Altered Function Research Articles

Habitual snoring in adolescents and its relationship to inhibitory control and attention.

Introduction. Sleep-disordered breathing (RBD), from habitual snoring to obstructive sleep apnea syndrome (OSAS), can influence brain functioning by affecting executive functions such as attention and inhibitory control. Objective. To analyze the association between snoring and executive functions, specifically attention, impulsivity/inhibitory control in Argentine adolescents. Population and methods. In 2018, a cross-sectional study was conducted on 831 adolescents attending public and private schools in La Pampa. Sleep duration, snoring, and the risk of OSAS were assessed using the pediatric sleep questionnaire (PSQ) and executive functions (attention and inhibitory control) using the Go/No-Go test. The association between SRT and executive functions was performed using a robust regression model adjusted for body mass index, hours of sleep, and physical activity. Results. About 10% of the participants were habitual snorers, and about 7% were at risk of OSA (positive PSQ), with no significant differences between sexes. Errors of commission (No-Go errors) (β= 2.06; -3.20, -0.92) and errors of omission (Go errors) (β= -0.66; -1.31, -0.01) were significantly higher in snorers vs.non-snorers. In addition, individuals at risk for OSAS showed significantly more commission errors (NoGo errors) than those without OSAS risk (β= -1.98; -3.31, -0.66). Conclusions. The associations between snoring and inattention and impulsivity, and between the risk of sleep apnea and lower inhibitory control found in the present study suggest alterations in executive functions due to sleep disorders.

Association between airway microbiota and systemic inflammation markers in non-small cell lung cancer patients

Growing evidences have suggested the airway microbiota may participate in lung cancer progression. However, little was known about the relationship between airway microbiota and lung cancer associated systemic inflammation. Here we aimed to explore the association between sputum microbiota and systemic inflammation in lung cancer. The microbiota of spontaneous sputum samples from 51 non-small cell lung cancer (NSCLC) patients and 6 patients with lung benign nodules were sequenced via 16 S rRNA sequencing. Neutrophil-lymphocyte ratio (NLR), platelet–lymphocyte ratio (PLR) and C reactive protein (CRP) were used to represent systemic inflammation. Patients were divided into 2 groups based on level of inflammatory biomarkers respectively (CRP_low versus CRP_high; NLR_low versus NLR_high; PLR_low versus PLR_high). α-diversity was significantly decreased in CRP_high and NLR_high patients. β diversity analysis based on weighted unifrac distance indicated that microbial community structure differed significantly between patients with different inflammation status. Lefse identified genera Porphyromonas, Selenomonas, Moryella, Megasphaera, Corynebacterium were enriched in CRP_low group. Compared with NLR_high, genera Veillonella, Neisseria, Bulleidia, Moryella were enriched in NLR_low group. For patients with different PLR level, genera Veillonella, Prevotella, Moryella, Selenomonas were increased in PLR_ low patients. Function analysis identified propionate metabolism pathway was significantly enriched in CRP_low and PLR_low groups. Moreover, RDA analysis showed that compared with PLR, NLR and CRP had strongest association with microbial community. Airway microbial structure differed between lung cancer with different systemic inflammation status. Patients with relative high inflammation status were associated with alteration of specific airway genera and microbial metabolic function.

Cardiac dilation, energy stress and ventricular remodeling: insights from prolonged voluntary exercise in male mice with TAC-induced HFpEF.

Exercise in heart failure with preserved ejection fraction (HFpEF) remains a hot topic, although current treatment strategies have not been shown to improve the long-term prognosis of HFpEF. Previous studies have mostly focused on the roles of endurance training, the mechanisms underlying long-term voluntary exercise have not been elucidated. The purpose of the present analysis was to evaluate alterations in cardiac function in HFpEF mice (HFpEF-Sed) after 6 weeks of voluntary running (HFpEF-Ex), investigate mechanisms, and compare the effects with fluoxetine (HFpEF-FLX). We found that voluntary exercise, instead of fluoxetine intervention, significantly improved left ventricular end-diastolic internal diameter (LVIDd) and the rate of change in anterior wall thickness (ATW) in HFpEF mice. The exercise capacity of HFpEF-Sed mice was significantly reduced, but prolonged voluntary running significantly reversed the expression of myocardial BNP, TNF-α, and IL-6, α-MHC, and β-MHC in HFpEF-Sed mice, along with myocardial fiber disorders accompanied by massive inflammatory cell infiltrates. Importantly, myocardial Complex III and Complex V, Mfn2, Drp1, p62, and LC3 II/I expression in HFpEF-Sed mice were all significantly different from those of normal mice, whereas voluntary exercise significantly reversed these expressions. These findings strongly suggest that long-term voluntary exercise is effective in avoiding acute and chronic energy stress in HFpEF-Sed mice, which is consistent with the mechanism of current first-line treatment for HFpEF. This notion was further supported by electron microscopy results, which showed no pathological features in cardiomyocyte mitochondrial morphology after prolonged voluntary exercise. Additionally, fluoxetine was found to inhibit depressive-like behavior in HFpEF mice.

P-61 EYE SEE YOU: GRAVES' OPHTHALMOPATHY: FIRST OCCURRENCE 10 YEARS POST-THYROIDECTOMY

Abstract Introduction Graves' ophthalmopathy is most commonly associated with Graves' disease and less frequently with Hashimoto's thyroiditis. Graves’ ophthalmopathy is also known as thyroid-associated ophthalmopathy or thyroid eye disease, because it sometimes occurs in patients with euthyroid or hypothyroid chronic autoimmune thyroiditis. While de novo Graves’ ophthalmopathy has been seen after definitive treatment with radioactive iodine, it is uncommon after total thyroidectomy. Clinical Case We report the case of a 74-year-old female, non-smoker, with a history of nodular goiter who underwent total thyroidectomy. Ten years post-surgery, the patient reported unilateral exophthalmos in the left eye accompanied by retro-orbital pain. Neck ultrasound showed no residual thyroid tissue, additionally, the levels for thyroid-stimulating hormone receptor antibodies (TRAb), thyroid peroxidase antibodies (TPOAb), and antithyroglobulin antibodies (TGAb) were negative. Consequently, ophthalmologic and neurological evaluation as well as orbital magnetic resonance imaging (MRI) were recommended. Initially, the histopathological result of nodular goiter and the negative TRAB levels ruled out Graves' disease. However, the orbital MRI did not reveal any other causes or local lesions, raising the suspicion of Graves' ophthalmopathy despite negative TRAB levels. Given the patient's active ophthalmopathy (clinical activity score 4), treatment with methylprednisolone was initiated, with symptomatic improvement by the end of therapy. Two years later, an elevated TRAB level was detected for the first time, and neck ultrasound revealed residual tissue in the left thyroid bed. We attributed this to the antibodies stimulation on a possible minimal residual thyroid tissue, which was undetectable on periodic ultrasound for a over 10 years, but which subsequently became hyperplastic. Therefore, corroborating the anamnestic, clinical and paraclinical data, the diagnosis of Graves' ophtalmopathy with positive TRAB has been confirmed. The most recent follow-up revealed an improved but still active nature of the ophthalmopathy (clinical activity score 3), hence, treatment with methylprednisolone and mycophenolate sodium was reinitiated. The patient is being closely monitored to establish the best ongoing therapeutic approach. Conclusion The development of Graves' ophthalmopathy after total thyroidectomy for nodular goiter is a rare occurrence with several proposed mechanisms. These include the release of thyroid autoantigens post-surgery triggering an autoimmune response, potential alterations in antigen-presenting cell function influencing immune reactions, and the impact of postoperative infections on immune modulation. While the exact pathways remain speculative, understanding these mechanisms could enhance our approach to monitoring and managing autoimmune complications in thyroid surgery patients.Figure 1:Orbital MRIThe orbital MRI shows that the posterior pole of the right eyeball is approximately 3 mm anterior to the interzygomatic line and the posterior pole of the left eyeball is at the level of the interzygomatic line. The distance between the interzygomatic line and the anterior pole of the eyeball is approximately 25 mm on the right side and 23 mm on the left side. Bilateral extraocular muscles with increased thickness, homogeneous enhancement, more intense on the right side.

Osteopathic Manipulative Treatment for Postconcussive Symptoms: A Case Report.

Concussions are a common form of mild traumatic brain injury characterized by a transient alteration of cerebral function leading to a range of physical, cognitive, and emotional symptoms. Postconcussive symptoms (PCSs) usually resolve in about a week but can persist in 10% to 15% of patients. If left untreated, PCS can profoundly affect a patient's life. The authors present a case of a previously healthy patient who dealt with residual headaches and anxiety for 10 months after a head injury. She was treated with osteopathic manipulative treatment (OMT), which helped resolve her headaches and her anxiety. The OMT techniques applied during treatment included balanced ligamentous tension, myofascial release, and osteopathy in the cranial field techniques. OMT is a nonpharmacological, noninvasive treatment that can benefit patients suffering with PCS. The authors would like to increase the awareness of clinicians and researchers for OMT's potential positive outcomes for PCS, as part of a multifactorial approach to care.

Functional connectivity and metabolic brain alterations in sleepwalkers.

Disorders of arousal (DoA) are characterized by an intermediate state between wakefulness and deep sleep, leading to incomplete awakenings from NREM sleep. Multimodal studies have shown subtle neurophysiologic alterations even during wakefulness in DoA. The aim of this study was to explore the brain functional connectivity in DoA and the metabolic profile of the anterior and posterior cingulate cortex, given its pivotal role in cognitive and emotional processing. Fifteen consecutive patients with DoA (9 males, mean age 26.3 ± 7.7) and 15 age- and sex-matched healthy controls (8 males, mean age 25.8 ± 3.6) were enrolled. All participants underwent a protocol including sleep and psychological evaluation scales and multimodal brain MRI with resting-state functional MRI and 1H-MR spectroscopy. The independent component analysis disclosed an altered resting-state functional connectivity (FC) in the patients' sensory motor network, with a higher connectivity strength in opercular cortex, precuneus, occipital pole, and lingual gyrus. The seed-based analysis revealed a decreased FC between posterior cingulate cortex (PCC) and several cerebral areas. Finally, spectroscopic imaging revealed a reduced content of glutamine in the PCC (p < 0.001). The increased connectivity in the sensory-motor network of DoA patients could constitute a "facilitatory medium" enhancing motor circuit activation, while the connectivity and metabolic alterations of PCC might represent a trait functional feature, contributing to a dysfunctional arousal process and the difficulty to reach a complete awareness during DoA episodes. In addition, these alterations at rest might be related to daytime impairment reported by patients, requiring new strategies for DoA management.

Obstructive sleep apnea and structural and functional brain alterations: a brain-wide investigation from clinical association to genetic causality

BackgroundObstructive sleep apnea (OSA) is linked to brain alterations, but the specific regions affected and the causal associations between these changes remain unclear.MethodsWe studied 20 pairs of age-, sex-, BMI-, and education- matched OSA patients and healthy controls using multimodal magnetic resonance imaging (MRI) from August 2019 to February 2020. Additionally, large-scale Mendelian randomization analyses were performed using genome-wide association study (GWAS) data on OSA and 3935 brain imaging-derived phenotypes (IDPs), assessed in up to 33,224 individuals between December 2023 and March 2024, to explore potential genetic causality between OSA and alterations in whole brain structure and function.ResultsIn the cohort study, OSA patients exhibited significantly lower fractional amplitude of low-frequency fluctuation and regional homogeneity in the right posterior cerebellar lobe and bilateral superior and middle frontal gyrus, while showing higher levels in the left occipital lobe and left posterior central gyrus. Decreased fractional anisotropy (FA) but increased apparent diffusion coefficient (ADC) was shown in the bilateral superior longitudinal fasciculus. According to the results of Affiliation file 2: table s6, it is the ADC value of right superior longitudinal fasciculus was shown a positive correlation with the lowest oxygen saturation. In the Mendelian randomization analyses, the area of left inferior temporal sulcus (OR: 0.89; 95% CI: 0.82–0.96), rfMRI connectivity ICA100 edge 893 (OR: 0.88; 95% CI: 0.82–0.96), ICA100 edge 951 (OR: 0.89; 95% CI: 0.82–0.97), and ICA100 edge 1213 (OR: 0.89; 95% CI: 0.82–0.96) were significantly decreased in OSA. Conversely, mean thickness of G-front-inf-Triangul in right hemisphere (OR: 1.14; 95% CI: 1.05–1.23), mean orientation dispersion index in right tapetum (OR: 1.13; 95% CI: 1.04–1.23), and rfMRI connectivity ICA100 edge 258 (OR: 1.13; 95% CI: 1.04–1.22) showed opposite results.ConclusionsNerve fiber damage and imbalances in neuronal activity across multiple brain regions caused by hypoxia, particularly the frontal lobe, underlie the structural and the functional connectivity impairments in OSA.

In vitro Analysis of the Pharmaceutical Interactions between Verapamil Hydrochloride and Citric Acid

The objective of this study is to investigate the combination of drug-drug interactions involving different functional groups by assessing the interaction of a BCS class IV compound (Verapamil Hydrochloride) with Citric acid in various ratios, thereby enhancing the understanding of pharmacological implications. This study elucidated the compatibility between Verapamil Hydrochloride (HCl) and Citric acid, demonstrating an approach to enhance the solubility, permeability, and bioavailability of poorly water-soluble drugs in pharmaceutical applications. The method of solvent evaporation was utilized for the preparation of solid dispersions. This process involved dissolving the active pharmaceutical ingredient and citric acid in ethanol, evaporating the solvent to yield a solvent-free film, and mechanically reducing the residue using a mortar and pestle. The resultant fine powder was sieved through a 40-mesh filter and appropriately stored in vials for subsequent analyses. FT-IR spectra and an HPLC-sensitive method were employed to evaluate the solubility profile and interaction dynamics of the compound. FT-IR spectra of VPM HCl and its physical mixtures with citric acid at ratios of 1:3, 1:5, and 1:7 were obtained using an FT-IR spectrophotometer. The spectra revealed structural and functional group alterations, quantified by analyzing the magnitude and cumulative area of the peaks corresponding to the structural constituents. In accordance with the established linearity, the retention times for VPM HCl, Sample 1, Sample 2, and Sample 3 were recorded as 6.8 ± 0.2, 2.7 ± 0.1, 5.5 ± 0.2, and 3.8 ± 0.1 minutes, respectively, across a concentration range of 1–100 µg/mL. For all analytes, the intra-assay and inter-assay biases were observed to be within 15% and 13.4%, respectively. Furthermore, In vitro evaluations of physical combinations of Verapamil HCl and Citric acid samples revealed minimal interaction. These findings emphasize the stability and compatibility of Verapamil HCl and citric acid, demonstrating citric acid’s role as a reliable excipient for enhancing drug solubility and bioavailability without compromising therapeutic integrity.

Altered Sertoli Cell Function Contributes to Spermatogenic Arrest in Dogs with Chronic Asymptomatic Orchitis

Acquired infertility due to chronic asymptomatic orchitis (CAO) is a common finding in male dogs. It is characterized by spermatogenic arrest, a significant reduction in spermatogonia, immune cell infiltration and a disruption of the blood–testis barrier. Sertoli cells are a key factor for spermatogenesis and the testicular micromilieu. We hypothesize altered Sertoli cell function to be involved in the pathogenesis of canine CAO. Consequently, the aim was to gain further insights into the spermatogonial stem cell niche and Sertoli cell function in CAO-affected dogs. Therefore, the testicular expression of the Sertoli cell-derived factors bFGF, GDNF, WNT5A, BMP4, CXCL12 and LDHC were evaluated in 15 CAO testis tissues and 10 normospermic controls by relative quantitative real-time PCR (qPCR). Additionally, the protein expression patterns of bFGF, GDNF and WNT5A were visualized immunohistochemically (IHC). This study revealed an overexpression of bFGF (IHC, p &lt; 0.0001), GDNF (qPCR, p = 0.0036), WNT5A (IHC, p = 0.0066) and CXCL12 (qPCR, p = 0.0003) and a reduction in BMP4 (qPCR, p = 0.0041) and LDHC (qPCR, p = 0.0003) in CAO-affected testis in dogs, clearly confirming impaired Sertoli cell function in canine CAO. Sertoli cell function is essential for spermatogenesis and must be considered for potential therapeutic approaches.

The efficacy analysis of robotic versus laparoscopic ipsilateral uretero-ureterostomy for upper urinary tract duplications in pediatric population.

To review and compare robot-assisted ipsilateral ureteroureterostomy (RALUU) and laparoscopic ipsilateral uretero-ureterostomy (LUU) in terms of efficacy and outcomes. Clinical data of 65 children with complete renal ureteral duplication deformity admitted to the First Affiliated Hospital of Zhengzhou University from January 2015 to December 2022 were collected. Among these, 42 patients underwent laparoscopic ureteroureterostomy (LUU), designated as the LUU group, while 23 patients received robot-assisted laparoscopic ureteroureterostomy (RALUU), designated as the RALUU group. We compared the two groups regarding surgical duration, intraoperative blood loss, postoperative drainage duration, length of hospital stay, changes in anterior-posterior diameter (APD) of the affected renal pelvis pre- and postoperatively, changes in ureteral diameter, and alterations in renal function. The postoperative drainage duration (Z = 2.375, P = 0.024) and length of hospital stay (t = 2.142, P = 0.038) were shorter in the RALUU group compared to the LUU group, with statistically significant differences. However, there were no statistically significant differences in surgical duration (t = -1.465, P = 0.153) and intraoperative blood loss (Z = 1.679, P = 0.097) between the two groups. Complications occurred in three patients in the LUU group (two cases of anastomotic stricture and one case of stump syndrome), while no long-term complications were reported in the RALUU group, with no significant difference between the groups (χ2 = 0.482, P = 0.488). Both groups exhibited a tendency for improvement in APD, ureteral diameter (UD), and differential renal function (DRF) pre- and postoperatively. However, further analysis revealed that changes in APD (ΔAPD, t = -1.132, P = 0.284), DRF (ΔDRF, Z = 1.865, P = 0.073), and UD (ΔUD, t = 1.562, P = 0.064) did not show statistically significant differences between the two groups. Both RALUU and LUU are safe and effective treatments for children with complete renal ureteral duplication anomalies. Compared to LUU, RALUU is associated with shorter postoperative drainage duration and hospital stay.

Advances in lacrimal gland organoid development: Techniques and therapeutic applications.

The human lacrimal gland (LG), located above the outer orbital region within the frontal bone socket, is essential in maintaining eye surface health and lubrication. It is firmly anchored to the orbital periosteum by the connective tissue, and it is vital for protecting and lubricating the eye by secreting lacrimal fluid. Disruption in the production, composition, or secretion of lacrimal fluid can lead to dry eye syndrome, a condition characterized by ocular discomfort and potential eye surface damage. This review explores the recent advancements in LG organoid generation using tissues and stem cells, highlighting cutting-edge techniques in biomaterial-based and scaffold-free technologies. Additionally, we shed light on the complex pathophysiology of LG dysfunction, providing insights into the LG physiological roles while identifying strategies for generating LG organoids and exploring their potential clinical applications. Alterations in LG morphology or secretory function can affect the tear film stability and quality, leading to various ocular pathological conditions. This comprehensive review underlines the critical crosslink of LG organoid development with disease modeling and drug screening, underscoring their potential for advancing therapeutic applications.

Plasma levels of glial fibrillary acidic protein and neurofilament light chain in patients with chronic migraine: a multicenter case-control study.

Plasma glial fibrillary acidic protein (pGFAP) and plasma neurofilament light chain (pNfL) levels reflect astrocyte activation and neuronal damage, respectively. Whether these phenomena play a role in migraine is unknown. This study aimed to compare pGFAP and pNfL levels in patients with chronic migraine (CM) and age-matched controls and to analyze their relation with clinical features. The study evaluated two independent cohorts of patients, including in total 58 CM and 69 controls. pGFAP and pNfL were quantified with single molecule array (Simoa) technology. Demographic and clinical data were collected for each subject; differences in NfL/GFAP levels between CM and controls were evaluated in analyses adjusted for the effect of age and sex; clinical characteristics associated with NfL/GFAP levels were separately evaluated in the two cohorts. In both cohorts, we did not find a significant difference in pGFAP or pNFL levels between CM and matched controls. The study did not find any correlation between pGFAP or pNfL levels and any migraine characteristics (namely presence of migraine aura, attack frequency, migraine intensity, years of disease). Our negative results support the assumption that migraine represents a benign condition, characterized by transient functional brain alterations and not by the accumulation over time of neuroaxonal damage and/or associated astrocyte activation detectable by neurodegeneration marker proteins.

Effect of Multiyear Biodegradable Plastic Mulch on Soil Microbial Community, Assembly, and Functioning

The increasing use of biodegradable plastic mulch like polybutylene adipate terephthalate (PBAT) has raised concerns about its long-term environmental impact. In this study, we investigated the effects of multiyear PBAT mulch application on bacterial and fungal communities, assembly mechanisms, and key ecological functions. The microbial community diversity and composition were significantly altered after multiyear biodegradable plastic mulching. We observed that PBAT treatment enriched specific bacterial genera, such as Pantoea, potentially involved in plastic degradation, and fungal genera like Cephaliophora and Stephanosporaceae, which may play a role in organic matter decomposition. A null model analysis revealed that bacterial community assembly was largely shaped by deterministic processes, with stronger environmental selection pressures in PBAT-treated soils, while fungal communities were more influenced by stochastic processes. In addition, multiyear PBAT mulch application also impacted the functionality of the soil microbial communities. PBAT exposure enhanced biofilm formation in aerobic bacteria, promoting aerobic degradation processes while also reducing the abundance of stress-tolerant bacteria. Additionally, PBAT altered key microbial functions related to carbon, nitrogen, and sulfur cycling. Notably, the fungal communities exhibited functional shifts, with an increase in saprotrophic fungi being beneficial for nutrient cycling, alongside a potential rise in plant pathogenic fungi. These findings underscore the multiyear ecological impacts of biodegradable plastics, suggesting microbial adaptation to plastic degradation and changes in key ecological functions, with implications for agricultural sustainability and bioremediation strategies.

Metabolic reprogramming and immunological changes in the microenvironment of esophageal cancer: future directions and prospects

BackgroundEsophageal cancer (EC) is the seventh-most prevalent cancer worldwide and is a significant contributor to cancer-related mortality. Metabolic reprogramming in tumors frequently coincides with aberrant immune function alterations, and extensive research has demonstrated that perturbations in energy metabolism within the tumor microenvironment influence the occurrence and progression of esophageal cancer. Current treatment modalities for esophageal cancer primarily include encompass chemotherapy and a limited array of targeted therapies, which are hampered by toxicity and drug resistance issues. Immunotherapy, particularly immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 pathway, has exhibited promising results; however, a substantial proportion of patients remain unresponsive. The optimization of these immunotherapies requires further investigation. Mounting evidence underscores the importance of modulating metabolic traits within the tumor microenvironment (TME) to augment anti-tumor immunotherapy.MethodsWe selected relevant studies on the metabolism of the esophageal cancer tumor microenvironment and immune cells based on our searches of MEDLINE and PubMed, focusing on screening experimental articles and reviews related to glucose metabolism, amino acid metabolism, and lipid metabolism, as well their interactions with tumor cells and immune cells, published within the last five years. We analyzed and discussed these studies, while also expressing our own insights and opinions.ResultsA total of 137 articles were included in the review: 21 articles focused on the tumor microenvironment of esophageal cancer, 33 delved into research related to glucose metabolism and tumor immunology, 30 introduced amino acid metabolism and immune responses, and 17 focused on the relationship between lipid metabolism in the tumor microenvironment and both tumor cells and immune cells.ConclusionThis article delves into metabolic reprogramming and immune alterations within the TME of EC, systematically synthesizes the metabolic characteristics of the TME, dissects the interactions between tumor and immune cells, and consolidates and harnesses pertinent immunotherapy targets, with the goal of enhancing anti-tumor immunotherapy for esophageal cancer and thereby offering insights into the development of novel therapeutic strategies.

Atrial fibrillation versus. atrial myopathy in thrombogenesis: Two sides of the same coin?

Atrial fibrillation (AF) and atrial myopathy are recognized contributors to cardiovascular morbidity, particularly ischemic stroke. AF poses an elevated risk of thrombogenesis due to irregular heart rhythm leading to blood stasis and clot formation. Atrial myopathy, marked by structural and functional alterations in the atria, is emerging as a crucial factor influencing thromboembolic events, independently of AF. This narrative review article provides an overview of the interwoven relationship between AF and atrial myopathy in thrombogenesis, focusing on the epidemiology, risk factors, and clinical implications of these two entities. The discussion encompasses the association between AF burden and stroke risk, evaluating current evidence and guidelines for anticoagulant therapy. Additionally, it explores the role of atrial myopathy in the pathogenesis of thromboembolic events, emphasizing the patient's clinical profile assessed by the CHA2DS2-VASc score. The manuscript provides insights into ongoing trials and future perspectives, discussing potential advancements in antithrombotic therapy, fibrin clot dynamics, and anti-inflammatory strategies. This comprehensive review challenges the conventional perception of AF as a sole cause of stroke, urging a holistic approach to risk assessment of thrombogenesis and management in the high-risk population that AF patients constitute.

The Cul3 ubiquitin ligase engages Insomniac as an adaptor to impact sleep and synaptic homeostasis.

Mutations of the Cullin-3 (Cul3) E3 ubiquitin ligase are associated with autism and schizophrenia, neurological disorders characterized by sleep disturbances and altered synaptic function. Cul3 engages dozens of adaptor proteins to recruit hundreds of substrates for ubiquitination, but the adaptors that impact sleep and synapses remain ill-defined. Here we implicate Insomniac (Inc), a conserved protein required for normal sleep and synaptic homeostasis in Drosophila, as a Cul3 adaptor. Inc binds Cul3 in vivo, and mutations within the N-terminal BTB domain of Inc that weaken Inc-Cul3 associations impair Inc activity, suggesting that Inc function requires binding to the Cul3 complex. Deletion of the conserved C-terminus of Inc does not alter Cul3 binding but abolishes Inc activity in the context of sleep and synaptic homeostasis, indicating that the Inc C-terminus has the properties of a substrate recruitment domain. Mutation of a conserved, disease-associated arginine in the Inc C-terminus also abolishes Inc function, suggesting that this residue is vital for recruiting Inc targets. Inc levels are negatively regulated by Cul3 in neurons, consistent with Inc degradation by autocatalytic ubiquitination, a hallmark of Cullin adaptors. These findings link Inc and Cul3 in vivo and support the notion that Inc-Cul3 complexes are essential for normal sleep and synaptic function. Furthermore, these results indicate that dysregulation of conserved substrates of Inc-Cul3 complexes may contribute to altered sleep and synaptic function in autism and schizophrenia associated with Cul3 mutations.

Reorganization of gray matter networks in patients with Moyamoya disease

Patients with Moyamoya disease (MMD) exhibit significant alterations in brain structure and function, but knowledge regarding gray matter networks is limited. The study enrolled 136 MMD patients and 99 healthy controls (HCs). Clinical characteristics and gray matter network topology were analyzed. Compared to HCs, MMD patients exhibited decreased clustering coefficient (Cp) (P = 0.006) and local efficiency (Eloc) (P = 0.013). Ischemic patients showed decreased Eloc and increased characteristic path length (Lp) compared to asymptomatic and hemorrhagic patients (P < 0.001, Bonferroni corrected). MMD patients had significant regional abnormalities, including decreased degree centrality (DC) in the left medial orbital superior frontal gyrus, left orbital inferior frontal gyrus, and right calcarine fissure and surrounding cortex (P < 0.05, FDR corrected). Increased DC was found in bilateral olfactory regions, with higher betweenness centrality (BC) in the right median cingulate, paracingulate fusiform gyrus, and left pallidum (P < 0.05, FDR corrected). Ischemic patients had lower BC in the right hippocampus compared to hemorrhagic patients, while hemorrhagic patients had decreased DC in the right triangular part of the inferior frontal gyrus compared to asymptomatic patients (P < 0.05, Bonferroni corrected). Subnetworks related to MMD and white matter hyperintensity volume were identified. There is significant reorganization of gray matter networks in patients compared to HCs, and among different types of patients. Gray matter networks can effectively detect MMD-related brain structural changes.

Human papillomavirus, vaginal microbiota and metagenomics: the interplay between development and progression of cervical cancer

Persistent infection with oncogenic human papillomavirus (HPV) types, such as HPV 16 or 18, is a major factor in cervical cancer development. However, only a small percentage of infected women develop cancer, indicating that other factors are involved. Emerging evidence links vaginal microbiota with HPV persistence and cancer progression. Alterations in microbial composition, function, and metabolic pathways may contribute to this process. Despite the potential of metagenomics to explore these interactions, studies on the vaginal microbiota’s role in cervical cancer are limited. This review systematically examines the relationship between cervical microbiota, HPV, and cervical cancer by analyzing studies from PubMed, EBSCO, and Scopus. We highlight how microbial diversity influences HPV persistence and cancer progression, noting that healthy women typically have lower microbiota diversity and higher Lactobacillus abundance compared to HPV-infected women, who exhibit increased Gardenella, Prevotella, Sneathia, Megasphaera, Streptococcus, and Fusobacterium spp., associated with dysbiosis. We discuss how microbial diversity is associated with HPV persistence and cancer progression, noting that studies suggest healthy women typically have lower microbiota diversity and higher Lactobacillus abundance, while HPV-infected women exhibit increased Gardnerella, Prevotella, Sneathia, Megasphaera, Streptococcus, and Fusobacterium spp., indicative of dysbiosis. Potential markers such as Gardnerella and Prevotella have been identified as potential microbiome biomarkers associated with HPV infection and cervical cancer progression. The review also discusses microbiome-related gene expression changes in cervical cancer patients. However, further research is needed to validate these findings and explore additional microbiome alterations in cancer progression.

P0171 IL-36 signaling as a drug target in Crohn’s disease patients with IL36RN mutations

Abstract Background The IL-36 signaling pathway has recently been identified as a key regulator of intestinal homeostasis and inflammation. However, the role of mutations in the IL-36R signaling pathway in the pathogenesis of inflammatory bowel disease remains unclear. Methods Mutations in the IL-36 receptor antagonist (IL-36RA, IL36RN) were identified in a cohort of 86 ulcerative colitis patients, 244 Crohn’s disease patients and 45 non-inflamed controls by whole exome sequencing followed by targeted Sanger sequencing. In-depth immune cell profiling of one IL36RN-mutated patient was performed using mass cytometry and multiplexed immunoassays. Overexpression experiments and functional assays characterized identified IL36RN mutations. Clinical and molecular responses of one IL36RN-mutated patient to a combined treatment with the IL-36R-blocking antibody spesolimab and the TNF-blocker certolizumab-pegol were assessed by fecal calprotectin, endoscopy, multiplexed immunoassays and mass cytometry. Results We identified four Crohn’s disease patients with heterozygous missense mutations in IL36RN. Experimental overexpression and functional assays demonstrated that two identified mutations resulted in a reduced protein expression of IL-36RA. In-depth immune profiling of one IL36RN-mutated patient revealed an increased response of PBMCs to IL-36 stimulation and elevated serum levels of IL-36-regulated cytokines. Administration of the IL-36R-blocking antibody spesolimab in combination with certolizumab-pegol over a period of 22 weeks to this patient resulted in a reduction of intestinal inflammation and alterations in immune cell composition and function. Conclusion Our findings indicate that pathogenic IL36RN mutations may contribute to the pathogenesis of Crohn’s disease in a subset of patients and that inhibiting IL-36 signaling in combination with TNF-blockade could offer a personalized therapeutic approach for these patients. Disclaimer Spesolimab was made available based on an out-of-scope request. Boehringer Ingelheim was given the opportunity to review this abstract as a courtesy. Boehringer Ingelheim had no role in the design, analysis or interpretation of the results in this study.

Large-scale functional network connectivity alterations in adolescents with major depression and non-suicidal self-injury.

Non-suicidal self-injury (NSSI) is prevalent among adolescent populations worldwide, yet its neuropathological mechanisms remain unclear. This study aimed to investigate brain functional differences in NSSI patients by utilizing large-scale functional networks and examining their correlation with clinical outcomes. Cross-sectional clinical and functional magnetic resonance imaging (fMRI) data were collected from 42 patients and 47 healthy controls. Independent component analysis (ICA) was utilized to investigate changes in both intra-network and inter-network functional connectivity. We then investigated the potential association between functional network connectivity and clinical self-injurious behavior. The results revealed significant abnormalities in intra-network functional connectivity within the left middle cingulum gyrus, right angular gyrus, and middle frontal gyrus in patients with NSSI. Additionally, we found altered inter-network connectivity patterns, particularly between higher-order cognitive networks and primary sensory networks, suggesting potential disruptions in multisensory integration and emotional regulation in these patients. This study revealed significant alterations in large-scale functional network connectivity in adolescents with depression and NSSI, particularly in networks related to emotion regulation and cognitive control. These findings provide novel perspectives on the neurobiological mechanisms of NSSI and suggest possible avenues for early intervention and treatment.