Functional Relevance Research Articles

Neuronal parts list and wiring diagram for a visual system

A catalogue of neuronal cell types has often been called a ‘parts list’ of the brain1, and regarded as a prerequisite for understanding brain function2,3. In the optic lobe of Drosophila, rules of connectivity between cell types have already proven to be essential for understanding fly vision4,5. Here we analyse the fly connectome to complete the list of cell types intrinsic to the optic lobe, as well as the rules governing their connectivity. Most new cell types contain 10 to 100 cells, and integrate information over medium distances in the visual field. Some existing type families (Tm, Li, and LPi)6–10 at least double in number of types. A new serpentine medulla (Sm) interneuron family contains more types than any other. Three families of cross-neuropil types are revealed. The consistency of types is demonstrated by analysing the distances in high-dimensional feature space, and is further validated by algorithms that select small subsets of discriminative features. We use connectivity to hypothesize about the functional roles of cell types in motion, object and colour vision. Connectivity with ‘boundary types’ that straddle the optic lobe and central brain is also quantified. We showcase the advantages of connectomic cell typing: complete and unbiased sampling, a rich array of features based on connectivity and reduction of the connectome to a substantially simpler wiring diagram of cell types, with immediate relevance for brain function and development.

Cell-type specific methylation changes in the newborn child associated to obstetric pain relief

Although it is widely known that various pharmaceuticals affect the methylome, the knowledge of the effects from anesthesia is limited, and nearly nonexistent regarding the effects of obstetric anesthesia on the newborn child. Using sequencing based-methylation data and a reference-based statistical deconvolution approach we performed methylome-wide association studies (MWAS) of neonatal whole blood, and for each cell-type specifically, to detect methylation variations that are associated with the pain relief administered to the mother during delivery. Significant findings were replicated in a different dataset and followed-up with gene ontology analysis to pinpoint biological functions of potential relevance to these neonatal methylation alterations. The MWAS analyses detected methylome-wide significant (q<0.1) alterations in the newborn for laughing gas in granulocytes (two CpGs, p<5.50x10-9, q = 0.067), and for pudendal block in monocytes (five CpGs across three loci, p<1.51 x10-8, q = 0.073). Suggestively significant findings (p<1.00x10-6) were detected for both treatments for bulk and all cell-types, and replication analyses showed consistent significant enrichment (odds ratios ranging 3.47–39.02; p<4.00×10−4) for each treatment, suggesting our results are robust. In contrast, we did not observe any overlap across treatments, suggesting that the treatments are associated with different alterations of the neonatal blood methylome. Gene ontology analyses of the replicating suggestively significant results indicated functions related to, for example, cell differentiation, intracellular membrane-bound organelles and calcium transport. In conclusion, for the first time, we investigated and detected effect of obstetric pain-relief on the blood methylome in the newborn child. The observed differences suggest that anesthetic treatment, such as laughing gas or pudendal block, may alter the neonatal methylome in a cell-type specific manner. Some of the observed alterations are part of gene ontology terms that previously have been suggested in relation to anesthetic treatment, supporting its potential role also in obstetric anesthesia.

Optimizando la evaluación de la mano desde una perspectiva de funcionalidad

The primary goal of this manuscript is to provide a functional perspective on hand physical examination. Therefore, the key points that are considered necessary to make a functional approach to the hand were compiled from bibliographic sources and the experience of the authors. Since it is an anatomical structure with high relevance for functionality, it is commented that it represents 33 % of the functionality of an upper extremity, for this it is relevant to know how to approach it based on the functionality, which is why the evaluation of the hand and fingers is essential, emphasizing their mobility, performing quantitative and qualitative measurements such as the use of indices of mobility and the useof a finger goniometer, the measurement of force can be measured in the same ways with the use of manual muscle examination and hand dynamometry, respectively, and thus consider biomechanical concepts such as the use of levers .For these reasons, it is necessary to implement an assessment of the hand and fingers focused on functionality, keeping in mind the factors that could modify the examination and thus be able to report an assessment more oriented to the patient's deficiencies and needs. Keywords: Hand; fingers; functionality; strength; evaluation

An 18-gene signature of recurrence-associated endothelial cells predicts tumor progression and castration resistance in prostate cancer

BackgroundThe prognostic and therapeutic implications of endothelial cells (ECs) heterogeneity in prostate cancer (PCa) are poorly understood.MethodsWe investigated associations of EC heterogeneity with PCa recurrence and castration resistance in 8 bulk transcriptomic and 4 single-cell RNA-seq cohorts. A recurrence-associated EC (RAEC) signature was constructed by comparing 11 machine learning algorithms through nested cross-validation. Functional relevances of RAEC-specific genes were also tested.ResultsA subset of ECs was significantly associated with recurrence in primary PCa and named RAECs. RAECs were characteristic of tip and immature cells and were enriched in migration, angiogenesis, and collagen-related pathways. We then developed an 18-gene RAEC signature (RAECsig) representative of RAECs. Higher RAECsig scores independently predicted tumor recurrence and performed better or comparably compared to clinicopathological factors and commercial gene signatures in multiple PCa cohorts. Of the 18 RAECsig genes, FSCN1 was upregulated in ECs from PCa with higher Gleason scores; and the silencing of FSCN1, TMEME255B, or GABRD in ECs either attenuated tube formation or inhibited PCa cell proliferation. Finally, higher RAECsig scores predicted castration resistance in both primary and castration-resistant PCa.ConclusionThis study establishes an endothelial signature that links a subset of ECs to prostate cancer recurrence and castration resistance.

Relevance of G protein-coupled receptor (GPCR) dynamics for receptor activation, signalling bias and allosteric modulation.

G protein-coupled receptors (GPCRs) are one of the major drug targets. In recent years, computational drug design for GPCRs has mainly focused on static structures obtained through X-ray crystallography, cryogenic electron microscopy (cryo-EM) or in silico modelling as a starting point for virtual screening campaigns. However, GPCRs are highly flexible entities with the ability to adopt different conformational states that elicit different physiological responses. Including this knowledge in the drug discovery pipeline can help to tailor novel conformation-specific drugs with an improved therapeutic profile. In this review, we outline our current knowledge about GPCR dynamics that is relevant for receptor activation, signalling bias and allosteric modulation. Ultimately, we highlight new technological implementations such as time-resolved X-ray crystallography and cryo-EM as well as computational algorithms that can contribute to a more comprehensive understanding of receptor dynamics and its relevance for GPCR functionality.

Cognitive Correlates of Risky Decision-Making in Individuals with and without ADHD: A Meta-analysis.

This meta-analytic study aims to investigate the cognitive correlates of risky decision-making in individuals with attention-deficit/hyperactivity disorder (ADHD) and typically developing (TD) individuals. A systematic analysis of existing literature was conducted, encompassing 38 studies (496 ADHD and 1493 TD). Findings revealed a consistent propensity for riskier decision-making in individuals with ADHD, supported by significant correlations with attention, cognitive flexibility, inhibitory control, time perception, and working memory. The study underscores the relevance of these cognitive functions in shaping decision-making tendencies, with nuanced patterns observed within the ADHD and TD subgroups. Individuals with ADHD often demonstrate altered patterns of correlation, reflecting the specific cognitive challenges characteristic of the disorder.

Fermionic and Bosonic Partition Functions at Imaginary Chemical Potential as Bloch Functions

In this work it is pointed out that the phase transitions of the <i>d</i>+1 Gross-Neveu (fermionic) and <I>CP<SUP>N</SUP></I><sup>−1</sup> (bosonic) models at finite temperature and imaginary chemical potential can be mapped to transformations of Hubbard-like regular hexagonal to square lattice with the intermediate steps to be specific surfaces (irregular hexagonal kind) with an ordered construction based on the even indexed Bloch-Wigner-Ramakrishnan polylogarithm function. The zeros and extrema of the Clausen <i>Cl<sub>d</sub></i>(<i>θ</i>) function play an important role to the analysis since they allow us not only to study the fermionic and bosonic theories and their phase transitions but also the possibility to explore the existence of conductors arising from the correspondence between the partition functions of the two models and the Bloch and Wannier functions that play a crucial role in the tight-binding approximation in solid state physics. The main aim of this work is not only to unveil the relevance of the canonical partition functions of a fermionic and a bosonic model to Bloch states by using an imaginary chemical potential but also to examine the overlap between two Bloch wave-functions that differ by a lattice momentum that calculates the momentum transfer of a Bloch wave during the interaction with a lattice point of a hexagonal construction.

On the Relevance of Magnetic Correlation Functions in Energetic Particle Transport Theory

On the Relevance of Magnetic Correlation Functions in Energetic Particle Transport Theory

Hypoxia A Typical Target in Human Lung Cancer Therapy.

Lung cancer (LC) is the leading cause of cancer-related death globally. Comprehensive knowledge of the cellular and molecular etiology of LC is perilous for the development of active treatment approaches. Hypoxia in cancer is linked with malignancy, and its phenotype is implicated in the hypoxic reaction, which is being studied as a prospective cancer treatment target. The hypervascularization of the tumor is the main feature of human LC, and hypoxia is a major stimulator of neo-angiogenesis. It was seen that low oxygen levels in human LC are a critical aspect of this lethal illness. However, as there is a considerable body of literature espousing the presumed functional relevance of hypoxia in LC, the direct measurement of oxygen concentration in Human LC is yet to be determined. This narrative review aims to show the importance and as a future target for novel research studies that can lead to the perception of LC therapy in hypoxic malignancies.

Bioinformatics analysis of markers based on m6A related to prognosis combined with immune invasion of rectal adenocarcinoma.

Colorectal cancer (CRC) is a common form of cancer, with rectal cancer accounting for approximately one-third of all cases. Among rectal cancers, 95% are classified as rectal adenocarcinoma (READ). Emerging evidence suggests that long noncoding RNAs (lncRNAs) play a significant role in the development and progression of various cancers. In our study, we aimed to identify differentially expressed lncRNAs potentially associated with m6A and establish a risk assessment model to predict clinical outcomes for READ patients. The READ dataset from the TCGA database was utilized in this study to synergistically and logically integrate m6A and lncRNA, while employing bioinformatics technology for the identification of suitable biomarkers. A risk prediction model comprising m6A-associated lncRNAs was constructed to investigate the prognostic, diagnostic, and biological functional relevance of these m6A-related lncRNAs. Our research builds a composed of three related to m6A lncRNA rectal gland cancer prognosis model, and the model has been proved in the multi-dimensional can serve as the potential of the prognosis of rectal gland cancer biomarkers. Our study constructed a prognostic model of rectal adenocarcinoma consisting of three related m6A lncRNAs: linc00702, ac106900.1 and al583785.1. The model has been validated as a potential prognostic biomarker for rectal cancer in multiple dimensions, aiming to provide clinicians with an indicator to assess the duration of straight adenocarcinoma. This enables early detection of rectal cancer and offers a promising target for immunotherapy.

The reduced function allele SLCO1B1 c.521T>C is of no practical relevance for the renal graft function over the first post-transplant year in patients treated with mycophenolic acid.

It is unclear whether renal transplant recipients treated with mycophenolic acid (MPA) who carry the reduced-function allele at polymorphism SLCO1B1 c.521T>C differ from their wild-type peers regarding renal outcomes and tolerability. We aimed to estimate the effect of this polymorphism on the graft function (estimated glomerular filtration rate, eGFR) over the first 12 post-transplant months in patients on MPA-based maintenance immunosuppression. In a 12-month observational cohort study, consecutive adult patients were repeatedly assessed for eGFR. The SLCO1B1 c.521C>T variant allele carriers (exposed) and wild-type subjects (controls) were balanced on a range of demographic, medical, and genetic variables at baseline, and eGFR trajectory was estimated with further adjustment for time-varying covariates. A subset of patients were assessed for exposure to MPA 5-7 days after the transplantation. The adjusted eGFR slopes from day 1 to day 28 (daily), and from day 28 to day 365 (monthly) were practically identical in exposed (n = 86) and control (n = 168) patients [geometric means ratios (GMR) = 0.99, 95% confidence interval (CI) = 0.92-1.06 and GMR = 0.98, 0.94-1.01, respectively]. The rates of adverse renal outcomes and possible MPA-related adverse effects were low, and similar in exposed and controls [rate ratios (RR) = 0.94, 0.49-1.84 and RR = 1.08, 0.74-1.58, respectively]. The pharmacokinetic analysis did not signal meaningful differences regarding exposure to MPA, overall (exposed n = 23, control n = 45), if cotreated with cyclosporine (n = 17 vs. n = 26) or with tacrolimus (n = 8 vs. n = 17). In patients treated with MPA, variant allele SLCO1B1 c.521T>C appears of no practical relevance regarding the 12-month renal graft function, MPA safety and exposure to MPA at early steady-state.

Exosome miR-4738-3p-mediated regulation of COL1A2 through the NF-κB and inflammation signaling pathway alleviates osteoarthritis low-grade inflammation symptoms.

This study aimed to elucidate the roles of microRNA (miR)-4738-3p and the collagen type I alpha 2 chain (COL1A2) gene in the pathogenesis of osteoarthritis (OA) through bioinformatics analysis and cellular assays. The GSE55235 dataset was analyzed using the weighted gene co-expression network analysis (WGCNA) method to identify gene modules associated with OA. Key overlapping genes were identified from these modules and the GSE55235-differential expressed genes (DEGs). The expression levels of selected genes were determined in C28/I2 cells using the quantitative real-time polymerase chain reaction (qRT-PCR). The interaction between miR-4738-3p and COL1A2 was examined in the context of interleukin 1 beta (IL-1β) induction. Exosome characterization was achieved through transmission electron microscopy (TEM), western blotting (WB), and other analyses. The study also investigated the functional relevance of miR-4738-3p in OA pathology through various molecular and cellular assays. Our findings revealed that the green module exhibited a strong correlation with the OA phenotype in the GSE55235 dataset, with COL1A2 emerging as a hub gene and miR-4738-3p as its key downstream target. IL-1β induction suggested that COL1A2 is involved in inflammation and apoptosis, while miR-4738-3p appeared to play an antagonistic role. The analysis of exosomes underscored the significance of miR-4738-3p in cellular communication, with an enhanced level of exo-miR-4738-3p antagonizing IL-1β-induced inflammation and promoting cell survival. Conversely, a reduction in exo-miR-4738-3p led to increased cell damage. This study established a clear regulatory relationship between miR-4738-3p and COL1A2, with the nuclear factor kappa B (NF-κB) signaling pathway playing a central role in this regulation. The miR-4738-3p significantly influences the OA-associated inflammation, primarily through modulation of COL1A2 and the NF-κB pathway. Therefore, targeting miR-4738-3p offers a potential therapeutic approach for OA, with exosome miR-4738-3p presenting a promising strategy.

The relationship between muscle strength and quality with functional performance in women mid- to long-term after Roux-en-Y gastric bypass

BACKGROUND: The reduction of muscle mass and strength commonly observed after bariatric surgery might negatively affect the individual physical function. Muscle quality is also of functional relevance in different populations, but its significance in patients who underwent bariatric surgery has yet to be explored. OBJECTIVE: To examine the association between muscle strength and quality with physical function in women mid- to long-term after Roux-en-Y gastroplasty (RYGB). METHODS: In this cross-sectional study, 133 women (43.7± 9.9 years) who have undergone RYGB at least two years before the study were included. All participants underwent body composition evaluation using DEXA and knee extensors peak moment (PM) using an isokinetic dynamometer. Muscle quality (MQ) was obtained through the ratio between absolute PM and dominant leg fat-free mass. Physical function was measured through the 30-second sit-to-stand (30-STS), 6-minute walking (6-MWT), and timed up-and-go (TUG) tests. RESULTS: Differences between PM tertiles were observed for 30-STS and 6-MWT tests. However, statistical significance disappeared when adjusting for age. Regarding PM relative to body weight, all functional tests were significantly different between tertiles. Comparing functional performance according to MQ tertiles, differences were found for 30-STS and 6-MWT tests, but significance disappeared when adjusting for age. Absolute PM was correlated to the 30-STS performance and 6-MWT, while PM relative to body mass and MQ were correlated with all functional tests. CONCLUSIONS: Muscle strength and quality seem to be associated with physical function in women mid-to-long-term after RYGB, but strength relative to bodyweight outperformed absolute strength and MQ.

Skull-Derived Myeloid Cells Augment T Cell Responses and Suppress Glioblastoma Growth

INTRODUCTION: Recent studies have implicated skull marrow as a functional myeloid reservoir in CNS pathology. However, its contribution to malignancy remains unexplored. METHODS: Fluorescently labeled calvarial flaps were transplanted onto syngeneic glioblastoma-bearing mice, followed by flow cytometric profiling of tumor-infiltrative leukocytes. To assay the functional relevance of SDMCs, tumor-bearing C57BL/6 mice were treated with preemptive calvarial ablation (13 Gy irradiation), or conversely intracalvarial AMD3100 to augment myeloid egress from marrow niches. Tumor burden was monitored via survival and bioluminescent imaging. RESULTS: 72 h following CMFDA-stained calvarial transplantation into tumor-bearing Balb/C mice, 40.3% of tumor-infiltrative myeloid cells were fluorescent and thus skull-derived; transplantation in an alternative longitudinal model (GFP+ flaps, C57BL/6) validated that SDMCs were robust and viable at 3 weeks post-operatively. As MHCII+ cells were disproportionately enriched among SDMCs (87.9% vs 67.3%, p = 0.012), we interrogated the immunogenicity of these cells through targeted ablation. Skull-ablated mice had reduced infiltration by antigen-presenting cells than controls (cDCs: 1.1% vs 4.5%, p = 0.002; macrophages: 14.4% vs 36.6%, p < 0.001) and 6-fold greater necrosis (67.7% vs 13.5% apoptotic, p < 0.001), suggesting an impaired ability to mount a controlled, adaptive immune response. The stimulatory role of SDMCs was further demonstrated via intracalvarial AMD3100 administration, which through its promotion of myeloid precursor egress (0.26% vs 0.02%, p < 0.001) and cDC2 infiltration (10.4% vs 3.0%, p = 0.003) yielded robust CD4+ T cell activation and effector memory differentiation. These differences were clinically meaningful, as skull irradiation accelerated tumor growth and attenuated survival compared to controls, while AMD3100 treatment accomplished the opposite (median OS: 17d vs 22d, p < 0.001; 26.5d vs 22d, p = 0.006). CONCLUSIONS: The preferential polarization of SDMCs into immunostimulatory APCs warrants the continued exploration of local marrow-targeting agents (e.g., AMD3100) as therapeutic modalities.

Weighting the structural connectome: Exploring its impact on network properties and predicting cognitive performance in the human brain.

Brain function does not emerge from isolated activity, but rather from the interactions and exchanges between neural elements that form a network known as the connectome. The human connectome consists of structural and functional aspects. The structural connectome (SC) represents the anatomical connections, and the functional connectome represents the resulting dynamics that emerge from this arrangement of structures. As there are different ways of weighting these connections, it is important to consider how such different approaches impact study conclusions. Here, we propose that different weighted connectomes result in varied network properties, and while neither superior the other, selection might affect interpretation and conclusions in different study cases. We present three different weighting models, namely, number of streamlines (NOS), fractional anisotropy (FA), and axon diameter distribution (ADD), to demonstrate these differences. The later, is extracted using recently published AxSI method and is first compared to commonly used weighting methods. Moreover, we explore the functional relevance of each weighted SC, using the Human Connectome Project (HCP) database. By analyzing intelligence-related data, we develop a predictive model for cognitive performance based on graph properties and the National Institutes of Health (NIH) toolbox. Results demonstrate that the ADD SC, combined with a functional subnetwork model, outperforms other models in estimating cognitive performance.

Abstract 347: Tumor necrosis factor related apoptosis inducing ligand (TRAIL)-induced cytokine production in TNBC promotes neutrophil chemotaxis and immune suppression

Abstract Background: TRAIL induces apoptosis in many preclinical cancer models including breast cancers and has been extensively studied as a potential cancer therapeutic. However, its efficacy in clinical trials is limited, suggesting an unknown modulatory mechanism responsible for lack of TRAIL activity in vivo. Here, we describe that TRAIL treatment elicits transcriptional changes in TNBC cells that alter the immune milieu. Method: We performed RNAseq of MDA-MB-231 cells treated with TRAIL for different time points, followed by validation with RT-PCR in various TNBC cells. RNAi, silencing key differentially regulated genes, along with RT-PCR, ELISA and CHIP assays, were used to validate RNAseq findings. Elucidation of the functional relevance of the outcome was supported both in vitro and in vivo by chemotaxis assay, cytotoxicity assay, RNAseq analysis of donor isolated neutrophils and intravital microscopy, CODEX analysis in TNBC xenografts from mice treated with the TRAIL respectively. Results: TRAIL treatment of the TNBC significantly induced expression of several cytokines, such as CXCLs 1, 2, 3, 8,11 and IL6, both in vitro and in vivo which are known to affect neutrophil function. Mechanistically, induction of these cytokines was predominantly mediated by death receptor 5 and caspase-8 protein, but not caspase-8 enzymatic activity. GSEA of the RNAseq data indicated that NFKB pathway was significantly enriched. Concordantly, we confirmed that both canonical NFKB1 and non-canonical NFKB2 pathways were activated by TRAIL in vitro and in vivo. However, the induction of the cytokine mRNAs was primarily dependent on the NFKB2 pathway. Neutrophils isolated from healthy human donors incubated with supernatants from TNBC cells in vitro indicated that TRAIL-induced CXCLs and IL6 significantly increased neutrophil chemotaxis. Additionally, CODEX analysis as well as intravital imaging confirmed that TRAIL treatment increases the number of neutrophils in the tumor. Preincubation of neutrophils with supernatants from TRAIL-treated TNBC significantly inhibited their cytotoxic effect against TNBCs. Further, transcriptome analysis of neutrophils incubated with either TRAIL or supernatant of TRAIL treated TNBC revealed significant enrichment of expression of inflammatory cytokine genes, immune modulating and immune checkpoint genes like PDL1. Functional studies with these neutrophils confirmed their suppressive effect on T cell function as well as the effect of TRAIL on decreased neutrophil apoptosis. Conclusion: Collectively, our study suggests the novel role of TRAIL-induced NFKB2-dependent cytokine production promoting neutrophil chemotaxis and immune suppression. This study implies that alterations in the innate immune system may modulate the effects of TRAIL on TNBC tumors. Citation Format: Manjari Kundu, Yoshimi Endo Greer, Lisa Ann Ridnour, David A Wink, Yeap S. Ng, Roberto Weigert, Stan Lipkowitz. Tumor necrosis factor related apoptosis inducing ligand (TRAIL)-induced cytokine production in TNBC promotes neutrophil chemotaxis and immune suppression [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 347.

Application of algebraic operations on fuzzy numbers

The main difficulty in working with fuzzy quantities is that, even in the case of the simplest relevance functions, as a result of elementary operations carried out on them, relevance functions of a complex form requiring a large number of parameters are formed. Therefore, the article analyzes the approximation of the current relevance functions and the results of operations performed on them by triangular, exponential, and trapezoidal functions of a certain class depending on a set number of parameters. In this case, there is an opportunity to build relatively simple basic operations that do not exceed the class of selected functions.

Hsa_circ_0004872 alleviates meningioma progression by sponging miR-190a-3p/PTEN signaling

BackgroundMeningioma, the most prevalent intracranial tumor, possesses a significant propensity for malignant transformation. Circular RNAs (circ-RNAs), a class of non-coding RNAs, have emerged as crucial players in tumorigenesis. This study explores the functional relevance of hsa_circ_0004872, a specific circ-RNA, in the context of meningioma.MethodsMolecular structure and stability of hsa_circ_0004872 were elucidated through PCR identification. Meningioma cell proliferation and apoptosis were assessed using the CCK-8 assay and flow cytometry, respectively. Gene and protein expression were analyzed via qRT-PCR and western blot. Molecular interactions were confirmed through dual-luciferase reporter gene and RIP assays.ResultsHsa_circ_0004872, derived from exons 2 to 4 of the host gene MAPK1, demonstrated enhanced stability compared to its host MAPK1. Clinical data described that hsa_circ_0004872 was reduced in meningioma tissues and cell lines, and negatively correlated to poor survival rate of meningioma patients. Overexpression of hsa_circ_0004872 exhibited inhibitory effects on cell proliferation and promotion of apoptosis in vitro. Subsequent investigations unveiled a direct interaction between hsa_circ_0004872 and miR-190a-3p, leading to the activation of the PI3K/AKT signaling pathway through targeting PTEN. Notably, miR-190a-3p silence accelerated the apoptosis and proliferation inhibition of meningioma cells by inactivating PTEN/PI3K/AKT signaling, while miR-190a-3p overexpression showed an opposite effect, which greatly reversed the anti-tumor effects of hsa_circ_0004872 overexpression.ConclusionIn summary, our findings highlighted the intricate role of hsa_circ_0004872 in meningioma, shedding light on the regulatory mechanisms involving circ-RNAs in tumor progression. This positions hsa_circ_0004872 as a potential key regulatory factor in meningioma with implications for future therapeutic interventions.

The direction of theta and alpha travelling waves modulates human memory processing.

To support a range of behaviours, the brain must flexibly coordinate neural activity across widespread brain regions. One potential mechanism for this coordination is a travelling wave, in which a neural oscillation propagates across the brain while organizing the order and timing of activity across regions. Although travelling waves are present across the brain in various species, their potential functional relevance has remained unknown. Here, using rare direct human brain recordings, we demonstrate a distinct functional role for travelling waves of theta- and alpha-band (2-13 Hz) oscillations in the cortex. Travelling waves propagate in different directions during separate cognitive processes. In episodic memory, travelling waves tended to propagate in a posterior-to-anterior direction during successful memory encoding and in an anterior-to-posterior direction during recall. Because travelling waves of oscillations correspond to local neuronal spiking, these patterns indicate that rhythmic pulses of activity move across the brain in different directions for separate behaviours. More broadly, our results suggest a fundamental role for travelling waves and oscillations in dynamically coordinating neural connectivity, by flexibly organizing the timing and directionality of network interactions across the cortex to support cognition and behaviour.

Atlas of cardiac endothelial cell enhancer elements linking the mineralocorticoid receptor to pathological gene expression.

Endothelial cells play crucial roles in physiology and are increasingly recognized as therapeutic targets in cardiovascular disease. Here, we analyzed the regulatory landscape of cardiac endothelial cells by assessing chromatin accessibility, histone modifications, and 3D chromatin organization and confirmed the functional relevance of enhancer-promoter interactions by CRISPRi-mediated enhancer silencing. We used this dataset to explore mechanisms of transcriptional regulation in cardiovascular disease and compared six different experimental models of heart failure, hypertension, or diabetes. Enhancers that regulate gene expression in diseased endothelial cells were enriched with binding sites for a distinct set of transcription factors, including the mineralocorticoid receptor (MR), a known drug target in heart failure and hypertension. For proof of concept, we applied endothelial cell-specific MR deletion in mice to confirm MR-dependent gene expression and predicted direct MR target genes. Overall, we have compiled here a comprehensive atlas of cardiac endothelial cell enhancer elements that provides insight into the role of transcription factors in cardiovascular disease.