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Formal total synthesis of eni-codeinone and eni-codeine was accomplished via the total synthesis of eni-neopinone attained in 14 steps from β-bromoethylbenzene. The key steps included (i) enzymatic dihydroxylation of β-bromoethylbenzene with E. coli JM109 (pDTG601a), an organism that overexpresses toluene dioxygenase, (ii) a Heck reaction to establish C-13 stereogenic center, (iii) aldol condensation, and (iv) 1,6-conjugate addition of the ethylamino side chain to C9. Several other modes of construction of the C-9 and C-14 centers were also investigated: Mannich cyclization, and azaPrins reaction. The synthesis of eni-codeinone was formalized by intersecting Fukuyama's recently published approach. Experimental and spectral data are provided for all new compounds. Key words: synthesis of morphine alkaloids, eni-codeinone synthesis, eni-neopinone synthesis, enzymatic dihydroxylation of aromatics, Heck reaction. On a realise une synthese totale formelle de l'eni-codeinone et de l'eni-codeine par le biais d'une synthese totale de l'eni-neopinone qui a ete obtenue en quatorze etapes a partir du β-bromoethylbenzene. Les etapes cles comportent (i) une dihydroxylation enzymatique du β-bromoethylbenzene a l'aide d'E. coli JM109 (pDTG601a), un organisme qui imite la dioxygenase du toluene, (ii) une reaction de Heck pour etablir le centre stereogenique en C-13, (iii) une condensation aldolique et (iv) une addition 1,6-conjuguee de la chaine laterale ethylamino sur le site C-9. On a aussi examine plusieurs autres modes de construction des centres C-9 et C-14, dont une cyclisation de Mannich et une reaction aza-Prins. La synthese de l'eni-codeinone a ete formalisee en procedant a une intersection avec la methode de Fukuyama publiee recemment. Les donnees experimentales et spectrales pour tous les nouveaux produits. Mois-cles : synthese d'alcaloides de la morphine, synthese de l'eni-codeinone, synthese de l'eni-neopinone, dihydroxylation enzymatique de produits aromatiques, reaction de Heck., Introduction There has not been a shortage of interest in new synthetic approaches to morphine (1) in the last decade. The most recent review, published in 2011, (1) summarized all [...]

This study investigates the goal/habit imbalance theory of compulsion in obsessive-compulsive disorder (OCD), which postulates enhanced habit formation, increased automaticity, and impaired goal/habit arbitration. It directly tests these hypotheses using newly developed behavioral tasks. First, OCD patients and healthy participants were trained daily for a month using a smartphone app to perform chunked action sequences. Despite similar procedural learning and attainment of habitual performance (measured by an objective automaticity criterion) by both groups, OCD patients self-reported higher subjective habitual tendencies via a recently developed questionnaire. Subsequently, in a re-evaluation task assessing choices between established automatic and novel goal-directed actions, both groups were sensitive to re-evaluation based on monetary feedback. However, OCD patients, especially those with higher compulsive symptoms and habitual tendencies, showed a clear preference for trained/habitual sequences when choices were based on physical effort, possibly due to their higher attributed intrinsic value. These patients also used the habit-training app more extensively and reported symptom relief post-study. The tendency to attribute higher intrinsic value to familiar actions may be a potential mechanism leading to compulsions and an important addition to the goal/habit imbalance hypothesis in OCD. We also highlight the potential of smartphone app training as a habit reversal therapeutic tool., Competing Interests: PB, MH, MG, MB, AM, TP, AS No competing interests declared, NF NAF in the past three years has received research funding paid to her institution from the NIHR, COST Action and Orchard. She has received payment for lectures from the Global Mental Health Academy and for expert advisory work on psychopharmacology from the Medicines and Healthcare Products Regulatory Agency and an honorarium from Elsevier for editorial work. She has additionally received financial support to attend meetings from the British Association for Psychopharmacology, European College for Neuropsychopharmacology, Royal College of Psychiatrists, International College for Neuropsychopharmacology, World Psychiatric Association, International Forum for Mood and Anxiety Disorders, American College for Neuropsychopharmacology. In the past she has received funding from various pharmaceutical companies for research into the role of SSRIs and other forms of medication as treatments for OCD and for giving lectures and attending scientific meetings, TR TWR discloses consultancy with Cambridge Cognition and receives research grants from Shionogi & Co. He also has editorial honoraria from Springer Verlag and Elsevier, (© 2023, Banca et al.)

In current telerobotics and telemanipulator applications, operators must perform a wide variety of tasks, often with a high risk associated with failure. A system designed to generate data-based behavioural estimations using observed operator features could be used to reduce risks in industrial teleoperation. This paper describes a non-invasive bio-mechanical feature capture method for teleoperators used to trial novel human-error rate estimators which, in future work, are intended to improve operational safety by providing behavioural and postural feedback to the operator. Operator monitoring studies were conducted in situ using the MASCOT teleoperation system at UKAEA RACE; the operators were given controlled tasks to complete during observation. Building upon existing works for vehicle-driver intention estimation and robotic surgery operator analysis, we used 3D point-cloud data capture using a commercially available depth camera to estimate an operator's skeletal pose. A total of 14 operators were observed and recorded for a total of approximately 8 h, each completing a baseline task and a task designed to induce detectable but safe collisions. Skeletal pose was estimated, collision statistics were recorded, and questionnaire-based psychological assessments were made, providing a database of qualitative and quantitative data. We then trialled data-driven analysis by using statistical and machine learning regression techniques (SVR) to estimate collision rates. We further perform and present an input variable sensitivity analysis for our selected features., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Piercy, Herrmann, Cangelosi, Zoulias and Lopez.)

Structural magnetic resonance imaging (MRI) quality is known to impact and bias neuroanatomical estimates and downstream analysis, including case-control comparisons, and a growing body of work has demonstrated the importance of careful quality control (QC) and evaluated the impact of image and image-processing quality. However, the growing size of typical neuroimaging datasets presents an additional challenge to QC, which is typically extremely time and labour intensive. One of the most important aspects of MRI quality is the accuracy of processed outputs, which have been shown to impact estimated neurodevelopmental trajectories. Here, we evaluate whether the quality of surface reconstructions by FreeSurfer (one of the most widely used MRI processing pipelines) interacts with clinical and demographic factors. We present a tool, FSQC, that enables quick and efficient yet thorough assessment of outputs of the FreeSurfer processing pipeline. We validate our method against other existing QC metrics, including the automated FreeSurfer Euler number, two other manual ratings of raw image quality, and two popular automated QC methods. We show strikingly similar spatial patterns in the relationship between each QC measure and cortical thickness; relationships for cortical volume and surface area are largely consistent across metrics, though with some notable differences. We next demonstrate that thresholding by QC score attenuates but does not eliminate the impact of quality on cortical estimates. Finally, we explore different ways of controlling for quality when examining differences between autistic individuals and neurotypical controls in the Autism Brain Imaging Data Exchange (ABIDE) dataset, demonstrating that inadequate control for quality can alter results of case-control comparisons., Competing Interests: J.S., R.A.I.B., and A.F.A.-B. hold shares in and are directors of Centile Bioscience Inc. A.F.A.-B. receives consulting income from Octave Bioscience. Other authors report no related funding support, financial or potential conflicts of interest., (© 2023 Massachusetts Institute of Technology. Published under a Creative Commons Attribution 4.0 International (CC BY 4.0) license.)

Habits are a powerful route to efficiency; the ability to constantly shift between goal-directed and habitual strategies, as well as integrate them into behavioral output, is key to optimal performance in everyday life. When such ability is impaired, it may lead to loss of control and to compulsive behavior. Habits have successfully been induced and investigated in rats using methods such as overtraining stimulus-response associations and outcome devaluation, respectively. However, such methods have ineffectively measured habits in humans because (1) human habits usually involve more complex sequences of actions than in rats and (2) of pragmatic impediments posed by the extensive time (weeks or even months), it may take for routine habits to develop. We present here a novel behavioral paradigm-a mobile-phone app methodology-for inducing and measuring habits in humans during their everyday schedule and environment. It assumes that practice is key to achieve automaticity and proficiency and that the use of a hierarchical sequence of actions is the best strategy for capturing the cognitive mechanisms involved in habit formation (including "chunking") and consolidation. The task is a gamified self-instructed and self-paced app on a mobile phone that enables subjects to learn and practice two sequences of finger movements, composed of chords and single presses. It involves a step-wise learning procedure in which subjects begin responding to a visual and auditory cued sequence by generating responses on the screen using four fingers. Such cues progressively disappear throughout 1 month of training, enabling the subject ultimately to master the motor skill involved. We present preliminary data for the acquisition of motor sequence learning in 29 healthy individuals, each trained over a month period. We demonstrate an asymptotic improvement in performance, as well as its automatic nature. We also report how people integrate the task into their daily routine, the development of motor precision throughout training, and the effect of intermittent reinforcement and reward extinction in habit preservation. The findings help to validate this "real world" app for measuring human habits., (Copyright © 2020 Banca, McNamee, Piercy, Luo and Robbins.)

Work and study increasingly rely on the use of technologies requiring individuals to switch attention rapidly between emails, texts and tasks. This has led to healthy people having problems of attention and concentration and difficulties getting into the "flow," which impedes goal attainment and task completion. Possibly related to this, there is an increasing diagnosis of attention deficit hyperactivity disorder (ADHD) and prescriptions of drugs such as methylphenidate. In addition to ADHD, attention is impaired in other neuropsychiatric disorders, such as schizophrenia and in traumatic brain injury (TBI). Based on neuropsychological and neuroimaging evidence, we developed "Decoder," a novel game for targeted cognitive training of visual sustained attention on an iPad. We aimed to investigate the effects of cognitive training in 75 healthy young adults randomly assigned to a Cognitive Training (8 h of playing Decoder over 4 weeks; n = 25), Active Control (8 h of playing Bingo over 4 weeks; n = 25) or Passive Control (continuation of activities of daily living; n = 25) group. Results indicated that cognitive training with Decoder was superior to both control groups in terms of increased target sensitivity (A') on the Cambridge Neuropsychological Test Automated Battery Rapid Visual Information processing (CANTAB RVP) test, indicating significantly improved sustained visual attention. Individuals playing Decoder also showed significantly better performance on the Trail Making Test (TMT) compared with those playing Bingo. Significant differences in visual analogue scales were also found between the two gaming groups, such that Decoder received higher ratings of enjoyment, task-related motivation and alertness across all hours of game play. These data suggest that cognitive training with Decoder is an effective non-pharmacological method for enhancing attention in healthy young adults, which could be extended to clinical populations in which attentional problems persist.

One type of obsessive-compulsive disorder (OCD) is characterized by contamination fears and compulsive cleansing. Few effective treatments are available for this debilitating condition. Compulsive symptoms, such as excessive washing, are believed to be mediated by cognitive inflexibility-arguably the most striking cognitive impairment in OCD. In this study, we investigated the effects of two novel smartphone interventions on cognitive flexibility and OCD symptoms in healthy individuals with OCD-like contamination fears. In the first intervention, participants watched a brief video recording of themselves engaging in handwashing on a smartphone, four times a day, for a total of one week (N = 31). The second intervention was similar except that participants watched themselves repeatedly touching a disgust-inducing object (N = 31). In a third (control) "intervention", participants watched themselves performing sequential hand movements (N = 31). As hypothesized, the two smartphone interventions, unlike the control, improved cognitive flexibility; as assessed on the Intradimensional-Extradimensional Set Shifting task (a sensitive marker of cognitive flexibility). The two interventions, unlike the control, also improved OCD symptoms (measured with the Obsessive-Compulsive Inventory-Revised and Yale-Brown Obsessive-Compulsive Scale). Finally, we found high levels of adherence to the interventions. These findings have significant clinical implications for OCD.

Background: Cognitive training is effective in patients with mild cognitive impairment but does not typically address the motivational deficits associated with older populations with memory difficulties., Methods: We conducted a randomized controlled trial of cognitive training using a novel memory game on an iPad in 42 patients with a diagnosis of amnestic mild cognitive impairment assigned to either the cognitive training (n=21; 8 hours of gameplay over 4 weeks) or control (n=21; clinic visits as usual) groups., Results: Significant time-by-pattern-by-group interactions were found for cognitive performance in terms of the number of errors made and trials needed on the Cambridge Neuropsychological Test Automated Battery Paired Associates Learning task (P=.044; P=.027). Significant time-by-group interactions were also found for the Cambridge Neuropsychological Test Automated Battery Paired Associates Learning first trial memory score (P=.002), Mini-Mental State Examination (P=.036), the Brief Visuospatial Memory Test (P=.032), and the Apathy Evaluation Scale (P=.026). Within-group comparisons revealed highly specific effects of cognitive training on episodic memory. The cognitive training group maintained high levels of enjoyment and motivation to continue after each hour of gameplay, with self-confidence and self-rated memory ability improving over time., Conclusions: Episodic memory robustly improved in the cognitive training group. "Gamified" cognitive training may also enhance visuospatial abilities in patients with amnestic mild cognitive impairment. Gamification maximizes engagement with cognitive training by increasing motivation and could complement pharmacological treatments for amnestic mild cognitive impairment and mild Alzheimer's disease. Larger, more controlled trials are needed to replicate and extend these findings., (© The Author 2017. Published by Oxford University Press on behalf of CINP.)

In addition to causing distress and disability to the individual, neuropsychiatric disorders are also extremely expensive to society and governments. These disorders are both common and debilitating and impact on cognition, functionality and wellbeing. Cognitive enhancing drugs, such as cholinesterase inhibitors and methylphenidate, are used to treat cognitive dysfunction in Alzheimer's disease and attention deficit hyperactivity disorder, respectively. Other cognitive enhancers include specific computerized cognitive training and devices. An example of a novel form of cognitive enhancement using the technological advancement of a game on an iPad that also acts to increase motivation is presented. Cognitive enhancing drugs, such as methylphenidate and modafinil, which were developed as treatments, are increasingly being used by healthy people. Modafinil not only affects 'cold' cognition, but also improves 'hot' cognition, such as emotion recognition and task-related motivation. The lifestyle use of 'smart drugs' raises both safety concerns as well as ethical issues, including coercion and increasing disparity in society. As a society, we need to consider which forms of cognitive enhancement (e.g. pharmacological, exercise, lifelong learning) are acceptable and for which groups (e.g. military, doctors) under what conditions (e.g. war, shift work) and by what methods we would wish to improve and flourish.

Understanding the ability to survive in an aerosol leads to better understanding of the hazard posed by pathogenic organisms and can inform decisions related to the control and management of disease outbreaks. This basic survival information is sometimes lacking for high priority select agents such as the filoviruses which cause severe disease with high case fatality rates and can be acquired through the aerosol route. Microthreads in the form of spiders' webs were used to capture aerosolised filoviruses, and the decay rates of Zaire ebolavirus and Marburgvirus were determined. Results were compared to data obtained using a Goldberg drum to measure survival as a dynamic aerosol. The two methods of obtaining aerostability information are compared., (Crown Copyright © 2011. Published by Elsevier B.V. All rights reserved.)