Reduced systolic wave generation and increased peripheral wave reflection in chronic heart failure

In human heart failure the role of wave generation by the ventricle and wave reflection by the vasculature is contentious. The aim of this study was to compare wave generation and reflection in normal subjects with patients with stable compensated heart failure. Twenty-nine normal subjects and 67 patients with heart failure (New York Heart Association class II or III) were studied by noninvasive techniques applied to the common carotid artery. Data were analyzed by wave intensity analysis to determine the nature and direction of waves during the cardiac cycle. The energy carried by an early systolic forward compression wave (S wave) generated by the left ventricle and responsible for acceleration of flow in systole was significantly reduced in subjects with heart failure (P < 0.001), and the timing of the peak of this wave was delayed. In contrast, reflection of this wave was increased in subjects with heart failure (P < 0.001), but the timing of reflections with respect to the S wave was unchanged. The energy of an expansion wave generated by the heart in protodiastole was unaffected by heart failure. The carotid artery wave speed and the augmentation index did not significantly differ between subjects with heart failure compared with normal individuals. The ability of the left ventricle to generate a forward compression wave is markedly impaired in heart failure. Increased wave reflection serves to maintain systolic blood pressure but also places an additional load on cardiac function in heart failure.     

Is extinction the hallmark of operant discrimination?: Reinforcement and S effects

Using a successive discrimination procedure with rats, three experiments investigated the contribution of reinforcement rate and amount of S(Delta) exposure on the acquisition of an operant discrimination. S(D) components and were always 2 min in length, while S(Delta) (extinction) components were either 1 min or 4 min in length; responses in S(D) were reinforced on one of four schedules. In Experiment 1, each of eight groups were exposed to one possible combination of rate of reinforcement and S(Delta) component length. At every level of reinforcement, the 4 min S(Delta) groups acquired the discrimination more quickly. However, within each level of reinforcement, the proportions of responding in S(D) as a function cumulative S(Delta) exposure were equivalent, regardless of the number of reinforcers earned in S(D), suggesting that extinction is the "hallmark" of discrimination. Experiment 2 sought to replicate these results in a within-subjects design, and although the 4 min S(Delta) conditions always produced superior discriminations, the lack of discriminated responding in some conditions suggested that stimulus disparity was reduced. Experiment 3 clarified those results and extended the finding that the acquisition of operant discrimination closely parallels extinction of responding in S(Delta). In sum, it appears that higher reinforcement rates and longer S(Delta) exposure facilitate the acquisition of discriminated operant responding.     

Normal levels of Rac1 are important for dendritic but not axonal development in hippocampal neurons

Background information. Rho family GTPases are required for cytoskeletal reorganization and are considered important for the maturation of neurons. Among these proteins, Rac1 is known to play a crucial role in the regulation of actin dynamics, and a number of studies indicate the involvement of this protein in different steps of vertebrate neuronal maturation. There are two distinct Rac proteins expressed in neurons, namely the ubiquitous Rac1 and the neuron‐specific Rac3. The specific functions of each of these GTPases during early neuronal development are largely unknown. Results. The combination of the knockout of Rac3 with Rac1 down‐regulation by siRNA (small interfering RNA) has been used to show that down‐regulation of Rac1 affects dendritic development in mouse hippocampal neurons, without affecting axons. F‐actin levels are strongly decreased in neuronal growth cones following down‐regulation of Rac1, and time‐lapse analysis indicated that the reduction of Rac1 levels decreases growth‐cone dynamics. Conclusions. These results show that normal levels of endogenous Rac1 activity are critical for early dendritic development, whereas dendritic outgrowth is not affected in hippocampal neurons from Rac3‐null mice. On the other hand, early axonal development appears normal after Rac1 down‐regulation. Our findings also suggest that the initial establishment of neuronal polarity is not affected by Rac1 down‐regulation.     

Genome-wide linkage disequilibrium analysis in bread wheat and durum wheat.

Bread wheat and durum wheat were examined for linkage disequilibrium (LD) using microsatellite markers distributed across the genome. The allele database consisted of 189 bread wheat accessions genotyped at 370 loci and 93 durum wheat accessions genotyped at 245 loci. A significance level of p < 0.001 was set for all comparisons. The bread and durum wheat collections showed that 47.9% and 14.0% of all locus pairs were in LD, respectively. LD was more prevalent between loci on the same chromosome compared with loci on independent chromosomes and was highest between adjacent loci. Only a small fraction (bread wheat, 0.9%; durum wheat, 3.2%) of the locus pairs in LD showed R2 values > 0.2. The LD between adjacent locus pairs extended (R2 > 0.2) approximately 2-3 cM, on average, but some regions of the bread and durum wheat genomes showed high levels of LD (R2 = 0.7 and 1.0, respectively) extending 41.2 and 25.5 cM, respectively. The wheat collections were clustered by similarity into subpopulations using unlinked microsatellite data and the software Structure. Analysis within subpopulations showed 14- to 16-fold fewer locus pairs in LD, higher R2 values for those pairs in LD, and LD extending further along the chromosome. The data suggest that LD mapping of wheat can be performed with simple sequence repeats to a resolution of <5 cM.     

The tumor suppressor eIF3e mediates calcium-dependent internalization of the L-type calcium channel CaV1.2

Voltage-gated calcium channels (VGCCs) convert electrical activity into calcium (Ca2+) signals that regulate cellular excitability, differentiation, and connectivity. The magnitude and kinetics of Ca2+ signals depend on the number of VGCCs at the plasma membrane, but little is known about the regulation of VGCC surface expression. We report that electrical activity causes internalization of the L-type Ca2+ channel (LTC) CaV1.2 and that this is mediated by binding to the tumor suppressor eIF3e/Int6 (eukaryotic initiation factor 3 subunit e). Using total internal reflection microscopy, we identify a population of CaV1.2 containing endosomes whose rapid trafficking is strongly regulated by Ca2+. We define a domain in the II-III loop of CaV1.2 that binds eIF3e and is essential for the activity dependence of both channel internalization and endosomal trafficking. These findings provide a mechanism for activity-dependent internalization and trafficking of CaV1.2 and provide a tantalizing link between Ca2+ homeostasis and a mammalian oncogene.     

Two-state model of acto-myosin attachment-detachment predicts C-process of sinusoidal analysis

The force response of activated striated muscle to length perturbations includes the so-called C-process, which has been considered the frequency domain representation of the fast single-exponential force decay after a length step (phases 1 and 2). The underlying molecular mechanisms of this phenomenon, however, are still the subject of various hypotheses. In this study, we derived analytical expressions and created a corresponding computer model to describe the consequences of independent acto-myosin cross-bridges characterized solely by 1), intermittent periods of attachment (t(att)) and detachment (t(det)), whose values are stochastically governed by independent probability density functions; and 2), a finite Hookian stiffness (k(stiff)) effective only during periods of attachment. The computer-simulated force response of 20,000 (N) cross-bridges making up a half-sarcomere (F(hs)(t)) to sinusoidal length perturbations (L(hs)(t)) was predicted by the analytical expression in the frequency domain, (F(hs)(omega)/L(hs)(omega))=(t(att)/t(cycle))Nk(stiff)(iomega/(t(att)(-1)+iomega)), where t(att) = mean value of t(att), t(cycle) = mean value of t(att) + t(det), k(stiff) = mean stiffness, and omega = 2pi x frequency of perturbation. The simulated force response due to a length step (L(hs)) was furthermore predicted by the analytical expression in the time domain, F(hs)(t)=(t(att)/t(cycle))Nk(stiff)L(hs)e(-t/t(att)). The forms of these analytically derived expressions are consistent with expressions historically used to describe these specific characteristics of a force response and suggest that the cycling of acto-myosin cross-bridges and their associated stiffnesses are responsible for the C-process and for phases 1 and 2. The rate constant 2pic, i.e., the frequency parameter of the historically defined C-process, is shown here to be equal to t(att)(-1). Experimental results from activated cardiac muscle examined at different temperatures and containing predominately alpha- or beta-myosin heavy chain isoforms were found to be consistent with the above interpretation.     

The loss of adaptive plasticity during long periods of environmental stasis

Adaptive plasticity allows populations to adjust rapidly to environmental change. If this is useful only rarely, plasticity may undergo mutational degradation and be lost from a population. We consider a population of constant size N undergoing loss of plasticity at functional mutation rate m and with selective advantage s associated with loss. Environmental change events occur at rate theta per generation, killing all individuals that lack plasticity. The expected time until loss of plasticity in a fluctuating environment is always at least tau, the expected time until loss of plasticity in a static environment. When mN > 1 and N theta > 1, we find that plasticity will be maintained for an average of at least 10(8) generations in a single population, provided tau > 18/theta. In a metapopulation, plasticity is retained under the more lenient condition tau > 1.3/theta, irrespective of mN, for a modest number of demes. We calculate both exact and approximate solutions for tau and find that it is linearly dependent only on the logarithm of N, and so, surprisingly, both the population size and the number of demes in the metapopulation make little difference to the retention of plasticity. Instead, tau is dominated by the term 1/(m+s/2).     

WNT10B functional dualism: beta-catenin/Tcf-dependent growth promotion or independent suppression with deregulated expression in cancer

We found aberrant DNA methylation of the WNT10B promoter region in 46% of primary hepatocellular carcinoma (HCC) and 15% of colon cancer samples. Three of 10 HCC and one of two colon cancer cell lines demonstrated low or no expression, and 5-aza-2'deoxycytidine reactivated WNT10B expression with the induction of demethylation, indicating that WNT10B is silenced by DNA methylation in some cancers, whereas WNT10B expression is up-regulated in seven of the 10 HCC cell lines and a colon cancer cell line. These results indicate that WNT10B can be deregulated by either overexpression or silencing in cancer. We found that WNT10B up-regulated beta-catenin/Tcf activity. However, WNT10B-overexpressing cells demonstrated a reduced growth rate and anchorage-independent growth that is independent of the beta-catenin/Tcf activation, because mutant beta-catenin-transduced cells did not suppress growth, and dominant-negative hTcf-4 failed to alleviate the growth suppression by WNT10B. Although WNT10B expression alone inhibits cell growth, it acts synergistically with the fibroblast growth factor (FGF) to stimulate cell growth. WNT10B is bifunctional, one function of which is involved in beta-catenin/Tcf activation, and the other function is related to the down-regulation of cell growth through a different mechanism. We suggest that FGF switches WNT10B from a negative to a positive cell growth regulator.