mol/mol of ATPase was found. The ESR spectra showed signals from spin-spin interactions between two radicals corresponding to a distance of about 15 A between labels bound to adjacent sites on the enzyme. This indicates that the minimal functional unit of the Ca2+-ATPase is a dimer with the nucleotide-binding sites in close proximity.

Identification of a novel common genetic risk factor for lumbar disk disease.

CONTEXT: Lumbar disk disease (LDD) is one of the most common musculoskeletal diseases, with a prevalence of about 5%. A tryptophan (Trp) allele (Trp2) was recently discovered in the COL9A2 gene that is associated with dominantly inherited LDD but is only present in about 4% of Finnish patients with LDD. OBJECTIVE: To determine if other collagen IX gene sequence variations play a role in the pathogenesis of LDD. DESIGN AND SETTING: Case-control study conducted from February 1997 to May 1998 at university hospitals in Finland. PARTICIPANTS: A total of 171 individuals with LDD (evaluated clinically and by magnetic resonance imaging or computed tomography) and 321 controls without LDD (186 healthy individuals, 83 patients with primary osteoarthritis, 31 with rheumatoid arthritis, and 21 with chondrodysplasias). MAIN OUTCOME MEASURES: Frequencies of sequence variations covering the entire coding sequences and exon boundaries of the collagen IX genes, COL9A1, COL9A2, and COL9A3, which code for the alpha1, alpha2, and alpha3 chains of the protein, detected by conformation-sensitive gel electrophoresis and confirmed by sequencing, compared between individuals with and without LDD. RESULTS: Mutation analysis of all 3 collagen IX genes resulted in identification of an Arg103-->Trp (arginine-->tryptophan) substitution in the alpha3 chain (Trp3 allele). The frequency of the Trp3 allele was 12.2% in LDD cases, excluding 7 individuals who were carriers of the previously identified Gln326-->Trp (glutamine-->tryptophan) substitution in the alpha2 chain (Trp2 allele), and was 4.7% among controls. The difference in the frequency was statistically significant (P =.000013). Presence of at least 1 Trp3 allele increases risk of LDD about 3-fold. CONCLUSION: This study led to the identification of a novel common genetic risk factor for LDD, confirming that genetic risk factors likely play a significant role in LDD.

Intradomain distances in the regulatory domain of the myosin head in prepower and postpower stroke states: fluorescence energy transfer.

The relative movement of the catalytic and regulatory domains of the myosin head (S1) is likely to be the force generating conformational change in the energy transduction of muscle [Rayment, I., Holden, H. M., Whittaker, M., Yohn, C. B., Lorenz, M., Holmes, K. C., and Milligan, R. A. (1993) Science 261, 58-65]. To test this model we have measured, using frequency-modulated FRET, three distances between the catalytic domain and regulatory domains and within the regulatory domain of myosin. The donor/acceptor pairs included MHC cys707 and ELC cys177; ELC cys177 and RLC cys154; and ELC cys177 and gizzard RLC cys108. The IAEDANS (donor) or acceptor (DABMI or IAF) labeled light chains (ELC and RLC) were exchanged into monomeric myosin and the distances were measured in the putative prepower stroke states (in the presence of MgATP or ADP/AlF(4-)) and the postpower stroke states (ADP and the absence of nucleotides). For each of the three distances, the donor/acceptor pairs were reversed to minimize uncertainty in the distance measured, arising from probe orientational factors. The distances obtained from FRET were in close agreement with the distances in the crystal structure. Importantly, none of the measured distances varied by more than 2 A, putting a strong constraint on the extent of conformational changes within S1. The maximum axial movement of the distal part of myosin head was modeled using FRET distance changes within the myosin head reported here and previously. These models revealed an upper bound of 85 A for a swing of the regulatory domain with respect to the catalytic domain during the power stroke. Additionally, an upper bound of 22 A could be contributed to the power stroke by a reorientation of RLC with respect to the ELC during the power stroke.

Cardiovascular reactivity, Type A behavior, and coronary heart disease: comparisons between myocardial infarction patients and controls during laboratory-induced stress.

Cardiovascular responses to a series of laboratory stressors were examined in middle-aged Type A and Type B men. The subjects were 30 patients with diagnosed myocardial infarction (NYHA Class 1) and 26 age-matched healthy controls. All subjects were nonsmokers in the normotensive range, and none were on medication. Blood pressure, heart rate, forearm blood flow and resistance, and impedance cardiography-determined response variables were obtained during performance and recovery periods of both mental and physical tasks. The patients showed elevated reactivity in systolic blood pressure and cardiac output and prolonged systolic time ratio during mental stress tasks and elevated total peripheral resistance and lower cardiac output and stroke volume during physical tasks, as compared with control subjects. Thus, the difference in blood pressure reactivity between patients and controls appeared to be primarily dependent on the vascular component during physical tasks, whereas the mental tasks promoted a hemodynamic response pattern more consistent with beta adrenergic activation. Type A men, irrespective of coronary status, showed larger systolic and diastolic blood pressure response to both mental and physical stress than did Type B men.

Psychophysiological effects of cardiac rehabilitation in post-myocardial infarction patients.

Psychophysiological reactivity and cardiovascular functioning were assessed in 40 patients with coronary heart disease before and after taking part in either a Type A modification training program or a control condition. Treated patients showed an overall attenuated heart rate (HR) response and prolonged diastolic time to mental stress performance, during recovery and rest periods, as compared lo control patients. No other measure, including impedance-cardiography-derived measures, differentiated the two groups. The treatment group showed reduction from before lo after treatment in 24-hr minimum IIR level and decreased frequencies of premature ventricular contractions, whereas the control group showed an opposite trend. Results from an exercise test suggested the same direction for resting IIR and double-product levels. The two groups did not differ in maximal systolic and diastolic blood pressure or in maximal double-product levels, despite a differential development, in favor of the treatment group, in maximal work capacity.

Social interaction, cardiovascular activation and the Type A behavior pattern.

The purpose of the study was to explore the relationship between social interaction and cardiovascular activity during a conflict-inducing communication task in Type A and B subjects. One of the subjects, the leader, was instructed to lead the other subject, the follower, through defined routes on a city map merely by help of instructions. The subjects were facing each other on each side of a screen which allowed eye contact but shielded the maps from view. 40 male students (mean age 24 years) exhibiting Type A or Type B behavior according to the Videotaped Structured Interview participated in the study. The results demonstrated large cardiovascular increases during task performance, particularly for leaders, in systolic blood pressure and heart rate. There were no main effects of Type A vs. Type B, but dyads composed of two Type As showed larger increase in diastolic blood pressure during the conflict phase of the task compared to dyads composed of Type Bs.

Recovery following thiopentone or propofol anaesthesia assessed by computerized coordination measurements.

Quantitative measurements of coordination ability and performance speed were carried out on 76 female day-case patients undergoing minor gynaecological operations. The women were assigned at random to the anaesthetic agent used, propofol 2.5 mg/kg or thiopentone 4 mg/kg. Spacing control, timing control and performance speed were recorded using a newly developed computerized coordination ability test system. The patients were tested once before the operation and 0.5, 1 and 2 h after awakening. Postoperatively the initial impairment and the subsequent regression towards preoperative test results were very similar whether the anaesthetic agent was propofol or thiopentone. Although the test apparatus was able to detect even minor differences, no postoperative test showed statistically significant differences between the two groups. We find it reasonable to conclude that there is no difference in recovery of coordination ability following propofol- or thiopentone-induced anaesthesia.

Computerized coordination ability testing.

Quantitative measurements of coordination ability were carried out on 76 women with a median age of 37, range 15 to 60. Spacing control, timing control and performance speed were recorded using newly developed computerized equipment, Catsys, presented in this paper. Twenty-three subjects were re-examined 2-3 months after the first measurements. A fair or even high degree of reproducibility of tests was found. Normal values for the entire group and correlation values for the re-examined group are presented. The results from this small study implies that the Catsys may be useful, e.g., in future clinical neurological practice of diagnostics and follow up on patients, in occupational medicine for detection of neurotoxic effects of various neurotoxic substances, in evaluation of drug effects and side effects and for testing people in occupations where normal coordination skills are absolutely necessary.

Measurement of water filtration in skeletal muscle in man by an osmotic transient method.

Water filtration in the human forearm was determined with a new method using a hyperoncotic transient of albumin solution infused into the brachial artery. Baseline dilution of labelled albumin in deep forearm vein plasma in excess of the contribution from arterial blood and from infusate was assumed to originate from extravascular water filtered into the blood by the transient. The filtration coefficient (Fc) was determined as the ratio between filtered water and increase in colloid osmotic pressure in the blood samples, and gives the filtrative water permeability in the exchange areas of the microcirculation. In 10 normal volunteers, Fc was 0.00082 ml (ml mmHg)-1 (SD=0.00007). Multiplication of Fc by plasma flow in the forearm gave a filtration capacity (Kf) of 0.0036 ml (100 ml tissue min mmHg)-1 (SD=0.00137). This filtration capacity (Kf) represents that of fast flowing regions in the forearm muscles, but it is of the same order of magnitude as the capillary filtration coefficient (CFC) determined plethysmographically for the entire forearm by the venous stasis technique.

Vascular recruitment in forearm muscles during exercise.

Blood flow and filtration of water across the vascular bed in human forearm muscles were studied at rest and during graded exercise with a hand ergometer. Blood flow was measured by dye dilution and water filtration was determined after injection of hyperoncotic albumin solution (23%) in the brachial artery creating a tissue to blood ultrafiltration measureable as a dilution in the effluent blood. The filtration constants were expressed as a filtration coefficient Fc (ml water/ml plasma mmHg increase in oncotic pressure), and, multiplying by the plasma flow, as a filtration capacity Kf (ml water/100 ml tissue min mmHg increase in oncotic pressure). During the increase in plasma flow induced by exercise, Fc remained constant at about 0.0007, but Kf increased in parallel with the hyperaemia from 0.0031 to 0.038 when plasma flow increased from 4 to 48 ml (100 ml min)-1. The data suggest a more massive recruitment of exchange area during exercise (a factor 12) than suspected on the basis of ultrafiltration in animals made with the prolonged venous stasis technique (showing a factor 2-5). The estimated variability in exchange surface area indicates, that animal studies of muscle circulation, whether pertaining to capillary permeability or capillary filtration should gain by an independent estimate of the number of capillaries that are flowing during the particular experimental situation.