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Differences and similarities in the neuropsychological profile of dementia with Lewy bodies and Alzheimer's disease in the early stage.

The literature concerning the neuropsychological profile of dementia with Lewy bodies (DLB) reports contrasting data even though a main impairment in attentional and visuospatial processes is mostly pointed out. In the present study, two selected groups, one of 12 DLB and the other of 12 Alzheimer's disease (AD) patients, both in the early stage of the disease, were matched for age, education and Mini Mental State Examination (MMSE). A comprehensive neuropsychological assessment and three scales to evaluate fluctuating cognition were administered. Significant differences were found between the two groups on attentional domain, memory, constructional and visuoperceptual abilities and fluctuation scales.

Aged↗

Hydrogen exchange kinetics of RNase A and the urea:TMAO paradigm.

A key paradigm in the biology of adaptation holds that urea affects protein function by increasing the fluctuations of the native state, while trimethylamine N-oxide (TMAO) affects function in the opposite direction by decreasing the normal fluctuations of the native ensemble. Using urea and TMAO separately and together, hydrogen exchange (HX) studies on RNase A at pH* 6.35 were used to investigate the basic tenets of the urea:TMAO paradigm. TMAO (1 M) alone decreases HX rate constants of a select number of sites exchanging from the native ensemble, and low urea alone increases the rate constants of some of the same sites. Addition of TMAO to urea solutions containing RNase A also suppresses HX rate constants. The data show that urea and TMAO independently or in combination affect the dynamics of the native ensemble in opposing ways. The results provide evidence in support of the counteraction aspect of the urea:TMAO paradigm linking structural dynamics with protein function in urea-rich organs and organisms. RNase A is so resistant to urea denaturation at pH* 6.35 that even in the presence of 4.8 M urea, the native ensemble accounts for >99.5% of the protein. An essential test, devised to determine the HX mechanism of exchangeable protons, shows that over the 0-4.8 M urea concentration range nearly 80% of all observed sites convert from EX2 to EX1. The slow exchange sites are all EX1; they do not exhibit global exchange even at urea concentrations (5.8 M) well into the denaturation transition zone, and their energetically distinct activated complexes leading to exchange gives evidence of residual structure. Under these experimental conditions, the use of DeltaG(HX) as a basis for HX analysis of RNase A urea denaturation is invalid.

Adaptation, Physiological↗

Random dynamics of the Morris-Lecar neural model.

Determining the response characteristics of neurons to fluctuating noise-like inputs similar to realistic stimuli is essential for understanding neuronal coding. This study addresses this issue by providing a random dynamical system analysis of the Morris-Lecar neural model driven by a white Gaussian noise current. Depending on parameter selections, the deterministic Morris-Lecar model can be considered as a canonical prototype for widely encountered classes of neuronal membranes, referred to as class I and class II membranes. In both the transitions from excitable to oscillating regimes are associated with different bifurcation scenarios. This work examines how random perturbations affect these two bifurcation scenarios. It is first numerically shown that the Morris-Lecar model driven by white Gaussian noise current tends to have a unique stationary distribution in the phase space. Numerical evaluations also reveal quantitative and qualitative changes in this distribution in the vicinity of the bifurcations of the deterministic system. However, these changes notwithstanding, our numerical simulations show that the Lyapunov exponents of the system remain negative in these parameter regions, indicating that no dynamical stochastic bifurcations take place. Moreover, our numerical simulations confirm that, regardless of the asymptotic dynamics of the deterministic system, the random Morris-Lecar model stabilizes at a unique stationary stochastic process. In terms of random dynamical system theory, our analysis shows that additive noise destroys the above-mentioned bifurcation sequences that characterize class I and class II regimes in the Morris-Lecar model. The interpretation of this result in terms of neuronal coding is that, despite the differences in the deterministic dynamics of class I and class II membranes, their responses to noise-like stimuli present a reliable feature.

Animals↗

Trypanosoma cruzi induces edematogenic responses in mice and invades cardiomyocytes and endothelial cells in vitro by activating distinct kinin receptor (B1/B2) subtypes.

Trypanosoma cruzi, the protozoan that causes Chagas' heart disease, invades endothelial cells in vitro by activating the B2 kinin receptor (B2R). Here, we demonstrate that mice infected with trypomastigotes develop potent edema after treatment with the angiotensin-converting enzyme (ACE) (or kininase II) inhibitor captopril. Experiments performed with specific kinin receptor (B2R/B1R) antagonists and knockout mice revealed that the early-phase (3-h) edema is mediated by the constitutive B2R, whereas the late-phase (24-h) response depends on stimulation of the up-regulated B1R. Given previous evidence that parasite invasion of cells expressing B2R is potentiated by captopril, we investigated the prerequisites for in vitro infection of Chinese hamster ovary cells overexpressing either B1R or B2R, human umbilical vein endothelial cells activated by lipopolysaccharide, and neonatal rat cardiomyocytes. Our results indicate that captopril potentiates parasite invasion regardless of the kinin (B2/B1) activation pathways, whereas DL-2-mercaptomethyl-3-guanidino-ethylthiopropanoic acid (MGTA), an inhibitor of kininase I (carboxypeptidase M/N), selectively decreases parasite infectivity for B1R-expressing cells. These data suggest that formation of the B1R agonist, i.e., [des-Arg] kinins, critically depends on the processing action of kininase I, here proposed as a potential pathogenesis cofactor. Collectively, our data suggest that fluctuations in the levels of kininases may modulate parasite infectivity and pathological outcome in Chagas' disease.

Animals↗

The noise conversion method for oscillatory systems.

The paper addresses a method for calculating the amplitude and phase power spectral density (PSD) functions of an oscillatory system (resonator, oscillator, bandpass filter, selective circuit, etc.) via the PSDs of its intrinsic noise sources and relevant transformation coefficients. A systematic description of the method is given for the scalar and vector noises. As an illustration, the noise transformation coefficients are derived for a piezoelectric series branch with fluctuating motional inductance, capacity, and losses, in which static capacity is disregarded. We then clarify the rules regarding the shaping of either PSD function. The importance of this method resides in the fact that it enables us to study particular finite ranges of the PSD function without using differential equations.

Journal Article↗

Phenylalanine fluorescence studies of calcium binding to N-domain fragments of Paramecium calmodulin mutants show increased calcium affinity correlates with increased disorder.

Calmodulin (CaM) is a ubiquitous, essential calcium-binding protein that regulates diverse protein targets in response to physiological calcium fluctuations. Most high-resolution structures of CaM-target complexes indicate that the two homologous domains of CaM are equivalent partners in target recognition. However, mutations between calcium-binding sites I and II in the N-domain of Paramecium calmodulin (PCaM) selectively affect calcium-dependent sodium currents. To understand these domain-specific effects, N-domain fragments (PCaM(1-75)) of six of these mutants were examined to determine whether energetics of calcium binding to sites I and II or conformational properties had been perturbed. These PCaM((1-75)) sequences naturally contain 5 Phe residues but no Tyr or Trp; calcium binding was monitored by observing the reduction in intrinsic phenylalanine fluorescence at 280 nm. To assess mutation-induced conformational changes, thermal denaturation of the apo PCaM((1-75)) sequences, and calcium-dependent changes in Stokes radii were determined. The free energy of calcium binding to each mutant was within 1 kcal/mole of the value for wild type and calcium reduced the R(s) of all of them. A striking trend was observed whereby mutants showing an increase in calcium affinity and R(s) had a concomitant decrease in thermal stability (by as much as 18 degrees C). Thus, mutations between the binding sites that increased disorder and reduced tertiary constraints in the apo state promoted calcium coordination. This finding underscores the complexity of the linkage between calcium binding and conformational change and the difficulty in predicting mutational effects.

Amino Acid Sequence↗

Dementia with Lewy bodies.

BACKGROUND: Dementia with Lewy bodies (DLB) is a common dementia subtype that has only been recognised in the past decade and that remains widely underdiagnosed. AIMS: To review the pathological and clinical features of DLB, to consider methods of investigation and diagnosis, and to recommend safe and effective management strategies. METHOD: A selective review was made of the key literature. RESULTS: Using operationalised criteria, DLB can be clinically diagnosed with an accuracy similar to that achieved for Alzheimer's disease or Parkinson's disease. Underdetection is largely due to poor definition of the criterion of cognitive fluctuation. Ancillary investigations, particularly neuroimaging, can aid in differential diagnosis. Extreme caution in the use of neuroleptic medication is advised. Cholinesterase inhibitors may be particularly effective in DLB. CONCLUSIONS: Clinicians should be aware of DLB as part of a spectrum of Lewy body disorders. Neuroleptic sensitivity reactions and good response to cholinergic therapies are important aspects of management.

Aged↗

The effects of age, death period and birth cohort on asthma mortality rates in Australia.

SETTING AND OBJECTIVE: We assessed the relative effects of age, gender, period of death and birth cohort on asthma mortality rates in Australia from 1907 to 2000. DESIGN: Asthma mortality data obtained from the Australian Institute of Health and Welfare were adjusted for changes to the International Classification of Diseases and examined for changes over time and age, period and cohort effects. RESULTS: Age-adjusted period asthma mortality rates indicated epidemics during the mid 1960s and 1980s, predominantly affecting those aged 5-34 years. The main 1960s epidemic coincided with the introduction of high-dose, non-selective beta-sympathomimetic amines. There was a gradual rise in mortality rates in younger age groups, with rates rising from 0.5/100 000 males and 0.9/100 000 females in the 1940s to a peak of 3/100 000 for both sexes in 1966. Fluctuations in mortality rates were influenced by period of death and birth cohort. There was an increased risk of death from asthma with increasing age. CONCLUSION: There was no overall trend in asthma mortality rates in any age group. The 1960s epidemic was probably treatment related. Other increases in mortality occurring despite therapeutic advances may reflect increasing prevalence and highlight the need for ongoing surveillance.

Adolescent↗

Molecular evolution of dengue 2 virus in Puerto Rico: positive selection in the viral envelope accompanies clade reintroduction.

Dengue virus is a circumtropical, mosquito-borne flavivirus that infects 50-100 million people each year and is expanding in both range and prevalence. Of the four co-circulating viral serotypes (DENV-1 to DENV-4) that cause mild to severe febrile disease, DENV-2 has been implicated in the onset of dengue haemorrhagic fever (DHF) in the Americas in the early 1980s. To identify patterns of genetic change since DENV-2's reintroduction into the region, molecular evolution in DENV-2 from Puerto Rico (PR) and surrounding countries was examined over a 20 year period of fluctuating disease incidence. Structural genes (over 20 % of the viral genome), which affect viral packaging, host-cell entry and immune response, were sequenced for 91 DENV-2 isolates derived from both low- and high-prevalence years. Phylogenetic analyses indicated that DENV-2 outbreaks in PR have been caused by viruses assigned to subtype IIIb, originally from Asia. Variation amongst DENV-2 viruses in PR has since largely arisen in situ, except for a lineage-replacement event in 1994 that appears to have non-PR New World origins. Although most structural genes have remained relatively conserved since the 1980s, strong evidence was found for positive selection acting on a number of amino acid sites in the envelope gene, which have also been important in defining phylogenetic structure. Some of these changes are exhibited by the multiple lineages present in 1994, during the largest Puerto Rican outbreak of dengue, suggesting that they may have altered disease dynamics, although their functional significance will require further investigation.

Dengue↗

Ca2(+)-activated K+ channel from human erythrocyte membranes: single channel rectification and selectivity.

The Ca(+)-activated K+ channel of the human red cell membrane was characterized with respect to rectification and selectivity using the patch-clamp technique. In inside-out patches exposed to symmetric solutions of K+, Rb+, and NH+4, respectively, inward rectifying i-V curves were obtained. The zero current conductances were: K+ (23.5 pS +/- 3.2) greater than NH+4 (14.2 pS +/- 1.2) greater than Rb+ (11.4 pS +/- 1.8). With low extracellular K+ concentrations (substitution with Na+) the current fluctuations reversed close to the Nernst potential for the K ion and the rectification as well as the i-V slopes decreased. With mixed intracellular solutions of K+ and Na+ enhanced rectification were observed due to a Na+ block of outward currents. From bi-ionic reversal potentials the following permeability sequence (PK/PX was calculated: K+ (1.0) greater than Rb+ (1.4 +/- 0.1) greater than NH+4 (8.5 +/- 1.3) greater than Li+ (greater than 50); Na+ (greater than 110); Cs+ (much greater than 5). Li+, Na+, and Cs+ were not found to carry any current, and only minimum values of the permeability ratios were estimated. Tl+ was permeant, but the permeability and conductance were difficult to quantify, since with this ion the single channel activity was extremely low and the channels seemed to inactivate. The inward rectification in symmetric solutions indicate an asymmetric open channel structure, and the different selectivity sequences based on conductances and permeabilities reflect inter-ionic interactions in the permeation process.

Ammonia↗

[Tuberculosis in Iceland. 1976].

Because of signs of tuberculous lesions in old skeletons it can be stated with certainty that tuberculosis has occurred in the country shortly after the settlement. From that time and up to the seventeenth century, little or nothing is known about the occurrence of the disease. A few preserved descriptions of diseases and deaths indicate that tuberculosis has existed in the country before the advent of qualified physicians in 1760. On the basis of papers and reports from the first physicians and the first tuberculosis registers the opinions is set forth that the disease has been rare up to the latter part of the nineteenth century. During the two last decades of that century the disease began to spread more rapidly and increased steadily up to the turn of the century. Although reporting of the disease was started in the last decade of the nineteenth century the reporting was first ordered by law with the passage of the first tuberculosis Act in the year 1903. With this legislation official measures for tuberculosis control work really started in the country. The first sanatorium was built in 1910. In 1921 the tuberculosis Act was revised and since then practically all the expenses for the hospitalization and treatment of tuberculous cases has been defrayed by the state. In the year 1935 organized tuberculosis control work was begun and a special physician appointed to direct it. From then on systematic surveys were made, partly in health centers i.e. tuberculosis clinics, which were established in the main towns, and partly by means of transportable X ray units in outlying rural areas of the country. In 1939 the tuberculosis Act was again revised with special reference to the surveys and the activities of the tuberculosis clinics. This act is still in force. Some items of it are described. The procedure of the surveys and the methods of examination are described. The great majority of subjects were tuberculin tested and all positive reactors X rayed. Furthermore, X ray examination was made in all cases where tuberculin examination had not been made or was incomplete. The negative reactors were not X rayed. The tuberculin tests were percutaneous, cutaneous and intracutaneous. The X ray examination during the first years was performed by means of fluoroscopy and roentgenograms were made in all doubtful cases. In 1945 when the survey of the capital city of Reykjavík was made and comprised a total of 43,595 persons photoroentgenograms were made. After 1948 only this method together with tuberculin testing was used in all the larger towns in the country. During the period 1940-1945 such surveys were carried out in 12 medical districts, or parts thereof and included 58,837 persons or 47 percent of the entire population. The attendance in these surveys ranged from 89.3 percent to 100 percent of those considered able to attend. In the capital city, Reykjavík, the attendance was 99.32 percent. The course and prevalence of tuberculosis in Iceland from 1911 to 1970 are traced on the basis of tuberculosis reporting registers, mortality records which were ordered by law in 1911, tuberculin surveys and post mortem examinations. The deficiencies of these sources are pointed out. Since 1939 the morbidity rates are accurate. The number of reported cases of tuberculosis increases steadily up to the year 1935, when 1.6 percent of the population is reported to have active tuberculosis at the end of that year. Thereafter it begins to decline gradually the first years but abruptly in 1939, then without doubt because of the revision of the tuberculosis legislation and more exact reporting regulations. After that year the fall is almost constant with rather small fluctuations as regards new cases, relapses and total number of reported cases remaining on register at the end of each year. In 1950 the new cases are down to 1.6 per thousand and at the end of the year the rate for those remaining on register is 6.9 per thousand. In the year 1954 there is a noteworthy drop both in new cases and the total number reported, doubtless because of the new specific medication which began in 1952. In 1960 the new cases are down to 0.4, relapses 0.2 and the rate for those remaining on register at the end of the year 2.4 per thousand. And in 1970 the rate for the same categories are: new 0.2, relapses 0.06, and remaining at the end of the year 0.5 per thousand. At the beginning of the period, when registration of deaths was initiated, tuberculosis mortality was found to be about 150 per 100,000 population. During the next two decades it increases, irregularly but persistently, to reach a peak of 217 in 1925. It remained high for the next seven years, dropped suddenly to 154 in 1933, and then, apart from a slight temporary increase during the years of the second world war, continued to fall rapidly reaching 20 per 100,000 population in 1950. In the period from 1930-50 the tuberculous death rate thus dropped a little over 90 percent. In the year 1952, when specific tuberculosis medical treatment was initiated (streptomycin, isoniazid and PAS) the death rate dropped to 14 per 100,000 population and the next year further down to 9 and since 1956 it never exceeded 5 per 100,000. From the year 1962 the tuberculosis mortality has never been over 2 per 100,000 population. The mortality rates have been broken down to reveal the role of age and sex specific death rates over some selected five year periods. Also the rates are shown according to different forms of the disease, pulmonary, meningeal and other forms. The highest proportionate mortality (60%) was observed in the 15-19 year age group between 1926 and 1930. From 1911 to 1930 tuberculous meningitis caused a remarkably high number of deaths, fluctuating between 20 and 50 per 100,000 population. Since 1956 not a single death from this form of the disease has occurred. Up to that year the highest meningitis death-rate consistently occurred in infancy and early childhood. Sex-specific tuberculosis death rates indicate that in every age-group the disease is more dangerous to women. Between 1941 and 1945, when the combined mortality-rate began to drop sharply, it was the rate for the males, which was first affected. Due to the very steep decline in tuberculosis mortality especially from 1952 tuberculosis mortality figures can no longer be considered the right criterion for the spread and course of the disease. The infection and morbidity rates are from then on the best measures of the prevalence and course of the disease. Tuberculosis infection-rates obtained through tuberculin testing on a comparatively broad scale, especially in school children 7-13 years of age, show a progressive reduction in tuberculosis infection in the country as a whole. These tuberculin surves on school children were initiated by the district health officers in the second decade of the century and therefore now extend over 60 years. The procedure of the tuberculin surveys and the methods used are mentioned. The shortcomings of these surveys and their importance are discussed. The value of the surveys is considered doubtful as long as the examinations are performed without any guidance or coordination. About the year 1930 the total percentage tuberculin tested in the age group 7-13 years was a little over 10 percent. In the year 1935 the director of tuberculosis control sent all the health officers instructions on how to perform the tuberculin testing together with some encouragement to perform such surveys. That year about 43 percent of the 7-13 years population was tested and in 1945 the percentage was 75. Between 1965 and 1970 the attendance percentage was 85. The tested 7-13 years age group showed in 1935 26.1 percent positive reaction, in 1945 10.1 percent, in 1955 5.3 percent and in 1970 0.7 percent. In 1970 0.2 percent of the 7 years old children reacted positively and 1.1 percent of those 13 years of age. the decline of the infection rate in this age group is remarkable. The very few BCG vaccinated children were excluded from the surveys. In the tuberculosis surveys made in the years 1940-1945, which covered 12 medical districts or parts thereof, extensive tuberculin examinations were performed. The results of these surveys showed that the infection rate was higher among male adults than females. This difference was notable after the age of 15 and especially in isolated and thinly populated rural districts. In urban and more thickly populated rural districts the infection rate was much higher. BCG vaccination was first used in Iceland in 1945. Only few persons were vaccinated in the first two years. In 1948 a systematic vaccination was proposed in the country to supplement the tuberculosis-control plan. The vaccination was particularly meant for the age group 12-29 where the risk of infection appeared to be greatest. However, at the end of the year 1950 a total of only about 6,900 persons had been vaccinated mostly groups of school children, young adults and contacts of tuberculosis cases. Most of the children and adults were born between the years 1929 and 1936 but in none of these years did the vaccination exceed 15 percent of those born in any one of the years concerned. Because of the rapid decline in the tuberculosis infection rate, morbidity and mortality in the country this vaccination plan was abandoned and changed at the end of the year 1950. After that only few groups of people were vaccinated, i.e. tuberculosis contacts, medical students, student nurses, adults studying abroad and persons who asked for vaccination. Between 1950 and 1970 only about 7,000 people have been vaccinated. So the total number of BCG vaccinations up to the end of 1970 has not exceeded 14,000 in the country. Therefore it seems most unlikely that the relatively few BCG vaccinations, given in recent years can be expected to have had much influence in speeding up the downward trend of the disease in the country. (ABSTRACT TRUNCATED)

Age Distribution↗

Genetic analysis of simian immunodeficiency virus expressed in milk and selectively transmitted through breastfeeding.

To develop effective intervention strategies that prevent breast milk transmission of human immunodeficiency virus (HIV), we must understand the specific viral properties and mechanisms responsible for infant infection. We have used lactating rhesus macaques infected with a pathogenic simian immunodeficiency virus (SIV) stock to analyze the viral genotypes expressed in plasma and milk throughout the disease course and to identify those variants ultimately transmitted to infants through breastfeeding. In these studies we observed mother-to-infant transmission of SIV/Delta(B670) by eight females during the chronic phase of disease, and we analyzed by heteroduplex tracking assays and sequence analysis the distribution and fluctuations in viral genotypes expressed. Each female expressed multiple V1 envelope genotypes in milk near the time of transmission, while a single genotype was found in each of the infants. Variants transmitted to infants were not expressed throughout the maternal disease course but were only detected near the time of transmission. The emergence of the transmitted genotype in the dam typically occurred in plasma before milk and was coincident with increased milk viral loads. Transmitted genotypes tended to be longer and more glycosylated and had a less negative charge over the V1 region compared to viral genotypes expressed in milk but not transmitted. These observations demonstrate that specific viral genotypes are selectively transmitted to infants through breastfeeding and support the hypothesis that transmission occurs as genotypes adapt for efficient expression in milk.

Amino Acid Sequence↗

Molecular dynamics of apo-adenylate kinase: a distance replica exchange method for the free energy of conformational fluctuations.

A large domain motion in adenylate kinase from E. coli (AKE) is studied with molecular dynamics. AKE undergoes a large-scale rearrangement of its lid and AMP-binding domains when the open form closes over its substrates, AMP, and Mg2+-ATP, whereby the AMP-binding and lid domains come closer to the core. The third domain, the core, is relatively stable during this motion. A reaction coordinate that monitors the distance between the AMP-binding and core domains is selected to be able to compare with the results of energy transfer experiments. Sampling along this reaction coordinate is carried out by using a distance replica exchange method (DREM), where systems that differ by a restraint potential enforcing different reaction coordinate values are independently simulated with periodic attempts at exchange of these systems. Several methods are used to study the efficiency and convergence properties of the DREM simulation and compared with an analogous non-DREM simulation. The DREM greatly accelerates the rate and extent of configurational sampling and leads to equilibrium sampling as measured by monitoring collective modes obtained from a principal coordinate analysis. The potential of mean force along the reaction coordinate reveals a rather flat region for distances from the open to a relatively closed AKE conformation. The potential of mean force for smaller distances has a distinct minimum that is quite close to that found in the closed form X-ray structure. In concert with a decrease in the reaction coordinate distance (AMP-binding-to-core distance) the lid-to-core distance of AKE also decreases. Therefore, apo AKE can fluctuate from its open form to conformations that are quite similar to its closed form X-ray structure, even in the absence of its substrates.

Adenosine Monophosphate↗

Identifying the control structure of multijoint coordination during pistol shooting.

The question of degrees of freedom in the control of multijoint movement is posed as the problem of discovering how the motor control system constrains the many possible combinations of joint postures to stabilize task-dependent essential variables. Success at a task can be achieved, in principle, by always adopting a particular joint combination. In contrast, we propose a more selective control strategy: variations of the joint configuration that leave the values of essential task variables unchanged are predicted to be less controlled (i.e., stabilized to a lesser degree) than joint configuration changes that shift the values of the task variables. Our experimental task involved shooting with a laser pistol at a target under four conditions. The seven joint angles of the arm were obtained from the recorded positions of markers on the limb segments. The joint configurations observed at each point in normalized time were analyzed with respect to trial-to-trial variability. Different hypotheses about relevant task variables were used to define sets of joint configurations ("uncontrolled manifolds" or UCMs) that, if realized, would leave essential task variables unchanged. The variability of joint configurations was decomposed into components lying parallel to those sets and components lying in their complement. The orientation of the gun's barrel relative to a vector pointing from the gun to the target was the task variable most successful at showing a difference between the two components of joint variability. This variable determines success at the task. Throughout the movement, not only while the gun was pointing at the target, fluctuations of joint configuration that affected this variable were much reduced compared with fluctuations that did not affect this variable. The UCM principle applied to relative gun orientation thus captures the structure of the motor control system across different parts of joint configuration space as the movement evolves in time. This suggests a specific control strategy in which changes of joint configuration that are irrelevant to success at the task are selectively released from control. By contrast, constraints representing an invariant spatial position of the gun or of the arm's center of mass structured joint configuration variability in the early and mid-portion of the movement trajectory, but not at the time of shooting. This specific control strategy is not trivial, because a target can be hit successfully also by controlling irrelevant directions in joint space equally to relevant ones. The results indicate that the method can be successfully used to determine the structure of coordination in joint space that underlies the control of the essential variables for a given task.

Adult↗

Proton-induced cation current in embryonic rat spinal cord neurons changes ion dependency over time in vitro.

A rapid increase in proton concentration [H+]0 induces Na+ conductance in a variety of cell types. Here we report that H+ trigger a cation-selective channel whose ion dependency changes over time in culture. Whole-cell recordings of ventral spinal cord neurons dissociated at E15 and cultured for up to 14 days revealed that more than 80% had H(+)-induced inward current responses exhibiting a rapid decay phase. The current response was activated beginning about pH 6.8. Following decay, several minutes were required for complete recovery. More modest decreases in pH, which by themselves failed to activate this current, depressed those triggered by effective changes in pH. The currents recorded from cells in culture for less than 7 days could be abolished completely in the absence of Ca2+ and persisted in Na(+)-free and Ba(2+)-containing solutions. Ensemble analysis of current fluctuations recorded at the peak of the current allowed us to estimate a unitary channel conductance of 7.0 pS and a mean open time of 4.1 ms. In neurons cultured 2 weeks or more, protons induced an inward current response with similar kinetic properties, but with [Na+]0 dependency. Thus, proton-activated cation conductance in embryonic rat spinal cord neurons is self-limiting and involves brief openings of cation-selective channels whose ion dependency changes over time in culture.

Animals↗

Analysis of DNA polymerase reaction products for detecting hepatitis B virus in serum--comparison with spot hybridization technique.

An assay for DNA polymerase reaction products using slab gel electrophoresis and autoradiography was compared with the spot hybridization technique for the detection of hepatitis B virus DNA in 317 blood samples. The former could identify the nature and size of DNA on electrophoresis, and reduce potentially false-positive results due to artifacts. Discordant results between the two methods occurred in 36 of 317 samples; 22 were positive by the spot technique alone, and 14 were positive by the analysis of DNA polymerase reaction products alone. However, the samples positive with the spot test alone showed weak radioactive signals on electrophoresis/autoradiography that were often interpreted as "inconclusive" by blind observations. Correlation of hepatitis B e antigen/antibody with hepatitis B virus DNA was studied in 91 patients with various chronic liver diseases. Discordant results, i.e., presence of the DNA in antibody positive sera, or its absence in the antigen positive sera, were obtained in 15 (19%) cases. Such patients tended to have advanced liver disease with fluctuating serum aminotransferase levels. Analysis of DNA polymerase reaction products by slab gel electrophoresis and autoradiography is not only sensitive, but is also as specific as the Southern blot technique in the detection of hepatitis B virus DNA in serum, and may prove useful in selected samples, especially where no cloned hepatitis B virus DNA is available, or in search of new hepatitis B virus-like viruses.

Adult↗

DNA replication in the fission yeast: robustness in the face of uncertainty.

DNA replication, the process of duplication of a cell's genetic content, must be carried out with great precision every time the cell divides, so that genetic information is preserved. Control mechanisms must ensure that every base of the genome is replicated within the allocated time (S-phase) and only once per cell cycle, thereby safeguarding genomic integrity. In eukaryotes, replication starts from many points along the chromosome, termed origins of replication, and then proceeds continuously bidirectionally until an opposing moving fork is encountered. In contrast to bacteria, where a specific site on the genome serves as an origin in every cell division, in most eukaryotes origin selection appears highly stochastic: many potential origins exist, of which only a subset is selected to fire in any given cell, giving rise to an apparently random distribution of initiation events across the genome. Origin states change throughout the cell cycle, through the ordered formation and modification of origin-associated multisubunit protein complexes. State transitions are governed by fluctuations of cyclin-dependent kinase (CDK) activity and guards in these transitions ensure system memory. We present here DNA replication dynamics, emphasizing recent data from the fission yeast Schizosaccharomyces pombe, and discuss how robustness may be ensured in spite of (or even assisted by) system randomness.

DNA Replication↗

Hydrogen exchange in chymotrypsin inhibitor 2 probed by denaturants and temperature.

Hydrogen exchange of chymotrypsin inhibitor 2 has been measured in the presence of low concentrations of GdmCl and at different temperatures. The study of exchange at different temperatures allows us to obtain the activation enthalpies for the local exchange processes, and the change in enthalpy between the closed, exchange-incompetent, forms and the open, exchange-competent, forms. From the GdmCl dependence of exchange, an m-value, which is a measure of the new surface area exposed to solvent in the equilibrium between open and closed forms, can be determined for individual protons. This parameter therefore provides information about the structural nature of the opening reactions. In the absence of denaturant, exchange from native and native-like states dominates. As GdmCl concentration is increased, opening reactions that involve global unfolding are selectively promoted for the majority of amide protons. Three classes of protons emerge: for one set of protons, there is a linear and weak dependence on denaturant, indicating that the dominant opening reaction is the same throughout the range of GdmCl concentrations and involves local fluctuations with exposure of little new surface. For another set of protons, the most slowly exchanging residues, a linear, but much stronger, denaturant dependence is observed. For these protons, global unfolding dominates, and the m-values are similar to that obtained by equilibrium GdmCl denaturation measured by fluorescence under identical conditions. For the remaining protons, the GdmCl-dependence is weak at low GdmCl concentrations and increases at higher GdmCl concentrations. No segment of sub-global unfolding could be identified. Rather, all protons appear to merge together at high GdmCl concentrations to the global unfolding reaction.

Guanidine↗