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Sleep is the brain state when cortical activity decreases and memory consolidates. However, in human epileptic patients, including genetic epileptic seizures such as Dravet syndrome, sleep is the preferential period when epileptic spike-wave discharges (SWDs) appear, with more severe epileptic symptoms in female patients than male patients, which influencing patient sleep quality and memory. Currently, seizure onset mechanisms during sleep period still remain unknown. Our previous work has shown that the sleep-like state-dependent synaptic potentiation mechanism can trigger epileptic SWDs (Zhang et al., 2021). In this study, using one heterozygous (het) knock-in (KI) transgenic mice (GABAA receptor γ2 subunit Gabrg2Q390X mutation) and an optogenetic method, we hypothesized that slow-wave oscillations (SWOs) themselves in vivo could trigger epileptic seizures. We found that epileptic SWDs in het Gabrg2+/Q390X KI mice exhibited preferential incidence during NREM sleep period, accompanied by motor immobility/ facial myoclonus/vibrissal twitching, with more frequent incidence in female het KI mice than male het KI mice. Optogenetic induced SWOs in vivo significantly increased epileptic seizure incidence in het Gabrg2+/Q390X KI mice with increased duration of NREM sleep or quiet-wakeful states. Furthermore, suppression of SWO-related homeostatic synaptic potentiation by 4-(diethylamino)-benzaldehyde (DEAB) injection (i.p.) greatly decreased seizure incidence in het KI mice, suggesting that SWOs did trigger seizure activity in het KI mice. In addition, EEG delta-frequency (0.1-4 Hz) power spectral density during NREM sleep was significantly larger in female het Gabrg2+/Q390X KI mice than male het Gabrg2+/Q390X KI mice, which likely contributes to the gender difference in seizure incidence during NREM sleep/quiet-wake as that in human patients. Competing Interest Statement The authors have declared no competing interest.

Postpartum depression (PPD) rates in the United States are among the highest globally, and PPD can pose significant, long-term risks to families. Concurrently, perinatal cannabis use is increasing in prevalence and may exacerbate PPD. Although evidence links cannabis use with PPD, little is known about its impact on immediate depressive symptoms or depression trajectories across the perinatal period. Moreover, the potential impact of cannabis use on mother-child attachment, bonding, and emotional availability could intensify the effects of cannabis on PPD. This protocol study is a longitudinal investigation aimed at detecting initial signals of the daily and long-term associations between cannabis use, PPD symptoms, and the mother-infant relationship. Participants (N=20) were individuals carrying a singleton pregnancy who reported using cannabis at least twice weekly. Recruitment was through community outreach and online advertisements. Study participation began with a baseline laboratory assessment during pregnancy, which included surveys on mental health and substance use. Follow-ups were conducted virtually at 6 weeks post partum and in the laboratory at 6 months post partum and included additional surveys on infant development, aspects of the mother-infant relationship (eg, attachment), as well as behavioral interaction tasks. Each assessment was paired with a 2-week ecological momentary assessment burst, resulting in three bursts. To support retention, brief check-in visits were completed during the second and third trimesters (depending on gestational age at enrollment), and a postdelivery phone call was conducted within 2 weeks of delivery. A 2-level linear mixed-effect models will be used to examine both event-level and person-level associations of cannabis use with momentary negative affect, PPD symptoms, and attachment, bonding, and emotional availability. Interaction models will test whether these characteristics of the mother-child relationship intensify the association between cannabis use and PPD symptoms. This project received institutional review board approval on December 19, 2022, and was awarded funding on February 1, 2023. The recruitment goal of 20 participants was reached on September 4, 2024. Recruitment challenges were encountered early in the study, leading to successful adaptations in recruitment and data collection protocols. Follow-up data collection is ongoing, with completion expected by October 2025 and results anticipated by April 2026. Retention rates approach 100% at follow-up, and ecological momentary assessment compliance rates exceed those observed in nonpregnant samples (ie, >80%). This protocol study demonstrates our ability to collect momentary and longitudinal data to examine the daily and cumulative impact of cannabis use on PPD and the mother-infant relationship. These data are well-positioned to provide preliminary evidence on how cannabis use may shape depressive symptoms during a particularly high-risk period for maternal mental health. The findings will inform a larger-scale study and advance understanding of the potential effects of cannabis use on perinatal mental health. DERR1-10.2196/71302.

Resveratrol, a vasoactive phytoestrogen, has beneficial effects on cerebrovascular function. Previous research has shown that hormonal migraineurs have poorer cerebrovascular function than non-migraineur women. We aimed to investigate if resveratrol supplementation for three months could reduce the hormonal migraine burden index (HMBI: the number of days with menstrual migraine per month), reduce migraine-related disability and improve migraine-related quality of life. A randomised, double-blind, placebo-controlled, crossover, intervention trial was conducted in 62 hormonal migraineurs (mean age: 37.5 ± 0.8 years). Participants consumed 75 mg of resveratrol or matching placebo capsules twice daily for three months before crossing over to the other treatment arm. Participants completed a daily diary and the Headache Impact Test-6™, Migraine Disability Assessment and Migraine-Specific Quality of Life questionnaires at months 0, 3 and 6. The HMBI was the primary outcome and was calculated using data extracted from the participant’s diary. No differences in the HMBI (p = 0.895), the Headache Impact Test-6™, the Migraine Disability Assessment and Migraine-Specific Quality of Life were found between the resveratrol and placebo treatments. Resveratrol supplementation for three months did not affect the HMBI, the migraine-related disability or quality of life measures in our cohort of hormonal migraineurs.

Purpose For neurodevelopmental disorders (NDDs), etiological evaluation can be a diagnostic odyssey involving numerous genetic tests, underscoring the need to develop a streamlined algorithm maximizing molecular diagnostic yield for this clinical indication. Our objective was to compare the yield of exome sequencing (ES) with that of chromosomal microarray (CMA), the current first-tier test for NDDs. Methods We performed a PubMed scoping review and meta-analysis investigating the diagnostic yield of ES for NDDs as the basis of a consensus development conference. We defined NDD as global developmental delay, intellectual disability, and/or autism spectrum disorder. The consensus development conference included input from genetics professionals, pediatric neurologists, and developmental behavioral pediatricians. Results After applying strict inclusion/exclusion criteria, we identified 30 articles with data on molecular diagnostic yield in individuals with isolated NDD, or NDD plus associated conditions (such as Rett-like features). Yield of ES was 36% overall, 31% for isolated NDD, and 53% for the NDD plus associated conditions. ES yield for NDDs is markedly greater than previous studies of CMA (15–20%). Conclusion Our review demonstrates that ES consistently outperforms CMA for evaluation of unexplained NDDs. We propose a diagnostic algorithm placing ES at the beginning of the evaluation of unexplained NDDs.

Enhancement of acyl-CoA–dependent triacylglycerol (TAG) synthesis in vegetative tissues is widely discussed as a potential avenue to increase the energy density of crops. Here, we report the identification and characterization of Chlamydomonas reinhardtii diacylglycerol acyltransferase type two (DGTT) enzymes and use DGTT2 to alter acyl carbon partitioning in plant vegetative tissues. This enzyme can accept a broad range of acyl-CoA substrates, allowing us to interrogate different acyl pools in transgenic plants. Expression of DGTT2 in Arabidopsis thaliana increased leaf TAG content, with some molecular species containing very-long-chain fatty acids. The acyl compositions of sphingolipids and surface waxes were altered, and cutin was decreased. The increased carbon partitioning into TAGs in the leaves of DGTT2-expressing lines had little effect on transcripts of the sphingolipid/wax/cutin pathway, suggesting that the supply of acyl groups for the assembly of these lipids is not transcriptionally adjusted. Caterpillars of the generalist herbivore Spodoptera exigua reared on transgenic plants gained more weight. Thus, the nutritional value and/or energy density of the transgenic lines was increased by ectopic expression of DGTT2 and acyl groups were diverted from different pools into TAGs, demonstrating the interconnectivity of acyl metabolism in leaves.

Immunological health has been challenging to characterize but could be defined as the absence of immune pathology. While shared features of some immune diseases and the concept of immunologic resilience based on age-independent adaptation to antigenic stimulation have been developed, general metrics of immune health and its utility for assessing clinically healthy individuals remain ill defined. Here we integrated transcriptomics, serum protein, peripheral immune cell frequency and clinical data from 228 patients with 22 monogenic conditions impacting key immunological pathways together with 42 age- and sex-matched healthy controls. Despite the high penetrance of monogenic lesions, differences between individuals in diverse immune parameters tended to dominate over those attributable to disease conditions or medication use. Unsupervised or supervised machine learning independently identified a score that distinguished healthy participants from patients with monogenic diseases, thus suggesting a quantitative immune health metric (IHM). In ten independent datasets, the IHM discriminated healthy from polygenic autoimmune and inflammatory disease states, marked aging in clinically healthy individuals, tracked disease activities and treatment responses in both immunological and nonimmunological diseases, and predicted age-dependent antibody responses to immunizations with different vaccines. This discriminatory power goes beyond that of the classical inflammatory biomarkers C-reactive protein and interleukin-6. Thus, deviations from health in diverse conditions, including aging, have shared systemic immune consequences, and we provide a web platform for calculating the IHM for other datasets, which could empower precision medicine. A multimodal analysis of patients with 22 different immune-mediated monogenic diseases versus matched healthy controls leads to the development of the immune health metric, which could be implemented broadly to predict responses to aging, vaccination and other immune perturbations.

Social care practitioners are often under-represented in research activity and output. Evidence-based practice enables social care practitioners to develop/engage the skills to evaluate evidence and be more actively involved in research. REalist Synthesis Of non-pharmacologicaL interVEntions for antipsychotic-induced weight gain (RESOLVE) is a NIHR-funded study where realist synthesis is used to understand and explain how, why, for whom, and in what contexts non-pharmacological interventions help service users, with severe mental illness, to manage antipsychotic-induced weight gain. Social care practitioners are a key part of the team providing care for people living with severe mental illness and therefore supporting antipsychotic-induced weight gain. The current study, RESOLVE 2, uses realist evaluation and RESOLVE as an illustrative example to help understand why and how social care practitioners engage (or not) with research. Semi-structured, audio-recorded interviews will be undertaken with a purposive sample of approximately 20 social care practitioners working with people who have severe mental illness, are treated with antipsychotics, and have experienced weight gain. Participants will be recruited from NHS Trusts and recruitment avenues such as social media and personal networks. Topics discussed during interviews will include barriers and facilitators to engagement in research, current, and past engagement as well as recommendations for researchers and other practitioners. Interview recordings will be transcribed verbatim and analyzed using realist evaluation which will allow in-depth causal explanations for research engagement. Better understanding of research engagement by social care practitioners will allow for evidence-based practice and better patient outcomes within these settings.

Within microeukaryotes, genetic variation and functional variation sometimes accumulate more quickly than morphological differences. To understand the evolutionary history and ecology of such lineages, it is key to examine diversity at multiple levels of organization. In the dinoflagellate family Symbiodiniaceae, which can form endosymbioses with cnidarians ( e.g ., corals, octocorals, sea anemones, jellyfish), other marine invertebrates ( e.g. , sponges, molluscs, flatworms), and protists ( e.g ., foraminifera), molecular data have been used extensively over the past three decades to describe phenotypes and to make evolutionary and ecological inferences. Despite advances in Symbiodiniaceae genomics, a lack of consensus among researchers with respect to interpreting genetic data has slowed progress in the field and acted as a barrier to reconciling observations. Here, we identify key challenges regarding the assessment and interpretation of Symbiodiniaceae genetic diversity across three levels: species, populations, and communities. We summarize areas of agreement and highlight techniques and approaches that are broadly accepted. In areas where debate remains, we identify unresolved issues and discuss technologies and approaches that can help to fill knowledge gaps related to genetic and phenotypic diversity. We also discuss ways to stimulate progress, in particular by fostering a more inclusive and collaborative research community. We hope that this perspective will inspire and accelerate coral reef science by serving as a resource to those designing experiments, publishing research, and applying for funding related to Symbiodiniaceae and their symbiotic partnerships.

We treated 10 children with X-linked SCID (SCID-X1) using gammaretrovirus-mediated gene transfer. Those with sufficient follow-up were found to have recovered substantial immunity in the absence of any serious adverse events up to 5 years after treatment. To determine the influence of vector integration on lymphoid reconstitution, we compared retroviral integration sites (RISs) from peripheral blood CD3(+) T lymphocytes of 5 patients taken between 9 and 30 months after transplantation with transduced CD34(+) progenitor cells derived from 1 further patient and 1 healthy donor. Integration occurred preferentially in gene regions on either side of transcription start sites, was clustered, and correlated with the expression level in CD34(+) progenitors during transduction. In contrast to those in CD34(+) cells, RISs recovered from engrafted CD3(+) T cells were significantly overrepresented within or near genes encoding proteins with kinase or transferase activity or involved in phosphorus metabolism. Although gross patterns of gene expression were unchanged in transduced cells, the divergence of RIS target frequency between transduced progenitor cells and post-thymic T lymphocytes indicates that vector integration influences cell survival, engraftment, or proliferation.

We have characterized the mitochondrial genome of the dinoflagellate Amphidinium carterae. It contains just 3 identifiable protein-coding genes: cox1, cox3, and cob. No evidence for rRNA or tRNA genes was found. Expressed sequence tags (EST) sequences for the 3 genes suggest that RNA editing occurs in 2 cases removing an in-frame stop codon. Two of the transcripts (cob and cox1) lack a stop codon at the end of the gene. The genome contains a large amount of noncoding DNA including many fragmented copies of all the 3 genes and large numbers of inverted repeats. The genome, which contains about 70% AT, has undergone extensive recombination, possibly due to the inverted repeats. The highly reduced mitochondrial gene content supports the relationship of the dinoflagellates and apicomplexa as sister groups. [PUBLICATION ABSTRACT]