Metabolic Flux Modeling in Marine Ecosystems.

Ocean metabolism constitutes a complex, multiscale ensemble of biochemical reaction networks harbored within and between the boundaries of a myriad of organisms. Gaining a quantitative understanding of how these networks operate requires mathematical tools capable of solving in silico the resource allocation problem each cell faces in real life. Toward this goal, stoichiometric modeling of metabolism, such as flux balance analysis, has emerged as a powerful computational tool for unraveling the intricacies of metabolic processes in microbes, microbial communities, and multicellular organisms. Here, we provide an overview of this approach and its applications, future prospects, and practical considerations in the context of marine sciences. We explore how flux balance analysis has been employed to study marine organisms, help elucidate nutrient cycling, and predict metabolic capabilities within diverse marine environments, and highlight future prospects for this field in advancing our knowledge of marine ecosystems and their sustainability.

Educational and psychological interventions for managing atopic dermatitis (eczema).

BACKGROUND: Atopic dermatitis (eczema), can have a significant impact on well-being and quality of life for affected people and their families. Standard treatment is avoidance of triggers or irritants and regular application of emollients and topical steroids or calcineurin inhibitors. Thorough physical and psychological assessment is central to good-quality treatment. Overcoming barriers to provision of holistic treatment in dermatological practice is dependent on evaluation of the efficacy and economics of both psychological and educational interventions in this participant group. This review is based on a previous Cochrane review published in 2014, and now includes adults as well as children. OBJECTIVES: To assess the clinical outcomes of educational and psychological interventions in children and adults with atopic dermatitis (eczema) and to summarise the availability and principal findings of relevant economic evaluations. SEARCH METHODS: We searched the Cochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase, APA PsycINFO and two trials registers up to March 2023. We checked the reference lists of included studies and related systematic reviews for further references to relevant randomised controlled trials (RCTs) and contacted experts in the field to identify additional studies. We searched NHS Economic Evaluation Database, MEDLINE and Embase for economic evaluations on 8 June 2022. SELECTION CRITERIA: Randomised, cluster-randomised and cross-over RCTs that assess educational and psychological interventions for treating eczema in children and adults. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods, with GRADE to assess the certainty of the evidence for each outcome. Primary outcomes were reduction in disease severity, as measured by clinical signs, patient-reported symptoms and improvement in health-related quality-of-life (HRQoL) measures. Secondary outcomes were improvement in long-term control of symptoms, improvement in psychological well-being, improvement in standard treatment concordance and adverse events. We assessed short- (up to 16 weeks after treatment) and long-term time points (more than 16 weeks). MAIN RESULTS: We included 37 trials (6170 participants). Most trials were conducted in high-income countries (34/37), in outpatient settings (25/37). We judged three trials to be low risk of bias across all domains. Fifteen trials had a high risk of bias in at least one domain, mostly due to bias in measurement of the outcome. Trials assessed interventions compared to standard care. Individual educational interventions may reduce short-term clinical signs (measured by SCORing Atopic Dermatitis (SCORAD); mean difference (MD) -5.70, 95% confidence interval (CI) -9.39 to -2.01; 1 trial, 30 participants; low-certainty evidence) but patient-reported symptoms, HRQoL, long-term eczema control and psychological well-being were not reported. Group education interventions probably reduce clinical signs (SCORAD) both in the short term (MD -9.66, 95% CI -19.04 to -0.29; 3 studies, 731 participants; moderate-certainty evidence) and the long term (MD -7.22, 95% CI -11.01 to -3.43; 3 studies, 1424 participants; moderate-certainty evidence) and probably reduce long-term patient-reported symptoms (SMD -0.47 95% CI -0.60 to -0.33; 2 studies, 908 participants; moderate-certainty evidence). They may slightly improve short-term HRQoL (SMD -0.19, 95% CI -0.36 to -0.01; 4 studies, 746 participants; low-certainty evidence), but may make little or no difference to short-term psychological well-being (Perceived Stress Scale (PSS); MD -2.47, 95% CI -5.16 to 0.22; 1 study, 80 participants; low-certainty evidence). Long-term eczema control was not reported. We don't know whether technology-mediated educational interventions could improve short-term clinical signs (SCORAD; 1 study; 29 participants; very low-certainty evidence). They may have little or no effect on short-term patient-reported symptoms (Patient Oriented Eczema Measure (POEM); MD -0.76, 95% CI -1.84 to 0.33; 2 studies; 195 participants; low-certainty evidence) and probably have little or no effect on short-term HRQoL (MD 0, 95% CI -0.03 to 0.03; 2 studies, 430 participants; moderate-certainty evidence). Technology-mediated education interventions probably slightly improve long-term eczema control (Recap of atopic eczema (RECAP); MD -1.5, 95% CI -3.13 to 0.13; 1 study, 232 participants; moderate-certainty evidence), and may improve short-term psychological well-being (MD -1.78, 95% CI -2.13 to -1.43; 1 study, 24 participants; low-certainty evidence). Habit reversal treatment may reduce short-term clinical signs (SCORAD; MD -6.57, 95% CI -13.04 to -0.1; 1 study, 33 participants; low-certainty evidence) but we are uncertain about any effects on short-term HRQoL (Children's Dermatology Life Quality Index (CDLQI); 1 study, 30 participants; very low-certainty evidence). Patient-reported symptoms, long-term eczema control and psychological well-being were not reported. We are uncertain whether arousal reduction therapy interventions could improve short-term clinical signs (Eczema Area and Severity Index (EASI); 1 study, 24 participants; very low-certainty evidence) or patient-reported symptoms (visual analogue scale (VAS); 1 study, 18 participants; very low-certainty evidence). Arousal reduction therapy may improve short-term HRQoL (Dermatitis Family Impact (DFI); MD -2.1, 95% CI -4.41 to 0.21; 1 study, 91 participants; low-certainty evidence) and psychological well-being (PSS; MD -1.2, 95% CI -3.38 to 0.98; 1 study, 91 participants; low-certainty evidence). Long-term eczema control was not reported. No studies reported standard care compared with self-help psychological interventions, psychological therapies or printed education; or adverse events. We identified two health economic studies. One found that a 12-week, technology-mediated, educational-support programme may be cost neutral. The other found that a nurse practitioner group-education intervention may have lower costs than standard care provided by a dermatologist, with comparable effectiveness. AUTHORS' CONCLUSIONS: In-person, individual education, as an adjunct to conventional topical therapy, may reduce short-term eczema signs compared to standard care, but there is no information on eczema symptoms, quality of life or long-term outcomes. Group education probably reduces eczema signs and symptoms in the long term and may also improve quality of life in the short term. Favourable effects were also reported for technology-mediated education, habit reversal treatment and arousal reduction therapy. All favourable effects are of uncertain clinical significance, since they may not exceed the minimal clinically important difference (MCID) for the outcome measures used (MCID 8.7 points for SCORAD, 3.4 points for POEM). We found no trials of self-help psychological interventions, psychological therapies or printed education. Future trials should include more diverse populations, address shared priorities, evaluate long-term outcomes and ensure patients are involved in trial design.

The role of psychological formulation in inpatient settings in supporting staff empathy and therapeutic optimism for adults diagnosed with borderline personality disorder: A pre- and post-vignette study.

WHAT IS KNOWN ON THE SUBJECT?: Psychological formulation brings together a service user story and expertise, with psychological knowledge, research, and practitioners clinical experience to make sense of a service users' presentation (thinking about their difficulties but also strengths). Evidence into the effectiveness of formulation is largely anecdotal, qualitative, or small scale. Although this is very valuable research, there is not a lot of research which quantitatively evidences the role of formulation for service users or services. Quantitative evidence that does exist is also conflicting. Considering how widely psychological formulation is used, and the governing guidelines that recognize this as a core competency for psychological practitioners, it is important to continue to add to the evidence base. WHAT THE PAPER ADDS TO EXISTING KNOWLEDGE?: Psychological formulation can increase staff empathy and hope. This could help service users to feel more understood and hopeful. Formulation; however, did not impact feelings of personal distress in staff. This research may suggest a need for the two distinct processes (i.e. team formulation and reflective practice) to support all components of empathy within inpatient services. Psychological formulation could support the provision of psychologically informed care within inpatient services, of which promotes effective care delivery. ABSTRACT: OBJECTIVES: National Health Service (NHS) values, such as empathy and therapeutic optimism, are integral when supporting service users with complex mental health presentations. There is some evidence to suggest that psychological formulation can increase empathy and optimism in healthcare professionals. This study, therefore, aimed to investigate whether a psychological formulation of a hypothetical service user with a complex presentation, typically labelled with a diagnosis of borderline personality disorder (BPD), increased empathy and therapeutic optimism in professionals working in mental health inpatient services. METHOD: Sixty-six mental health professionals working in NHS inpatient services took part in a pre- and post-vignette study. Participants were asked to read a case vignette about a hypothetical service user, with a diagnostic label of BPD, and complete questionnaires capturing levels of empathy and therapeutic optimism. Participants were then randomized into two conditions and either asked to read the same information again (control condition) or read a psychological formulation based on the same hypothetical service user (intervention condition). The findings were analysed using a series of ANCOVAs/ANCOHETs. RESULTS: Two constructs of empathy (i.e. perspective taking and empathic concern), and therapeutic optimism significantly increased following exposure to the psychological formulation when compared to the control group condition. CONCLUSION: This study warrants further replication. These initial findings; however, indicate that psychological formulation can significantly increase the ability to perspective take, display empathic concern, and hold therapeutic optimism towards service users with a presentation associated with a diagnosis of BPD.

Individual factors as predictors of secondary traumatic stress and burnout in forensic inpatient staff.

WHAT IS KNOWN ON THE SUBJECT: Secondary traumatic stress (STS) is the indirect traumatisation of a person through the stress of helping or knowing about other's trauma. Burnout is gradual exhaustion in response to long-term work-related stress. Both have negative psychological, physiological and/or organisational consequences; however, the existing research in forensic health care professionals (FHCPs) is limited. One study explored STS in FCHPs and found that lower psychological flexibility (ability to adapt) was a predictor of greater STS. Existing research on burnout in FHCPs suggests that individual differences, such as the ways in which we cope (talking to people vs. using substances), may predict burnout levels. WHAT THE PAPER ADDS TO EXISTING KNOWLEDGE: Prevalence findings add to the recent evidence base, which also found moderate levels of burnout. However, this study is the first to find high levels of secondary traumatic stress in FHCPs. Similar to existing literature, the study's findings suggest that FHCP's with lower levels of psychological flexibility and more maladaptive coping strategies may experience greater STS and burnout symptoms, while staff who use more adaptive coping strategies may experience less burn-out. Unexpectedly, staff who reported a more anxious attachment style were burnt-out; however, there are limitations to this finding. WHAT ARE THE IMPLICATIONS FOR PRACTICE: Policies and practices in forensic settings should reflect the risk of STS and burnout. Practices or interventions should enhance adaptive coping strategies and psychological flexibility, such as Resilience Enhancement Programmes or Acceptance and Commitment Therapy (ACT). ABSTRACT: INTRODUCTION: Secondary traumatic stress (STS) and burnout literature in inpatient forensic health care professionals (FHCPs) is limited, despite the psychological, physiological and organisational consequences. AIMS: This study aimed to further this limited evidence base, investigating predictors of STS and burnout in FHCPs. METHOD: 98 healthcare professionals working in two UK forensic inpatient settings completed measures assessing: burnout, STS, psychological flexibility, coping style, attachment style and a demographic questionnaire recording length of service and the sex of staff. RESULTS: Results indicated high STS and moderate burnout levels. The main predictors of STS and burnout were poorer psychological flexibility and greater maladaptive coping styles, whereas lower burnout was predicted by greater adaptive coping styles and an anxious attachment style. DISCUSSION: This study has contributed towards a limited evidence base and indicates poorer psychological flexibility and greater maladaptive coping may be risk factors for STS and burnout in FHCPs, whereas greater maladaptive coping may be a protective factor. IMPLICATION FOR PRACTICE: The findings suggest that interventions such as Acceptance and Commitment Therapy (ACT) and coping skills interventions, may offer protective benefits to inpatient forensic healthcare professionals.

Measuring the Social Impact of Burn injuries in Australia: An Adaptation of the Life Impact Burn Recovery Evaluation - The Aus-LIBRE Profile.

Burn survivors can experience social participation challenges throughout their recovery. The aim of this study was to develop a novel Australian English translation of the Life Impact Burn Recovery Evaluation (LIBRE) Profile, the Aus-LIBRE Profile. This study consisted of three stages: 1) translation of the LIBRE Profile from American to Australian English by Australian researchers/burns clinicians; 2) piloting and cognitive evaluation of the Aus-LIBRE Profile with burn survivors to assess the clarity and consistency of the interpretation of each individual item, and 3) review of the Aus-LIBRE Profile by colleagues who identify as Aboriginal Australians for cross-cultural validation. In stage 2, investigators administered the translated questionnaire to 20 Australian patients with burn injuries in the outpatient clinic (10 patients from xx and 10 patients from yy). Face validity of the Aus-LIBRE Profile was tested in 20 burns survivors (11 females) ranging from 21 to 74 years (median age 43 years). The total body surface area (TBSA) burned ranged from 1% to 50% (median 10%). Twelve language changes were made based on the feedback from the burn clinicians/researchers, study participants and colleagues who identify as Aboriginal Australians. Using a formal translation process, the Aus-LIBRE Profile was adapted for use in the Australian burn population. The Aus-LIBRE Profile will require psychometric validation and testing in the Australian burn patient population before broader application of the scale.

Investigating the use of finerenone in children with chronic kidney disease and proteinuria: design of the FIONA and open-label extension studies.

INTRODUCTION: Proteinuria is a modifiable risk factor for chronic kidney disease (CKD) progression in children. Finerenone, a selective, non-steroidal, mineralocorticoid receptor antagonist (MRA) has been approved to treat adults with CKD associated with type 2 diabetes mellitus (T2DM) following results from the phase III clinical trials FIDELIO-DKD (NCT02540993) and FIGARO-DKD (NCT02545049). In a pre-specified pooled analysis of both studies (N = 13,026), finerenone was shown to have an acceptable safety profile and was efficacious in decreasing the risk of adverse kidney and cardiovascular outcomes and of proteinuria. OBJECTIVE: FIONA and the associated open-label extension (OLE) study aim to demonstrate that combining finerenone with an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) is safe, well-tolerated, and effective in sustainably reducing urinary protein excretion in children with CKD and proteinuria. DESIGN: FIONA (NCT05196035; Eudra-CT: 2021-002071-19) is a randomized (2:1), double-blind, placebo-controlled, multicenter, phase III study of 6 months' duration in approximately 219 pediatric patients. Patients must have a clinical diagnosis of CKD (an eGFR ≥ 30 mL/min/1.73 m2 if ≥ 1 to < 18 years or a serum creatinine level ≤ 0.40 mg/dL for infants 6 months to < 1 year) with significant proteinuria despite ACEi or ARB usage. The primary objective is to demonstrate that finerenone, added to an ACEi or ARB, is superior to placebo in reducing urinary protein excretion. FIONA OLE (NCT05457283; Eudra-CT: 2021-002905-89) is a single-arm, open-label study, enrolling participants who have completed FIONA. The primary objective of FIONA OLE is to provide long-term safety data. FIONA has two primary endpoints: urinary protein-to-creatinine ratio (UPCR) reduction of ≥ 30% from baseline to day 180 and percent change in UPCR from baseline to day 180. A sample size of 198 participants (aged 2 to < 18 years) in FIONA will provide at least 80% power to reject the null hypothesis of either of the two primary endpoints. CONCLUSION: FIONA is evaluating the use of finerenone in children with CKD and proteinuria. Should safety, tolerability, and efficacy be demonstrated, finerenone could become a useful additional therapeutic agent in managing proteinuria and improving kidney outcomes in children with CKD. TRIAL REGISTRATION: ClinicalTrials.gov NCT05196035. Registered on 19 January 2022.

Ensemble Detection of DNA Engineering Signatures.

Synthetic biology is creating genetically engineered organisms at an increasing rate for many potentially valuable applications, but this potential comes with the risk of misuse or accidental release. To begin to address this issue, we have developed a system called GUARDIAN that can automatically detect signatures of engineering in DNA sequencing data, and we have conducted a blinded test of this system using a curated Test and Evaluation (T&E) data set. GUARDIAN uses an ensemble approach based on the guiding principle that no single approach is likely to be able to detect engineering with perfect accuracy. Critically, ensembling enables GUARDIAN to detect sequence inserts in 13 target organisms with a high degree of specificity that requires no subject matter expert (SME) review.

Precursors to infant sensorimotor synchronization to speech and non-speech rhythms: A longitudinal study.

Impaired sensorimotor synchronization (SMS) to acoustic rhythm may be a marker of atypical language development. Here, Motion Capture was used to assess gross motor rhythmic movement at six time points between 5- and 11 months of age. Infants were recorded drumming to acoustic stimuli of varying linguistic and temporal complexity: drumbeats, repeated syllables and nursery rhymes. Here we show, for the first time, developmental change in infants' movement timing in response to auditory stimuli over the first year of life. Longitudinal analyses revealed that whilst infants could not yet reliably synchronize their movement to auditory rhythms, infant spontaneous motor tempo became faster with age, and by 11 months, a subset of infants decelerate from their spontaneous motor tempo, which better accords with the incoming tempo. Further, infants became more regular drummers with age, with marked decreases in the variability of spontaneous motor tempo and variability in response to drumbeats. This latter effect was subdued in response to linguistic stimuli. The current work lays the foundation for using individual differences in precursors of SMS in infancy to predict later language outcomes. RESEARCH HIGHLIGHT: We present the first longitudinal investigation of infant rhythmic movement over the first year of life Whilst infants generally move more quickly and with higher regularity over their first year, by 11 months infants begin to counter this pattern when hearing slower infant-directed song Infant movement is more variable to speech than non-speech stimuli In the context of the larger Cambridge UK BabyRhythm Project, we lay the foundation for rhythmic movement in infancy to predict later language outcomes.

Cortical tracking of visual rhythmic speech by 5- and 8-month-old infants: Individual differences in phase angle relate to language outcomes up to 2 years.

It is known that the rhythms of speech are visible on the face, accurately mirroring changes in the vocal tract. These low-frequency visual temporal movements are tightly correlated with speech output, and both visual speech (e.g., mouth motion) and the acoustic speech amplitude envelope entrain neural oscillations. Low-frequency visual temporal information ('visual prosody') is known from behavioural studies to be perceived by infants, but oscillatory studies are currently lacking. Here we measure cortical tracking of low-frequency visual temporal information by 5- and 8-month-old infants using a rhythmic speech paradigm (repetition of the syllable 'ta' at 2 Hz). Eye-tracking data were collected simultaneously with EEG, enabling computation of cortical tracking and phase angle during visual-only speech presentation. Significantly higher power at the stimulus frequency indicated that cortical tracking occurred across both ages. Further, individual differences in preferred phase to visual speech related to subsequent measures of language acquisition. The difference in phase between visual-only speech and the same speech presented as auditory-visual at 6- and 9-months was also examined. These neural data suggest that individual differences in early language acquisition may be related to the phase of entrainment to visual rhythmic input in infancy. RESEARCH HIGHLIGHTS: Infant preferred phase to visual rhythmic speech predicts language outcomes. Significant cortical tracking of visual speech is present at 5 and 8 months. Phase angle to visual speech at 8 months predicted greater receptive and productive vocabulary at 24 months.

Scar massage as an intervention for post-surgical scars: A practice survey of Australian hand therapists.

Introduction: Scar massage is a commonly used treatment in hand therapy. The current empirical evidence that supports it is disparate and of variable quality, with no established effective dosage and method proposed. This study aimed to identify the current practice among Australian hand therapists using massage as an intervention for scarring following surgery to the hand and upper limb. Methods: A purposely designed self-report online survey was emailed to current members of the Australian Hand Therapy Association (n = 958). Data collected included demographics, intervention techniques, conditions treated and protocols, scar assessment and knowledge and training about scar massage as a clinical intervention. Results: A total of 116 completed questionnaires were received (a response rate of 12.1%). All respondents used scar massage as part of their clinical practice with 98% to improve soft tissue glide (n = 114), 92% for hypersensitivity (n = 107), and 84% to increase hand function (n = 97). Only 18% (n = 21) of respondents used standardised outcome measures, and most therapists had learned scar massage from a colleague (81%). Conclusions: Commonalities in how respondents implemented scar massage were found. Participants reported relying primarily on clinical experience to inform their practice. Whilst scar massage was widely used, few respondents had received formal skills training or completed outcome measures regularly to formally evaluate its clinical efficacy or impact. Replication of this study with a larger international sample of participants is warranted to determine if these findings reflect general practice.

Decoding speech information from EEG data with 4-, 7- and 11-month-old infants: Using convolutional neural network, mutual information-based and backward linear models.

BACKGROUND: Computational models that successfully decode neural activity into speech are increasing in the adult literature, with convolutional neural networks (CNNs), backward linear models, and mutual information (MI) models all being applied to neural data in relation to speech input. This is not the case in the infant literature. NEW METHOD: Three different computational models, two novel for infants, were applied to decode low-frequency speech envelope information. Previously-employed backward linear models were compared to novel CNN and MI-based models. Fifty infants provided EEG recordings when aged 4, 7, and 11 months, while listening passively to natural speech (sung or chanted nursery rhymes) presented by video with a female singer. RESULTS: Each model computed speech information for these nursery rhymes in two different low-frequency bands, delta and theta, thought to provide different types of linguistic information. All three models demonstrated significant levels of performance for delta-band neural activity from 4 months of age, with two of three models also showing significant performance for theta-band activity. All models also demonstrated higher accuracy for the delta-band neural responses. None of the models showed developmental (age-related) effects. COMPARISONS WITH EXISTING METHODS: The data demonstrate that the choice of algorithm used to decode speech envelope information from neural activity in the infant brain determines the developmental conclusions that can be drawn. CONCLUSIONS: The modelling shows that better understanding of the strengths and weaknesses of each modelling approach is fundamental to improving our understanding of how the human brain builds a language system.

Protecting Personhood: A Classic Grounded Theory.

The importance of perceiving and considering patients as healthcare partners has been increasingly promoted. Healthcare systems around the world are now highly interested in patient engagement, participation, collaboration, and partnership. Healthcare professionals are advised that patients, as autonomous beings, should be active in and responsible for a portion of their own care. The study presented here focused on patients' perceptions of interprofessional collaboration. It was conducted using the classic grounded theory methodology. The theory of protecting personhood emerged as the core concept of hospitalized patients, cared for by interprofessional healthcare teams. This theory encapsulates the process hospitalized patients go through to find balance in their sense of self, oscillating between personhood and patienthood in the unfamiliar hospital environment. The process consists of four stages: the stage of introspection, during which hospitalized patients become aware of their self as a person and as a patient; the stage of preservation, when patients find a balance between the sense of personhood and patienthood; the stage of rupture, wherein patients experience an imbalance between their sense of personhood and patienthood; and the stage of reconciliation, in which personhood is restored. The theory of protecting personhood offers insights into a better understanding of hospitalized patients' experiences and strategies, revealing the importance of relationships, and the driving force of empowerment. This study is about patients' perspectives of interprofessional healthcare teams. A grounded theory process allowed the emergence of patients' concerns and expectations, leading to a substantive theory grounded in the patients' data.

Neural phase angle from two months when tracking speech and non-speech rhythm linked to language performance from 12 to 24 months.

Atypical phase alignment of low-frequency neural oscillations to speech rhythm has been implicated in phonological deficits in developmental dyslexia. Atypical phase alignment to rhythm could thus also characterize infants at risk for later language difficulties. Here, we investigate phase-language mechanisms in a neurotypical infant sample. 122 two-, six- and nine-month-old infants were played speech and non-speech rhythms while EEG was recorded in a longitudinal design. The phase of infants' neural oscillations aligned consistently to the stimuli, with group-level convergence towards a common phase. Individual low-frequency phase alignment related to subsequent measures of language acquisition up to 24 months of age. Accordingly, individual differences in language acquisition are related to the phase alignment of cortical tracking of auditory and audiovisual rhythms in infancy, an automatic neural mechanism. Automatic rhythmic phase-language mechanisms could eventually serve as biomarkers, identifying at-risk infants and enabling intervention at the earliest stages of development.

AZD5438 a GSK-3a/b and CDK inhibitor is antiapoptotic modulates mitochondrial activity and protects human neurons from mitochondrial toxins.

We previously reported that kenpaullone, which inhibits GSK-3a/b and CDKs inhibited CCCP mediated mitochondrial depolarisation and augments the mitochondrial network. To investigate the actions of this class of drug further, we compared the ability of kenpaullone, alsterpaullone, 1-azakenapaullone, AZD5438, AT7519 (CDK and GSK-3a/b inhibitors) and dexpramipexole and olesoxime (mitochondrial permeability transition pore inhibitors) to prevent CCCP mediated mitochondrial depolarisation and found that AZD5438 and AT7519, were the most effective. Furthermore, treatment with AZD5438 alone increased the complexity of the mitochondrial network. We also found that AZD5438 prevented the rotenone induced decrease in PGC-1alpha and TOM20 levels and that it mediated powerful anti-apoptotic effects and promoted glycolytic respiration. Importantly, experiments in human iPSC derived cortical and midbrain neurons showed AZD5438 mediated significant protective effects, preventing the neuronal cell death, and collapse in the neurite and mitochondrial network associated with rotenone treatment. These results suggest drugs that target GSK-3a/b and CDKs should be developed and assessed further as they may have significant therapeutic potential.

Expectations about precision bias metacognition and awareness.

Bayesian models of the mind suggest that we estimate the reliability or "precision" of incoming sensory signals to guide perceptual inference and to construct feelings of confidence or uncertainty about what we are perceiving. However, accurately estimating precision is likely to be challenging for bounded systems like the brain. One way observers could overcome this challenge is to form expectations about the precision of their perceptions and use these to guide metacognition and awareness. Here we test this possibility. Participants made perceptual decisions about visual motion stimuli, while providing confidence ratings (Experiments 1 and 2) or ratings of subjective visibility (Experiment 3). In each experiment, participants acquired probabilistic expectations about the likely strength of upcoming signals. We found these expectations about precision altered metacognition and awareness-with participants feeling more confident and stimuli appearing more vivid when stronger sensory signals were expected, without concomitant changes in objective perceptual performance. Computational modeling revealed that this effect could be well explained by a predictive learning model that infers the precision (strength) of current signals as a weighted combination of incoming evidence and top-down expectation. These results support an influential but untested tenet of Bayesian models of cognition, suggesting that agents do not only "read out" the reliability of information arriving at their senses, but also take into account prior knowledge about how reliable or "precise" different sources of information are likely to be. This reveals that expectations about precision influence how the sensory world appears and how much we trust our senses. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Building the Plant SynBio Toolbox through Combinatorial Analysis of DNA Regulatory Elements.

While the installation of complex genetic circuits in microorganisms is relatively routine, the synthetic biology toolbox is severely limited in plants. Of particular concern is the absence of combinatorial analysis of regulatory elements, the long design-build-test cycles associated with transgenic plant analysis, and a lack of naming standardization for cloning parts. Here, we use previously described plant regulatory elements to design, build, and test 91 transgene cassettes for relative expression strength. Constructs were transiently transfected into Nicotiana benthamiana leaves and expression of a fluorescent reporter was measured from plant canopies, leaves, and protoplasts isolated from transfected plants. As anticipated, a dynamic level of expression was achieved from the library, ranging from near undetectable for the weakest cassette to a ∼200-fold increase for the strongest. Analysis of expression levels in plant canopies, individual leaves, and protoplasts were correlated, indicating that any of the methods could be used to evaluate regulatory elements in plants. Through this effort, a well-curated 37-member part library of plant regulatory elements was characterized, providing the necessary data to standardize construct design for precision metabolic engineering in plants.

Cortical Tracking of Sung Speech in Adults vs Infants: A Developmental Analysis.

Here we duplicate a neural tracking paradigm, previously published with infants (aged 4 to 11 months), with adult participants, in order to explore potential developmental similarities and differences in entrainment. Adults listened and watched passively as nursery rhymes were sung or chanted in infant-directed speech. Whole-head EEG (128 channels) was recorded, and cortical tracking of the sung speech in the delta (0.5-4 Hz), theta (4-8 Hz) and alpha (8-12 Hz) frequency bands was computed using linear decoders (multivariate Temporal Response Function models, mTRFs). Phase-amplitude coupling (PAC) was also computed to assess whether delta and theta phases temporally organize higher-frequency amplitudes for adults in the same pattern as found in the infant brain. Similar to previous infant participants, the adults showed significant cortical tracking of the sung speech in both delta and theta bands. However, the frequencies associated with peaks in stimulus-induced spectral power (PSD) in the two populations were different. PAC was also different in the adults compared to the infants. PAC was stronger for theta- versus delta- driven coupling in adults but was equal for delta- versus theta-driven coupling in infants. Adults also showed a stimulus-induced increase in low alpha power that was absent in infants. This may suggest adult recruitment of other cognitive processes, possibly related to comprehension or attention. The comparative data suggest that while infant and adult brains utilize essentially the same cortical mechanisms to track linguistic input, the operation of and interplay between these mechanisms may change with age and language experience.

Inhibition of Anti-Inflammatory Macrophage Phenotype Reduces Tumour Growth in Mouse Models of Brain Metastasis.

Breast cancer brain metastasis is a significant clinical problem and carries a poor prognosis. Although it is well-established that macrophages are a primary component of the brain metastasis microenvironment, the role of blood-derived macrophages (BDM) and brain-resident microglia in the progression of brain metastases remains uncertain. The aim of this study, therefore, was to determine the role, specifically, of pro- and anti-inflammatory BDM and microglial phenotypes on metastasis progression. Initial in vitro studies demonstrated decreased migration of EO771 metastatic breast cancer cells in the presence of pro-inflammatory, but not anti-inflammatory, stimulated RAW 264.7 macrophages. In vivo, suppression of the anti-inflammatory BDM phenotype, specifically, via myeloid knock out of Krüppel-like Factor 4 (KLF4) significantly reduced EO771 tumour growth in the brains of C57BL/6 mice. Further, pharmacological inhibition of the anti-inflammatory BDM and/or microglial phenotypes, via either Colony Stimulating Factor 1 Receptor (CSF-1R) or STAT6 pathways, significantly decreased tumour burden in two different syngeneic mouse models of breast cancer brain metastasis. These findings suggest that switching BDM and microglia towards a more pro-inflammatory phenotype may be an effective therapeutic strategy in brain metastasis.

Simulation-Based Engineering of Time-Delayed Safety Switches for Safer Gene Therapies.

CRISPR-based gene editing is a powerful tool with great potential for applications in the treatment of many inherited and acquired diseases. The longer that CRISPR gene therapy is maintained within a patient, however, the higher the likelihood that it will result in problematic side effects such as off-target editing or immune response. One approach to mitigating these issues is to link the operation of the therapeutic system to a safety switch that autonomously disables its operation and removes the delivered therapeutics after some amount of time. We present here a simulation-based analysis of the potential for regulating the time delay of such a safety switch using one or two transcriptional regulators and/or recombinases. Combinatorial circuit generation identifies 30 potential architectures for such circuits, which we evaluate in simulation with respect to tunability, sensitivity to parameter values, and sensitivity to cell-to-cell variation. This modeling predicts one of these circuit architectures to have the desired dynamics and robustness, which can be further tested and applied in the context of CRISPR therapeutics.

From outcome measurement to improving health outcomes after lower limb amputation-A narrative review exploring outcome measurement from a clinical practice perspective.

Outcome measurement is essential to understand the impact of clinical interventions and the performance of services. Despite national and professional body encouragement, and successful examples of system level outcome measurement within some health care settings, many barriers still exist preventing outcome measurement from becoming embedded in clinical practice. This paper presents a narrative review which aims to describe the state of the outcome measurement evidence base in prosthetic rehabilitation, as applied in clinical practice, with a view to identifying areas for future work aimed at making outcome measurement in prosthetic rehabilitation a meaningful reality. A literature search of four databases was undertaken, following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis principals appropriate to narrative reviews, and using the search terms outcome, measur*, tool, scale, instrument, prosthe*, amput* and limb loss. A total of 1116 papers were identified. Following screening 35 papers, focusing on four main themes, were included in the review. Themes were: 1) What outcome domains should be measured? 2) How can these outcome domains be measured? 3) What are the barriers to outcome measurement? and 4) What can be learnt from examples of ROM in prosthetic rehabilitation? Findings suggest that successful outcome measurement is multifaceted. Understanding and embedding value at every step appears to be key to success. Addressing the questions of 'what' outcome domains to measure and 'how' to measure them, may help establish consensus. Routine outcome measurement practice at the clinical level should ensure data collection is valuable to clinical practice, makes use of information technology solutions and has organisational engagement.