Visual Information Is Predictively Encoded in Occipital Alpha/Low-Beta Oscillations.

Hierarchical predictive coding networks are a general model of sensory processing in the brain. Under neural delays, these networks have been suggested to naturally generate oscillatory activity in approximately the α frequency range (∼8-12 Hz). This suggests that α oscillations, a prominent feature of EEG recordings, may be a spectral "fingerprint" of predictive sensory processing. Here, we probed this possibility by investigating whether oscillations over the visual cortex predictively encode visual information. Specifically, we examined whether their power carries information about the position of a moving stimulus, in a temporally predictive fashion. In two experiments (N = 32, 18 female; N = 34, 17 female), participants viewed an apparent-motion stimulus moving along a circular path while EEG was recorded. To investigate the encoding of stimulus-position information, we developed a method of deriving probabilistic spatial maps from oscillatory power estimates. With this method, we demonstrate that it is possible to reconstruct the trajectory of a moving stimulus from α/low-ß oscillations, tracking its position even across unexpected motion reversals. We also show that future position representations are activated in the absence of direct visual input, demonstrating that temporally predictive mechanisms manifest in α/ß band oscillations. In a second experiment, we replicate these findings and show that the encoding of information in this range is not driven by visual entrainment. By demonstrating that occipital α/ß oscillations carry stimulus-related information, in a temporally predictive fashion, we provide empirical evidence of these rhythms as a spectral "fingerprint" of hierarchical predictive processing in the human visual system.SIGNIFICANCE STATEMENT "Hierarchical predictive coding" is a general model of sensory information processing in the brain. When in silico predictive coding models are constrained by neural transmission delays, their activity naturally oscillates in roughly the α range (∼8-12 Hz). Using time-resolved EEG decoding, we show that neural rhythms in this approximate range (α/low-ß) over the human visual cortex predictively encode the position of a moving stimulus. From the amplitude of these oscillations, we are able to reconstruct the stimulus' trajectory, revealing signatures of temporally predictive processing. This provides direct neural evidence linking occipital α/ß rhythms to predictive visual processing, supporting the emerging view of such oscillations as a potential spectral "fingerprint" of hierarchical predictive processing in the human visual system.

Maintenance infusion rate of oxytocin after initial 1-IU bolus for elective Cesarean delivery: a dose-finding study.

PURPOSE: The purpose of our study was to determine the minimum effective dose of oxytocin maintenance infusion required to maintain adequate uterine tone in 90% of patients (ED90) after administration of the initial bolus at elective Cesarean delivery (CD) under spinal anesthesia. METHODS: We conducted a prospective, double-blind dose-finding study with biased coin up-down design. Immediately after delivery, a 1-IU oxytocin bolus was administered, followed by a maintenance infusion. The obstetrician assessed the uterine tone by palpation as satisfactory or unsatisfactory. In case of unsatisfactory response, the dose for the next patient was increased by 2 IU·hr-1. For satisfactory response, the dose for the next patient was either decreased by 2 IU·hr-1 with a probability of 1/9, or remained unchanged. The primary outcome was a satisfactory uterine tone from five minutes after delivery until discharge from postanesthesia care unit. The secondary outcomes were blood loss, need for additional uterotonics, and side effects. RESULTS: We analyzed data for 40 patients. The ED90 of oxytocin maintenance infusion was 4.5 IU·hr-1 (95% confidence interval, 3.3 to 5.5) based on the isotonic regression estimator. The median [interquartile range] blood loss was 861 [553-1,181] mL; 18% received additional uterotonics, and 38% developed hypotension post delivery. CONCLUSION: Based on the results of this dose-finding study, we recommend a maintenance infusion rate of 4.5 IU·hr-1 following an oxytocin bolus of 1 IU for adequate uterine tone in pregnant patients undergoing elective CDs. This infusion rate is four-fold lower than that required without an initial bolus. STUDY REGISTRATION: ClinicalTrials.gov ( NCT04946006 ); first submitted 25 June 2021.

RéSUMé: OBJECTIF: L'objectif de notre étude était de déterminer la dose minimale efficace de perfusion d'entretien d'ocytocine nécessaire pour maintenir un tonus utérin adéquat chez 90 % des personnes parturientes (DE90) après l'administration du bolus initial lors d'une césarienne programmée sous rachianesthésie. MéTHODE: Nous avons réalisé une étude prospective et en double aveugle de détermination de la dose avec une méthodologie de conception biaisée type « up-and down ¼. Immédiatement après l'accouchement, un bolus d'ocytocine de 1 UI a été administré, suivi d'une perfusion d'entretien. L'obstétricien·ne a évalué le tonus utérin par palpation comme satisfaisant ou insatisfaisant. En cas de réponse insatisfaisante, la dose pour la personne suivante a été augmentée de 2 UI·h−1. Lors d'une réponse satisfaisante, la dose pour la personne suivante a été diminuée de 2 UI·h−1 avec une probabilité de 1/9, ou est restée inchangée. Le critère d'évaluation principal était un tonus utérin satisfaisant de cinq minutes après l'accouchement jusqu'à la sortie de la salle de réveil. Les critères d'évaluation secondaires étaient la perte de sang, la nécessité d'utérotoniques supplémentaires et les effets secondaires. RéSULTATS: Nous avons analysé les données de 40 patient·es. La DE90 de perfusion d'entretien d'ocytocine était de 4,5 UI·h−1 (intervalle de confiance à 95 %, 3,3 à 5,5) basé sur l'estimateur de régression isotonique. La perte de sang médiane [écart interquartile] était de 861 [553-1 181] mL; 18 % ont reçu des utérotoniques supplémentaires et 38 % ont développé une hypotension après l'accouchement. CONCLUSION: D'après les résultats de cette étude de détermination de la dose, nous recommandons un débit de perfusion d'entretien de 4,5 UI·h−1 après un bolus d'ocytocine de 1 UI pour un tonus utérin adéquat chez les personnes parturientes bénéficiant d'une césarienne programmée. Ce débit de perfusion est quatre fois inférieur à celui requis sans bolus initial. ENREGISTREMENT DE L'éTUDE: ClinicalTrials.gov ( NCT04946006 ); première soumission le 25 juin 2021.

An initial 'snapshot' of sensory information biases the likelihood and speed of subsequent changes of mind.

We often need to rapidly change our mind about perceptual decisions in order to account for new information and correct mistakes. One fundamental, unresolved question is whether information processed prior to a decision being made ('pre-decisional information') has any influence on the likelihood and speed with which that decision is reversed. We investigated this using a luminance discrimination task in which participants indicated which of two flickering greyscale squares was brightest. Following an initial decision, the stimuli briefly remained on screen, and participants could change their response. Using psychophysical reverse correlation, we examined how moment-to-moment fluctuations in stimulus luminance affected participants' decisions. This revealed that the strength of even the very earliest (pre-decisional) evidence was associated with the likelihood and speed of later changes of mind. To account for this effect, we propose an extended diffusion model in which an initial 'snapshot' of sensory information biases ongoing evidence accumulation.

Comparative effectiveness of psychological interventions for treating the psychological consequences of sexual abuse in children and adolescents: a network meta-analysis.

BACKGROUND: Following sexual abuse, children and young people may develop a range of psychological problems, including anxiety, depression, post-traumatic stress disorder (PTSD), and a range of behaviour problems. Those working with children and young people experiencing these problems may use one or more of a range of psychological approaches. OBJECTIVES: To assess the relative effectiveness of psychological interventions compared to other treatments or no treatment controls, to overcome psychological consequences of sexual abuse in children and young people up to 18 years of age. Secondary objectives To rank psychotherapies according to their effectiveness. To compare different 'doses' of the same intervention. SEARCH METHODS: In November 2022 we searched CENTRAL, MEDLINE, Embase, PsycINFO, 12 other databases and two trials registers. We reviewed the reference lists of included studies, alongside other work in the field, and communicated with the authors of included studies. SELECTION CRITERIA: We included randomised controlled trials comparing psychological interventions for sexually abused children and young people up to 18 years old with other treatments or no treatments. Interventions included: cognitive behavioural therapy (CBT), psychodynamic therapy, family therapy, child centred therapy (CCT), and eye movement desensitisation and reprocessing (EMDR). We included both individual and group formats. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, extracted data and assessed the risk of bias for our primary outcomes (psychological distress/mental health, behaviour, social functioning, relationships with family and others) and secondary outcomes (substance misuse, delinquency, resilience, carer distress and efficacy). We considered the effects of the interventions on all outcomes at post-treatment, six months follow-up and 12 months follow-up. For each outcome and time point with sufficient data, we performed random-effects network and pairwise meta-analyses to determine an overall effect estimate for each possible pair of therapies. Where meta-analysis was not possible, we report the summaries from single studies. Due to the low number of studies in each network, we did not attempt to determine the probabilities of each treatment being the most effective relative to the others for each outcome at each time point. We rated the certainty of evidence with GRADE for each outcome. MAIN RESULTS: We included 22 studies (1478 participants) in this review. Most of the participants were female (range: 52% to 100%), and were mainly white. Limited information was provided on socioeconomic status of participants. Seventeen studies were conducted in North America, with the remaining studies conducted in the UK (N = 2), Iran (N = 1), Australia (N = 1) and Democratic Republic of Congo (N = 1). CBT was explored in 14 studies and CCT in eight studies; psychodynamic therapy, family therapy and EMDR were each explored in two studies. Management as usual (MAU) was the comparator in three studies and a waiting list was the comparator in five studies. For all outcomes, comparisons were informed by low numbers of studies (one to three per comparison), sample sizes were small (median = 52, range 11 to 229) and networks were poorly connected. Our estimates were all imprecise and uncertain. Primary outcomes At post-treatment, network meta-analysis (NMA) was possible for measures of psychological distress and behaviour, but not for social functioning. Relative to MAU, there was very low certainty evidence that CCT involving parent and child reduced PTSD (standardised mean difference (SMD) -0.87, 95% confidence intervals (CI) -1.64 to -0.10), and CBT with only the child reduced PTSD symptoms (SMD -0.96, 95% CI -1.72 to -0.20). There was no clear evidence of an effect of any therapy relative to MAU for other primary outcomes or at any other time point. Secondary outcomes Compared to MAU, there was very low certainty evidence that, at post-treatment, CBT delivered to the child and the carer might reduce parents' emotional reactions (SMD -6.95, 95% CI -10.11 to -3.80), and that CCT might reduce parents' stress. However, there is high uncertainty in these effect estimates and both comparisons were informed only by one study. There was no evidence that the other therapies improved any other secondary outcome. We attributed very low levels of confidence for all NMA and pairwise estimates for the following reasons. Reporting limitations resulted in judgements of 'unclear' to 'high' risk of bias in relation to selection, detection, performance, attrition and reporting bias; the effect estimates we derived were imprecise, and small or close to no change; our networks were underpowered due to the low number of studies informing them; and whilst studies were broadly comparable with regard to settings, the use of a manual, the training of the therapists, the duration of treatment and number of sessions offered, there was considerable variability in the age of participants and the format in which the interventions were delivered (individual or group). AUTHORS' CONCLUSIONS: There was weak evidence that both CCT (delivered to child and carer) and CBT (delivered to the child) might reduce PTSD symptoms at post-treatment. However, the effect estimates are uncertain and imprecise. For the remaining outcomes examined, none of the estimates suggested that any of the interventions reduced symptoms compared to management as usual. Weaknesses in the evidence base include the dearth of evidence from low- and middle-income countries. Further, not all interventions have been evaluated to the same extent, and there is little evidence regarding the effectiveness of interventions for male participants or those from different ethnicities. In 18 studies, the age ranges of participants ranged from 4 to 16 years old or 5 to 17 years old. This may have influenced the way in which the interventions were delivered, received, and consequently influenced outcomes. Many of the included studies evaluated interventions that were developed by members of the research team. In others, developers were involved in monitoring the delivery of the treatment. It remains the case that evaluations conducted by independent research teams are needed to reduce the potential for investigator bias. Studies addressing these gaps would help to establish the relative effectiveness of interventions currently used with this vulnerable population.

Exploring the extent to which shared mechanisms contribute to motion-position illusions.

Motion-position illusions (MPIs) are visual motion illusions in which motion signals bias the perceived position of an object. Due to phenomenological similarities between these illusions, previous research has assumed that some are caused by common mechanisms. However, this assumption has yet to be directly tested. This study investigates this assumption by exploiting between-participant variations in illusion magnitude. During two sessions, 106 participants viewed the flash-lag effect, luminance flash-lag effect, Fröhlich effect, flash-drag effect, flash-grab effect, motion-induced position shift, twinkle-goes effect, and the flash-jump effect. For each effect, the magnitude of the illusion was reliable within participants, strongly correlating between sessions. When the pairwise correlations of averaged illusions magnitudes were explored, two clusters of statistically significant positively correlated illusions were identified. The first cluster comprised the flash-grab effect, motion-induced position shift, and twinkle-goes effect. The second cluster comprised the Fröhlich and flash-drag effect. The fact that within each of these two clusters, individual differences in illusion magnitude were correlated suggests that these clusters may reflect shared underlying mechanisms. An exploratory factor analysis provided additional evidence that these correlated clusters shared an underlying factor, with each cluster loading onto their own factor. Overall, our results reveal that, contrary to the prevailing perspective in the literature, while some motion-position illusions share processes, most of these illusions are unlikely to reflect any shared processes, instead implicating unique mechanisms.

Tracking dynamic adjustments to decision making and performance monitoring processes in conflict tasks.

How we exert control over our decision-making has been investigated using conflict tasks, which involve stimuli containing elements that are either congruent or incongruent. In these tasks, participants adapt their decision-making strategies following exposure to incongruent stimuli. According to conflict monitoring accounts, conflicting stimulus features are detected in medial frontal cortex, and the extent of experienced conflict scales with response time (RT) and frontal theta-band activity in the Electroencephalogram (EEG). However, the consequent adjustments to decision processes following response conflict are not well-specified. To characterise these adjustments and their neural implementation we recorded EEG during a modified Flanker task. We traced the time-courses of performance monitoring processes (frontal theta) and multiple processes related to perceptual decision-making. In each trial participants judged which of two overlaid gratings forming a plaid stimulus (termed the S1 target) was of higher contrast. The stimulus was divided into two sections, which each contained higher contrast gratings in either congruent or incongruent directions. Shortly after responding to the S1 target, an additional S2 target was presented, which was always congruent. Our EEG results suggest enhanced sensory evidence representations in visual cortex and reduced evidence accumulation rates for S2 targets following incongruent S1 stimuli. Results of a follow-up behavioural experiment indicated that the accumulation of sensory evidence from the incongruent (i.e. distracting) stimulus element was adjusted following response conflict. Frontal theta amplitudes positively correlated with RT following S1 targets (in line with conflict monitoring accounts). Following S2 targets there was no such correlation, and theta amplitude profiles instead resembled decision evidence accumulation trajectories. Our findings provide novel insights into how cognitive control is implemented following exposure to conflicting information, which is critical for extending conflict monitoring accounts.

Perceptual change-of-mind decisions are sensitive to absolute evidence magnitude.

To navigate the world safely, we often need to rapidly 'change our mind' about decisions. Current models assume that initial decisions and change-of-mind decisions draw upon common sources of sensory evidence. In two-choice scenarios, this evidence may be 'relative' or 'absolute'. For example, when judging which of two objects is the brightest, the luminance difference and luminance ratio between the two objects are sources of 'relative' evidence, which are invariant across additive and multiplicative luminance changes. Conversely, the overall luminance of the two objects combined is a source of 'absolute' evidence, which necessarily varies across symmetric luminance manipulations. Previous studies have shown that initial decisions are sensitive to both relative and absolute evidence; however, it is unknown whether change-of-mind decisions are sensitive to absolute evidence. Here, we investigated this question across two experiments. In each experiment participants indicated which of two flickering greyscale squares was brightest. Following an initial decision, the stimuli remained on screen for a brief period and participants could change their response. To investigate the effect of absolute evidence, the overall luminance of the two squares was varied whilst either the luminance difference (Experiment 1) or luminance ratio (Experiment 2) was held constant. In both experiments we found that increases in absolute evidence led to faster, less accurate initial responses and slower changes of mind. Change-of-mind accuracy decreased when the luminance difference was held constant, but remained unchanged when the luminance ratio was fixed. We show that the three existing change-of-mind models cannot account for our findings. We then fit three alternative models, previously used to account for the effect of absolute evidence on one-off decisions, to the data. A leaky competing accumulator model best accounted for the changes in behaviour across absolute evidence conditions - suggesting an important role for input-dependent leak in explaining perceptual changes of mind.

Iterative Catalysis in the Biosynthesis of Mitochondrial Complex II Inhibitors Harzianopyridone and Atpenin B.

The pentasubstituted pyridine natural products harzianopyridone and atpenins are potent inhibitors of mitochondrial complex II. We identified the pathways of these compounds from their fungal producers and uncovered that the biosynthetic steps require multiple iterative enzymes. In particular, a methyltransferase and a flavin-dependent monooxygenase are used iteratively to introduce C5 and C6 methoxy groups. The pathway unexpectedly requires the installation and removal of an N-methoxy group, which is proposed to be a directing group that tunes the reactivity of the pyridone ring, possibly through the alpha effect.

Black Lives Matter: We are in the Same Storm but we are not in the Same Boat.

Black Lives Matter is a clarion call for racial equality and racial justice. With the arrival of Africans as slaves in 1619, a racial hierarchy was formed in the United States. However, slavery is commonly dismissed as that less than noble aspect of the United States' history without really confronting the legacies of racial inequality and racial injustice left in its wake. White supremacy, based on the myths of white superiority and Black inferiority, have obscured racial inequality and racial injustice, resulting in blaming the victims. Using Black Lives Matter as a platform, we focus on some key considerations for theory, research, education, training, and practice in clinical, community, and larger systems contexts. Broadly, we focus on Black Lives Matter, literally; Black dehumanization; historical oppression; healing; and implications for the field of family therapy. More specifically, we draw attention to health disparities, mass incarceration and aggressive policing, intergenerational racial trauma, restorative justice, and antiracist work.

El movimiento Black Lives Matter (Las vidas de los negros son importantes) es un llamamiento a la igualdad y la justicia racial. Con la llegada de los africanos como esclavos en el año 1619, se formó una jerarquía racial en los Estados Unidos. Sin embargo, la esclavitud generalmente se desestima como el aspecto menos noble de la historia de los Estados Unidos sin afrontar realmente los legados de desigualdad e injusticia raciales que dejó. La supremacía blanca, basada en los mitos de la superioridad blanca y la inferioridad negra, han ocultado la desigualdad y la injusticia raciales, lo cual condujo a la culpabilización de las víctimas. Utilizando el movimiento Black Lives Matter como plataforma, nos centramos en algunas consideraciones clave para la teoría, la investigación, la educación, la capacitación y la práctica en contextos clínicos, comunitarios y en sistemas más grandes. En líneas generales, nos centramos en Black Lives Matter, literalmente; en la deshumanización de los negros, la opresión histórica, la recuperación, y las consecuencias para el área de la terapia familiar. Más específicamente, visibilizamos las desigualdades sanitarias, el encarcelamiento masivo y la vigilancia policial agresiva, el trauma racial intergeneracional, la justicia reparadora y la labor antirracista.

Use of a Fluorescent Analogue of a HBV Core Protein-Directed Drug To Interrogate an Antiviral Mechanism.

Heteroaryldihydropyrimidines (HAPs) are antiviral small molecules that enhance assembly of HBV core protein (Cp), lead to assembly of empty and defective particles, and suppress viral replication. These core protein allosteric modulators (CpAMs) bind to the pocket at the interface between two Cp dimers and strengthen interdimer interactions. To investigate the CpAM mechanism, we wanted to examine the cellular distributions of Cp and the CpAM itself. For this reason, we developed a fluorescently labeled CpAM, HAP-ALEX. In vitro, HAP-ALEX modulated assembly of purified Cp and at saturating concentrations induced formation of large structures. HAP-ALEX bound capsids and not dimers, making it a capsid-specific molecular tag. HAP-ALEX labeled HBV in transfected cells, with no detectable background with a HAP-insensitive Cp mutant. HAP-ALEX caused redistribution of Cp in a dose-dependent manner consistent with its 0.7 µM EC50, leading to formation of large puncta and an exclusively cytoplasmic distribution. HAP-ALEX colocalized with the redistributed Cp, but large puncta accumulated long before they appeared saturated with the fluorescent CpAM. CpAMs affect HBV assembly and localization; with a fluorescent CpAM both drug and target can be identified.

Metabolic shift in density-dependent stem cell differentiation.

BACKGROUND: Vascular progenitor cells (VPCs) derived from embryonic stem cells (ESCs) are a valuable source for cell- and tissue-based therapeutic strategies. During the optimization of endothelial cell (EC) inductions from mouse ESCs using our staged and chemically-defined induction methods, we found that cell seeding density but not VEGF treatment between 10 ng/mL and 40 ng/mL was a significant variable directing ESCs into FLK1+ VPCs during stage 1 induction. Here, we examine potential contributions from cell-to-cell signaling or cellular metabolism in the production of VPCs from ESCs seeded at different cell densities. METHODS: Using 1D 1H-NMR spectroscopy, transcriptomic arrays, and flow cytometry, we observed that the density-dependent differentiation of ESCs into FLK1+ VPCs positively correlated with a shift in metabolism and cellular growth. RESULTS: Specifically, cell differentiation correlated with an earlier plateauing of exhaustive glycolysis, decreased lactate production, lower metabolite consumption, decreased cellular proliferation and an increase in cell size. In contrast, cells seeded at a lower density of 1,000 cells/cm2 exhibited increased rates of glycolysis, lactate secretion, metabolite utilization, and proliferation over the same induction period. Gene expression analysis indicated that high cell seeding density correlated with up-regulation of several genes including cell adhesion molecules of the notch family (NOTCH1 and NOTCH4) and cadherin family (CDH5) related to vascular development. CONCLUSIONS: These results confirm that a distinct metabolic phenotype correlates with cell differentiation of VPCs.

Multivariate pattern analysis of event-related potentials predicts the subjective relevance of everyday objects.

Potentially decision-relevant stimuli have been proposed to undergo immediate semantic processing. The current study investigated whether information regarding the general desirability ('Wanting') of visually presented 'everyday' objects was rapidly and automatically processed. Participants completed a foreground task while their electroencephalogram (EEG) was recorded, and task-irrelevant images were presented in the background. Following this, participants rated the images with regards to Wanting and the potentially related attributes of Relevance, Familiarity, Aesthetic Pleasantness and Time Reference. Multivariate pattern classification was used to predict the ratings from patterns of EEG data. Prediction of Wanting and Relevance was possible between 100 and 150ms following stimulus presentation. The other dimensions could not be predicted. Wanting and Relevance ratings were highly correlated and displayed similar feature weight maps. The current results suggest that the general desirability and subjective relevance of everyday objects is rapidly and automatically processed for a wide range of visual stimuli.

Training on domestic violence and child safeguarding in general practice: a mixed method evaluation of a pilot intervention.

BACKGROUND: Children's exposure to domestic violence is a type of child maltreatment, yet many general practice clinicians remain uncertain of their child safeguarding responsibilities in the context of domestic violence. We developed an evidence-based pilot training on domestic violence and child safeguarding for general practice teams. The aim of this study was to test and evaluate its feasibility, acceptability and the direction of change in short-term outcome measures. METHODS: We used a mixed method design which included a pre-post questionnaire survey, qualitative analysis of free-text comments, training observations, and post-training interviews with trainers and participants. The questionnaire survey used a validated scale to measure participants' knowledge, confidence/ self-efficacy, and beliefs/ attitudes towards domestic violence and child safeguarding in the context of domestic violence. RESULTS: Eleven UK general practices were recruited (response rate 55%) and 88 clinicians attended the pilot training. Thirty-seven participants (42%) completed all pre-post questionnaires and nine were interviewed. All training sessions were observed. All six trainers were interviewed. General practice clinicians valued the training materials and teaching styles, opportunities for reflection and delivery by local trainers from both health and children's social services. The training elicited positive changes in total outcome score and knowledge and confidence/ self-efficacy sub scores which remained at 3-month follow up. However, the mean sub score of beliefs and attitudes did not change and the qualitative results were mixed. Two interviewees described changes in their clinical practice. Participants' suggestions for improving the training included incorporating more ethnic and class diversity in the material, using cases with multiple socio economic disadvantages, and addressing multi-agency collaboration in the context of changing and under-resourced services for children. CONCLUSIONS: The pilot training for general practice on child safeguarding in the context of domestic violence was feasible and acceptable. It elicited positive changes in clinicians' knowledge and confidence/ self-esteem. The extent to which clinical behaviour changed is unclear, but there are indications of changes in practice by some clinicians. The pilot training requires further refinement and evaluation before implementation.

Design and synthesis of N-[6-(Substituted Aminoethylideneamino)-2-Hydroxyindan-1-yl]arylamides as selective and potent muscarinic M1 agonists.

The observation that cholinergic deafferentation of circuits projecting from forebrain basal nuclei to frontal and hippocampal circuits occurs in Alzheimer's disease has led to drug-targeting of muscarinic M1 receptors to alleviate cognitive symptoms. The high homology within the acetylcholine binding domain of this family however has made receptor-selective ligand development challenging. This work presents the synthesis scheme, pharmacokinetic and structure-activity-relationship study findings for M1-selective ligand, LY593093. Pharmacologically the compound acts as an orthosteric ligand. The homology modeling work presented however will illustrate that compound binding spans from the acetylcholine pocket to the extracellular loops of the receptor, a common allosteric vestibule for the muscarinic protein family. Altogether LY593093 represents a growing class of multi-topic ligands which interact with the receptors in both the ortho- and allosteric binding sites, but which exert their activation mechanism as an orthosteric ligand.

Atheroprotective immunization with malondialdehyde-modified LDL is hapten specific and dependent on advanced MDA adducts: implications for development of an atheroprotective vaccine.

Immunization with homologous malondialdehyde (MDA)-modified LDL (MDA-LDL) leads to atheroprotection in experimental models supporting the concept that a vaccine to oxidation-specific epitopes (OSEs) of oxidized LDL could limit atherogenesis. However, modification of human LDL with OSE to use as an immunogen would be impractical for generalized use. Furthermore, when MDA is used to modify LDL, a wide variety of related MDA adducts are formed, both simple and more complex. To define the relevant epitopes that would reproduce the atheroprotective effects of immunization with MDA-LDL, we sought to determine the responsible immunodominant and atheroprotective adducts. We now demonstrate that fluorescent adducts of MDA involving the condensation of two or more MDA molecules with lysine to form malondialdehyde-acetaldehyde (MAA)-type adducts generate immunodominant epitopes that lead to atheroprotective responses. We further demonstrate that a T helper (Th) 2-biased hapten-specific humoral and cellular response is sufficient, and thus, MAA-modified homologous albumin is an equally effective immunogen. We further show that such Th2-biased humoral responses per se are not atheroprotective if they do not target relevant antigens. These data demonstrate the feasibility of development of a small-molecule immunogen that could stimulate MAA-specific immune responses, which could be used to develop a vaccine approach to retard or prevent atherogenesis.

Neural mechanisms of visual motion extrapolation.

Because neural processing takes time, the brain only has delayed access to sensory information. When localising moving objects this is problematic, as an object will have moved on by the time its position has been determined. Here, we consider predictive motion extrapolation as a fundamental delay-compensation strategy. From a population-coding perspective, we outline how extrapolation can be achieved by a forwards shift in the population-level activity distribution. We identify general mechanisms underlying such shifts, involving various asymmetries which facilitate the targeted 'enhancement' and/or 'dampening' of population-level activity. We classify these on the basis of their potential implementation (intra- vs inter-regional processes) and consider specific examples in different visual regions. We consider how motion extrapolation can be achieved during inter-regional signaling, and how asymmetric connectivity patterns which support extrapolation can emerge spontaneously from local synaptic learning rules. Finally, we consider how more abstract 'model-based' predictive strategies might be implemented. Overall, we present an integrative framework for understanding how the brain determines the real-time position of moving objects, despite neural delays.

Evaluation of magnetic resonance imaging for bladder cancer detection following transurethral resection of bladder tumour (TURBT).

PURPOSE: To evaluate the performance of MRI for detection of bladder cancer following transurethral resection of bladder tumour (TURBT). METHODS: This single-centre retrospective study included forty-one consecutive patients with bladder cancer who underwent bladder MRI after TURBT. Two uroradiologists retrospectively assessed the presence of tumour using bladder MRI with and without DWI (diffusion weighted imaging) using a five-point Likert scale. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated and inter-reader agreement was assessed. Histopathology was used as the reference standard. RESULTS: 24 out of 41 patients (58.5%) had no residual tumour or Tis (carcinoma in situ) after TURBT. Sensitivity, specificity, PPV and NPV for detection of tumour using T1WI (T1-weighted imaging) and T2WI (T2-weighted imaging) was 50.0%, 54.6%, 21.1%, and 81.8%, respectively and for T1WI, T2WI and DWI combined was 100%, 76.5%, 50.0% and 100%, respectively. Overestimation of tumour was more common than underestimation. MRI showed high accuracy for patients in whom there was no residual tumour (78.9%). Inter-reader agreement for tumour detection improved from fair (κ = 0.54) to moderate (κ = 0.70) when DWI was included. CONCLUSION: Non-contrast MRI with DWI showed high sensitivity and relatively high specificity for detection of residual tumour after TURBT. Inter-reader agreement improved from fair to moderate with the addition of DWI. MRI can be useful after TURBT in order to guide further management.

The Impact of Estrogen-Suppressing Contraceptives on Behavioral and Functional Difficulties in Borderline Personality Disorder.

Borderline Personality Disorder (BPD) is characterized by rapidly shifting emotional, interpersonal, and behavioral symptoms, and is often co-morbid with mood and anxiety disorders. Females are more likely to be diagnosed with BPD than males and exhibit greater functional impairment. Hormonal fluctuations, particularly in estrogen levels, may influence the manifestation of BPD symptoms. Here we investigated the influence of estrogen-suppressing contraceptives on behavioral and functional difficulties in BPD. The analytical sample included 348 females ages 18-50 undergoing residential treatment for psychiatric disorders, with 131 having a BPD diagnosis. Patients were categorized based on their contraceptive method: 1) Estrogen-suppressing contraceptives (N=145) and 2) Naturally cycling (N=203). Interaction models tested the impact of estrogen-suppressing contraceptives on the relationship between BPD diagnosis and behavioral and functional difficulties at admission and discharge, assessed by the four Behavior and Symptom Identification Scale (BASIS-32) domains: difficulties in relationships, daily living, depression/anxiety, and impulsivity. Females with a BPD diagnosis were more likely to use estrogen-suppressing contraceptives compared to those without BPD (p=0.04). However, estrogen-suppressing contraceptive use was not associated with behavioral and functional difficulties at admission, discharge, or over time. Estrogen-suppressing contraceptives moderated the association between BPD diagnosis and difficulties in relationships (p=0.004), difficulties in daily living (p=0.01), and depression/anxiety symptoms (p=0.004). Patients with BPD expressed increased behavioral and functional difficulties at admission, discharge, and over time only if naturally cycling (p<0.003). Our findings suggest that estrogen-suppressing contraceptives may help to regulate the rapidly shifting emotional, interpersonal, and behavioral symptoms in females with BPD by stabilizing estrogen levels.