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Abstract Rapid discovery and synthesis of future materials requires intelligent data acquisition strategies to navigate large design spaces. A popular strategy is Bayesian optimization, which aims to find candidates that maximize material properties; however, materials design often requires finding specific subsets of the design space which meet more complex or specialized goals. We present a framework that captures experimental goals through straightforward user-defined filtering algorithms. These algorithms are automatically translated into one of three intelligent, parameter-free, sequential data collection strategies (SwitchBAX, InfoBAX, and MeanBAX), bypassing the time-consuming and difficult process of task-specific acquisition function design. Our framework is tailored for typical discrete search spaces involving multiple measured physical properties and short time-horizon decision making. We demonstrate this approach on datasets for TiO2 nanoparticle synthesis and magnetic materials characterization, and show that our methods are significantly more efficient than state-of-the-art approaches. Overall, our framework provides a practical solution for navigating the complexities of materials design, and helps lay groundwork for the accelerated development of advanced materials.

Abstract Objective Mitochondrial impairments have been implicated in the pathogenesis of Fragile X‐associated tremor/ataxia syndrome (FXTAS) based on analysis of mitochondria in peripheral tissues and cultured cells. We sought to assess whether mitochondrial abnormalities present in postmortem brain tissues of patients with FXTAS are also present in plasma neuron‐derived extracellular vesicles (NDEVs) from living carriers of fragile X messenger ribonucleoprotein1 (FMR1) gene premutations at an early asymptomatic stage of the disease continuum. Methods We utilized postmortem frozen cerebellar and frontal cortex samples from a cohort of eight patients with FXTAS and nine controls and measured the quantity and activity of the mitochondrial proteins complex IV and complex V. In addition, we evaluated the same measures in isolated plasma NDEVs by selective immunoaffinity capture targeting L1CAM from a separate cohort of eight FMR1 premutation carriers and four age‐matched controls. Results Lower complex IV and V quantity and activity were observed in the cerebellum of FXTAS patients compared to controls, without any differences in total mitochondrial content. No patient‐control differences were observed in the frontal cortex. In NDEVs, FMR1 premutation carriers compared to controls had lower activity of Complex IV and Complex V, but higher Complex V quantity. Interpretation Quantitative and functional abnormalities in mitochondrial electron transport chain complexes IV and V seen in the cerebellum of patients with FXTAS are also manifest in plasma NDEVs of FMR1 premutation carriers. Plasma NDEVs may provide further insights into mitochondrial pathologies in this syndrome and could potentially lead to the development of biomarkers for predicting symptomatic FXTAS among premutation carriers and disease monitoring.

This study aims to evaluate the association of depressive symptoms and their severity with overall disability and disability domains, and to assess temporal changes in these associations. Data from the National Health and Nutrition Examination Survey (NHANES) 2013–2018 were analyzed. A total of 15,565 participants were included, with 1383 (8.19 %) reporting depressive symptoms. Depressive symptoms were strongly associated with overall disability (aOR = 7.82; 95 % CI = 6.27, 9.75; p

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder caused by an expansion of 55-200 CGG repeats (premutation) in the 5'-UTR of the FMR1 gene. Bidirectional transcription at FMR1 locus has been demonstrated and specific alternative splicing of the Antisense FMR1 (ASFMR1) gene has been proposed to have a contributing role in the pathogenesis of FXTAS. The structure of ASFMR1 gene is still uncharacterized and it is currently unknown how many isoforms of the gene are expressed and at what level in premutation carriers (PM) and if they may contribute to the premutation pathology. In this study, we characterized the ASFMR1 gene structure and the transcriptional landscape by using PacBio SMRT sequencing with target enrichment (IDT customized probe panel). We identified 45 ASFMR1 isoforms ranging in sizes from 523 bp to 6 Kb, spanning approximately 59 kb of genomic DNA. Multiplexing and sequencing of six human brain samples from PM samples and normal control (HC) were carried out on the PacBio Sequel platform. We validated the presence of these isoforms by qRT-PCR and Sanger sequencing and characterized the acceptor and donor splicing site consensus sequences. Consistent with previous studies conducted in other tissue types, we found a high expression of ASFMR1 isoform Iso131bp in brain samples of PM as compared to HC, while no differences in expression levels were observed for the newly identified isoforms IsoAS1 and IsoAS2. We investigated the role of the splicing regulatory protein Sam68 which we did not observe in the alternative splicing of the ASFMR1 gene. Our study provides a useful insight into the structure of ASFMR1 gene and transcriptional landscape along with the expression pattern of various newly identified novel isoforms and on their potential role in premutation pathology.

ABSTRACT Background Premutation alleles of the FMR1 X‐linked gene containing CGG repeat expansions ranging from 55 to 200 are associated with diverse late‐onset neurological involvements, including most severe disorder termed Fragile X‐associated Tremor/Ataxia Syndrome (FXTAS). It is intriguing that at least one‐third of male, and a much lower than predicted from the X‐linkage proportion of female carriers are free of this syndrome. This suggests the existence of secondary genetic factors modifying the risk of neurological involvements in these carriers. Considering the occasional presence of parkinsonian features in FXTAS, we explored the possibility that the Parkinson's Disease Polygenic Risk Score (PD PRS) is related to the occurrence of FXTAS or less severe neurological involvements, in premutation carriers. Methods The Genome‐wide SNP genotyping and clinical data on neurological status were obtained from 250 unrelated affected and non‐affected male and female adult carriers of the premutation. The medians for the Parkinson’s Disease Polygenic Risk Score (PD PRS) were compared between the groups of asymptomatic and neurologically affected carriers, and the association of PD PRS with neurological involvement in context with the other known risk factors was explored by fitting univariate and multiple logistic regression models. Results There was a significant difference between the medians from the asymptomatic versus neurologically affected (FXTAS+) groups (p = 0.009). The FXTAS+ status was significantly associated with age at testing (p

IntroductionDepression is prevalent after traumatic brain injury (TBI). However, there is a lack of understanding of the brain-based correlates of depression post-TBI. This systematic review aimed to synthesize findings of structural and functional magnetic resonance imaging (MRI) studies to identify consistently reported neural correlates of depression post-TBI.MethodsA search for relevant published studies was conducted through OVID (MEDLINE, APA PsycINFO, and Embase), with an end date of August 3rd, 2023. Fourteen published studies were included in this review.ResultsTBI patients with depression exhibited distinct changes in diffusion- based white matter fractional anisotropy, with the direction of change depending on the acuteness or chronicity of TBI. Decreased functional connectivity (FC) of the salience and default mode networks was prominent alongside the decreased volume of gray matter within the insular, dorsomedial prefrontal, and ventromedial prefrontal cortices. Seven studies reported the correlation between observed neuroimaging and depression outcomes. Of these studies, 42% indicated that FC of the bilateral medial temporal lobe subregions was correlated with depression outcomes in TBI.DiscussionThis systematic review summarizes existing neuroimaging evidence and reports brain regions that can be leveraged as potential treatment targets in future studies examining depression post-TBI.

Background Despite the frequent co-occurrence of depression and diabetes, gender differences in their relationship remain unclear. Aims This exploratory study examined if gender modifies the association between depressive symptoms, prediabetes and diabetes with cognitive-affective and somatic depressive symptom clusters. Method Cross-sectional analyses were conducted on 29 619 participants from the 2007–2018 National Health and Nutrition Examination Survey. Depressive symptoms were measured by the nine-item Patient Health Questionnaire. Multiple logistic regression was used to analyse the relationship between depressive symptoms and diabetes. Multiple linear regression was used to analyse the relationship between depressive symptom clusters and diabetes. Results The odds of having depressive symptoms were greater in those with diabetes compared to those without. Similarly, total symptom cluster scores were higher in participants with diabetes. Statistically significant diabetes–gender interactions were found in the cognitive-affective symptom cluster model. Mean cognitive-affective symptom scores were higher for females with diabetes (coefficient = 0.23, CI: 0.10, 0.36, P = 0.001) than males with diabetes (coefficient = −0.05, CI: −0.16, 0.07, P = 0.434) when compared to the non-diabetic groups. Conclusions Diabetes was associated with higher cognitive-affective symptom scores in females than in males. Future studies should examine gender differences in causal pathways and how diabetic states interact with gender and influence symptom profiles.

Background: Serodiagnosis of TORCH infections should be performed in pre-pregnancy and reproductive-age women to prevent vertical transmission. Herein, we conducted a 5-year cross-sectional retrospective study in childbearing age women to provide prevalence data. Also, stratifying the cohort into three age groups, we identified those most susceptible to acute TORCH infections. Methods: Between 2019 and 2023, serum samples from 2286 childbearing age women attending the “R. Dulbecco” University Hospital of Catanzaro were collected. Screening for TORCH pathogens, such as: Toxoplasma gondii (TOX), Cytomegalovirus (CMV), Rubella Virus (RUB), Parvovirus B19 (ParvoB19), Herpes Simplex Virus types 1 and 2 (HSV1, HSV2) and Treponema pallidum was carried out using serological tests. Chemiluminescent immunoassay was performed to detect TOX, CMV and ParvoB19 Immunoglobulin M (IgM) and Immunoglobulin G (IgG) antibodies, while Enzyme Linked Fluorescent Assay was performed to detect RUB IgM and IgG antibodies and CMV and TOX IgG Avidity. Enzyme Linked Immunosorbent Assay was performed to detect HSV1 IgG, HSV2 IgG, HSV1/2 IgM, T. pallidum total antibodies and RUB IgG Avidity. Binomial logistic regression models were developed to compare seroprevalence rates among different age groups. Results: The highest immunological protection was observed for RUB infection (87 %), probably associated with vaccination practice, followed by HSV1 and CMV (82 % and 63 %). The 16–25 year age group results as the most susceptible to acute infections as demonstrated by odds of CMV IgM positivity (primary infection) which decreased with age. Conclusions: The TORCH serological screening program should be implemented in women before pregnancy to formulate strategies for serological screening of childbearing age women and guiding clinicians in making decisions.

Sonidegib is a Hedgehog pathway inhibitor (HHIs) used as first-line systemic treatment for patients with advanced basal cell carcinoma (aBCC). Alopecia is reported as a frequent adverse event (AE), occurring in 49% of patients. Forty-five patients with aBCC were treated with sonidegib between December 2022 and December 2023; among them, 11/45 patients developed alopecia. Trichoscopic features included yellow dots, black dots, exclamation mark hairs, and broken hairs. Upon LC-OCT examination, yellow dots were seen as dilated follicular dark spaces containing malted nonhomogeneous material and outlined by bright collarets; black dots corresponded to normal-sized follicular ostia filled with bright, homogeneous material and cadaverized hair; exclamation mark hairs were short dark dysmorphic hairs with a different size of proximal and distal end and broken hairs were short dysmorphic hairs. LC-OCT may provide additional insights of early signs and clinical evolution of sonidegib-induced alopecia in patients with aBCC.

Background: Fragile X syndrome, with an approximate incidence rate of 1 in 4000 males to 1 in 8000 females, is the most prevalent genetic cause of heritable intellectual disability and the most common monogenic cause of autism spectrum disorder. The full mutation of the Fragile X Messenger Ribonucleoprotein-1 gene, characterized by an expansion of CGG trinucleotide repeats (>200 CGG repeats), leads to fragile X syndrome. Currently, there are no targeted treatments available for fragile X syndrome. In a recent large multi-site trial, FXLEARN, the effects of the mGluR5 negative allosteric modulator, AFQ056 (mavoglurant), were investigated, but did not show a significant impact of AFQ056 on language development in children with fragile X syndrome aged 3–6 years. Objectives: The current analyses from biospecimens collected in the FXLEARN study aimed to determine whether AFQ056 affects the level of potential biomarkers associated with Akt/mTOR and matrix metalloproteinase 9 signaling in young individuals with fragile X syndrome. Previous research has indicated that these biomarkers play crucial roles in the pathophysiology of fragile X syndrome. Design: A double-blind placebo-controlled parallel-group flexible-dose forced titration design. Methods: Blood samples for biomarkers were collected during the FXLEARN at baseline and subsequent visits (1- and 8-month visits). Biomarker analyses included fragile X messenger ribonucleoprotein-1 genotyping by Southern blot and PCR approaches, fragile X messenger ribonucleoprotein-1 mRNA levels determined by PCR, matrix metalloproteinase 9 levels’ detection using a magnetic bead panel, and targets of the Akt/mTOR signaling pathway with their phosphorylation levels detected. Results: This research revealed that administering AFQ056 does not affect the expression levels of the investigated blood biomarkers in young children with fragile X syndrome. Conclusion: Our findings of the lack of association between clinical improvement and biomarkers’ levels in the treatment group are in line with the lack of benefit observed in the FXLEARN study. These findings indicate that AFQ056 does not provide benefits as assessed by primary or secondary endpoints. Registration: ClincalTrials.gov NCT02920892.

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.

This study contributes to a greater understanding of the utility of molecular biomarkers to identify clinical phenotypes of fragile X syndrome (FXS). Correlations of baseline clinical trial data (molecular measures-FMR1 mRNA, CYFIP1 mRNA, MMP9 and FMRP protein expression levels, nonverbal IQ, body mass index and weight, language level, NIH Toolbox, adaptive behavior rating, autism, and other mental health correlates) of 59 participants with FXS ages of 6-32 years are reported. FMR1 mRNA expression levels correlated positively with adaptive functioning levels, expressive language, and specific NIH Toolbox measures. The findings of a positive correlation of MMP-9 levels with obesity, CYFIP1 mRNA with mood and autistic symptoms, and FMR1 mRNA expression level with better cognitive, language, and adaptive functions indicate potential biomarkers for specific FXS phenotypes. These may be potential markers for future clinical trials for targeted treatments of FXS.

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.

Multiple lines of evidence suggest a central role for the endocannabinoid system (ECS) in the neuronal development and cognitive function and in the pathogenesis of fragile X syndrome (FXS). This review describes the ECS, its role in the central nervous system, how it is dysregulated in FXS, and the potential role of cannabidiol as a treatment for FXS. FXS is caused by deficiency or absence of the fragile X messenger ribonucleoprotein 1 (FMR1) protein, FMRP, typically due to the presence of >200 cytosine, guanine, guanine sequence repeats leading to methylation of the FMR1 gene promoter. The absence of FMRP, following FMR1 gene-silencing, disrupts ECS signaling, which has been implicated in FXS pathogenesis. The ECS facilitates synaptic homeostasis and plasticity through the cannabinoid receptor 1, CB1, on presynaptic terminals, resulting in feedback inhibition of neuronal signaling. ECS-mediated feedback inhibition and synaptic plasticity are thought to be disrupted in FXS, leading to overstimulation, desensitization, and internalization of presynaptic CB1 receptors. Cannabidiol may help restore synaptic homeostasis by acting as a negative allosteric modulator of CB1, thereby attenuating the receptor overstimulation, desensitization, and internalization. Moreover, cannabidiol affects DNA methylation, serotonin 5HT1A signal transduction, gamma-aminobutyric acid receptor signaling, and dopamine D2 and D3 receptor signaling, which may contribute to beneficial effects in patients with FXS. Consistent with these proposed mechanisms of action of cannabidiol in FXS, in the CONNECT-FX trial the transdermal cannabidiol gel, ZYN002, was associated with improvements in measures of social avoidance, irritability, and social interaction, particularly in patients who are most affected, showing ≥90% methylation of the FMR1 gene.

BackgroundCarriers of the FMR1 premutation are at increased risk of developing a late-onset progressive neurodegenerative disease, fragile X-associated tremor/ataxia syndrome (FXTAS), characterized by intention tremor, gait ataxia, and cognitive decline. Cross-sectional studies to date have provided evidence that neuropsychological changes, such as executive function alterations, or subtle motor changes, may precede the onset of formal FXTAS, perhaps characterizing a prodromal state. However, the lack of longitudinal data has prevented the field from forming a clear picture of progression over time within individuals, and we lack consensus regarding early markers of risk and measures that may be used to track response to intervention.MethodsThis was a longitudinal study of 64 male FMR1 premutation carriers (Pm) without FXTAS at study entry and 30 normal controls (Nc), aged 40 to 80 years (Pm M = 60.0 years; Nc M = 57.4 years). Fifty of the Pm and 22 of the Nc were re-assessed after an average of 2.33 years, and 37 Pm and 20 Nc were re-assessed a third time after an average of another 2.15 years. Eighteen of 64 carriers (28%) converted to FXTAS during the study to date. Neuropsychological assessments at each time point, including components of the Cambridge Neuropsychological Test Automated Battery (CANTAB), tapped domains of episodic and working memory, inhibitory control, visual attention, planning, executive control of movement, and manual speed and dexterity. Age-based mixed models were used to examine group differences in change over time on the outcomes in the full sample, and differences were further evaluated in 15 trios (n = 45; 15 Pm "converters," 15 Pm "nonconverters," 15 Nc) that were one-one matched on age, education, and socioeconomic status.ResultsCompared to Nc, Pm showed significantly greater rates of change over time in visual working memory, motor dexterity, inhibitory control, and manual movement speed. After multiple comparison correction, significant effects remained for motor dexterity. Worsening inhibitory control and slower manual movements were related to progression in FXTAS stage, but these effects became statistically non-significant after correcting for multiple comparisons. Higher FMR1 mRNA correlated with worsening manual reaction time but did not survive multiple comparisons and no other molecular measures correlated with neuropsychological changes. Finally, trio comparisons revealed greater rate of decline in planning and manual movement speed in Pm converters compared to Pm nonconverters.ConclusionsAccelerated decline in executive function and subtle motor changes, likely mediated by frontocerebellar circuits, may precede, and then track with the emergence of formal FXTAS symptoms. Further research to develop and harmonize clinical assessment of FMR1 carriers across centers is needed to prepare for future prophylactic and treatment trials for this disorder.

The blackberry poses a threat as an invasive plant in various regions worldwide, where it aggressively competes with native species and risks delicate ecosystems. Livestock grazing has emerged as a potential strategy to mitigate its spread. This study investigated the effects of seasonal variations and altitude on the chemical composition and in vitro degradability of blackberry leaves. The leaves accessible to goats were collected in the Northwestern Italian Alps across all seasons at three altitudes (low: 450 m, medium: 700 m, high: 1000 m). The findings indicated that blackberry leaves can serve as a cost-effective, high-protein, and high-fiber feed for ruminants in these regions. However, the goats exhibited a limited capacity for fiber degradation. Furthermore, the nutritional value of these leaves was significantly influenced by the season, altitude, and their interaction. Spring leaves had the highest protein content (241.9 g/kg dry matter) and the best digestibility, with lower lignin levels (69 g/kg dry matter). At higher altitudes, lignin content decreased significantly during winter compared to the other seasons, resulting in a significant increase in fiber degradability. These insights offer crucial guidance for optimizing the utilization of the blackberry plant in goat feeding systems and underscores the necessity of considering both seasonal and altitudinal factors in grazing management practices.

BackgroundFragile X syndrome (FXS) is associated with dysregulated endocannabinoid signaling and may therefore respond to cannabidiol therapy.DesignCONNECT-FX was a double-blind, randomized phase 3 trial assessing efficacy and safety of ZYN002, transdermal cannabidiol gel, for the treatment of behavioral symptoms in children and adolescents with FXS.MethodsPatients were randomized to 12 weeks of ZYN002 (250 mg or 500 mg daily [weight-based]) or placebo, as add-on to standard of care. The primary endpoint assessed change in social avoidance (SA) measured by the Aberrant Behavior Checklist-Community Edition FXS (ABC-CFXS) SA subscale in a full cohort of patients with a FXS full mutation, regardless of the FMR1 methylation status. Ad hoc analyses assessed efficacy in patients with ≥ 90% and 100% methylation of the promoter region of the FMR1 gene, in whom FMR1 gene silencing is most likely.ResultsA total of 212 patients, mean age 9.7 years, 75% males, were enrolled. A total of 169 (79.7%) patients presented with ≥ 90% methylation of the FMR1 promoter and full mutation of FMR1. Although statistical significance for the primary endpoint was not achieved in the full cohort, significant improvement was demonstrated in patients with ≥ 90% methylation of FMR1 (nominal P = 0.020). This group also achieved statistically significant improvements in Caregiver Global Impression-Change in SA and isolation, irritable and disruptive behaviors, and social interactions (nominal P-values: P = 0.038, P = 0.028, and P = 0.002). Similar results were seen in patients with 100% methylation of FMR1. ZYN002 was safe and well tolerated. All treatment-emergent adverse events (TEAEs) were mild or moderate. The most common treatment-related TEAE was application site pain (ZYN002: 6.4%; placebo: 1.0%).ConclusionsIn CONNECT-FX, ZYN002 was well tolerated in patients with FXS and demonstrated evidence of efficacy with a favorable benefit risk relationship in patients with ≥ 90% methylation of the FMR1 gene, in whom gene silencing is most likely, and the impact of FXS is typically most severe.Trial registrationThe CONNECT-FX trial is registered on Clinicaltrials.gov (NCT03614663).

Some individuals with autism spectrum disorder (ASD) carry functional mutations rarely observed in the general population. We explored the genes disrupted by these variants from joint analysis of protein-truncating variants (PTVs), missense variants and copy number variants (CNVs) in a cohort of 63,237 individuals. We discovered 72 genes associated with ASD at false discovery rate (FDR) ≤ 0.001 (185 at FDR ≤ 0.05). De novo PTVs, damaging missense variants and CNVs represented 57.5%, 21.1% and 8.44% of association evidence, while CNVs conferred greatest relative risk. Meta-analysis with cohorts ascertained for developmental delay (DD) (n = 91,605) yielded 373 genes associated with ASD/DD at FDR ≤ 0.001 (664 at FDR ≤ 0.05), some of which differed in relative frequency of mutation between ASD and DD cohorts. The DD-associated genes were enriched in transcriptomes of progenitor and immature neuronal cells, whereas genes showing stronger evidence in ASD were more enriched in maturing neurons and overlapped with schizophrenia-associated genes, emphasizing that these neuropsychiatric disorders may share common pathways to risk.

BackgroundTranscranial alternating current stimulation (tACS) alters cortical excitability with low-intensity alternating current and thereby modulates aberrant brain oscillations. Despite the recent increase in studies investigating the feasibility and efficacy of tACS in treating neuropsychiatric disorders, its mechanisms, as well as optimal stimulation parameters, are not fully understood.ObjectivesThis systematic review aimed to compile human research on tACS for neuropsychiatric disorders to delineate typical treatment parameters for these conditions and evaluate its outcomes.MethodsA search for published studies and unpublished registered clinical trials was conducted through OVID (MEDLINE, PsycINFO, and Embase), ClinicalTrials.gov, and the International Clinical Trials Registry Platform. Studies utilizing tACS to treat neuropsychiatric disorders in a clinical trial setting were included.ResultsIn total, 783 published studies and 373 clinical trials were screened; 53 published studies and 70 clinical trials were included. Published studies demonstrated a low risk of bias, as assessed by the Joanna Briggs Institute Critical Appraisal Tools. Neurocognitive, psychotic, and depressive disorders were the most common disorders treated with tACS. Both published studies (58.5%) and registered clinical trials (52%) most commonly utilized gamma frequency bands and tACS was typically administered at an intensity of 2 mA peak-to-peak, once daily for 20 or fewer sessions. Although the targeted brain locations and tACS montages varied across studies based on the outcome measures and specific pathophysiology of the disorders, the dorsolateral prefrontal cortex (DLPFC) was the most common target in both published studies (30.2%) and registered clinical trials (25.6%). Across studies that published results on tACS outcome measures, tACS resulted in enhanced symptoms and/or improvements in overall psychopathology for neurocognitive (all 11 studies), psychotic (11 out of 14 studies), and depressive (7 out of 8 studies) disorders. Additionally, 17 studies reported alterations in the power spectrum of the electroencephalogram around the entrained frequency band at the targeted locations following tACS.ConclusionBehavioral and cognitive symptoms have been positively impacted by tACS. The most consistent changes were reported in cognitive symptoms following gamma-tACS over the DLPFC. However, the paucity of neuroimaging studies for each neuropsychiatric condition highlights the necessity for replication studies employing biomarker- and mechanism-centric approaches.

Objective: Depression and obesity are highly comorbid conditions with shared biological mechanisms. It remains unclear how depressive symptoms and body mass index (BMI) interact in relation to inflammation. This cross-sectional study investigated the independent associations of depressive symptoms and BMI with high sensitivity C-reactive protein (hs-CRP), as well as the moderating role of BMI on the depressive symptoms-hs-CRP association. Methods: Participants (n = 8827) from the 2015–2018 National Health and Nutrition Examination Surveys were aged ≥20 with a BMI ≥18.5 kg/m2, completed the Depression Screener, and had hs-CRP data. Multivariable linear regression was used to analyze hs-CRP in relation to depressive symptoms and BMI. An interaction term was included to examine whether the depressive symptoms-hs-CRP relationship differs depending on BMI. Results: There was a slight, albeit non-significant, increase in hs-CRP levels with each one-point increase in depressive symptoms (aCoef.Estm. = 0.01, 95% CI = −0.05, 0.06, p = 0.754). Participants with overweight (aCoef.Estm. = 1.07, 95% CI = 0.61, 1.53, p

BackgroundPrior literature suggests a dose-response relationship between physical activity (PA) and depressive symptoms. The intensity and domain of PA are suggested to be critical to its protective effect against depression; however, existing literature has shown mixed results. ObjectiveThe purpose of this population-based study is to examine the associations between depressive symptoms and weekly duration of (1) total PA and (2) PA subset by intensity, domain, or both. MethodsA cross-sectional analysis of National Health and Nutrition Examination Survey data from 2007 to 2018 was conducted using multivariable logistic and linear regression models and survey weights. Participants (N=29,730) were 20 years and older and completed the Physical Activity Questionnaire and Depression Screener. The primary outcome was the presence of depressive symptoms, and the secondary outcomes were cognitive-affective and somatic symptoms of depression. ResultsParticipants (N=29,730) had a weighted mean age of 47.62 (SD 16.99) years, and 15,133 (51.34%) were female. On average, participants without depressive symptoms engaged in 10.87 hours of total PA per week, whereas participants with depressive symptoms engaged in 8.82 hours (P.05). Participants with an increased weekly duration of recreational PA had decreases in depressive symptom odds (adjusted odds ratio [aOR] 0.965, 95% CI 0.944-0.986) and in somatic (adjusted coefficient [aβ]=–0.016, 95% CI –0.022 to –0.009) and cognitive-affective (aβ=–0.015, 95% CI –0.023 to –0.007) symptoms. When recreational PA was subset by intensity, participants with an increased weekly duration of vigorous-intensity recreational PA had decreases in depressive symptom odds (aOR 0.926, 95% CI 0.883-0.972) and in somatic (aβ=–0.021, 95% CI –0.032 to –0.010) and cognitive-affective (aβ=–0.022, 95% CI –0.035 to –0.009) symptoms. However, significant associations were not seen for the weekly duration of work-related, moderate- or vigorous-intensity PAs (all P>.05). ConclusionsFindings suggest that recreational, not work-related PA is associated with reduced symptoms of depression. Future studies should explore the impact of the different types and contexts of PA on depressive symptomatology.

BackgroundThere is evidence for a significant excess of kinetic upper limb tremor in non-FXTAS female FMR1 premutation carriers. The present study explores the possibility that this tremor is associated with various other features reminiscent of those occurring in syndromic FXTAS.Sample/methodsThis study analyzed the data from an Australian cohort of 48 asymptomatic premutation women. We utilized spiral drawings from CRST, representing action tremor; the CRST total tremor; and ICARS- kinetic tremors/cerebellar ataxia scales. Cognitive tests (involving executive functioning) included SDMT, TMT, two subtests of the WAIS-III: MR and Similarities. Spearman Rank correlations assessed the relationships between the above measures, and the Chi-square tested hypothesis about the association between the white matter hyperintensities (wmhs) in the splenium of corpus callosum assessed from MR images and spiral drawings scores.ResultsThe spiral drawing scores were significantly correlated with all three non-verbal cognitive test scores, and with the CRST scores; the latter correlated with all four cognitive test measures. Similarities (verbal) scores correlated with CRST, ICARS, and with the remaining cognitive scores. Ordered spiral scores’ categories were significantly associated with the degree of splenium involvement.ConclusionThis study showed that, in non-FXTAS premutation female carriers, sub-symptomatic forms of kinetic tremor were associated with a broader motor, and cognitive (especially executive) dysfunction.

IntroductionMetformin has been used as a targeted treatment to potentially improve cognition and slow the typical IQ decline that occurs during development among individuals with fragile X syndrome (FXS). In this follow-up study, we are following the trajectory of IQ and adaptive behavior changes over 1 to 3 years in individuals with FXS who are clinically treated with metformin in an open label trial.MethodIndividuals with FXS ages 6 to 25 years (mean 13.15 ± 5.50) and nonverbal IQ mean 57.69 (±15.46) were treated for 1–3 years (1.88 ± 0.63). They all had a baseline IQ test using the Leiter-III non-verbal cognitive assessment and the Vineland-III adaptive behavior assessment before the start of metformin. Repeat Leiter-III and Vineland-III were completed after at least 1 year of metformin (500–1,000 mg/dose given twice a day).ResultThere were no significant changes in non-verbal IQ or in the adaptive behavior measurements at FDR

This study aims to evaluate the efficacy of Texture Profile Analysis on homogenized cooked patties, referred to as TPAH, in accurately predicting patty texture and distinguishing between various patty types, similar to traditional TPA. Eight types of patties (96 samples), comprising one meat patty, one commercial pea protein-based patty, and six homemade pea protein-based patties, underwent analysis for hardness, cohesiveness, gumminess, chewiness, resilience, and springiness. All parameters measured by both methods exhibited similar variations, except for springiness. Homogenization maintained the ability to differentiate between different types of patties and generally reduced the load, albeit in a manner dependent on the type of product. For instance, the hardness decreased from 32.6 to 29.6 N for the meat patty, from 18.7 to 10.0 N for the homemade patties, and from 17.4 to 5.0 N for the commercial patty. The meat patty exhibited a greater consistency with a 9.2 % drop, while the homemade vegetable patties experienced a drop of 46.5 %, and the commercial patty even more so with 71.3 %. Canonical Discriminant Analysis applied to the two methods demonstrated the superior performance of TPAH compared to TPA. The TPAH method has proven to be valuable in predicting and comparing the texture of cooked patties.

Colorectal cancer (CRC) is one of the most common malignancies and a relevant cause of cancer-related deaths worldwide. Dysregulation of microRNA (miRNA) expression has been associated with the development and progression of various cancers, including CRC. Among them, miR-221 emerged as an oncogenic driver, whose high expression is associated with poor patient prognosis. The present study was conceived to investigate the anti-CRC activity of miR-221 silencing based on early clinical data achieved from a first-in-human study by our group. Going back from bedside to bench, we demonstrated that LNA-i-miR-221 reduces cell viability, induces apoptosis in vitro, and impairs tumor growth in preclinical in vivo models of CRC. Importantly, we disclosed that miR-221 directly targets TP53BP2, which, together with TP53INP1, is known as a positive regulator of the TP53 apoptotic pathway. We found that (1) both these genes are overexpressed following miR-221 inhibition, (2) the strong anti-tumor activity of LNA-i-miR-221 was selectively observed on TP53 wild-type cells, and (3) this activity was reduced in the presence of the TP53-inhibitor Pifitrin-α. Our data pave the way to further investigations on TP53 functionality as a marker predictive of response to miR-221 silencing, which might be relevant for clinical applications.

Maternal microbial dysbiosis has been implicated in adverse postnatal health conditions in offspring, such as obesity, cancer, and neurological disorders. We observed that the progeny of mice fed a Westernized diet (WD) with low fiber and extra fat exhibited higher frequencies of stereotypy, hyperactivity, cranial features and lower FMRP protein expression, similar to what is typically observed in Fragile X Syndrome (FXS) in humans. We hypothesized that gut dysbiosis and inflammation during pregnancy influenced the prenatal uterine environment, leading to abnormal phenotypes in offspring. We found that oral in utero supplementation with a beneficial anti-inflammatory probiotic microbe, Lactobacillus reuteri, was sufficient to inhibit FXS-like phenotypes in offspring mice. Cytokine profiles in the pregnant WD females showed that their circulating levels of pro-inflammatory cytokine interleukin (Il)-17 were increased relative to matched gravid mice and to those given supplementary L. reuteri probiotic. To test our hypothesis of prenatal contributions to this neurodevelopmental phenotype, we performed Caesarian (C-section) births using dissimilar foster mothers to eliminate effects of maternal microbiota transferred during vaginal delivery or nursing after birth. We found that foster-reared offspring still displayed a high frequency of these FXS-like features, indicating significant in utero contributions. In contrast, matched foster-reared progeny of L. reuteri-treated mothers did not exhibit the FXS-like typical features, supporting a key role for microbiota during pregnancy. Our findings suggest that diet-induced dysbiosis in the prenatal uterine environment is strongly associated with the incidence of this neurological phenotype in progeny but can be alleviated by addressing gut dysbiosis through probiotic supplementation.

Fragile X (FXS) and Turner (TS) syndromes are X-chromosome-associated disorders. Herein, we report the case of a girl in middle childhood with bicuspid aortic valve in infancy, growth failure, global developmental delay (GDD), visual problems, and coexisting attention-deficit/hyperactivity and anxiety disorders. A high-resolution karyotype in 20 cells revealed 46,X,Idic(X)(p11.21)[19]/45,X[1], suggestive of variant TS. Given her atypical phenotype, subsequent DNA testing was performed. Four FMR1 cytosine-guanine-guanine repeats (30, 410, 580 and 800) were identified, confirming the additional FXS diagnosis. This case study highlights the importance of additional genetic testing in individuals with atypical variant TS, such as unexplained GDD and distinct facial characteristics. The additional FXS diagnosis prompted new therapeutic development for the patient to advance precision healthcare.