Atypical behaviour and connectivity in SHANK3-mutant macaques.

Mutation or disruption of the SH3 and ankyrin repeat domains 3 (SHANK3) gene represents a highly penetrant, monogenic risk factor for autism spectrum disorder, and is a cause of Phelan-McDermid syndrome. Recent advances in gene editing have enabled the creation of genetically engineered non-human-primate models, which might better approximate the behavioural and neural phenotypes of autism spectrum disorder than do rodent models, and may lead to more effective treatments. Here we report CRISPR-Cas9-mediated generation of germline-transmissible mutations of SHANK3 in cynomolgus macaques (Macaca fascicularis) and their F1 offspring. Genotyping of somatic cells as well as brain biopsies confirmed mutations in the SHANK3 gene and reduced levels of SHANK3 protein in these macaques. Analysis of data from functional magnetic resonance imaging revealed altered local and global connectivity patterns that were indicative of circuit abnormalities. The founder mutants exhibited sleep disturbances, motor deficits and increased repetitive behaviours, as well as social and learning impairments. Together, these results parallel some aspects of the dysfunctions in the SHANK3 gene and circuits, as well as the behavioural phenotypes, that characterize autism spectrum disorder and Phelan-McDermid syndrome.

Myxoid epithelioid smooth muscle tumor of the vulva: A distinct entity with MEF2D::NCOA2 gene fusion.

Smooth muscle tumors are the most common mesenchymal tumors of the female genital tract, including the vulva. Since vulvar smooth muscle tumors are rare, our understanding of them compared to their uterine counterparts continues to evolve. Herein, we present two cases of morphologically distinct myxoid epithelioid smooth muscle tumors of the vulva with novel MEF2D::NCOA2 gene fusion. The tumors involved 24 and 37-year-old women. Both tumors presented as palpable vulvar masses that were circumscribed, measuring 2.8 and 5.1 cm in greatest dimension. Histologically, they were composed of epithelioid to spindle-shaped cells with minimal cytologic atypia and prominent myxoid matrix. Rare mitotic figures were present (1-3 mitotic figures per 10 high-power field (HPF)), and no areas of tumor necrosis were identified. By immunohistochemistry, the neoplastic cells strongly expressed smooth muscle actin, calponin, and desmin, confirming smooth muscle origin. Next-generation sequencing identified identical MEF2D::NCOA2 gene fusions. These two cases demonstrate that at least a subset of myxoid epithelioid smooth muscle tumors of the vulva represent a distinct entity characterized by a novel MEF2D::NCOA2 gene fusion. Importantly, recognition of the distinct morphologic and genetic features of these tumors is key to understanding the biological potential of these rare tumors.

Manipulating d-Band Center of Nickel by Single-Iodine-Atom Strategy for Boosted Alkaline Hydrogen Evolution Reaction.

Ni-based electrocatalysts have been predicted as highly potential candidates for hydrogen evolution reaction (HER); however, their applicability is hindered by an unfavorable d-band energy level (Ed). Moreover, precise d-band structural engineering of Ni-based materials is deterred by appropriative synthesis methods and experimental characterization. Herein, we meticulously synthesize a special single-iodine-atom structure (I-Ni@C) and characterize the Ed manipulation via resonant inelastic X-ray scattering (RIXS) spectroscopy to fill this gap. The complex catalytic mechanism has been elucidated via synchrotron radiation-based multitechniques (SRMS) including X-ray absorption fine structure (XAFS), in situ synchrotron radiation-based Fourier transform infrared (SR-FTIR) spectroscopy, and near ambient pressure X-ray photoelectron spectroscopy (NAP-XPS). In particular, RIXS is innovatively applied to reveal the precise regulation of Ni Ed of I-Ni@C. Consequently, the role of such single-iodine-atom strategy is confirmed to not only facilitate the moderate Ed of the Ni site for balancing the adsorption/desorption capacities of key intermediates but also act as a bridge to enhance the electronic interaction between Ni and the carbon shell for forming a localized polarized electric field conducive to H2O dissociation. As a result, I-Ni@C exhibits an enhanced alkaline hydrogen evolution performance with an overpotential of 78 mV at 10 mA/cm2 and superior stability, surpassing the majority of the reported Ni-based catalysts. Overall, this study has managed to successfully tailor the d-band center of materials from the SRMS perspective, which has crucial implications for nanotechnology, chemistry, catalysis, and other fields.

Undifferentiated Round Cell Sarcoma With CRTC1::SS18 Fusion: Expanding Clinicopathologic Features of a Rare Translocation Sarcoma With Prominent Desmoplastic Stroma.

Undifferentiated round cell sarcomas (URCS) represent a diverse group of tumors, including conventional Ewing sarcoma, round cell sarcoma with EWSR1/FUS-non-ETS fusions, CIC-rearranged sarcoma, and sarcoma with BCOR alterations. Since 2018, 3 cases of URCS with a novel CRTC1::SS18 gene fusion have been reported in the literature. Herein, we report 3 additional cases of CRTC1::SS18 sarcoma, thereby doubling the number of described cases and expanding the clinicopathologic features of this rare translocation sarcoma. Together with the previously reported cases, we show that the male-to-female ratio is 1:2 with a median age of 34 years (range, 12-42 years). Tumors occurred primarily in intramuscular locations involving the lower extremity. Histologically, all tumors contained uniform round-to-epithelioid cells with a moderate amount of eosinophilic cytoplasm growing in sheets and nests with prominent desmoplastic stroma reminiscent of desmoplastic small round cell tumor. Immunohistochemical results were nonspecific, demonstrating variable expression of CD99 (patchy), ALK, GATA3, and cyclin D1. RNA sequencing revealed CRTC1::SS18 gene fusions in all cases, involving exons 1 to 2 of CRTC1 (the 5' partner gene) on chromosome 19 and either exon 2 or exon 4 of SS18 (the 3' partner gene) on chromosome 18. The clinical course was variable. Although 1 previously reported case demonstrated aggressive behavior with a fatal outcome, 2 others had a relatively indolent course with gradual growth for 6 to 7 years prior to resection. Two cases developed metastatic disease, including 1 case with bilateral lung metastasis and 1 with locoregional spread to a lymph node. By analyzing the clinicopathologic features, we aimed to improve recognition of this rare translocation sarcoma to better understand its biologic potential, optimize patient management, and expand the current classification of URCS.

EWSR1::WT1 Fusions in Neoplasms Other Than Conventional Desmoplastic Small Round Cell Tumor: Three Tumors Occurring Outside the Female Genital Tract.

Desmoplastic small round cell tumor (DSRCT) is a high-grade, primitive round cell sarcoma classically associated with prominent desmoplastic stroma, coexpression of keratin and desmin, and a characteristic EWSR1::WT1 gene fusion. DSRCT typically arises in the abdominopelvic cavity of young males with diffuse peritoneal spread and poor overall survival. Although originally considered to be pathognomonic for DSRCT, EWSR1::WT1 gene fusions have recently been detected in rare tumors lacking the characteristic morphologic and immunohistochemical features of DSRCT. Here, we report 3 additional cases of neoplasms other than conventional DSCRCT with EWSR1::WT1 gene fusions that occurred outside the female genital tract. Two occurred in the abdominopelvic cavities of a 27-year-old man and a 12-year-old girl, whereas the third arose in the axillary soft tissue of an 85-year-old man. All cases lacked prominent desmoplastic stroma and were instead solid and cystic with peripheral fibrous pseudocapsules and occasional intervening fibrous septa. Necrosis was either absent (1/3) or rare (2/3), and mitotic activity was low (<1 to 3 per 10 hpf). In immunohistochemical studies, there was expression of smooth muscle actin (3/3) and desmin (3/3), rare to focal reactivity for EMA (2/3), and variable expression of CK AE1/AE3 (1/3). Myogenin and MyoD1 were negative, and C-terminus-specific WT1 was positive in both cases tested (2/2). All 3 tumors followed a more indolent clinical course with 2 cases demonstrating no evidence of disease at 20 and 44 months after resection. The patient from case 3 died of other causes at 14 months with no evidence of recurrence. DNA methylation profiling showed that the 3 cases clustered with DSRCT; however, they demonstrated fewer copy number variations with 2 cases having a flat profile (0% copy number variation). Differential methylation analysis with hierarchical clustering further showed variation between the 3 cases and conventional DSRCT. Although further study is needed, our results, in addition to previous reports, suggest that EWSR1::WT1 gene fusions occur in rare and seemingly distinctive tumors other than conventional DSRCT with indolent behavior. Proper classification of these unusual soft tissue tumors with EWSR1::WT1 gene fusions requires direct correlation with tumor morphology and clinical behavior, which is essential to avoid overtreatment with aggressive chemotherapy.

Novel CRTC1::MRTFB(MKL2) Gene Fusion Detected in Myxoid Mesenchymal Neoplasms With Myogenic Differentiation Involving Bone and Soft Tissues.

Appropriate classification of fusion-driven bone and soft tissue neoplasms continues to evolve, often relying on the careful integration of morphologic findings with immunohistochemical, molecular, and clinical data. Herein, we present 3 cases of a morphologically distinct myxoid mesenchymal neoplasm with myogenic differentiation and novel CRTC1::MRTFB (formerly MKL2) gene fusion. Three tumors occurred in 1 male and 2 female patients with a median age of 72 years (range: 28-78). Tumors involved the left iliac bone, the right thigh, and the left perianal region with a median size of 4.0 cm (4.0-7.6 cm). Although 1 tumor presented as an incidental finding, the other 2 tumors were noted, given their persistent growth. At the time of the last follow-up, 1 patient was alive with unresected disease at 6 months, 1 patient was alive without evidence of disease at 12 months after surgery, and 1 patient died of disease 24 months after diagnosis. On histologic sections, the tumors showed multinodular growth and were composed of variably cellular spindle to round-shaped cells with distinct brightly eosinophilic cytoplasm embedded within a myxoid stroma. One tumor showed overt smooth muscle differentiation. Cytologic atypia and mitotic activity ranged from minimal (2 cases) to high (1 case). By immunohistochemistry, the neoplastic cells expressed focal smooth muscle actin, h-caldesmon, and desmin in all tested cases. Skeletal muscle markers were negative. Next-generation sequencing detected nearly identical CRTC1::MRTFB gene fusions in all cases. We suggest that myxoid mesenchymal tumors with myogenic differentiation harboring a CRTC1::MRTFB fusion may represent a previously unrecognized, distinctive entity that involves soft tissue and bone. Continued identification of these novel myxoid neoplasms with myogenic differentiation will be important in determining appropriate classification, understanding biologic potential, and creating treatment paradigms.

Immunometabolic changes and potential biomarkers in CFS peripheral immune cells revealed by single-cell RNA sequencing.

The pathogenesis of Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) remains unclear, though increasing evidence suggests inflammatory processes play key roles. In this study, single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMCs) was used to decipher the immunometabolic profile in 4 ME/CFS patients and 4 heathy controls. We analyzed changes in the composition of major PBMC subpopulations and observed an increased frequency of total T cells and a significant reduction in NKs, monocytes, cDCs and pDCs. Further investigation revealed even more complex changes in the proportions of cell subpopulations within each subpopulation. Gene expression patterns revealed upregulated transcription factors related to immune regulation, as well as genes associated with viral infections and neurodegenerative diseases.CD4+ and CD8+ T cells in ME/CFS patients show different differentiation states and altered trajectories, indicating a possible suppression of differentiation. Memory B cells in ME/CFS patients are found early in the pseudotime, indicating a unique subtype specific to ME/CFS, with increased differentiation to plasma cells suggesting B cell overactivity. NK cells in ME/CFS patients exhibit reduced cytotoxicity and impaired responses, with reduced expression of perforin and CD107a upon stimulation. Pseudotime analysis showed abnormal development of adaptive immune cells and an enhanced cell-cell communication network converging on monocytes in particular. Our analysis also identified the estrogen-related receptor alpha (ESRRA)-APP-CD74 signaling pathway as a potential biomarker for ME/CFS in peripheral blood. In addition, data from the GSE214284 database confirmed higher ESRRA expression in the monocyte cell types of male ME/CFS patients. These results suggest a link between immune and neurological symptoms. The results support a disease model of immune dysfunction ranging from autoimmunity to immunodeficiency and point to amyloidotic neurodegenerative signaling pathways in the pathogenesis of ME/CFS. While the study provides important insights, limitations include the modest sample size and the evaluation of peripheral blood only. These findings highlight potential targets for diagnostic biomarkers and therapeutic interventions. Further research is needed to validate these biomarkers and explore their clinical applications in managing ME/CFS.

Live-born autosomal ring chromosomes at the Johns Hopkins Hospital Cytogenomics Laboratory: Case series-Spanning 52 years of experience in a single center.

Ring chromosomes (RCs) are a structural aberration that can be tolerated better in acrocentric or gonosomal chromosomes. Complete RCs arise from telomere-telomere fusions. Alternatively, genomic imbalances corresponding to the ends of the chromosomal arms can be seen with RC formation. RCs are unstable in mitosis, result in mosaicism, and are associated with a "ring syndrome," which presents with growth and development phenotypes and differs from those features more frequently observed with pure terminal copy number changes. Due to variability in mosaicism, size, and genomic content, clear genotype-phenotype correlations may not always be possible. Given the rarity of RCs, this historical data is invaluable. We performed a retrospective review of individuals bearing RCs to investigate the incidence in our laboratory. This work details the methods and features seen in association with twenty-three autosomal RCs. In decreasing order, the most frequently seen autosomal RCs were 18, 22, 4, 13, 17, and 9. The additional cases detail clinical and cytogenomic events similar to those reported in RCs. As methodologies advance, insights may be gleaned from following up on these cases to improve genotype-phenotype correlations and understand the cryptic differences or other predisposing factors that lead to ring formation and development.

Inhibition of α-Amino-3-Hydroxy-5-Methyl-4-Isoxazolepropionic Acid Receptors Ameliorates Atrial Inflammation and Vulnerability to Atrial Fibrillation in Rats with Anxiety Disorders.

ABSTRACT: Previous studies have found that anxiety disorders may increase the incidence of atrial fibrillation (AF). More and more studies have shown that α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) are involved in the occurrence and development of cardiovascular diseases. However, the role of AMPARs in AF associated with anxiety disorder remains unclear. The aim of this study was to investigate the effect of AMPARs on AF susceptibility in rats with anxiety disorder and its possible mechanism. The anxiety disorder rat model was established by unpredictable empty bottle stimulation and was treated with AMPARs agonist and antagonist. Our results showed that AMPARs antagonist treatment significantly reduced sympathetic activity, improved heart rate variability, shortened action potential duration, prolonged effective refractory period, reduced AF induction rate, and improved cardiac electrical remodeling and the expression of inflammatory factors. In addition, inhibition of AMPARs reduced the phosphorylation of IκBα and p65. Our experimental results suggest that inhibition of AMPARs can reduce autonomic remodeling, improve atrial electrical remodeling, and suppress myocardial inflammation, which provides a potential therapeutic strategy for the treatment of AF associated with anxiety disorder.

Telomere extension occurs at most chromosome ends and is uncoupled from fill-in in human cancer cells.

Telomeres are thought to be maintained by the preferential recruitment of telomerase to the shortest telomeres. The extension of the G-rich telomeric strand by telomerase is also believed to be coordinated with the complementary synthesis of the C strand by the conventional replication machinery. However, we show that under telomere length-maintenance conditions in cancer cells, human telomerase extends most chromosome ends during each S phase and is not preferentially recruited to the shortest telomeres. Telomerase rapidly extends the G-rich strand following telomere replication but fill-in of the C strand is delayed into late S phase. This late C-strand fill-in is not executed by conventional Okazaki fragment synthesis but by a mechanism using a series of small incremental steps. These findings highlight differences between telomerase actions during steady state versus nonequilibrium conditions and reveal steps in the human telomere maintenance pathway that may provide additional targets for the development of anti-telomerase therapeutics.

Prevalence of postprandial hypotension in older adults: a systematic review and meta-analysis.

BACKGROUND: Older adults with postprandial hypotension (PPH) increase susceptibility to falls, syncope, stroke, acute cardiovascular diseases and even death. However, the prevalence of this condition varies significantly across studies. We aimed to determine the prevalence of PPH in older adults. METHODS: Web of Science, PubMed, Cochrane Library, Embase and CINAHL were searched from their inception until February 2023. Search terms included 'postprandial period', 'hypotension' and 'postprandial hypotension'. Eligible studies were assessed using the Joanna Briggs Institute tool. Meta-analyses were performed among similar selected studies. RESULTS: Thirteen eligible studies were included, and data from 3,021 participants were pooled. The meta-analysis revealed a PPH prevalence of 40.5% [95% confidence interval (CI): 0.290-0.519] in older adults, and this was prevalent in the community (32.8%, 95% CI: 0.078-0.647, n = 1,594), long-term healthcare facility (39.4%, 95% CI: 0.254-0.610, n = 1,062) and geriatrics department of hospitals (49.3%, 95% CI: 0.357-0.630, n = 365). The pooled results showed significant heterogeneity (I2 > 90%), partially related to the different ages, sex, pre-prandial systolic blood pressure levels of participants, or the different criteria and methodology used to diagnose PPH. CONCLUSIONS: PPH is a prevalent condition in older adults. Further research is needed to confirm this result, and priority should be given to establishing international consensus on PPH diagnostic criteria and designing its diagnostic procedure.

Serum-free medium for recombinant protein expression in insect cells.

The baculovirus expression vector system (BEVS) has been widely used to produce recombinant proteins because of several advantages, such as eukaryotic post-translational modifications similar to those in mammalian cells, high expression levels and safety, and large gene capacity. Usually, insect cell culture requires 5%‒10% fetal bovine serum, which has many adverse effects, including high cost, heterogeneity between batches, complex composition, and pollution risks. Therefore, serum-free medium (SFM) is indispensable for the production of recombinant proteins in insect cell culture. Here, the most commonly used insect cell lines and three insect cell media, namely basic medium, SFM, and chemically defined medium, are summarized. The basic components of insect cell SFM are similar to those of other cells but contain special components. The components, functions, and issues of different SFM used for insect cell culture are reviewed. In recent years, some special additives have been demonstrated to increase recombinant protein expression yield and quality in BEVS, and the functions and possible mechanisms of small-molecule additives are reviewed herein. Finally, future perspectives of SFM used in BEVS for recombinant protein production are discussed.

Association of pyrethroids exposure with asthma in US children and adolescents: a nationally representative cross-sectional study.

Pyrethroids (PYR) are among the most widely used insecticides in households, leading to substantial exposure. Children and adolescents, especially during growth spurts, have a reduced capacity to effectively metabolize these insecticides. The relationship between PYR exposure and asthma in these age groups remains poorly understood, highlighting the need for further research.We used data from the 2007-2014 National Health and Nutrition Examination Survey, which included 1181 children aged 6-11 years and 1258 adolescents aged 12-19 years. The concentration of the PYR metabolite 3-phenoxybenzoic acid (3-PBA) in urine was quantified using solid-phase extraction-high-performance liquid chromatography-heated electrospray ionization tandem mass spectrometry. Asthma was defined based on self-reported doctor diagnoses from the questionnaire. PYR exposure was measured using urine samples collected simultaneously with the questionnaire. We explored the association between PYR exposure and asthma using multiple logistic regression analyses, adjusting for potential confounders.Multiple logistic regression analyses revealed no significant association between PYR exposure and asthma in children and adolescent boys (all P > 0.05). In contrast, PYR exposure was significantly associated with asthma in adolescent girls aged 12-19 years. Specifically, for "ever asthma," the odds ratios (ORs) were 2.49 (95% CI = 1.03-5.97) in the second quartile of PYR exposure and 2.48 (95% CI = 1.04-5.91) in the third quartile, each in comparison to the first quartile. For "current asthma," in comparison to the first quartile, the ORs were 3.99 (95% CI = 1.55-10.26) in the second quartile of PYR exposure, 3.39 (95% CI = 1.32-8.70) in the third quartile, and 2.93 (95% CI = 1.24-6.90) in the fourth quartile.Conclusions:Our study found a significant association between PYR exposure and asthma in adolescent girls, whereas no significant association was observed in children and adolescent boys. These findings suggest potential sex and age differences in susceptibility to PYR exposure. Further research is warranted to confirm these results and elucidate the underlying mechanisms.

Effect of Epidermoid Cysts on the Efficacy of Intralesional Corticosteroid Therapy for Hypertrophic Scars and Keloids: A Prospective Pilot Study.

BACKGROUND: Patients with hypertrophic scars (HSs) or keloids occasionally have epidermoid cysts (ECs), and the effect of ECs on the effectiveness of intralesional corticosteroids (ILCs) treatment in these patients has not been reported. OBJECTIVE: This study aims to evaluate the influence of ECs on the outcomes of ILCs treatment in patients with HSs or keloids. MATERIALS AND METHODS: This prospective study included 572 patients with keloids ( n = 461) or HSs ( n = 111). Patients received intralesional triamcinolone acetonide injection (0.05 mL/injection) at a concentration of 40 mg/mL and every 28 days for 4 sessions, with a 1-year follow-up. RESULTS: A higher incidence of ECs was observed in keloid patients (16.92%) compared with HSs patients (7.21%). Keloid patients with ECs were older ( p = .008) and had a longer disease duration ( p = .0148), higher Vancouver scar scale (VSS) scores ( p = .04), and greater thickness ( p = .006). Keloid patients with ECs showed less improvement in VSS scores ( p < .0001) and thickness ( p < .0001) after ILCs treatment, with a higher recurrence rate ( p < .0001). The overall complication rate in keloid patients with ECs after ILCs treatment was 49.51%. CONCLUSION: Epidermoid cysts under keloids were associated with a poor response to ILCs therapy. Therefore, it is recommended to incorporate ultrasonography as a routine examination for keloid patients to aid in better decision making in clinical practice.

Environmental exposure to per- and polyfluoroalkyl substances mixture and asthma in adolescents.

BACKGROUND: Previous epidemiological studies about the relationship between per- and polyfluoroalkyl substances (PFAS) concentrations and adolescent asthma have typically examined single PFAS, without considering the mixtures effects of PFAS. METHODS: Using data from the 2013-2018 National Health and Nutrition Examination Survey (NHANES), 886 adolescents aged 12-19 years were included in this study. We explored the association between PFAS mixture concentrations and adolescent asthma using weighted quantile sum (WQS) regression and Bayesian kernel machine regression (BKMR) models, respectively. RESULTS: After adjusting for confounders, the results of the WQS regression and BKMR models were consistent, with mixed exposure to the five PFAS not significantly associated with asthma in all adolescents. The association remained nonsignificant in the subgroup analysis by sex. CONCLUSIONS: Our study demonstrated no significant association between mixed exposure to PFAS and adolescent asthma, and more large cohort studies are needed to confirm this in the future.

Expert consensus on perioperative integrated skincare for noninvasive energy-based device aesthetic procedures in clinical practice in China.

BACKGROUND: Noninvasive energy-based device (NI-EBD) aesthetic procedures has recently gained widespread usage for treating various skin conditions, enhancing skin texture and performing rejuvenation-related procedures. However, practically all NI-EBD procedures result in variable degrees of damage to the skin barrier, inducing pathological and physiological processes such as oxidative stress and inflammation, and only a small percentage of individuals possess the innate ability to restore it. OBJECTIVE: To introduce the concept of integrated skincare and establish standardized operational procedures for perioperative integrated skincare, and furnish a theoretical basis for clinical diagnosis and treatment performed by professional medical aestheticians. METHODS: The author leveraged domestic and international guidelines, clinical practice expertise and evidence-based research, adapting them to suit the specific circumstances in China. RESULTS: The consensus were provided four parts, including concept and essence of integrated skincare, integrated skincare significance during the perioperative phase of NI-EBD procedures, active ingredients and functions of effective skincare products, standardized perioperative skincare procedure for NI-EBD procedures and precautions. For the standardized perioperative skincare procedure, four recommendations were listed according to different stages during NI-EBD procedures. CONCLUSION: These recommendations create the 'Expert Consensus on Perioperative Integrated Skincare for Noninvasive Energy-Based Device Aesthetic Procedures in Clinical Practice in China'.

Deciphering feedback regulation of prostaglandin F2α in blood stasis syndrome using nitrogen-doped porous transition metal carbides.

Blood stasis syndrome (BSS) has persistent health risks; however, its pathogenesis remains elusive. This obscurity may result in missed opportunities for early intervention, increased susceptibility to chronic diseases, and reduced accuracy and efficacy of treatments. Metabolomics, employing the matrix-assisted laser desorption/ionization (MALDI) strategy, presents distinct advantages in biomarker discovery and unraveling molecular mechanisms. Nonetheless, the challenge is to develop efficient matrices for high-sensitivity and high-throughput analysis of diverse potential biomarkers in complex biosamples. This work utilized nitrogen-doped porous transition metal carbides and nitrides (NP-MXene) as a MALDI matrix to delve into the molecular mechanisms underlying BSS pathogenesis. Structural optimization yielded heightened peak sensitivity (by 1.49-fold) and increased peak numbers (by 1.16-fold) in clinical biosamples. Validation with animal models and clinical serum biosamples revealed significant differences in metabolic fingerprints between BSS and control groups, achieving an overall diagnostic efficacy of 0.905 (95% CI, 0.76-0.979). Prostaglandin F2α was identified as a potential biomarker (diagnostics efficiency of 0.711, specificity = 0.7, sensitivity = 0.6), and pathway enrichment analysis disclosed disruptions in arachidonic acid metabolism in BSS. This innovative approach not only advances comprehension of BSS pathogenesis, but also provides valuable insights for personalized treatment and diagnostic precision.

Early blood immune molecular alterations in cynomolgus monkeys with a PSEN1 mutation causing familial Alzheimer's disease.

INTRODUCTION: More robust non-human primate models of Alzheimer's disease (AD) will provide new opportunities to better understand the pathogenesis and progression of AD. METHODS: We designed a CRISPR/Cas9 system to achieve precise genomic deletion of exon 9 in cynomolgus monkeys using two guide RNAs targeting the 3' and 5' intron sequences of PSEN1 exon 9. We performed biochemical, transcriptome, proteome, and biomarker analyses to characterize the cellular and molecular dysregulations of this non-human primate model. RESULTS: We observed early changes of AD-related pathological proteins (cerebrospinal fluid Aß42 and phosphorylated tau) in PSEN1 mutant (ie, PSEN1-ΔE9) monkeys. Blood transcriptome and proteome profiling revealed early changes in inflammatory and immune molecules in juvenile PSEN1-ΔE9 cynomolgus monkeys. DISCUSSION: PSEN1 mutant cynomolgus monkeys recapitulate AD-related pathological protein changes, and reveal early alterations in blood immune signaling. Thus, this model might mimic AD-associated pathogenesis and has potential utility for developing early diagnostic and therapeutic interventions. HIGHLIGHTS: A dual-guide CRISPR/Cas9 system successfully mimics AD PSEN1-ΔE9 mutation by genomic excision of exon 9. PSEN1 mutant cynomolgus monkey-derived fibroblasts exhibit disrupted PSEN1 endoproteolysis and increased Aß secretion. Blood transcriptome and proteome profiling implicate early inflammatory and immune molecular dysregulation in juvenile PSEN1 mutant cynomolgus monkeys. Cerebrospinal fluid from juvenile PSEN1 mutant monkeys recapitulates early changes of AD-related pathological proteins (increased Aß42 and phosphorylated tau).

Evaluation of nocturnal apnea and airflow limitation as indicators for cognitive dysfunction in patients with chronic obstructive pulmonary disease/obstructive sleep apnea hypopnea syndrome overlap syndrome.

OBJECTIVE: The aim of this study is to investigate how much intermittent hypoxemia and airflow limitation contribute to cognitive impairment in overlap syndrome (OS), which is the coexistence of two common diseases, obstructive sleep apnea hypopnea syndrome (OSAHS) and chronic obstructive pulmonary disease (COPD). METHODS: We conducted a cross-sectional study of patients with OSAHS, COPD or OS, compared with normal controls, to determine the association between sleep apnea/pulmonary function-related indicators and cognitive dysfunction in individuals with OSAHS, COPD or OS. RESULTS: A total of 157 participants were recruited. Both OSAHS and OS presented lower adjusted Montreal cognitive assessment (MoCA) scores compared with COPD group. In addition, the MoCA score was significantly lower in COPD group compared with control group. The incidence of cognitive impairment was 57.4% in OSAHS group, and 78% in OS group, which were significantly higher than COPD group (29%) and control group (8.8%). Furthermore, a broader range of cognitive domains were affected in OS group compared with OSAHS group. Elevated levels of oxygen desaturation index (ODI) and/or apnea hypopnea index (AHI) were positively correlated with increased Epworth sleeping scale (ESS) in OSAHS and OS. Forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1) and peak expiratory flow (PEF) were positively correlated with cognitive scores in OSAHS but not in OS. Serum level of hypoxia-inducible factor-1α (HIF-1α) was significantly higher in OS. Logistic regression identified ODI as an independent risk factor for cognitive impairment in OS, while severity of snoring and PEF were independent risk factors in OSAHS. DISCUSSION: This study revealed significant cognitive impairment in OS, OSAHS and COPD. Sleep-related indicators are warranted in OS patients for detection, differentiation and grading of cognitive impairment, whereas pulmonary functions are warranted in OSAHS patients for detection and early intervention of cognitive impairment.

A novel rat model of Dravet syndrome recapitulates clinical hallmarks.

Dravet syndrome (DS) is a debilitating infantile epileptic encephalopathy characterized by seizures induced by high body temperature (hyperthermia), sudden unexpected death in epilepsy (SUDEP), cognitive impairment, and behavioral disturbances. The most common cause of DS is haploinsufficiency of the SCN1A gene, which encodes the voltage-gated sodium channel Nav1.1. In current mouse models of DS, the epileptic phenotype is strictly dependent on the genetic background and most mouse models exhibit drastically higher SUDEP rates than patients. Therefore, we sought to develop an alternative animal model for DS. Here, we report the generation and characterization of a Scn1a halploinsufficiency rat model of DS by disrupting the Scn1a allele. Scn1a+/- rats show reduced Scn1a expression in the cerebral cortex, hippocampus and thalamus. Homozygous null rats die prematurely. Heterozygous animals are highly susceptible to heat-induced seizures, the clinical hallmark of DS, but are otherwise normal in survival, growth, and behavior without seizure induction. Hyperthermia-induced seizures activate distinct sets of neurons in the hippocampus and hypothalamus in Scn1a+/- rats. Electroencephalogram (EEG) recordings in Scn1a+/- rats reveal characteristic ictal EEG with high amplitude bursts with significantly increased delta and theta power. After the initial hyperthermia-induced seizures, non-convulsive, and convulsive seizures occur spontaneously in Scn1a+/- rats. In conclusion, we generate a Scn1a haploinsufficiency rat model with phenotypes closely resembling DS, providing a unique platform for establishing therapies for DS.