Time and memory distrust shape the dynamics of recollection and belief-in-occurrence.

The current study examined how people's metamemory judgments of recollection and belief-in-occurrence change over time. Furthermore, we examined to what extent these judgments are affected by memory distrust - the subjective appraisal of one's memory functioning - as measured by the Memory Distrust Scale (MDS) and the Squire Subjective Memory Scale (SSMQ). Participants (N = 234) studied pictorial stimuli and were tested on some of these stimuli later in the same session, but were tested on other stimuli 1, 2, 4, 8, and 17 days later. Recollection and belief ratings were correlated highly and followed similar declining patterns over time. However, belief decreased relatively more slowly than recollection, such that the discrepancy between recollection and belief increased over time. Memory distrust moderated the association between recollection and belief, with this association being weaker among people who reported greater (versus lower) memory distrust. Memory distrust also interacted with retention period to predict memory judgments. Two measures of memory distrust diverged in their predictive power. In particular, only the MDS predicted the spontaneous reporting of nonbelieved memories. Our results provide support to the theoretical perspective that belief-in-occurrence is a summative judgment informed not only by recollective phenomenology but also by metamemorial beliefs.

Preparing for Otoferlin gene therapy trials: A survey of NHS Paediatric Audiology and Cochlear Implant services on diagnosis and management of Auditory Neuropathy Spectrum Disorder.

OBJECTIVES: Gene therapy for monogenic hearing loss is on the horizon. The first trials in patients with Auditory Neuropathy Spectrum Disorder (ANSD) due to pathogenic variants in the Otoferlin (OTOF) gene will open this year. In the UK, the new NHS Genomic Medicine Service (GMS) offers genetic testing in each child diagnosed with congenital or early onset sensorineural hearing loss. This survey study aims to map preexisting clinical pathways for the diagnosis and management of children with ANSD and identify opportunities for improvement in early identification of OTOF- related ANSD. METHODS: A Google form with 24 questions in English covering the ANSD clinical pathway was developed with clinicians involved in the diagnosis and management ANSD. The survey was disseminated via email to all Lead clinicians of NHS Tertiary Paediatric Audiology and Cochlear Implant Services within the UK. RESULTS: Data was received from 27 (34 %) NHS Tertiary Paediatric Audiology Services and 8 (n = 57 %) Paediatric Cochlear Implant Services. Services follow existing national guidance and provide multidisciplinary care with structured patient pathways for referral, diagnosis, and management of children with ANSD and multidisciplinary input throughout. Clinicians are aware of the genetic causes of ANSD and new processes for genetic testing, but do not uniformly refer children with ANSD for testing for OTOF pathogenic variants. As such, they had difficulty estimating numbers of children with OTOF pathogenic variants under their care. CONCLUSION: Those results highlight the urgency of implementing hearing gene panel sequencing for all children with ANSD to provide opportunities for early diagnosis and candidacy for OTOF gene therapy trials.

Enlarged Vestibular Aqueduct and Associated Inner Ear Malformations: Hearing Loss Prognostic Factors and Data Modeling from an International Cohort.

ACKGROUND: There is a need to operationalize existing clinical data to support precision medicine in progressive hearing loss (HL). By utilizing enlarged vestibular aqueduct (EVA) and its associated inner ear abnormalities as an exemplar, we model data from a large international cohort, confirm prognostic factors for HL, and explore the potential to generate a prediction model to optimize current management paradigms. METHODS: An international retrospective cohort study. Regression analyses were utilized to model frequency-specific HL and identify prognostic factors for baseline average HL severity and progression. Elastic-net regression and machine learning (ML) techniques were utilized to predict future average HL progression based upon routinely measurable clinical, genetic, and radiological data. RESULTS: Higher frequencies of hearing were lost more severely. Prognostic factors for HL were the presence of incomplete partition type 2 (coefficient 12.95 dB, P=.011, 95% CI 3.0-22 dB) and presence of sac signal heterogeneity (P=.009, 95% CI 0.062-0.429) on magnetic resonance imaging. Elastic-net regression outperformed the ML algorithms (R2 0.32, mean absolute error 11.05 dB) with coefficients for baseline average hearing level and the presence of sac heterogeneity contributing the most to prediction outcomes. CONCLUSION: Incomplete partition type 2 and endolymphatic sac signal heterogeneity phenotypes should be monitored closely for hearing deterioration and need for early audiological rehabilitation/cochlear implant. Preliminary prediction models have been generated using routinely collected health data in EVA. This study showcases how international collaborative research can use exemplar techniques to improve precision medicine in relatively rare disease entities.

Effects of cueing multiple memories of eating on people's judgments about their diet.

Past research shows that recalling a single positive health-related experience, such as exercising, can encourage people's subsequent healthy behaviours. In contrast, we reasoned that attempting to recall many healthy experiences might elicit a metacognitive experience of difficulty that would lead people to perceive themselves as less healthy, and perhaps to make other health-related judgments based on this perception. In two pre-registered experiments (combined N = 729), participants recalled either "few" or "many" instances of eating either healthily or unhealthily, before rating the healthiness of their diets and completing measures of their eating preferences and choices. Contrary to our predictions, our pre-registered analyses provided minimal evidence that the number of memories people retrieved affected their judgments. However, exploratory mediation analyses suggested that two counteracting effects may have occurred, whereby retrieving more (un)healthy memories led people to identify as more (un)healthy, yet also created a sense of subjective difficulty that partially or wholly negated these effects. These findings suggest that whereas probing people's dietary memories might sometimes lead to healthier self-perceptions and dietary choices, we should also consider the possibility of backfire effects.

Design and Pharmacological Chaperone Effects of N-(4'-Phenylbutyl)-DAB Derivatives Targeting the Lipophilic Pocket of Lysosomal Acid α-Glucosidase.

This study provides the first example of a strategy to design a practical ligand toward lysosomal acid α-glucosidase (GAA) focusing on N-alkyl derivatives of 1,4-dideoxy-1,4-imino-d-arabinitol (DAB). The optimized N-4'-(p-trifluoromethylphenyl)butyl-DAB (5g) showed a Ki value of 0.73 µM, which was 353-fold higher affinity than N-butyl-DAB (3f) without a terminal phenyl group. Docking analysis showed that the phenyl part of 5g was accommodated in a lipophilic pocket. Furthermore, the p-trifluoromethyl group effectively suppresses the fluctuation of the phenyl group, allowing it to produce a stable bonding form with GAA. 5g increased the midpoint of the protein's protein denaturation temperature (Tm) by 6.6 °C above that in the absence of the ligand and acted as a "thermodynamic stabilizer" to improve the thermal stability of rhGAA. 5g dose-dependently increased intracellular GAA activities in Pompe patient's fibroblasts with the M519V mutation; its effect was comparable to that of DNJ, which is under clinical trials.

Preference for cheap-and-easy memory verification strategies is strongest among people with high memory distrust.

When choosing strategies for verifying one's memory, people are more influenced by the perceived cost of using a strategy than by its likelihood of yielding reliable information (i.e., cheap-strategy bias). The current preregistered study investigated whether people with high memory distrust are less likely to exhibit this bias than their low memory distrust counterparts. Participants (N = 535) imagined a scenario in which they witnessed an accident and were then led by friends to question their memories about the accident. Participants had to propose five strategies for verifying that particular memory. Following this, they rated each strategy's cost, reliability, and their likelihood of using it, as well as completing two validated measures of trait memory distrust. Contrary to our prediction, compared with participants with low memory distrust, participants with higher memory distrust exhibited a larger cheap-strategy bias. Follow-up analyses suggested that compared with memory-trusters, memory distrusters' strategy choices were more influenced by a strategy's perceived cost, and less influenced by its perceived reliability. Our results suggest that people who are more skeptical about their memories may be more cynical about the worthwhileness of verifying their memory, which could make them especially susceptible to misinformation acceptance and false memory creation.

Standardised ido-BR1 Cucumber Extract Improved Parameters Linked to Moderate Osteoarthritis in a Placebo-controlled Study.

BACKGROUND: According to the World Health Organization, osteoarthritis (OA) is one of the 10 most disabling diseases in developed countries, with worldwide estimates of 9.6% prevalence in men and 18.0% in women over 60 years old. Its management is not well established and involves the use of high doses of painkillers coupled with anti-inflammatory agents. OBJECTIVE: In the search for alternatives to manage the disease, previous studies have shown superior properties of Q-ActinTM in managing OA-related pain compared with standard treatments. Qactin is a cucumber extract with the anti-inflammatory iminosugar idoBR1 standardised to over 1%. This study investigated the effects of different doses (20 mg, 100 mg) of Q-Actin in a longitudinal placebo-controlled experiment. METHODS: There were 101 patients with knee OA enrolled for the 180-day study, with 91 patients completing it. Patients were grouped into a placebo group (PLBO), as well as a 20mg dose (Q-Actin 1) and 100 mg dose (Q-Actin 2) groups. The PLBO group received cellulose in capsules identical to the Q-Actin capsules. RESULTS: There was a significant improvement in the pain-related parameters over time that was dose-dependent. CONCLUSION: This study clearly demonstrated the effectiveness of Q-Actin compared to placebo in the management of pain related to moderate osteoarthritis.

Saccharomyces genome database update: server architecture, pan-genome nomenclature, and external resources.

As one of the first model organism knowledgebases, Saccharomyces Genome Database (SGD) has been supporting the scientific research community since 1993. As technologies and research evolve, so does SGD: from updates in software architecture, to curation of novel data types, to incorporation of data from, and collaboration with, other knowledgebases. We are continuing to make steps toward providing the community with an S. cerevisiae pan-genome. Here, we describe software upgrades, a new nomenclature system for genes not found in the reference strain, and additions to gene pages. With these improvements, we aim to remain a leading resource for students, researchers, and the broader scientific community.

The spectrum of cochlear malformations in CHARGE syndrome and insights into the role of the CHD7 gene during embryogenesis of the inner ear.

PURPOSE: We reviewed the genotypes and the imaging appearances of cochleae in CHARGE patients from two large tertiary centres and analysed the observed cochlear anomalies, providing detailed anatomical description and a grading system. The goal was to gain insight into the spectrum of cochlear anomalies in CHARGE syndrome, and thus, in the role of the CHD7 gene in otic vesicle development. METHODS: We retrospectively reviewed CT and/or MR imaging of CHARGE patients referred to our institutions between 2005 and 2022. Cochlear morphology was analysed and, when abnormal, divided into 3 groups in order of progressive severity. Other radiological findings in the temporal bone were also recorded. Comparison with the existing classification system of cochlear malformation was also attempted. RESULTS: Cochlear morphology in our CHARGE cohort ranged from normal to extreme hypoplasia. The most common phenotype was cochlear hypoplasia in which the basal turn was relatively preserved, and the upper turns were underdeveloped. All patients in the cohort had absent or markedly hypoplastic semicircular canals and small, misshapen vestibules. Aside from a stenotic cochlear aperture (fossette) being associated with a hypoplastic or absent cochlear nerve, there was no consistent relationship between cochlear nerve status (normal, hypoplasia, or aplasia) and cochlear morphology. CONCLUSION: Cochlear morphology in CHARGE syndrome is variable. Whenever the cochlea was abnormal, it was almost invariably hypoplastic. This may shed light on the role of CHD7 in cochlear development. Accurate morphological description of the cochlea contributes to proper clinical diagnosis and is important for planning surgical treatment options.

Radiologic diagnosis of non-traumatic paediatric head and neck emergencies.

Imaging plays a crucial role in evaluating paediatric patients with non-traumatic head and neck lesions in an emergency setting because clinical manifestations of these entities can overlap. For this reason, radiologists must be familiar with the clinical and imaging findings of prevalent paediatric head and neck emergencies. In this review, we present techniques and imaging clues for common complications of pathological processes in the paediatric head and neck, with a focus on the clinical scenario as a starting point for the radiologic approach.

False remembering in real life: James Ost's contributions to memory psychology.

This special issue honours James Ost's (1973-2019) contributions to our understanding of false and distorted remembering. In our editorial, we introduce some of James' distinctive research themes including the experiences of people who retract "recovered" memories, social (e.g., co-witness and interviewer influence) and personality influences on false remembering, the nature of false remembering itself (e.g., different types of false memories; false memories vs. false beliefs), public understanding of (false) memory, and a historical link to the work of Frederic Bartlett. We illustrate these themes through a number of key publications. The unifying thread behind James' work is his core interest in false/distorted remembering in real-life (typically high-stake) situations, in line with his engagement with the British False Memory Society and his role as an expert witness in court trials. The articles included in this special issue elaborate on the research themes to which James devoted his career and his curiosity.

Introduction of C-alkyl branches to L-iminosugars changes their active site binding orientation.

L-ido-Deoxynojirimycin (L-ido-DNJ) itself showed no affinity for human lysosomal acid α-glucosidase (GAA), whereas 5-C-methyl-L-ido-DNJ showed a strong affinity for GAA, comparable to the glucose analog DNJ, with a Ki value of 0.060 µM. This excellent affinity for GAA and enzyme stabilization was observed only when methyl and ethyl groups were introduced. Docking simulation analysis revealed that the alkyl chains of 5-C-alkyl-L-ido-DNJs were stored in three different pockets, depending on their length, thereby the molecular orientation was changed. Comparison of the binding poses of DNJ and 5-C-methyl-L-ido-DNJ showed that they formed a common ionic interaction with Asp404, Asp518, and Asp616, but both the binding orientation and the distance between the ligand and each amino acid residue were different. 5-C-Methyl-L-ido-DNJ dose-dependently increased intracellular GAA activity in Pompe patient fibroblasts with the M519V mutation and also promoted enzyme transport to lysosomes. This study provides the first example of a strategy to design high-affinity ligands by introducing alkyl branches into rare sugars and L-sugar-type iminosugars to change the orientation of binding.

Memories people no longer believe in can still affect them in helpful and harmful ways.

People can come to "remember" experiences they never had, and these false memories-much like memories for real experiences-can serve a variety of helpful and harmful functions. Sometimes, though, people realize one of their memories is false, and retract their belief in it. These "retracted memories" continue to have many of the same phenomenological characteristics as their believed memories. But can they also continue to serve functions? Across four experiments, we asked subjects to rate the extent to which their retracted memories serve helpful and harmful functions and compared these functions with those served by "genuine" autobiographical memories. People rated their retracted memories as serving both helpful and harmful functions, much like their genuine memories. In addition, we found only weak relationships between people's belief in their memories and the extent to which those memories served perceived functions. These results suggest memories can serve functions even in the absence of belief and highlight the potential for false memories to affect people's thinking and behavior even after people have retracted them.

Borylated 2,3,4,5-Tetrachlorophthalimide and Their 2,3,4,5-Tetrachlorobenzamide Analogues: Synthesis, Their Glycosidase Inhibition and Anticancer Properties in View to Boron Neutron Capture Therapy.

Tetrachlorinated phthalimide analogues bearing a boron-pinacolate ester group were synthesised via two synthetic routes and evaluated in their glycosidase modulating and anticancer properties, with a view to use them in boron neutron capture therapy (BNCT), a promising radiation type for cancer, as this therapy does little damage to biological tissue. An unexpected decarbonylation/decarboxylation to five 2,3,4,5-tetrachlorobenzamides was observed and confirmed by X-ray crystallography studies, thus, giving access to a family of borylated 2,3,4,5-tetrachlorobenzamides. Biological evaluation showed the benzamide drugs to possess good to weak potencies (74.7-870 µM) in the inhibition of glycosidases, and to have good to moderate selectivity in the inhibition of a panel of 18 glycosidases. Furthermore, in the inhibition of selected glycosidases, there is a core subset of three animal glycosidases, which is always inhibited (rat intestinal maltase α-glucosidase, bovine liver ß-glucosidase and ß-galactosidase). This could indicate the involvement of the boron atom in the binding. These glycosidases are targeted for the management of diabetes, viral infections (via a broad-spectrum approach) and lysosomal storage disorders. Assays against cancer cell lines revealed potency in growth inhibition for three molecules, and selectivity for one of these molecules, with the growth of the normal cell line MCF10A not being affected by this compound. One of these molecules showed both potency and selectivity; thus, it is a candidate for further study in this area. This paper provides numerous novel aspects, including expedited access to borylated 2,3,4,5-tetrachlorophthalimides and to 2,3,4,5-tetrachlorobenzamides. The latter constitutes a novel family of glycosidase modulating drugs. Furthermore, a greener synthetic access to such structures is described.

Iminosugar Amino Acid idoBR1 Reduces Inflammatory Responses in Microglia.

(1) Background. Inflammation is reported to be a key factor in neurodegeneration. The microglia are immune cells present in the central nervous system; their activation results in the release of inflammatory cytokines and is thought to be related to aging and neurodegenerative disorders, such as Alzheimer's disease. (2) Methods. A mouse BV-2 microglia cell line was activated using LPS and the anti-inflammatory cucumber-derived iminosugar amino acid idoBR1, (2R,3R,4R,5S)-3,4,5-trihydroxypiperidine-2-carboxylic acid, was used alongside dexamethasone as the control to determine whether it could reduce the inflammatory responses. (3) Results. A dose-dependent reduction in the LPS-induced production of the proinflammatory factors TNFα, IL-6, and nitric oxide and the transcription factor NF-κB was found. (4) Conclusions. Further investigations of the anti-inflammatory effects of idoBR1 in other models of neurodegenerative diseases are warranted.

Front-of-pack health imagery on both 'healthy' and 'unhealthy' foods leads people to misremember seeing health claims: Two memory experiments.

Front-of-pack health imagery can shape people's inferences about food products' health benefits, even leading people to falsely remember reading health claims they never saw. However, research has typically examined these effects in situations where participants have little contextual information to guide their inferences about a product. The present research aimed to replicate the finding that front-of-pack health imagery leads participants to falsely remember reading health claims. It also extends that finding, by exploring whether this effect is moderated by the presence of contextual information signaling the product's actual 'healthiness'. In two pre-registered experiments, participants saw images of fictitious food products accompanied by written nutrition claims. Some of the products contained a health-related image whereas others did not. The supposed 'healthiness' of each product was manipulated by altering the color of the products' multiple traffic light (MTL) label (Experiment 1), or with an explicit healthiness statement (Experiment 2). Participants then attempted to remember the written claims that had appeared on each product's packaging. Health-related images increased participants' tendency to falsely remember reading health claims. But this was true regardless of whether or not participants saw contextual cues about the products' healthiness, either indirectly (Experiment 1) or directly (Experiment 2). These findings suggest that the presence of health imagery on a food product's package can lead consumers to infer health benefits, even when other, more direct cues indicate that the product is unhealthy. This research informs debates on safeguarding consumers from potentially misleading health claims, through the regulation of imagery in food marketing.

Isolation and Characterisation of Quercitrin as a Potent Anti-Sickle Cell Anaemia Agent from Alchornea cordifolia.

Alchornea cordifolia Müll. Arg. (commonly known as Christmas Bush) has been used traditionally in Africa to treat sickle cell anaemia (a recessive disease, arising from the S haemoglobin (Hb) allele), but the active compounds are yet to be identified. Herein, we describe the use of sequential fractionation coupled with in vitro anti-sickling assays to purify the active component. Sickling was induced in HbSS genotype blood samples using sodium metabisulphite (Na2S2O5) or through incubation in 100% N2. Methanol extracts of A. cordifolia leaves and its sub-fractions showed >70% suppression of HbSS erythrocyte sickling. The purified compound demonstrated a 87.2 ± 2.39% significant anti-sickling activity and 93.1 ± 2.69% erythrocyte sickling-inhibition at 0.4 mg/mL. Nuclear magnetic resonance (NMR) spectra and high-resolution mass spectroscopy identified it as quercitrin (quercetin 3-rhamnoside). Purified quercitrin also inhibited the polymerisation of isolated HbS and stabilized sickle erythrocytes membranes. Metabolomic comparisons of blood samples using flow-infusion electrospray-high resolution mass spectrometry indicated that quercitrin could convert HbSS erythrocyte metabolomes to be like HbAA. Sickling was associated with changes in antioxidants, anaerobic bioenergy, and arachidonic acid metabolism, all of which were reversed by quercitrin. The findings described could inform efforts directed to the development of an anti-sickling drug or quality control assessments of A. cordifolia preparations.

Enlarged Vestibular Aqueduct: Disease Characterization and Exploration of Potential Prognostic Factors for Cochlear Implantation.

OBJECTIVES: There is an unmet need to match the anticipated natural history of hearing loss (HL) in enlarged vestibular aqueduct (EVA) with clinical management strategies. The objectives of this study are therefore to provide a detailed case characterization of an EVA cohort and explore the relationship between candidate prognostic factors and timing of cochlear implant (CI) surgery. STUDY DESIGN: A multicenter retrospective review of patients diagnosed with EVA. SETTING: Patient data recruitment across three CI centers in the UK. PATIENTS: One hundred fifty patients with a radiological diagnosis of EVA from January 1995 to January 2021. MAIN OUTCOME MEASURES: Age at audiological candidacy for CI and age at first implant surgery. RESULTS: EVA was predominately a bilateral condition (144/ 150) with increased prevalence in women (M:F, 64:86). 51.7% of patients failed new-born hearing screening, with 65.7% having HL diagnosed by 1 year. Initial moderate to severe and severe to profound HL were reported most frequently. In 123 patients, median age that audiological candidacy for CI was met for at least one ear was 2.75 years. Median age at first CI was 5 years (140/150).Pendred syndrome (confirmed in 73 patients) and ethnicity, were not significantly associated with earlier CI surgery. Multivariate linear regression demonstrated that male patients have first CI surgery significantly earlier than females (coefficient -0.43, 95% CI [-0.82, -0.05), p-value = 0.028). CONCLUSIONS: This large UK EVA cohort provides evidence that patients should be closely monitored for CI candidacy within the first 3 years of life. Significantly, male gender is emerging as an independent prognostic factor for earlier assessment and first CI surgery.

Synthesis of (+)-(R)-Tiruchanduramine.

The absolute stereochemistry of the marine alkaloid (+)-(R)-tiruchanduramine was established via a convergent total synthesis in six steps and 15.5% overall yield from Fmoc-D-Dab(Boc)-OH.

Patient, parental and multi-disciplinary team rationale for non-implantation following the paediatric cochlear implantation assessment.

OBJECTIVES: To assess paediatric patients referred to the cochlear implant team, who despite undergoing the assessment, did not receive cochlear implantation. To identify the underlying reasons for this. METHODS: A retrospective case-note review of patients was assessed from June 2014 to June 2019 at two separate London teaching hospitals with paediatric cochlear implantation programmes. RESULTS: A total of 921 paediatric patients were assessed during the study period across both institutions. And, 196 (21%) did not proceed with the surgery. The decision not to undergo surgery was primarily parental/patient-directed in 114 (61%) and cochlear implant team-directed in 74 (39%). In total, eight (4%) patients exited the programme without a documented reason. DISCUSSION: A myriad of factors influenced the decision-making process for clinicians, patients and parents. The most cited parental/patient rationale against implantation was the wish to continue current means of communication 40 (35%), followed by concern regarding the risks of surgery 18 (15.8%) and the wish to allow the patient to make future decisions independently in view of the future technology 7 (6.1%). Cochlear implant team-directed decisions were largely due to being outside of the NICE criteria 27 (36.5%) or the risks of general anaesthesia 19 (25.7%) in addition to communication concerns 11 (14.9%). CONCLUSION: Decision-making in cochlear implantation should not be underestimated. Extensive discussion and exploration of options with the multi-disciplinary team can aid decision-making, but the timescale and appreciation of the consequences of the decision inevitably lead to pressure. Exploration of reasons for non-implantation emphasises the importance of a multi-professional approach to manage these patients.