Stress Impairs Intentional Memory Control through Altered Theta Oscillations in Lateral Parietal Cortex.

Accumulating evidence suggests that forgetting is not necessarily a passive process but that we can, to some extent, actively control what we remember and what we forget. Although this intentional control of memory has potentially far-reaching implications, the factors that influence our capacity to intentionally control our memory are largely unknown. Here, we tested whether acute stress may disrupt the intentional control of memory and, if so, through which neural mechanism. We exposed healthy men and women to a stress (n = 27) or control (n = 26) procedure before they aimed repeatedly to retrieve some previously learned cue-target pairs and to actively suppress others. While control participants showed reduced memory for suppressed compared with baseline pairs in a subsequent memory test, this suppression-induced forgetting was completely abolished after stress. Using magnetoencephalography (MEG), we show that the reduced ability to suppress memories after stress is associated with altered theta activity in the inferior temporal cortex when the control process (retrieval or suppression) is triggered and in the lateral parietal cortex when control is exerted, with the latter being directly correlated with the stress hormone cortisol. Moreover, the suppression-induced forgetting was linked to altered connectivity between the hippocampus and right dorsolateral prefrontal cortex (PFC), which in turn was negatively correlated to stress-induced cortisol increases. These findings provide novel insights into conditions under which our capacity to actively control our memory breaks down and may have considerable implications for stress-related psychopathologies, such as posttraumatic stress disorder (PTSD), that are characterized by unwanted memories of distressing events.SIGNIFICANCE STATEMENT It is typically assumed that forgetting is a passive process that can hardly be controlled. There is, however, evidence that we may actively control, to some extent, what we remember and what we forget. This intentional memory control has considerable implications for mental disorders in which patients suffer from unwanted (e.g., traumatic) memories. Here, we demonstrate that the capacity to intentionally control our memory breaks down after stress. Using magnetoencephalography (MEG), we show that this stress-induced memory control deficit is linked to altered activity in the lateral parietal cortex and the connectivity between the hippocampus and right prefrontal cortex (PFC). These findings provide novel insights into conditions under which memory control fails and are highly relevant in the context of stress-related psychopathologies.

A subgroup of light-driven sodium pumps with an additional Schiff base counterion.

Light-driven sodium pumps (NaRs) are unique ion-transporting microbial rhodopsins. The major group of NaRs is characterized by an NDQ motif and has two aspartic acid residues in the central region essential for sodium transport. Here we identify a subgroup of the NDQ rhodopsins bearing an additional glutamic acid residue in the close vicinity to the retinal Schiff base. We thoroughly characterize a member of this subgroup, namely the protein ErNaR from Erythrobacter sp. HL-111 and show that the additional glutamic acid results in almost complete loss of pH sensitivity for sodium-pumping activity, which is in contrast to previously studied NaRs. ErNaR is capable of transporting sodium efficiently even at acidic pH levels. X-ray crystallography and single particle cryo-electron microscopy reveal that the additional glutamic acid residue mediates the connection between the other two Schiff base counterions and strongly interacts with the aspartic acid of the characteristic NDQ motif. Hence, it reduces its pKa. Our findings shed light on a subgroup of NaRs and might serve as a basis for their rational optimization for optogenetics.

Cartilaginous choristoma of the tongue.

Choristomas are lesions composed of normal cells or tissues occurring in an abnormal location. Cartilaginous choristomas of the oral mucosa are rare and occur preferentially on the tongue and less often in sites such as the soft palate and gingiva. Oral lesions are generally covered by integral mucosa and can occur at any age. The present study describes a case of a 73-year-old female presenting with an asymptomatic cartilaginous choristoma on the ventral surface of the tongue which had developed over a period of 3 years. The clinical presentation and management of the case are discussed and the literature is reviewed. This is the 28th reported case of a cartilaginous choristoma of the tongue and the third with a ventral localisation.

Rat ceruloplasmin: a new labile copper binding site and zinc/copper mosaic.

Ceruloplasmin (Cp) is a copper-containing multifunctional oxidase of plasma, an antioxidant, an acute-phase protein and a free radical scavenger. The structural organization of Cp causes its sensitivity to proteolysis and ROS (reactive oxygen species), which can alter some of the important Cp functions. Elucidation of the orthorhombic crystal structure of rat Cp at 2.3 Å resolution revealed the basis for stronger resistance of rat Cp to proteolysis and a new labile copper binding site. The presence of this site appears as a very rare and distinctive feature of rat Cp as was shown by sequence alignment of ceruloplasmin, hephaestin and zyklopen in the Deuterostomia taxonomic group. The trigonal crystal form of rat Cp at 3.2 Å demonstrates unexpected partial substitution of copper by zinc.

Crystal structure of vancomycin.

BACKGROUND: Vancomycin and other related glycopeptide antibiotics are clinically very important because they often represent the last line of defence against bacteria that have developed resistance to antibiotics. Vancomycin is believed to act by binding nascent cell wall mucopeptides terminating in the sequence D-Ala-D-Ala, weakening the resulting cell wall. Extensive NMR and other studies have shown that the formation of asymmetric antibiotic dimers is important in peptide binding. Despite intensive efforts the crystal structure of vancomycin has been extremely difficult to obtain, partly because high-resolution data were unavailable, and partly because the structure was too large to be solved by conventional "direct methods'. RESULTS: Using low-temperature synchrotron X-ray data combined with new ab initio techniques for solving the crystallographic phase problem, we have succeeded in determining the crystal structure of vancomycin at atomic resolution. The structure provides much detailed information that should prove invaluable in modelling and mechanistic studies. CONCLUSIONS: Our structure confirms that vancomycin exists as an asymmetric dimer. The dimer conformation allows the docking of two D-Ala-D-Ala peptides in opposite directions; these presumably would be attached to different glycopeptide strands. In the crystal, one of the binding pockets is occupied by an acetate ion that mimics the C terminus of the nascent cell wall peptide; the other is closed by the asparagine sidechain, which occupies the place of a ligand. The occupied binding pocket exhibits high flexibility but the closed binding pocket is relatively rigid. We propose that the asparagine sidechain may hold the binding pocket in a suitable conformation for peptide docking, swinging out of the way when the peptide enters the binding pocket.

Influence of internal dynamics on accuracy of protein NMR structures: derivation of realistic model distance data from a long molecular dynamics trajectory.

In order to study the effect of internal dynamics on the accuracy of NMR structures in detail, we generated NOE distance data from a long molecular dynamics trajectory of BPTI. Cross-relaxation rates were calculated from the trajectory by analysis of the appropriate proton-proton vector autocorrelation functions. A criterion for the convergence of correlation functions was developed, and the analysis was restricted to those correlation functions that had converged within the simulation time. Effective distances were determined from the calculated cross-relaxation rates. Internal dynamics affected the derived distances in a realistic way, since they were subject both to radial averaging (which increases the cross-relaxation rate) and angular averaging (which decreases the cross-relaxation rate). The comparison of the effective distances with average distance between the protons during the trajectory showed that for most the effects of angular and distance averaging essentially cancel out. For these distances, the effective distance derived from an NOE is therefore a very good estimate of the average distance, or the distance in the average structure. However, for about 10% of the distances, the effective distance was more than 10% larger than the average distance, while for about 5%, it was more than 10% smaller, in some cases by more than 2 A. Little correlation is observed between the effects on cross-relaxation rates to different protons of the same residue. The results of this analysis have implications for the way structures are calculated from NOE distance data. For many distances, the assumption of a rigid structure is valid, and large error bounds would result in the loss of too much information content. On the other hand, the error bounds very often employed are not wide enough for some of the effects seen in our study.

Subthalamic deep brain stimulation improves auditory sensory gating deficit in Parkinson's disease.

OBJECTIVE: While motor effects of dopaminergic medication and subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson's disease (PD) patients are well explored, their effects on sensory processing are less well understood. Here, we studied the impact of levodopa and STN-DBS on auditory processing. METHODS: Rhythmic auditory stimulation (RAS) was presented at frequencies between 1 and 6Hz in a passive listening paradigm. High-density EEG-recordings were obtained before (levodopa ON/OFF) and 5months following STN-surgery (ON/OFF STN-DBS). We compared auditory evoked potentials (AEPs) elicited by RAS in 12 PD patients to those in age-matched controls. Tempo-dependent amplitude suppression of the auditory P1/N1-complex was used as an indicator of auditory gating. RESULTS: Parkinsonian patients showed significantly larger AEP-amplitudes (P1, N1) and longer AEP-latencies (N1) compared to controls. Neither interruption of dopaminergic medication nor of STN-DBS had an immediate effect on these AEPs. However, chronic STN-DBS had a significant effect on abnormal auditory gating characteristics of parkinsonian patients and restored a physiological P1/N1-amplitude attenuation profile in response to RAS with increasing stimulus rates. CONCLUSIONS: This differential treatment effect suggests a divergent mode of action of levodopa and STN-DBS on auditory processing. SIGNIFICANCE: STN-DBS may improve early attentive filtering processes of redundant auditory stimuli, possibly at the level of the frontal cortex.

Predictive timing functions of cortical beta oscillations are impaired in Parkinson's disease and influenced by L-DOPA and deep brain stimulation of the subthalamic nucleus.

Cortex-basal ganglia circuits participate in motor timing and temporal perception, and are important for the dynamic configuration of sensorimotor networks in response to exogenous demands. In Parkinson's disease (PD) patients, rhythmic auditory stimulation (RAS) induces motor performance benefits. Hitherto, little is known concerning contributions of the basal ganglia to sensory facilitation and cortical responses to RAS in PD. Therefore, we conducted an EEG study in 12 PD patients before and after surgery for subthalamic nucleus deep brain stimulation (STN-DBS) and in 12 age-matched controls. Here we investigated the effects of levodopa and STN-DBS on resting-state EEG and on the cortical-response profile to slow and fast RAS in a passive-listening paradigm focusing on beta-band oscillations, which are important for auditory-motor coupling. The beta-modulation profile to RAS in healthy participants was characterized by local peaks preceding and following auditory stimuli. In PD patients RAS failed to induce pre-stimulus beta increases. The absence of pre-stimulus beta-band modulation may contribute to impaired rhythm perception in PD. Moreover, post-stimulus beta-band responses were highly abnormal during fast RAS in PD patients. Treatment with levodopa and STN-DBS reinstated a post-stimulus beta-modulation profile similar to controls, while STN-DBS reduced beta-band power in the resting-state. The treatment-sensitivity of beta oscillations suggests that STN-DBS may specifically improve timekeeping functions of cortical beta oscillations during fast auditory pacing.

Ultrahigh resolution drug design I: details of interactions in human aldose reductase-inhibitor complex at 0.66 A.

The first subatomic resolution structure of a 36 kDa protein [aldose reductase (AR)] is presented. AR was cocrystallized at pH 5.0 with its cofactor NADP+ and inhibitor IDD 594, a therapeutic candidate for the treatment of diabetic complications. X-ray diffraction data were collected up to 0.62 A resolution and treated up to 0.66 A resolution. Anisotropic refinement followed by a blocked matrix inversion produced low standard deviations (<0.005 A). The model was very well ordered overall (CA atoms' mean B factor is 5.5 A2). The model and the electron-density maps revealed fine features, such as H-atoms, bond densities, and significant deviations from standard stereochemistry. Other features, such as networks of hydrogen bonds (H bonds), a large number of multiple conformations, and solvent structure were also better defined. Most of the atoms in the active site region were extremely well ordered (mean B approximately 3 A2), leading to the identification of the protonation states of the residues involved in catalysis. The electrostatic interactions of the inhibitor's charged carboxylate head with the catalytic residues and the charged coenzyme NADP+ explained the inhibitor's noncompetitive character. Furthermore, a short contact involving the IDD 594 bromine atom explained the selectivity profile of the inhibitor, important feature to avoid toxic effects. The presented structure and the details revealed are instrumental for better understanding of the inhibition mechanism of AR by IDD 594, and hence, for the rational drug design of future inhibitors. This work demonstrates the capabilities of subatomic resolution experiments and stimulates further developments of methods allowing the use of the full potential of these experiments.

Persuasion for the purpose of cancer risk reduction: a discussion.

We comment on the preceding papers by Gerrard and Vernon concerning persuasion, perceived risk, and cancer-relevant behavior. Our purpose is to highlight several challenges for future investigators. First, relations between health cognition and health behavior (such as the link between perceived vulnerability and protective behaviors) are likely to be moderated by other variables, including individual differences and situational contexts. Second, we encourage health communication researchers to consider how persuasion is contextualized in social relationships and to employ mechanisms from the literature on social influence when promoting cancer prevention and early detection behaviors. Finally, we emphasize the importance of current feelings and anticipated emotions as motivators of salubrious actions.

Crystal structure of domain A of Thermus flavus 5S rRNA and the contribution of water molecules to its structure.

This is the first high resolution crystal structure of an RNA molecule made by solid phase chemical synthesis and representing a natural RNA. The structure of the domain A of Thermus flavus ribosomal 5S RNA is refined to R = 18% at 2.4 A including 159 solvent molecules. Most of the 2'-hydroxyl groups as well as the phosphate oxygens are involved either in specific hydrogen bonds in intermolecular contacts or to solvent molecules. The two U-G and G-U base-pairs are stabilized by H-bonds supplied via three water molecules to compensate for the lack of base-pair hydrogen bonds. The structure shows for the first time in detail the importance of highly ordered internal water in stabilizing an RNA structure.

The effects of message framing and ethnic targeting on mammography use among low-income women.

The authors examined the effects that differently framed and targeted health messages have on persuading low-income women to obtain screening mammograms. The authors recruited 752 women over 40 years of age from community health clinics and public housing developments and assigned the women randomly to view videos that were either gain or loss framed and either targeted specifically to their ethnic groups or multicultural. Loss-framed, multicultural messages were most persuasive. The advantage of loss-framed, multicultural messages was especially apparent for Anglo women and Latinas but not for African American women. These effects were stronger after 6 months than after 12 months.

Alternativas de propagação na produção de óleo essencial de Mentha canadensis L. no Litoral Norte Catarinense / Propagation alternatives for the production of Mentha canadensis L. essential oil at the Santa Catarina State northern coast

O gênero Mentha é cultivado mundialmente para a produção de óleo essencial, com ênfase no constituinte mentol, amplamente utilizado nas indústrias farmacêutica, cosmética, alimentícia e de higiene pessoal. Este trabalho teve como objetivo avaliar o efeito da utilização de diferentes estruturas de propagação e épocas de colheita de Mentha canadensis L. no Litoral Norte Catarinense. O delineamento experimental foi em blocos ao acaso em esquema fatorial 4x2, comparando quatro estruturas de propagação (estolões com 10, 15 e 20 cm de comprimento e estacas com 5 cm de comprimento) e duas épocas de colheita (95 dias após o plantio e 60 dias após a rebrota). Em cada colheita foi avaliado o crescimento vegetativo e produtividade de óleo essencial e de mentol. Na primeira colheita, houve maior acúmulo de massa seca de folhas, caules e total; produtividade de óleo essencial e de mentol quando o plantio foi realizado com mudas obtidas por estaquia. Na segunda colheita, no entanto, não houve diferença significativa entre os tratamentos para todas as variáveis analisadas. A primeira colheita resultou em médias superiores em relação à segunda colheita à exceção do plantio por estolão com 10 cm em todas as variáveis e estolão com 20 cm para a massa seca de caules. Os constituintes majoritários do óleo essencial foram mentol, mentona e neomentol. Os teores de mentol foram significativamente superiores na segunda colheita e de mentona na primeira colheita, sendo que o neomentol não apresentou diferença significativa em ambas as colheitas. Os resultados obtidos sugerem que a colheita antecipada da rebrota proporciona maior concentração de mentol no óleo essencial. O uso de estolões como estrutura de propagação pode ser considerada uma alternativa viável para menta, pois além de apresentar níveis similares de produção de óleo essencial e de mentol a partir da segunda colheita ao de áreas implantadas com mudas, diminui o custo de produção.

The genus Mentha is cultivated worldwide for essential oil production, with emphasis on its major constituent, menthol, which is used in the pharmaceutical, cosmetics, and food industries and for personal care. This work investigates the use of different propagation structures and harvesting times of Mentha canadensis L., in the Santa Catarina State north coast. The experimental design was in randomized blocks in a 4X2 factorial, comparing four propagation structures (stolon with 10, 15 and 20 cm and stem cuttings with 5 cm) and two harvesting times (95 days after planting and 60 days after the regrowth). In each harvesting time, the vegetative growth, essential oil and menthol productivities were evaluated. The first harvest showed greater leaf, branch and total dry mass accumulation, and essential oil and menthol productivities when stem cuttings were used. In the second harvest, no differences were observed for all evaluated variables. The first harvest resulted in higher averages than the second harvest, with exception in all variables for the use of stolon with 10 cm and in stem dry mass for stolon with 20 cm. The major constituents of the essential oil were menthol, menthone, neomenthol. The levels of menthol were significantly higher in the second harvest and of menthone in the first harvest, while neomenthol showed no significant difference. The results suggest that early harvest of the regrowth results in great menthol concentrations in the essential oil. The use of stolons as a propagation structure can be considered a viable alternative for mint, as it provides similar levels of essential oil and menthol productions after the second harvest, when compared to stem cuttings and also reduces the production cost.

Objective comparison of protein structures: error-scaled difference distance matrices.

Understanding of macromolecular function in many cases relies on the comparison of related structural models. Commonly used least-squares superposition methods suffer from bias introduced into the comparison process by the subjective choice of atoms employed for the superposition. Difference distance matrices are a more objective means of comparing structures as they do not depend on a particular superposition scheme. However, they suffer from very high noise originating from coordinate errors. Modern refinement programs allow the rigorous estimation of standard uncertainties for individual atomic positions. These errors can be propagated through the calculation of a difference distance matrix allowing one to assess the significance level of structural differences. An algorithm is presented which produces an intuitive graphical representation of difference distance matrices after normalization to their error levels. Two examples where its application was revealing are described. Alternatives are suggested for cases where rigorous estimation of individual errors by the inversion of the full least-squares matrix is not feasible. The method offers an unbiased way to detect significant similarities and differences between related structures, as encountered in studies of complexes and mutants or when multiple models are obtained from experiments such as crystal structures involving non-crystallographic symmetry or different crystal modifications, or ensembles derived from NMR spectroscopy.

A test of the validity of the method of constant stimuli as an index of heartbeat detection.

A heartbeat detection task, based on the method of constant stimuli (MCS), requires participants to judge which of a series of tones presented at different delays following a heartbeat are coincident with the heartbeat. Two experiments were conducted to test the validity of the MCS in assessing individual differences in the ability to detect heartbeat sensations. The first experiment found the MCS to be valid, in that about one-third of subjects met the criterion for classification as heartbeat detectors when the tones were presented with respect to their actual heartbeats, but only one subject met the criterion when the tones were presented with respect to previously recorded heartbeats. The second experiment manipulated the timing of the comparison intervals (i.e., R + 100-600 ms rather than R + 0-500 ms) to examine the validity of the median R-wave to tone interval as an index of temporal location of perceived heartbeats, and found it to be a valid index.

Crystallization and preliminary X-ray analysis of 3-deoxy-D-arabino-heptulosonate-7-phosphate synthase (tyrosine inhibitable) from Saccharomyces cerevisiae.

3-Deoxy-D-arabino-heptulosonate-7-phosphate synthase (E.C. 4.1.2.15) catalyses the first step in the biosynthesis of aromatic amino acids: the condensation of phophoenolpyruvate and erythrose 4-phosphate to 3-deoxy-D-arabino-heptulosonate-7-phosphate. Diffraction-quality crystals of the tyrosine-inhibitable form of the enzyme from Saccharomyces cerevisiae have been obtained by the hanging-drop vapour-diffusion method in the presence of polyethylene glycol. The crystals belong to the triclinic space group P1, with unit-cell parameters a = 81.5, b = 94.0, c = 104.6 A, alpha = 65.5, beta = 85.2, gamma = 75.0 degrees, and can be flash-cooled using glycerol as a cryoprotectant. A data set to 2.3 A has been collected at 120 K.

Ab initio structure determination of the lantibiotic mersacidin.

The crystal structure of mersacidin, a potential novel antibiotic against methicillin- and vancomycin-resistant Staphylococcus aureus strains, has been determined by ab initio methods. Despite all crystals being merohedrally twinned, an accurate structural model with an R value of 13.4% has been obtained at atomic resolution. With six molecules in the asymmetric unit and no atom heavier than sulfur, the structure corresponds to a protein of 120 amino acids and is the largest approximately equal-atom unknown structure solved by direct methods. In the crystal, the molecule assumes a compact fold different from that found by NMR in solution. Comparison of the NCS-related molecules reveals regions of variable flexibility. The region highly homologous to the related antibiotic actagardine is very rigid and possibly defines an essential building block of this class of new antibacterial substances.

Structure of balhimycin and its complex with solvent molecules.

Balhimycin is a naturally occurring glycopeptide antibiotic, related to vancomycin which acts by binding nascent bacterial cell-wall peptide ending in the sequence D-Ala-D-Ala. Crystals of balhimycin are monoclinic, space group P21, a = 20.48 (10), b = 43.93 (21), c = 27.76 (14) A, beta = 100.5 (5) degrees with four independent antibiotic molecules, three molecules of 2-methyl-2,4-pentanediol, two citrate ions, three acetate ions and 127.5 water molecules in the asymmetric unit. With an asymmetric unit larger than those of the smallest proteins and a solvent content of about 32%, the crystals have similar diffraction properties to those of small proteins. 27387 unique reflections were collected using synchrotron radiation. The structure was solved by a standard protein technique, the molecular-replacement method, using ureido-balhimycin as search model. The anisotropic refinement against all F2 data between 0.96 and 45 A converged to a conventional R value of 11.27% with R1= Sigma||Fo|-|Fc||/Sigma|Fo| for the 24623 data with I > 2sigma(I) and 12.58% for all 27387 data. The four monomers possess fairly similar conformations (r.m.s. deviation 0.7 A). Two antibiotic molecules form a tight dimer with antiparallel hydrogen bonds between the peptide backbone as well as between the vancosamine residues and the peptide backbone. In each of the two dimers, one binding pocket is occupied by a citrate ion and the other by an acetate ion. The dimer units are linked in the crystal by hydrogen bonds to form infinite chains.

Cardiovascular reactivity and adaptation to recurrent psychological stress: the moderating effects of evaluative observation.

The impact of evaluative observation on cardiovascular reactivity and adaptation to recurrent psychological stress was evaluated in 162 undergraduate men and women. All participants performed three mental arithmetic tasks with or without evaluative observation. Impedance cardiographic, blood pressure, task performance, and stress appraisal measures were recorded for each task. Evaluative observation moderated the effects of task repetition on cardiac reactivity but not vascular reactivity. The introduction of evaluative observation disrupted cardiac adaptation, resulting in a resurgence of beta-adrenergic cardiac reactivity (p < .005), whereas the removal of evaluative observation promoted cardiac adaptation. Evaluative observation also increased stress appraisals and slowed task performance. The results support the dual process theory of habituation, rather than stimulus comparator theory, but only partially support cognitive appraisal theory.