Patterns Of Dysregulation Research Articles

Localized Pantothenic Acid (Vitamin B5) Reductions Present Throughout the Dementia with Lewy Bodies Brain.

Localized pantothenic acid deficiencies have been observed in several neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease dementia (PDD), and Huntington's disease (HD), indicating downstream energetic pathway perturbations. However, no studies have yet been performed to see whether such deficiencies occur across the dementia with Lewy bodies (DLB) brain, or what the pattern of such dysregulation may be. Firstly, this study aimed to quantify pantothenic acid levels across ten regions of the brain in order to determine the localization of any pantothenic acid dysregulation in DLB. Secondly, the localization of pantothenic acid alterations was compared to that previously in AD, PDD, and HD brains. Pantothenic acid levels were determined in 20 individuals with DLB and 19 controls by ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) across ten brain regions. Case-control differences were determined by nonparametric Mann-Whitney U test, with the calculation of S-values, risk ratios, E-values, and effect sizes. The results were compared with those previously obtained in DLB, AD, and HD. Pantothenic acid levels were significantly decreased in six of the ten investigated brain regions: the pons, substantia nigra, motor cortex, middle temporal gyrus, primary visual cortex, and hippocampus. This level of pantothenic acid dysregulation is most similar to that of the AD brain, in which pantothenic acid is also decreased in the motor cortex, middle temporal gyrus, primary visual cortex, and hippocampus. DLB appears to differ from other neurodegenerative diseases in being the only of the four to not show pantothenic acid dysregulation in the cerebellum. Pantothenic acid deficiency appears to be a shared mechanism of several neurodegenerative diseases, although differences in the localization of this dysregulation may contribute to the differing clinical pathways observed in these conditions.

Emotional Dysregulation and Sleep Problems: A Transdiagnostic Approach in Youth.

Sleep is a complex phenomenon that affects several aspects of life, including cognitive functioning, emotional regulation, and overall well-being. Sleep disturbances, especially during adolescence, can negatively impact emotional regulation, making it a critical factor in targeting psychopathology. This study explores the interplay between emotional dysregulation (ED) and sleep patterns in a sample of 90 adolescent patients by means of self- and parent-rated clinical measures. Our findings reveal a bidirectional relationship between ED and sleep problems. Adolescents with higher affective instability experience poorer sleep quality, while those with worse sleep quality exhibit higher internalizing problems. Additionally, emotional reactivity is associated with disrupted circadian rhythms. These results emphasize the significance of addressing sleep problems in the context of psychopathology treatment, potentially leading to improved outcomes. Further research is needed to determine the most effective treatment strategies, including nonpharmacological and pharmacological interventions. Understanding the intricate relationship between sleep problems and emotion regulation offers insights for more targeted and effective treatment approaches for youths struggling with ED.

Deregulated Long Non-Coding RNAs (lncRNA) as Promising Biomarkers in Hidradenitis Suppurativa.

Background/Objectives: In recent times, epigenetics alterations in Hidradenitis suppurativa (HS) have been explored and exploited translationally to guide investigation of new therapeutic approaches. On the other hand, long noncoding RNAs (LncRNAs), main regulators of the epigenetic status of the human genome, have been scarcely investigated, notwithstanding their potential relevance in broad pathogenesis comprehension. Here, we aim to explore the methylation pattern of lncRNAs in HS. Methods: In this case-control study, 24 HS patients and age-, sex- and BMI-matched controls were analyzed to characterize the methylome of lncRNA genes in peripheral blood cells. Gene ontology analysis (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, protein-protein interaction (PPI) network, and MCODE analysis were performed. Results: A set of fifteen lncRNA genes exhibited significantly differential methylation patterns, with ten of them showing hypomethylation and five displaying hypermethylation at specific CpG sites. The hypomethylated lncRNA genes were DLEU2, MESTIT1, CASC2, TUG1, KCNQ1DN, PSORS1C3, PCA3, DSCR8, RFPL1S, and PVT1, while the hypermethylated ones were HAR1A, FAM66B, SNHG9, HCG9, and HCP5. These lncRNA genes have been linked to various important biological processes, including cell proliferation, apoptosis, inflammation, chronic inflammatory skin diseases, and wound healing. Their altered methylation status suggests potential roles in regulating these processes, and may contribute to HS pathogenesis and healing mechanisms. Conclusions: This study revealed an interesting dysregulation pattern of definite lncRNAs in the methylome which is linked to both the development of HS and its comorbidities. Epigenetically altered lncRNAs genes could represent useful biomarkers, and could help in guiding innovative treatment strategies.

Predicting calcium status in early lactation multiparous Holsteins using milk constituent analysis

Due to the unique challenges of supporting milk production, subclinical hypocalcemia (SCH) is common among early lacta­tion dairy cows. Though SCH immediately following parturi­tion may constitute normal adaptation to the transition period, there is growing evidence that cows with SCH beyond 4 days postpartum (DIM) have developed dyscalcemia, a pattern of calcium dysregulation that has been associated with negative health and production outcomes. Despite prevalence of dyscal­cemia ranging from 25% to 45%, identifying cows with dyscal­cemia remains a major challenge on commercial dairies. Our objective was to develop an algorithm for predicting dyscalce­mia status using Fourier-transform mid-infrared spectroscopic (FT MIR) analysis of milk samples at 3 and 4 DIM.

Probabilistic Scatter Plots for visualizing carbohydrate and lipid metabolism states in Non-Alcoholic Fatty Liver Disease

BackgroundNon-alcoholic fatty liver disease (NAFLD) is characterized by dysregulated carbohydrate and lipid metabolism, which are its primary features. However, traditional biochemical markers pose challenges for accurate quantification and visualization of metabolic states. This study introduces a novel states-based approach for accurate NAFLD assessment. MethodsJoint probabilistic distributions of triglycerides and glycemia were constructed using dual-indicator Probabilistic Scatter Plots based on clinical data (healthy controls: n = 1978; NAFLD patients: n = 471). Patterns of metabolic dysregulation were revealed through comparison against healthy profiles. Self-organizing feature mapping (SOFM) clustered the distributions into four dominant states. ResultsHealthy scatter plots demonstrated a distinct progression of sub-states ranging from very healthy to sub-healthy. In contrast, NAFLD plots exhibited shifted probability centers and outward divergence. SOFM clustering classified the states into: mild; moderate and severe lipid metabolism disorders; and carbohydrate metabolism disorders. ConclusionsProbabilistic Scatter Plots, when combined with SOFM clustering, facilitate a states-based quantification of NAFLD metabolic dysregulation. This method integrates multi-dimensional biochemical indicators and their distributions into a cohesive framework, enabling precise and intuitive visualization for personalized diagnosis and monitoring of prognostic developments.

Crosstalk of lysyl oxidase-like 1 and lysyl oxidase prolongs their half-lives and regulates liver fibrosis through Notch signal.

Lysyl oxidase (LOX) family members (LOX and LOXL1 to 4) are crucial copper-dependent enzymes responsible for cross-linking collagen and elastin. Previous studies have revealed that LOX and LOXL1 are the most dramatically dysregulated LOX isoforms during liver fibrosis. However, the crosstalk between them and the underlying mechanisms involved in the profibrotic behaviors of HSCs, as well as the progression of liver fibrosis, remain unclear. pCol9GFP-HS4,5Tg mice, Loxl1fl/flGfapCre mice, human HSC line, and primary HSCs were enrolled to study the dysregulation pattern, profibrotic roles, and the potential mechanisms of LOX and LOXL1 interaction involved in the myofibroblast-like transition of HSCs and liver fibrogenesis. LOX and LOXL1 were synergistically upregulated during liver fibrogenesis, irrespective of etiology, together orchestrating the profibrotic behaviors of HSCs. LOX and LOXL1 coregulated in HSCs, whereas LOXL1 dominated in the coregulation loop. Interestingly, the interaction between LOXL1 and LOX prolonged their half-lives, specifically enhancing the Notch signal-mediated myofibroblast-like transition of HSCs. Selective disruption of Loxl1 in Gfap+ HSCs deactivated the Notch signal, inhibited HSC activation, and relieved carbon tetrachloride-induced liver fibrosis. Our current study confirmed the synergistic roles and the underlying mechanisms of LOXL1 and LOX crosstalk in the profibrotic behaviors of HSCs and liver fibrosis progression, providing experimental evidence for further clear mechanism-based anti-LOXL1 strategy development in the therapy of liver fibrosis.

Abstract 3483: SIRT7 as a potential therapeutic target for drug resistance in lung adenocarcinoma: Insights from histone modification-related genes

Abstract Background: Lung cancer is one of the leading causes of cancer-related deaths worldwide. Understanding the molecular mechanisms underlying its development and progression is crucial for the development of targeted therapies. In recent years, histone modification has emerged as a key player in the epigenetic regulation of gene expression, and its involvement in lung cancer has gained significant attention. Histone modifications, including methylation, acetylation, phosphorylation, and ubiquitination, influence chromatin structure and, consequently, gene transcription. Aberrant histone modifications can lead to dysregulated gene expression patterns, contributing to the initiation and progression of lung cancer. In this study, we investigated the expression patterns of 55 histone modification-related genes and identified an epigenetic tumor regulator as a potential therapeutic target. Methods: We obtained 55 histone modification-related genes from dbHiMo (http://hme.riceblast.snu.ac.kr/). Transcriptomic (n= 576), clinical data (n=706) and survival data (n=641) of lung adenocarcinoma (LUAD) were downloaded from XenaTCGA database (https://xenabrowser.net/). The transcriptomic and IC50 values with 87 lung cancer cell lines and 310 drugs were downloaded from DepMap portal (https://depmap.org/portal/). RNA-seq data of GSE197555 was downloaded from GEO database (https://www.ncbi.nlm.nih.gov/geo/). All statistical analysis was performed using R. Results: Among a total of 55 genes related to histone modifications, 6 genes including KAT2A, SIRT7, CARM1, KDM5B, HDAC1 and PRMT3 were significantly overexpressed in tumor tissues in LUAD transcriptome data from TCGA. Out of these 6 genes, 3 (KAT2A, SIRT7 and CARM1) showed significant differences in survival analysis with disease-free interval in the adjuvant therapy-received TCGA LUAD dataset. All three demonstrated that as their expression levels increased, the prognosis became worse. The expression levels of SIRT7 and KAT2A were highly positively correlated with the IC50 value of trametinib, which is MEK inhibitor. Among these two genes, the expression level of SIRT7 was up-regulated in trametinib-treated group in resistance to MEK inhibitor in the H460 cell line. However, sensitive to MEK inhibitor in A549, the SIRT7 expression level was down-regulated in the trametinib-treated group. Conclusion: The histone modification-related gene SIRT7 was found to be associated with resistance to trametinib. In this study, these findings suggest that SIRT7 may serve as a potential therapeutic target related to drug resistance in combination therapy with dabrafenib and trametinib. Citation Format: Kyoung-Ho Pyo, YoungJoon Park, Gang-Taik Lee, Juwon Ahn, Su-Jin Choi, Qi Kejia, Taeku Lee, Youngtaek Kim, Joon Yeon Hwang, Byoung Chul Cho. SIRT7 as a potential therapeutic target for drug resistance in lung adenocarcinoma: Insights from histone modification-related genes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3483.

Diurnal cortisol, neuroinflammation, and neuroimaging visual rating scales in memory clinic patients

BackgroundNeuroinflammation is a hallmark of the Alzheimer’s disease (AD) pathogenic process. Cortisol dysregulation may increase AD risk and is related to brain atrophy. This cross-sectional study aims to examine interactions of cortisol patterns and neuroinflammation markers in their association with neuroimaging correlates. Method134 participants were recruited from the Karolinska University Hospital memory clinic (Stockholm, Sweden). Four visual rating scales were applied to magnetic resonance imaging or computed tomography scans: medial temporal lobe atrophy (MTA), global cortical atrophy (GCA), white matter lesions (WML), and posterior atrophy. Participants provided saliva samples for assessment of diurnal cortisol patterns, and underwent lumbar punctures for cerebrospinal fluid (CSF) sampling. Three cortisol measures were used: the cortisol awakening response, total daily output, and the ratio of awakening to bedtime levels. Nineteen CSF neuroinflammation markers were categorized into five composite scores: proinflammatory cytokines, other cytokines, angiogenesis markers, vascular injury markers, and glial activation markers. Ordinal logistic regressions were conducted to assess associations between cortisol patterns, neuroinflammation scores, and visual rating scales, and interactions between cortisol patterns and neuroinflammation scores in relation to visual rating scales. ResultHigher levels of angiogenesis markers were associated with more severe WML. Some evidence was found for interactions between dysregulated diurnal cortisol patterns and greater neuroinflammation-related biomarkers in relation to more severe GCA and WML. No associations were found between cortisol patterns and visual rating scales. ConclusionThis study suggests an interplay between diurnal cortisol patterns and neuroinflammation in relation to brain structure. While this cross-sectional study does not provide information on causality or temporality, these findings suggest that neuroinflammation may be involved in the relationship between HPA-axis functioning and AD.

Interferon and B-cell Signatures Inform Precision Medicine in Lupus Nephritis

IntroductionCurrent therapeutic management of lupus nephritis (LN) fails to induce long-term remission in over 50% of patients, highlighting the urgent need for additional options. MethodsWe analysed differentially expressed genes in peripheral blood from active LN (n=41) and active non-renal lupus (n=62) patients versus healthy controls (n=497) from the European PRECISESADS project (NTC02890121), and dysregulated gene modules in a discovery (n=26) and a replication (n=15) set of active LN cases. ResultsReplicated gene modules qualified for correlation analyses with serological markers, and regulatory network and druggability analysis. Unsupervised co-expression network analysis revealed 20 dysregulated gene modules and stratified the active LN population into three distinct subgroups. These subgroups were characterised by low, intermediate, and high interferon (IFN) signatures, with differential dysregulation of the “B cell” and “plasma cells/immunoglobulins” modules. Drugs annotated to the IFN network included CC-motif chemokine receptor 1 inhibitors, programmed death-ligand 1 inhibitors, and irinotecan, while the anti-CD38 daratumumab and proteasome inhibitor bortezomib showed potential for counteracting the “plasma cells/immunoglobulins” transcriptomic signature. In silico analysis demonstrated the low-IFN subgroup to benefit from calcineurin inhibition and the intermediate-IFN subgroup from B cell targeted therapies. High-IFN patients exhibited greater anticipated response to anifrolumab while daratumumab appeared beneficial for the intermediate-IFN and high-IFN subgroups. ConclusionIn summary, IFN upregulation and B and plasma cell gene dysregulation patterns revealed three LN patient subgroups, which may not necessarily represent distinct disease phenotypes but rather phases of the inflammatory processes during a renal flare, providing a conceptual framework for precision medicine in LN.

HCCDB v2.0: Decompose Expression Variations by Single-cell RNA-seq and Spatial Transcriptomics in HCC.

Large-scale transcriptomic data are crucial for understanding the molecular features of hepatocellular carcinoma (HCC). Integrated 15 transcriptomic datasets of HCC clinical samples, the first version of HCC database (HCCDB v1.0) was released in 2018. Through the meta-analysis of differentially expressed genes and prognosis-related genes across multiple datasets, it provides a systematic view of the altered biological processes and the inter-patient heterogeneities of HCC with high reproducibility and robustness. With four years having passed, the database now needs integration of recently published datasets. Furthermore, the latest single-cell and spatial transcriptomics have provided a great opportunity to decipher complex gene expression variations at the cellular level with spatial architecture. Here, we present HCCDB v2.0, an updated version that combines bulk, single-cell, and spatial transcriptomic data of HCC clinical samples. It dramatically expands the bulk sample size by adding 1656 new samples from 11 datasets to the existing 3917 samples, thereby enhancing the reliability of transcriptomic meta-analysis. A total of 182,832 cells and 69,352 spatial spots are added to the single-cell and spatial transcriptomics sections, respectively. A novel single-cell level and 2-dimension (sc-2D) metric is proposed as well to summarize cell type-specific and dysregulated gene expression patterns. Results are all graphically visualized in our online portal, allowing users to easily retrieve data through a user-friendly interface and navigate between different views. With extensive clinical phenotypes and transcriptomic data in the database, we show two applications for identifying prognosis-associated cells and tumor microenvironment. HCCDB v2.0 is available at http://lifeome.net/database/hccdb2.

Single-cell transcriptome revealed dysregulated RNA-binding protein expression patterns and functions in human ankylosing spondylitis.

To explore the expression characteristics and regulatory patterns of RBPs in different immune cell types of AS, and to clarify the potential key role of RBPs in the occurrence and development of AS disease. PBMC sample data from scRNA-seq (HC*29, AS*10) and bulk RNA-seq (NC*3, AS*5) were selected for correlation analysis. (1) Compared with the HC group, the numbers of B, DC (dendritic cells), CD14+ Mono and CD8+ T cells were increased in AS group, while the numbers of platelet (platelets), CD8+ NKT, CD16+ Mono (non-classical monocytes), Native CD4+ T and NK were decreased. (2) Through the analysis of RBP genes in B cells, some RBPs were found to play an important role in B cell differentiation and function, such as DDX3X, SFPQ, SRRM1, UPF2. (3) It may be related to B-cell receptor, IgA immunity, NOD-like receptor and other signaling pathways; Through the analysis of RBP genes in CD8+ T cells, some RBPs that play an important role in the immune regulation of CD8+ T were found, such as EIF2S3, EIF4B, HSPA5, MSL3, PABPC1 and SRSF7; It may be related to T cell receptor, TNF, IL17 and other signaling pathways. (4) Based on bulk RNA-seq, it was found that compared with HC and AS patients, differentially expressed variable splicing genes (RASGs) may play an important role in the occurrence and development of AS by participating in transcriptional regulation, protein phosphorylation and ubiquitination, DNA replication, angiogenesis, intracellular signal transduction and other related pathways. RBPs has specific expression characteristics in different immune cell types of AS patients, and has important regulatory functions. Its abnormal expression and regulation may be closely related to the occurrence and development of AS.

Unraveling the MicroRNA tapestry: exploring the molecular dynamics of locoregional recurrent rectal cancer.

Colorectal cancer (CRC) ranks as the third most prevalent malignancy globally, with a concerning rise in incidence among young adults. Despite progress in understanding genetic predispositions and lifestyle risk factors, the intricate molecular mechanisms of CRC demand exploration. MicroRNAs (miRNAs) emerge as key regulators of gene expression and their deregulation in tumor cells play pivotal roles in cancer progression. NanoString's nCounter technology was utilized to measure the expression of 827 cancer-related miRNAs in tumor tissue and adjacent non-involved normal colon tissue from five patients with locoregional CRC progression. These expression profiles were then compared to those from the primary colon adenocarcinoma (COAD) cohort in The Cancer Genome Atlas (TCGA). Intriguingly, 156 miRNAs showed a contrasting dysregulation pattern in reccurent tumor compared to their expression in the TCGA COAD cohort. This observation implies dynamic alterations in miRNA expression patterns throughout disease progression. Our exploratory study contributes to understanding the regulatory landscape of recurrent CRC, emphasizing the role of miRNAs in disease relapse. Notable findings include the prominence of let-7 miRNA family, dysregulation of key target genes, and dynamic changes in miRNA expression patterns during progression. Univariate Cox proportional hazard models highlighted miRNAs associated with adverse outcomes and potential protective factors. The study underscores the need for more extensive investigations into miRNA dynamics during tumor progression and the value of stage specific biomarkers for prognosis.

Network changes and compensation mechanisms of wake‐promoting neurons across AD continuum

AbstractBackgroundSleep is a complex process regulated by various neural mechanisms, including those promoting wakefulness, those promoting sleep, and those regulating the circadian clock. Recent research has revealed that wake‐promoting neurons, specifically those found in the noradrenergic locus ceruleus (LC), the orexinergic (ORX) neurons in the lateral hypothalamic area (LHA), and the histaminergic neurons in the hypothalamic tuberomammillary nucleus (TMN), are particularly vulnerable to the AD‐tau pathology found in the early stages of Alzheimer’s disease (AD). These studies have uncovered how these neurons accumulate AD‐tau, the extent to which they die in AD, and specific correlations with polysomnographic readings. Notably, a complex pattern of neuronal dysregulation within and among these wake‐promoting neurons has been observed, suggesting the existence of robust compensatory mechanisms in an attempt to overcome dysfunction. Thus, understanding the vulnerability of these nuclei to AD requires network‐based studies. These studies are crucial for informing disease‐specific treatment for sleep disturbance and identifying factors underlying the vulnerability of these neurons.MethodsResults from several ongoing experiments in the Grinberg Lab, including methods such as quantitative pathology, molecular profiling and clinicopathological correlationResultsFor example, the hypocretin (orexin) receptor 1 (HCRTR1) shows upregulation in orexin neurons from early AD stages, while no changes are observed in the LC or TMN. Additionally, while the LC shows an early pattern of upregulation of genes associated with neuroinflammation, early dysregulation in the ORX is related to synapse‐related genes. Furthermore, circadian genes such as CRY1 and CRY2 show upregulation in the ORX but downregulation in the TMN during AD progression.ConclusionThis talk will focus on current knowledge, including unpublished data, based on studies in humans, on the vulnerability of wake‐promoting neurons in AD, with a particular emphasis on similarities and contrasts in the patterns of dysregulation among these nuclei during AD progression, in conjunction with changes in the suprachiasmatic nucleus, the circadian clock, and regional expression of circadian genes.

Selective vulnerability of the suprachiasmatic nucleus in progressive Alzheimer’s Disease: A human postmortem study using spatial in‐situ proteomics

AbstractBackgroundAlzheimer’s Disease (AD) patients commonly experience sleep/wake (S/W) disturbances, such as sleep fragmentation and excessive daytime sleepiness. The S/W cycle is controlled by a complex system regulated by a master regulator, the suprachiasmatic nucleus (SCN) that controls wake‐ and sleep‐promoting nuclei. Despite its importance in orchestrating sleep architecture, little is known about the molecular changes that occur in the SCN during the progression of AD and how these changes contribute to S/W disturbances.MethodWe used postmortem brain tissue of 10 controls without AD pathology and 32 subjects with progressive AD stages. Our approach included quantitative neuropathological assessments of AVP and VIP‐expressing neurons in SCN and its adjacent hypothalamic region, the supraoptic nucleus (SON). We also used an in‐situ cell‐specific spatial proteomics platform [GeoMx Digital Spatial Profiling (DSP)] to probe levels of different pathological tau species and proteins commonly dysregulated in AD.ResultPreliminary findings reveal a significant decrease in SCN volume (∼75%) (Fig.1) and a loss of ∼58% AVP neurons and ∼41% VIP neurons in Braak stage (Braak) VI compared to Braak 0. The DSP results indicate that both neurons in the SCN have twice the burden of p‐tau levels as the SON (Fig.2‐right), and neurofibrillary tanglesAdditionally, SCN shows an increase in proteins associated with glia and immune responses (Fig.2‐left). Furthermore, an increase in microglial proteins is observed in the SCN in Braak I (Fig.3‐left). In contrast, the SON displays a milder pattern of protein dysregulation in Braak I (Fig.3‐right), consistent with its lower tau expression observed in histology and DSP.ConclusionSCN is vulnerable to AD pathology even in Braak I, which is characterized by volume loss, increased immune response protein dysregulation, and later neuronal loss, as well as p‐tau pathology. This pattern supports the idea that the SCN plays a role in S/W disturbances observed from early AD stages. Interestingly, its neighboring nucleus, SON, which also has AVP neurons, remained spared, providing opportunities for studies investigating factors related to selective vulnerability. Ongoing studies are addressing changes in the SCN and SON in intermediate AD stages.

Sleep disturbances, cortisol, and neuroimaging correlates among memory clinic patients

AbstractBackgroundSleep disturbances are increasingly acknowledged as a preclinical marker for Alzheimer’s disease (AD), however, the mechanisms underlying the association between sleep disturbances and dementia remain unclear. Sleep disturbances may affect AD through brain morphology changes and vascular damage, as sleep disturbances are known to be linked with altered grey‐ and white‐matter integrity. Moreover, sleep and brain changes may be linked with cortisol levels. Sleep disturbances have been proposed to parallel cortisol dysregulation, and older individuals with preclinical AD have altered awakening cortisol, a feature that is intensified among people also suffering from sleep disturbances.MethodThe study is based on 146 memory clinic patients from the Karolinska University Hospital memory clinic (Sweden). Participants are in the age range 47‐86 years and diagnosed with either subjective cognitive impairment or mild cognitive impairment. Self‐reported sleep disturbances are measured by the Karolinska Sleep Questionnaire. Brain imaging (MRI or CT) was used to semi‐quantify brain atrophy using four visual rating scales: Medial Temporal Atrophy, Global Cortical Atrophy, Koedam (posterior brain atrophy) and Fazekas (white‐matter lesions) scales. Lastly, saliva cortisol has been sampled 6 times daily to measure diurnal cortisol patterns.ResultOrdinal logistic regressions show significant associations between sleep disturbances and brain parameters. Insufficient sleep (OR = 1.30, p = 0.048) is associated with greater odds of white‐matter lesions, and apnea (OR = 1.26, p = 0.036) and snoring (OR = 1.38, p = 0.045) are associated with greater odds of posterior brain atrophy. Increased daytime sleepiness is associated with both reduced awakening cortisol (β = ‐0.03, p = 0.025) and a flattened cortisol curve (β = ‐0.04, p = 0.019). Apnea is associated with reduced awakening cortisol (β = ‐0.06, p = 0.013). However, cortisol was not found to significantly interact with sleep in predicting brain outcomes.ConclusionThese results show that various sleep disturbance parameters (short sleep duration, apnea, and snoring) are associated with neuroimaging correlates, while daytime sleepiness and apnea are associated with markers of dysregulated cortisol patterns. The results suggest that neuroimaging correlates and cortisol measures may clarify the mechanisms underlying the associations between sleep disturbance and cognitive impairment, and the combination of objective sleep measures and neuroimaging markers in future studies may further reveal the mechanisms.

Single nuclei transcriptomics in diabetic mice reveals altered brain hippocampal endothelial cell function, permeability, and behavior

Type 2 diabetes mellitus (T2DM) is a metabolic disorder with cerebrovascular and cardiovascular sequelae. Yet, a clear pattern of gene dysregulation by T2DM in dementia has yet to be defined. We used single nuclei RNA sequencing technology to profile the transcriptome of endothelial cells (EC) from anatomically defined hippocampus of db/db mice to identify differentially expressed (DE) genes, gene pathways and networks, predicted regulating transcription factors, and targets of DE long noncoding RNAs. We also applied gadolinium (Gd) enhanced magnetic resonance imaging (MRI) to assess blood brain barrier (BBB) permeability, and functionally assessed cognitive behavior. The murine gene expression profiles were then integrated with those of persons with Alzheimer's disease (AD) and vascular dementia (VaD).We reveal that the transcriptome of the diabetic hippocampal murine brain endothelium differs substantially from control wild types with molecular changes characterized by differential RNA coding and noncoding pathways enriched for EC signaling and for endothelial functions for neuroinflammation, endothelial barrier disruption, and neurodegeneration. Gd enhanced structural brain MRI linked endothelial molecular alterations to BBB dysfunction by neuroimaging. Integrated multiomics of hippocampal endothelial gene dysregulation associated with impairments in cognitive adaptive capacity. In addition, the diabetic transcriptome significantly and positively correlated with that of persons with AD and VaD. Taken together, our results from comprehensive, multilevel, integrated, single nuclei transcriptomics support the hypothesis of T2DM-mediated neuroinflammation and endothelial cell and barrier disruption as key mechanisms in cognitive decline in T2DM, thereby suggesting potential endothelial-specific molecular therapeutic targets.

Imbalanced glucocorticoid and mineralocorticoid stress hormone receptor function has sex-dependent and independent regulatory effects in the mouse hippocampus

Many stress-related neuropsychiatric disorders display pronounced sex differences in their frequency and clinical symptoms. Glucocorticoids are primary stress hormones that have been implicated in the development of these disorders but whether they contribute to the observed sex bias is poorly understood. Glucocorticoids signal through two closely related nuclear receptors, the glucocorticoid (GR) and mineralocorticoid receptor (MR). To elucidate the sex-specific and independent actions of glucocorticoids in the hippocampus, we developed knockout mice lacking hippocampal GR, MR, or both GR and MR. Mice deficient in hippocampal MR or both GR and MR showed an altered molecular phenotype of CA2 neurons and reduced anxiety-like behavior in both sexes, but altered stress adaptation behavior only in females and enhanced fear-motivated cue learning only in males. All three knockout mouse models displayed reduced sociability but only in male mice. Male and female mice deficient in both hippocampal GR and MR exhibited extensive neurodegeneration in the dentate gyrus. Global transcriptomic analysis revealed a marked expansion in the number of dysregulated genes in the hippocampus of female knockout mice compared to their male counterparts; however, the overall patterns of gene dysregulation were remarkably similar in both sexes. Within and across sex comparisons identified key GR and MR target genes and associated signaling pathways underlying the knockout phenotypes. These findings define major sex-dependent and independent effects of GR/MR imbalances on gene expression and functional profiles in the hippocampus and inform new strategies for treating men and women with stress-related neuropsychiatric disorders.

Opponent intrinsic brain network connectivity profiles associated with posttraumatic fear and dysphoria symptoms in trauma-exposed refugees.

Resting-state functional magnetic resonance imaging (rsfMRI) studies report functional alterations in the connectivity between intrinsic brain networks in posttraumatic stress disorder (PTSD), but PTSD heterogeneity is rarely considered. Evidence points to fear (e.g., reexperiencing) and dysphoria (e.g., withdrawal) symptom factors as important in PTSD presentations, including relating to variable emotion dysregulation patterns. This study, therefore, tested how fear and dysphoria posttraumatic symptoms were differentially associated with core network connectivity and emotion dysregulation behaviors in a large group of trauma-exposed refugees. A final sample of 77 trauma-exposed participants completed a rsfMRI scan. Independent component analysis identified active networks and functional network connectivity (FNC) between networks was assessed. Fear and dysphoria posttraumatic symptoms were partially correlated with FNCs, and linear regression models examined relationships with self-reported difficulties in emotion regulation. Twenty-three active networks were identified, eight being in the networks of interest (p < .05 false discovery rate-corrected). Fear and dysphoria symptoms were specifically related to connectivity patterns between two subnetworks of the default mode network (DMN). Fear symptoms were negatively associated with anterior dorsomedial DMN (admDMN) and temporoparietal DMN (tpDMN) connectivity; whereas dysphoria symptoms were positively associated with admDMN-tpDMN connectivity. Additionally, admDMN-tpDMN connectivity was positively predicted by goal-directed emotion dysregulation but negatively predicted by poor emotional clarity. Fear and dysphoria posttraumatic symptoms showed opponent associations with admDMN and tpDMN connectivity, potentially reflecting patterns of under- and overemotion dysregulation associated with these symptom profiles respectively. Findings highlight the importance of considering posttraumatic heterogeneity when constructing neural models of PTSD. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

The Impact of Neurotransmitters on the Neurobiology of Neurodegenerative Diseases.

Neurodegenerative diseases affect millions of people worldwide. Neurodegenerative diseases result from progressive damage to nerve cells in the brain or peripheral nervous system connections that are essential for cognition, coordination, strength, sensation, and mobility. Dysfunction of these brain and nerve functions is associated with Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis, and motor neuron disease. In addition to these, 50% of people living with HIV develop a spectrum of cognitive, motor, and/or mood problems collectively referred to as HIV-Associated Neurocognitive Disorders (HAND) despite the widespread use of a combination of antiretroviral therapies. Neuroinflammation and neurotransmitter systems have a pathological correlation and play a critical role in developing neurodegenerative diseases. Each of these diseases has a unique pattern of dysregulation of the neurotransmitter system, which has been attributed to different forms of cell-specific neuronal loss. In this review, we will focus on a discussion of the regulation of dopaminergic and cholinergic systems, which are more commonly disturbed in neurodegenerative disorders. Additionally, we will provide evidence for the hypothesis that disturbances in neurotransmission contribute to the neuronal loss observed in neurodegenerative disorders. Further, we will highlight the critical role of dopamine as a mediator of neuronal injury and loss in the context of NeuroHIV. This review will highlight the need to further investigate neurotransmission systems for their role in the etiology of neurodegenerative disorders.

Integrative analysis reveals early epigenetic alterations in high-grade serous ovarian carcinomas.

High-grade serous ovarian carcinoma (HGSOC) is the most lethal gynecological malignancy. To date, the profiles of gene mutations and copy number alterations in HGSOC have been well characterized. However, the patterns of epigenetic alterations and transcription factor dysregulation in HGSOC have not yet been fully elucidated. In this study, we performed integrative omics analyses of a series of stepwise HGSOC model cells originating from human fallopian tube secretory epithelial cells (HFTSECs) to investigate early epigenetic alterations in HGSOC tumorigenesis. Assay for transposase-accessible chromatin using sequencing (ATAC-seq), chromatin immunoprecipitation sequencing (ChIP-seq), and RNA sequencing (RNA-seq) methods were used to analyze HGSOC samples. Additionally, protein expression changes in target genes were confirmed using normal HFTSECs, serous tubal intraepithelial carcinomas (STICs), and HGSOC tissues. Transcription factor motif analysis revealed that the DNA-binding activity of the AP-1 complex and GATA family proteins was dysregulated during early tumorigenesis. The protein expression levels of JUN and FOSL2 were increased, and those of GATA6 and DAB2 were decreased in STIC lesions, which were associated with epithelial-mesenchymal transition (EMT) and proteasome downregulation. The genomic region around the FRA16D site, containing a cadherin cluster region, was epigenetically suppressed by oncogenic signaling. Proteasome inhibition caused the upregulation of chemokine genes, which may facilitate immune evasion during HGSOC tumorigenesis. Importantly, MEK inhibitor treatment reversed these oncogenic alterations, indicating its clinical effectiveness in a subgroup of patients with HGSOC. This result suggests that MEK inhibitor therapy may be an effective treatment option for chemotherapy-resistant HGSOC.