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PURPOSE: Fragile X syndrome (FXS) is a neurodevelopmental disorder, caused by an CGG repeat expansion (FM, > 200 CGG) in the fragile X messenger ribonucleoprotein 1 (FMR1) gene. Female carriers of a premutation (PM; 55-200 CGG) can transmit the PM allele, which, depending on the CGG allele size, can expand to an allele in the FM range in the offspring. METHODS: Carrier screening for FMR1 PM is not available in Thailand. This study aimed to investigate the prevalence of PM carriers among Thai reproductive women at the tertiary hospital. A total of 1250 females participated in this study; ages ranged from 20 to 45 years, mean of 30 years (S.D. = 6.27). RESULTS: Two carriers of a premutation allele, with 32,62 and 32,69 CGG repeats respectively, were identified. This corresponds to 1 in 600 women or 0.17% of the population. Further, three women carrying a gray zone allele (45-54 CGG repeats) were identified (29,51; 29,49; and 30,47 CGG repeats) which equals to 1:400 women or 0.25% of the population. No FM case was detected. CONCLUSIONS: This study heightens the importance of PM carrier screening of women of reproductive age, particularly for the higher risk of developing fragile X-associated primary ovarian insufficiency (FXPOI). Early identification of PM carrier status enhances family planning and fecundity alternatives and improves reproductive health outcomes leading to a better life.

In this study, the potential role and interaction of the APOε and KLOTHO genes on the penetrance of fragile X-associated tremor/ataxia syndrome (FXTAS) and on the IQ trajectory were investigated. FXTAS was diagnosed based on molecular, clinical and radiological criteria. Males with the premutation (PM) over 50 years, 165 with and 34 without an FXTAS diagnosis, were included in this study and were compared based on their APO (ε2-ε3-ε4) and KLOTHO variant (KL-VS) genotypes. The effect of APOε4 on FXTAS stage and on diagnosis did not differ significantly by KL-VS genotype with interaction effect p = 0.662 and p = 0.91, respectively. In the FXTAS individuals with an APOε2 allele, a marginal significance was observed towards a larger decline in verbal IQ (VIQ) in individuals with an APOε4 allele compared to those without an APOε4 allele (p = 0.071). In conclusion, our findings suggest that the APOε4 and KL-VS genotypes alone or through their interaction effect do not appear to predispose to either FXTAS diagnosis or stage in male carriers of the PM allele. A further study is needed to establish the trend of IQ decline in the FXTAS individuals who carry APOε4 with APOε2 compared to those without APOε4.

Fragile X (FMR1) premutation is a common mutation that affects about 1 in 200 females and 1 in 450 males and can lead to the development of fragile-X-associated tremor/ataxia syndrome (FXTAS). Although there is no targeted, proven treatment for FXTAS, research suggests that sulforaphane, an antioxidant present in cruciferous vegetables, can enhance mitochondrial function and maintain redox balance in the dermal fibroblasts of individuals with FXTAS, potentially leading to improved cognitive function. In a 24-week open-label trial involving 15 adults aged 60-88 with FXTAS, 11 participants successfully completed the study, demonstrating the safety and tolerability of sulforaphane. Clinical outcomes and biomarkers were measured to elucidate the effects of sulforaphane. While there were nominal improvements in multiple clinical measures, they were not significantly different after correction for multiple comparisons. PBMC energetic measures showed that the level of citrate synthase was higher after sulforaphane treatment, resulting in lower ATP production. The ratio of complex I to complex II showed positive correlations with the MoCA and BDS scores. Several mitochondrial biomarkers showed increased activity and quantity and were correlated with clinical improvements.

The course of pathophysiological mechanisms involved in fragile X-associated tremor/ataxia syndrome (FXTAS) remains largely unknown. Previous proteomics and metabolomics studies conducted in blood samples collected from FMR1 premutation carriers with FXTAS reported abnormalities in energy metabolism, and precursors of gluconeogenesis showed significant changes in plasma expression levels in FMR1 premutation carriers who developed FXTAS. We conducted an analysis of postmortem human brain tissues from 44 donors, 25 brains with FXTAS, and 19 matched controls. We quantified the metabolite relative abundance in the inferior temporal gyrus and the cerebellum using untargeted mass spectrometry (MS)-based metabolomics. We investigated how the metabolite type and abundance relate to the number of cytosine-guanine-guanine (CGG) repeats, to markers of neurodegeneration, and to the symptoms of FXTAS. A metabolomic analysis identified 191 primary metabolites, the data were log-transformed and normalized prior to the analysis, and the relative abundance was compared between the groups. The changes in the relative abundance of a set of metabolites were region-specific with some overlapping results; 22 metabolites showed alterations in the inferior temporal gyrus, while 21 showed differences in the cerebellum. The relative abundance of cytidine was decreased in the inferior temporal gyrus, and a lower abundance was found in the cases with larger CGG expansions; oleamide was significantly decreased in the cerebellum. The abundance of 11 metabolites was influenced by changes in the CGG repeat number. A histological evaluation found an association between the presence of microhemorrhages in the inferior temporal gyrus and a lower abundance of 2,5-dihydroxypyrazine. Our study identified alterations in the metabolites involved in the oxidative-stress response and bioenergetics in the brains of individuals with FXTAS. Significant changes in the abundance of cytidine and oleamide suggest their potential as biomarkers and therapeutic targets for FXTAS.

Carriers of the FMR1 premutation (PM) allele are at risk of one or more clinical conditions referred to as FX premutation-associated conditions (FXPAC). Since the FMR1 gene is on the X chromosome, the activation ratio (AR) may impact the risk, age of onset, progression, and severity of these conditions. The aim of this study was to evaluate the reliability of AR measured using different approaches and to investigate potential correlations with clinical outcomes. Molecular and clinical assessments were obtained for 30 PM female participants, and AR was assessed using both Southern blot analysis (AR-Sb) and methylation PCR (AR-mPCR). Higher ARs were associated with lower FMR1 transcript levels for any given repeat length. The higher AR-Sb was significantly associated with performance, verbal, and full-scale IQ scores, confirming previous reports. However, the AR-mPCR was not significantly associated (p > 0.05) with these measures. Similarly, the odds of depression and the number of medical conditions were correlated with higher AR-Sb but not correlated with a higher AR-mPCR. This study suggests that AR-Sb may be a more reliable measure of the AR in female carriers of PM alleles. However, further studies are warranted in a larger sample size to fully evaluate the methylation status in these participants and how it may affect the clinical phenotype.

Carriers of a premutation allele (PM) in the FMR1 gene are at risk of developing a number of Fragile X premutation asssociated disorders (FXPAC), including Fragile X-associated Tremor/Ataxia Syndrome (FXTAS), Fragile X-associated Primary Ovarian Insufficiency (FXPOI), and Fragile X-associated neuropsychiatric disorders (FXAND). We have recently reported somatic CGG allele expansion in female PM; however, its clinical significance remains unclear. The aim of this study was to examine the potential clinical association between somatic FMR1 allele instability and PM associated disorders. Participants comprised of 424 female PM carriers age 0.3- 90 years. FMR1 molecular measures and clinical information on the presence of medical conditions, were determined for all subjects for primary analysis. Two sub-groups of participants (age ≥ 25, N = 377 and age ≥ 50, N = 134) were used in the analysis related to presence of FXPOI and FXTAS, respectively. Among all participants (N = 424), the degree of instability (expansion) was significantly higher (median 2.5 vs 2.0, P = 0.026) in participants with a diagnosis of attention deficit hyperactivity disorder (ADHD) compared to those without. FMR1 mRNA expression was significantly higher in subjects with any psychiatric disorder diagnosis (P = 0.0017); specifically, in those with ADHD (P = 0.009), and with depression (P = 0.025). Somatic FMR1 expansion was associated with the presence of ADHD in female PM and FMR1 mRNA levels were associated with the presence of mental health disorders. The findings of our research are innovative as they suggest a potential role of the CGG expansion in the clinical phenotype of PM and may potentially guide clinical prognosis and management.

This is the first study to investigate instrumental activities of daily living in older autistic adults. We conducted interviews with fifteen adults (mean age = 60.1, SD = 7.4, range = 50-73) from Australia with no intellectual disability. Analysis included both deductive and inductive steps, to categorise responses using the Occupational Performance Model Australia and identify themes across participants' experiences. Strengths and challenges were unique to the individual, as were the methods they had developed to manage tasks. Challenges occurred mostly at the interaction between aspects of the environment (sensory, cognitive, social and cultural) and personal factors such as health conditions and sensory sensitivities. Enhanced person-environment fit is needed, as is a shift in wider sociocultural attitudes to enable comfort and autonomy in later life.

As autism is an invisible and often stigmatised condition, disclosing the diagnosis may lead to both support and/or discrimination. This mixed-methods questionnaire study examined autistic adults' experiences of disclosure in various contexts. The sample consisted of 393 participants aged 17-83 years from two longitudinal surveys. Almost all participants disclosed their diagnosis to someone, most commonly to friends. A significant minority of participants studying and/or working at the time had not disclosed to their education provider/employer. Content analysis of open-ended responses showed participants desired to gain understanding and support from disclosure but feared prejudice. While some received support, others encountered dismissiveness and misunderstanding. Findings highlight the need to improve autism understanding and reduce stigma within and beyond educational and employment contexts.

The fragile X mental retardation (FMR1) gene contains an expansion-prone CGG repeat within its 5' UTR. Alleles with 55-200 repeats are known as premutation (PM) alleles and confer risk for one or more of the FMR1 premutation (PM) disorders that include Fragile X-associated Tremor/Ataxia Syndrome (FXTAS), Fragile X-associated Primary Ovarian Insufficiency (FXPOI), and Fragile X-Associated Neuropsychiatric Disorders (FXAND). PM alleles expand on intergenerational transmission, with the children of PM mothers being at risk of inheriting alleles with > 200 CGG repeats (full mutation FM) alleles) and thus developing Fragile X Syndrome (FXS). PM alleles can be somatically unstable. This can lead to individuals being mosaic for multiple size alleles. Here, we describe a detailed evaluation of somatic mosaicism in a large cohort of female PM carriers and show that 94% display some evidence of somatic instability with the presence of a series of expanded alleles that differ from the next allele by a single repeat unit. Using two different metrics for instability that we have developed, we show that, as with intergenerational instability, there is a direct relationship between the extent of somatic expansion and the number of CGG repeats in the originally inherited allele and an inverse relationship with the number of AGG interruptions. Expansions are progressive as evidenced by a positive correlation with age and by examination of blood samples from the same individual taken at different time points. Our data also suggests the existence of other genetic or environmental factors that affect the extent of somatic expansion. Importantly, the analysis of candidate single nucleotide polymorphisms (SNPs) suggests that two DNA repair factors, FAN1 and MSH3, may be modifiers of somatic expansion risk in the PM population as observed in other repeat expansion disorders.

Assistive technologies have the potential to provide accessible support to people with varying needs and abilities, including older autistic adults. However, there is currently limited knowledge about how older autistic adults use technology in their daily lives, whether it is sufficient to meet their needs and whether they experience any barriers to technology use. To address these questions, we conducted semi-structured interviews with 15 autistic adults aged over 50 years. Using thematic analysis, we identified two major themes related to how older autistic adults use technology: 'Helping to Manage the External Environment' and 'Increasing Everyday Accessibility and Convenience'. Overall, participants reported experiencing a number of challenges associated with performing everyday activities and while technology was able to offer some assistance, a number of gaps still remain in meeting the support needs of this population. Based on these findings, we offer some guidelines and recommendations for technology use with this population to guide future research and practice.

Carers of adults on the autism spectrum often experience high levels of stress, worry, and caregiver burden. There are few studies identifying the predictors of carer mental well-being and none have been conducted in Australia. Data from the Autism Cooperative Research Centre for Living with Autism's Australian Longitudinal Study of Autism in Adulthood was used to test the conceptual model by Sonido et al. (Rev J Autism Dev Disord, 2019, https://doi.org/10.1007/s40489-019-00177-8) by (a) identifying the predictors of mental well-being for carers of adults on the spectrum, (b) using model selection to determine which predictors contribute to the model of best fit, and (c) testing for mediating relationships between the predictors. Several predictors were directly associated with carer psychological quality of life, including carer age, care recipient intellectual disability, and carer intolerance of uncertainty. Model selection strongly supported the inclusion of most clusters from the conceptual model. Some mediating relationships were found, such as care recipient depressive behaviours mediating the relationships between caregiver burden and psychological quality of life. Future studies of the conceptual model will improve understanding of the predictors of carer mental well-being and enable tailored interventions to improve the psychological health of carers of adults on the autism spectrum.

The fragile X-related disorders (FXDs) are a group of clinical conditions that result primarily from an unusual mutation, the expansion of a CGG-repeat tract in exon 1 of the FMR1 gene. Mouse models are proving useful for understanding many aspects of disease pathology in these disorders. There is also reason to think that such models may be useful for understanding the molecular basis of the unusual mutation responsible for these disorders. This review will discuss what has been learnt to date about mechanisms of repeat instability from a knock-in FXD mouse model and what the implications of these findings may be for humans carrying expansion-prone FMR1 alleles.

This study aims to characterize people with dementia who were charged with criminal offences between 1995 and 2020 and describe their offending. Court cases were derived from Australian legal databases and descriptive data were manually extracted from case reports. Of 62 people variously charged with homicide, assault, child sexual assault, breach of conditions, property and larceny offences, driving offences, perverting the course of justice and arson, 46 were identified as having executive dysfunction, either as stated by medical expert witnesses or implicitly, due to conditions like Huntington's disease and frontotemporal dementia. Offending history was found to differ depending on offence type and dementia type. Executive dysfunction appears to underly offending in the sample; furthermore, some disease factors may combine to 'inhibit' or 'permit' offending. Permitting factors include executive dysfunction and younger age at time of offending; inhibitory factors include dementia-related impacts on mobility, memory and reaction speed. [ABSTRACT FROM AUTHOR]

The DREAM (dimerization partner, RB-like, E2F, and multi-vulval class B) complex is an evolutionarily conserved transcriptional repression complex that coordinates nearly one thousand target genes, primarily associated with the cell cycle processes. The formation of the DREAM complex consequently inhibits cell cycle progression and induces cellular quiescence. Given its unique role in cell cycle control, the DREAM complex has gained significant interest across various physiological and pathological contexts, particularly in conditions marked by dysregulated cell cycles, such as cancer. However, the specific cancer types most significantly affected by alterations in the DREAM complex are yet to be determined. Moreover, the possibility of restoring or pharmacologically targeting the DREAM complex as a therapeutic intervention against cancer remains a relatively unexplored area of research and is currently under active investigation. In this review, we provide an overview of the latest advances in understanding the DREAM complex, focusing on its role in cancer. We also explore strategies for targeting the DREAM complex as a potential approach for cancer therapeutics. Advances in understanding the precise role of the DREAM complex in cancer, combined with ongoing efforts to develop targeted therapies, may pave the way for new options in cancer therapy. [ABSTRACT FROM AUTHOR]

Cultured meat (CM) is derived from the in vitro myogenesis of muscle satellite (stem) cells (MSCs) and offers a promising alternative protein source. However, the development of a cost-effective media formulation that promotes cell growth has yet to be achieved. In this study, laxogenin (LAX) and 5-alpha-hydroxy-laxogenin (5HLAX) were computationally screened against myostatin (MSTN), a negative regulator of muscle mass, because of their antioxidant properties and dual roles as MSTN inhibitors and enhancers of myogenesis regulatory factors. In silico analysis showed LXG and 5HLXG bound to MSTN with binding free energies of −7.90 and −8.50 kcal/mol, respectively. At a concentration of 10 nM, LAX and 5HLAX effectively inhibited the mRNA and protein expressions of MSTN, promoted myogenesis, and enhanced myotube formation and maturation. In addition, by acting as agonists of ROS downregulating factors, they exhibited antioxidative effects. This study shows that supplementation with LAX or 5HLAX at 10 nM in CM production improves texture, quality, and nutritional value. We believe this study fills a research gap on media development for myotube formation and maturation, which are important factors for large-scale in vitro CM production that improve product quality, nutritional value, and efficacy. [ABSTRACT FROM AUTHOR]

Over the past few decades, microtubules have been targeted by various anticancer drugs, including paclitaxel and eribulin. Despite their promising effects, the development of drug resistance remains a challenge. We aimed to define a novel cell death mechanism that targets microtubules using eribulin and to assess its potential in overcoming eribulin resistance. Notably, treating non-resistant breast cancer cells with eribulin led to increased microtubule acetylation around the nucleus and cell death. Conversely, eribulin-resistant (EriR) cells did not exhibit a similar increase in acetylation, even at half-maximal inhibitory concentrations. Interestingly, silencing the ATAT1 gene, which encodes the α-tubulin N-acetyltransferase 1 (the enzyme responsible for microtubule acetylation), induces eribulin resistance, mirroring the phenotype of EriR cells. Moreover, eribulin-induced acetylation of microtubules facilitates the transport of Ca2+ from the ER to the mitochondria, releasing cytochrome c and subsequent cell death. Transcriptome analysis of EriR cells revealed a significant downregulation of ER stress-induced apoptotic signals, particularly the activity of protein kinase RNA-like ER kinase (PERK), within the unfolded protein response signaling system. Pharmacological induction of microtubule acetylation through a histone deacetylase 6 inhibitor combined with the activation of PERK signaling using the PERK activator CCT020312 in EriR cells enhanced mitochondrial Ca2+ accumulation and subsequent cell death. These findings reveal a novel mechanism by which eribulin-induced microtubule acetylation and increased PERK activity lead to Ca2+ overload from the ER to the mitochondria, ultimately triggering cell death. This study offers new insights into strategies for overcoming resistance to microtubule-targeting agents. [ABSTRACT FROM AUTHOR]

Fungi are the prominent phytopathogens that have significant impact on the productivity of agriculture worldwide. Streptomyces species have been extensively studied for the production of various bioactive metabolites. These metabolites have been used as biocontrol agents for the management of diseases caused by phytopathogenic fungi. The purpose of this investigation is to assess the efficacy of Streptomyces sporoverrucosus B-1662, an antagonistic agent in the control of red pepper anthracnose caused by Colletotrichum acutatum KACC 42403 and apple anthracnose caused by Colletotrichum siamense CGCP6 (GYUN-10348). On the basis of the morphological, and molecular characterization using 16S rRNA, the strain B-1662 was determined to be S. sporoverrucosus. The strain B-1662 exhibited antagonistic activity against seven fungal phytopathogens, including C. acutatum KACC 42403 and C. siamense CGCP6. The culture filtrates (CF) from B-1662 showed antifungal activity against all seven fungal pathogens with greater inhibition rate (%) in comparison with a control. The bacterial suspensions of B-1662 showed an excellent biological control effect on the red pepper anthracnose and apple bitter rot using an in planta assay. The anthracnose disease rate (%) was controlled by over 90% with B-1662 cell suspensions at 105 to 107 CFU/mL. Compared to a control, the strain B-1662 played a more effective role in controlling the anthracnose disease in field conditions in both years 2022 and 2023. From the effective solvent fractions, the effect compound (dibutoxybutane) has been isolated exhibiting with antifungal effect. The genetic base underlying the biocontrol traits of B-1662 was characterized using the whole-genome sequence of B-1662, which was compared with closely related strains. Consequently, these results collectively suggest that S. sporoverrucosus B-1662 can aid in the management of red-pepper anthracnose. [ABSTRACT FROM AUTHOR]

Resilience is an increasingly popular concept in literature as a protective factor against mental ill-health. While elevated rates of anxiety and mood disorders occur in adults on the autism spectrum, there is a gap in literature investigating the application of resilience to this population. This brief report examined the factor structure and psychometric properties of the 10-item Connor-Davidson Resilience Scale in a sample of 95 autistic adults (M[subscript age]=44). Our findings provide evidence for a unidimensional structure and robust psychometric properties of the scale in an autistic population, in line with factorial studies involving the general population.

There is a gap in our knowledge of aging with autism. The present study examined the applicability of the popular gerontology concept of "aging well" to autistic adults. Using survey data, a model of "aging well" was operationalised and applied to 92 autistic adults and 60 controls. A very small proportion (3.3%) of autistic adults were found to be aging well. Significantly less autistic adults were "maintaining physical and cognitive functioning" and "actively engaging with life" in comparison to controls. Whilst important differences in health and functioning status were found, the current dominant model of "aging well" is limited for examining autistic individuals. Suggested adjustments include development of a broader, more flexible and strengths -based model.

Despite the high prevalence of depression and other mental illnesses in autistic adults, screening instruments such as the Patient Health Questionnaire (PHQ-9) have not been specifically validated in an autistic sample. Using data from two Autism CRC longitudinal studies (n = 581), confirmatory factor analysis supported the two-factor model (somatic and cognitive/affective) in the autistic sample and one-factor model in the community comparison sample. Confirmatory bifactor analysis also supported use of the PHQ-9 total score in autism. Good convergent validity was found with two measures of psychological well-being for PHQ-9 total and subdomain scores. The PHQ-9 is a useful tool for autism research allowing comparison across autistic and non-autistic participants.

Anxiety is present in high rates in both children and adults on the autism spectrum. An increasing number of studies have highlighted the potentially important role that intolerance of uncertainty may have in anxiety for those on the spectrum, as well as their interrelationships with sensory sensitivities and repetitive behaviours. In response to a lack of studies involving adults, this study examined self-report survey data regarding intolerance of uncertainty, sensory sensitivities, repetitive behaviours and anxiety in a sample of 176 adults on the autism spectrum (mean age = 42). Intolerance of uncertainty and anxiety were both found to be elevated relative to non-autistic adults (N = 116) and significant, positive correlations were found between intolerance of uncertainty, anxiety, repetitive behaviours and sensory sensitivities in those on the spectrum. Intolerance of uncertainty was found to be a significant mediator between sensory sensitivities and anxiety, as well as between anxiety and insistence on sameness behaviours. These results were not sensitive to age. Intolerance of uncertainty is an important factor to be considered in the conceptualisation and management of elevated rates of anxiety for adults on the autism spectrum.