LncRNA-Snhg3 regulates mouse hepatic glycogenesis under normal chow diet.

Long noncoding RNAs (lncRNAs) are strongly associated with glucose homeostasis, but their roles remain largely unknown. In this study, the potential role of lncRNA-Snhg3 in glucose metabolism was evaluated both in vitro and in vivo. Here, we found a positive relationship between Snhg3 and hepatic glycogenesis. Glucose tolerance improved in hepatocyte-specific Snhg3 knock-in (Snhg3-HKI) mice, while it worsened in hepatocyte-specific Snhg3 knockout (Snhg3-HKO) mice. Furthermore, hepatic glycogenesis had shown remarkable increase in Snhg3-HKI mice and reduction in Snhg3-HKO mice, respectively. Mechanistically, Snhg3 increased mRNA and protein expression levels of PPP1R3B through inducing chromatin remodeling and promoting the phosphorylation of protein kinase B. Collectively, these results suggested that lncRNA-Snhg3 plays a critical role in hepatic glycogenesis.

Disentangling gray matter atrophy and its neurotransmitter architecture in drug-naïve Parkinson's disease: an atlas-based correlation analysis.

Parkinson's disease is characterized by multiple neurotransmitter systems beyond the traditional dopaminergic pathway, yet their influence on volumetric alterations is not well comprehended. We included 72 de novo, drug-naïve Parkinson's disease patients and 61 healthy controls. Voxel-wise gray matter volume was evaluated between Parkinson's disease and healthy controls, as well as among Parkinson's disease subgroups categorized by clinical manifestations. The Juspace toolbox was utilized to explore the spatial relationship between gray matter atrophy and neurotransmitter distribution. Parkinson's disease patients exhibited widespread GM atrophy in the cerebral and cerebellar regions, with spatial correlations with various neurotransmitter receptors (FDR-P < 0.05). Cognitively impaired Parkinson's disease patients showed gray matter atrophy in the left middle temporal atrophy, which is associated with serotoninergic, dopaminergic, cholinergic, and glutamatergic receptors (FDR-P < 0.05). Postural and gait disorder patients showed atrophy in the right precuneus, which is correlated with serotoninergic, dopaminergic, gamma-aminobutyric acid, and opioid receptors (FDR-P < 0.05). Patients with anxiety showed atrophy in the right superior orbital frontal region; those with depression showed atrophy in the left lingual and right inferior occipital regions. Both conditions were linked to serotoninergic and dopaminergic receptors (FDR-P < 0.05). Parkinson's disease patients exhibited regional gray matter atrophy with a significant distribution of specific neurotransmitters, which might provide insights into the underlying pathophysiology of clinical manifestations and develop targeted intervention strategies.

A mutation-sensitive, multiplexed and amplification-free detection of nucleic acids by stretching single-molecule tandem hairpin probes.

The detection of nucleic acid sequences in parallel with the discrimination of single nucleotide variations (SNVs) is critical for research and clinical applications. A few limitations make the detection technically challenging, such as too small variation in probe-hybridization energy caused by SNVs, the non-specific amplification of false nucleic acid fragments and the few options of dyes limited by spectral overlaps. To circumvent these limitations, we developed a single-molecule nucleic acid detection assay without amplification or fluorescence termed THREF (hybridization-induced tandem DNA hairpin refolding failure) based on multiplexed magnetic tweezers. THREF can detect DNA and RNA sequences at femtomolar concentrations within 30 min, monitor multiple probes in parallel, quantify the expression level of miR-122 in patient tissues, discriminate SNVs including the hard-to-detect G-U or T-G wobble mutations and reuse the probes to save the cost. In our demonstrative detections using mock clinic samples, we profiled the let-7 family microRNAs in serum and genotyped SARS-CoV-2 strains in saliva. Overall, the THREF assay can discriminate SNVs with the advantages of high sensitivity, ultra-specificity, multiplexing, reusability, sample hands-free and robustness.

The BET inhibitor GNE-987 effectively induces anti-cancer effects in T-cell acute lymphoblastic leukemia by targeting enhancer regulated genes.

T-cell acute lymphoblastic leukemia (T-ALL) is a highly aggressive hematologic malignancy originating from T progenitor cells. It accounts for 15% of childhood and 25% of adult ALL cases. GNE-987 is a novel chimeric molecule developed using proteolysis-targeting chimeras (PROTAC) technology for targeted therapy. It consists of a potent inhibitor of the bromodomain and extraterminal (BET) protein, as well as the E3 ubiquitin ligase Von Hippel-Lindau (VHL), which enables the effective induction of proteasomal degradation of BRD4. Although GNE-987 has shown persistent inhibition of cell proliferation and apoptosis, its specific antitumor activity in T-ALL remains unclear. In this study, we aimed to investigate the molecular mechanisms underlying the antitumor effect of GNE-987 in T-ALL. To achieve this, we employed technologies including RNA sequencing (RNA-seq), chromatin immunoprecipitation sequencing (ChIP-seq) and CUT&Tag. The degradation of BET proteins, specifically BRD4, by GNE-987 has a profound impact on T-ALL cell. In in vivo experiments, sh-BRD4 lentivirus reduced T-ALL cell proliferation and invasion, extending the survival time of mice. The RNA-seq and CUT&Tag analyses provided further insights into the mechanism of action of GNE-987 in T-ALL. These analyses revealed that GNE-987 possesses the ability to suppress the expression of various genes associated with super-enhancers (SEs), including lymphoblastic leukemia 1 (LCK). By targeting these SE-associated genes, GNE-987 effectively inhibits the progression of T-ALL. Importantly, SE-related oncogenes like LCK were identified as critical targets of GNE-987. Based on these findings, GNE-987 holds promise as a potential novel candidate drug for the treatment of T-ALL.

Echinococcus multilocularis serpin regulates macrophage polarization and reduces gut dysbiosis in colitis.

Helminths serve as principal regulators in modulating host immune responses, and their excretory-secretory proteins are recognized as potential therapeutic agents for inflammatory bowel disease. Nevertheless, our comprehension of the mechanisms underlying immunoregulation remains restricted. This investigation delves into the immunomodulatory role of a secretory protein serpin (Emu-serpin), within the larval stage of Echinococcus multilocularis. Our observations indicate that Emu-serpin effectively alleviates dextran sulfate sodium-induced colitis, yielding a substantial reduction in immunopathology and an augmentation of anti-inflammatory cytokines. Furthermore, this suppressive regulatory effect is concomitant with the reduction of gut microbiota dysbiosis linked to colitis, as evidenced by a marked impediment to the expansion of the pathobiont taxa Enterobacteriaceae. In vivo experiments demonstrate that Emu-serpin facilitates the expansion of M2 phenotype macrophages while concurrently diminishing M1 phenotype macrophages, alongside an elevation in anti-inflammatory cytokine levels. Subsequent in vitro investigations involving RAW264.7 and bone marrow macrophages reveal that Emu-serpin induces a conversion of M2 macrophage populations from a pro-inflammatory to an anti-inflammatory phenotype through direct inhibition. Adoptive transfer experiments reveal the peritoneal macrophages induced by Emu-serpin alleviate colitis and gut microbiota dysbiosis. In summary, these findings propose that Emu-serpin holds the potential to regulate macrophage polarization and maintain gut microbiota homeostasis in colitis, establishing it as a promising candidate for developing helminth therapy for preventing inflammatory diseases.

Role of novel protein acylation modifications in immunity and its related diseases.

The cross-regulation of immunity and metabolism is currently a research hotspot in life sciences and immunology. Metabolic immunology plays an important role in cutting-edge fields such as metabolic regulatory mechanisms in immune cell development and function, and metabolic targets and immune-related disease pathways. Protein post-translational modification (PTM) is a key epigenetic mechanism that regulates various biological processes and highlights metabolite functions. Currently, more than 400 PTM types have been identified to affect the functions of several proteins. Among these, metabolic PTMs, particularly various newly identified histone or non-histone acylation modifications, can effectively regulate various functions, processes and diseases of the immune system, as well as immune-related diseases. Thus, drugs aimed at targeted acylation modification can have substantial therapeutic potential in regulating immunity, indicating a new direction for further clinical translational research. This review summarises the characteristics and functions of seven novel lysine acylation modifications, including succinylation, S-palmitoylation, lactylation, crotonylation, 2-hydroxyisobutyrylation, ß-hydroxybutyrylation and malonylation, and their association with immunity, thereby providing valuable references for the diagnosis and treatment of immune disorders associated with new acylation modifications.

Low and high-order topological disruption of functional networks in multiple system atrophy with freezing of gait: A resting-state study.

OBJECTIVE: Freezing of gait (FOG), a specific survival-threatening gait impairment, needs to be urgently explored in patients with multiple system atrophy (MSA), which is characterized by rapid progression and death within 10 years of symptom onset. The objective of this study was to explore the topological organisation of both low- and high-order functional networks in patients with MAS and FOG. METHOD: Low-order functional connectivity (LOFC) and high-order functional connectivity FC (HOFC) networks were calculated and further analysed using the graph theory approach in 24 patients with MSA without FOG, 20 patients with FOG, and 25 healthy controls. The relationship between brain activity and the severity of freezing symptoms was investigated in patients with FOG. RESULTS: Regarding global topological properties, patients with FOG exhibited alterations in the whole-brain network, dorsal attention network (DAN), frontoparietal network (FPN), and default network (DMN), compared with patients without FOG. At the node level, patients with FOG showed decreased nodal centralities in sensorimotor network (SMN), DAN, ventral attention network (VAN), FPN, limbic regions, hippocampal network and basal ganglia network (BG), and increased nodal centralities in the FPN, DMN, visual network (VIN) and, cerebellar network. The nodal centralities of the right inferior frontal sulcus, left lateral amygdala and left nucleus accumbens (NAC) were negatively correlated with the FOG severity. CONCLUSION: This study identified a disrupted topology of functional interactions at both low and high levels with extensive alterations in topological properties in MSA patients with FOG, especially those associated with damage to the FPN. These findings offer new insights into the dysfunctional mechanisms of complex networks and suggest potential neuroimaging biomarkers for FOG in patients with MSA.

Stage-dependent differential impact of network communication on cognitive function across the continuum of cognitive decline in Parkinson's disease.

OBJECTIVE: Our objective was to explore the patterns of resting-state network (RSN) connectivity alterations and investigate how the influences of individual-level network connections on cognition varied across clinical stages without assuming a constant relationship. METHODS: 108 PD patients with continuum of cognitive decline (PD-NC = 46, PD-MCI = 43, PDD = 19) and 34 healthy controls (HCs) underwent resting-state functional MRI and neuropsychological tests. Independent component analysis (ICA) and graph theory analyses (GTA) were employed to explore RSN connection changes. Additionally, stage-dependent differential impact of network communication on cognitive performance were examined using sparse varying coefficient modeling. RESULTS: Compared to HCs, the dorsal attention network (DAN) and dorsal sensorimotor network (dSMN) were central networks with decreased connections in PD-NC and PD-MCI stage, while the lateral visual network (LVN) emerged as a central network in patients with dementia. Additionally, connectivity of the cerebellum network (CBN) increased in the PD-NC and PD-MCI stages. GTA demonstrated decreased nodal metrics for DAN and dSMN, coupled with an increase for CBN. Moreover, the degree centrality (DC) values of DAN and dSMN exhibited a stage-dependent differential impact on cognitive performance across the continuum of cognitive decline. CONCLUSION: Our findings suggest that across the progression of cognitive impairment, the LVN gradually transitions into a core node with reduced connectivity, while the enhancement of connections in CBN diminishes. Furthermore, the non-linear relationship between the DC values of RSNs and cognitive decline indicates the potential for tailored interventions targeting specific stages.

Oxytocin Attenuates Sympathetic Innervation with Inhibition of Cardiac Mast Cell Degranulation in Rats after Myocardial Infarction.

Sympathetic hyperinnervation is the leading cause of fatal ventricular arrhythmia (VA) after myocardial infarction (MI). Cardiac mast cells cause arrhythmias directly through degranulation. However, the role and mechanism of mast cell degranulation in sympathetic remodeling remain unknown. We investigated the role of oxytocin (OT) in stabilizing cardiac mast cells and improving sympathetic innervation in rats. MI was induced by coronary artery ligation. Western blotting, immunofluorescence, and toluidine staining of mast cells were performed to determine the expression and location of target protein. Mast cells accumulated significantly in peri-infarcted tissues and were present in a degranulated state. They expressed OT receptor (OTR), and OT infusion reduced the number of degranulated cardiac mast cells post-MI. Sympathetic hyperinnervation was attenuated as assessed by immunofluorescence for tyrosine hydroxylase (TH). Seven days post-MI, the arrhythmia score of programmed electrical stimulation was higher in vehicle-treated rats with MI than in rats treated with OT. An in vitro study showed that OT stabilized mast cells via the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) signaling pathway. Further in vivo studies on OTR-deficient mice showed worsening mast cell degranulation and worsening sympathetic innervation. OT pretreatment inhibited cardiac mast cell degranulation post-MI and prevented sympathetic hyperinnervation, along with mast cell stabilization via the PI3K/Akt pathway. SIGNIFICANCE STATEMENT: This is the first study to elucidate the role and mechanism of oxytocin (OT) in inflammatory-sympathetic communication mediated sympathetic hyperinnervation after myocardial infarction (MI), providing new approaches to prevent fatal arrhythmias.

Super enhancer related gene ANP32B promotes the proliferation of acute myeloid leukemia by enhancing MYC through histone acetylation.

BACKGROUND: Acute myeloid leukemia (AML) is a malignancy of the hematopoietic system, and childhood AML accounts for about 20% of pediatric leukemia. ANP32B, an important nuclear protein associated with proliferation, has been found to regulate hematopoiesis and CML leukemogenesis by inhibiting p53 activity. However, recent study suggests that ANP32B exerts a suppressive effect on B-cell acute lymphoblastic leukemia (ALL) in mice by activating PU.1. Nevertheless, the precise underlying mechanism of ANP32B in AML remains elusive. RESULTS: Super enhancer related gene ANP32B was significantly upregulated in AML patients. The expression of ANP32B exhibited a negative correlation with overall survival. Knocking down ANP32B suppressed the proliferation of AML cell lines MV4-11 and Kasumi-1, along with downregulation of C-MYC expression. Additionally, it led to a significant decrease in H3K27ac levels in AML cell lines. In vivo experiments further demonstrated that ANP32B knockdown effectively inhibited tumor growth. CONCLUSIONS: ANP32B plays a significant role in promoting tumor proliferation in AML. The downregulation of ANP32B induces cell cycle arrest and promotes apoptosis in AML cell lines. Mechanistic analysis suggests that ANP32B may epigenetically regulate the expression of MYC through histone H3K27 acetylation. ANP32B could serve as a prognostic biomarker and potential therapeutic target for AML patients.

The BET PROTAC inhibitor GNE-987 displays anti-tumor effects by targeting super-enhancers regulated gene in osteosarcoma.

BACKGROUND: Osteosarcoma (OS) is one of the most common primary malignant tumors of bone in children, which develops from osteoblasts and typically occurs during the rapid growth phase of the bone. Recently, Super-Enhancers(SEs)have been reported to play a crucial role in osteosarcoma growth and metastasis. Therefore, there is an urgent need to identify specific targeted inhibitors of SEs to assist clinical therapy. This study aimed to elucidate the role of BRD4 inhibitor GNE-987 targeting SEs in OS and preliminarily explore its mechanism. METHODS: We evaluated changes in osteosarcoma cells following treatment with a BRD4 inhibitor GNE-987. We assessed the anti-tumor effect of GNE-987 in vitro and in vivo by Western blot, CCK8, flow cytometry detection, clone formation, xenograft tumor size measurements, and Ki67 immunohistochemical staining, and combined ChIP-seq with RNA-seq techniques to find its anti-tumor mechanism. RESULTS: In this study, we found that extremely low concentrations of GNE-987(2-10 nM) significantly reduced the proliferation and survival of OS cells by degrading BRD4. In addition, we found that GNE-987 markedly induced cell cycle arrest and apoptosis in OS cells. Further study indicated that VHL was critical for GNE-987 to exert its antitumor effect in OS cells. Consistent with in vitro results, GNE-987 administration significantly reduced tumor size in xenograft models with minimal toxicity, and partially degraded the BRD4 protein. KRT80 was identified through analysis of the RNA-seq and ChIP-seq data. U2OS HiC analysis suggested a higher frequency of chromatin interactions near the KRT80 binding site. The enrichment of H3K27ac modification at KRT80 was significantly reduced after GNE-987 treatment. KRT80 was identified as playing an important role in OS occurrence and development. CONCLUSIONS: This research revealed that GNE-987 selectively degraded BRD4 and disrupted the transcriptional regulation of oncogenes in OS. GNE-987 has the potential to affect KRT80 against OS.

MZ1, a BRD4 inhibitor, exerted its anti-cancer effects by suppressing SDC1 in glioblastoma.

BACKGROUND: Glioblastoma (GBM) is a relatively prevalent primary tumor of the central nervous system in children, characterized by its high malignancy and mortality rates, along with the intricate challenges of achieving complete surgical resection. Recently, an increasing number of studies have focused on the crucial role of super-enhancers (SEs) in the occurrence and development of GBM. This study embarks on the task of evaluating the effectiveness of MZ1, an inhibitor of BRD4 meticulously designed to specifically target SEs, within the intricate framework of GBM. METHODS: The clinical data of GBM patients was sourced from the Chinese Glioma Genome Atlas (CGGA) and the Gene Expression Profiling Interactive Analysis 2 (GEPIA2), and the gene expression data of tumor cell lines was derived from the Cancer Cell Line Encyclopedia (CCLE). The impact of MZ1 on GBM was assessed through CCK-8, colony formation assays, EdU incorporation analysis, flow cytometry, and xenograft mouse models. The underlying mechanism was investigated through RNA-seq and ChIP-seq analyses. RESULTS: In this investigation, we made a noteworthy observation that MZ1 exhibited a substantial reduction in the proliferation of GBM cells by effectively degrading BRD4. Additionally, MZ1 displayed a notable capability in inducing significant cell cycle arrest and apoptosis in GBM cells. These findings were in line with our in vitro outcomes. Notably, MZ1 administration resulted in a remarkable decrease in tumor size within the xenograft model with diminished toxicity. Furthermore, on a mechanistic level, the administration of MZ1 resulted in a significant suppression of pivotal genes closely associated with cell cycle regulation and epithelial-mesenchymal transition (EMT). Interestingly, our analysis of RNA-seq and ChIP-seq data unveiled the discovery of a novel prospective oncogene, SDC1, which assumed a pivotal role in the tumorigenesis and progression of GBM. CONCLUSION: In summary, our findings revealed that MZ1 effectively disrupted the aberrant transcriptional regulation of oncogenes in GBM by degradation of BRD4. This positions MZ1 as a promising candidate in the realm of therapeutic options for GBM treatment.

LncRNA MEG3 suppresses erastin-induced ferroptosis of chondrocytes via regulating miR-885-5p/SLC7A11 axis.

BACKGROUND: Ferroptosis is involved in osteoarthritis development; however, the roles of long noncoding RNAs (lncRNAs), including lncRNA MEG3, in the regulation of ferroptosis in osteoarthritis are still unclear. METHODS: In this study, qRT‒PCR and Western blotting assays were used to detect the expression of lncRNA MEG3, miR-885-5p, SLC7A11 and GPX4; MDA and CCK-8 assays were applied to analyse cellular MDA levels and cell viability, respectively. RESULT: Erastin elevated cellular MDA levels and decreased the viability of chondrocytes and the erastin-induced decline in cell viability was reversed by a ferroptosis inhibitor (ferrostatin-1). Erastin downregulated lncRNA MEG3, SLC7A11 and GPX4 and upregulated miR-885-5p. Silencing of lncRNA MEG3 increased miR-885-5p and downregulated SLC7A11 and GPX4 and further sensitized chondrocytes to erastin-induced ferroptosis. In contrast, overexpression of lncRNA MEG3 had opposite effects. Dual luciferase assays confirmed binding between lncRNA MEG3 and miR-885-5p and between miR-885-5p and the 3'UTR of SLC7A11. In the synovial fluids from patients with osteoarthritis compared with synovial fluids from normal controls, the RNA levels of lncRNA MEG3 and SLC7A11 were decreased and the miR-885-5p expression level was increased. CONCLUSION: Our findings indicated that lncRNA MEG3 overexpression alleviated ferroptosis in chondrocytes by affecting the miR-885-5p/SLC7A11 signalling pathway.

Absolute Configuration of 12S-Deoxynortryptoquivaline from Ascidian-Derived Fungus Aspergillus clavatus Determined by Anisotropic NMR and Chiroptical Spectroscopy.

Tryptoquivalines are highly toxic metabolites initially isolated from the fungus Aspergillus clavatus. The relative and absolute configuration of tryptoquivaline derivates was primarily established by comparison of the chemical shifts, NOE data, and ECD calculations. A de novo determination of the complete relative configuration using NMR spectroscopy was challenging due to multiple spatially separated stereocenters, including one nonprotonated carbon. In this study, we isolated a new tryptoquivaline derivative, 12S-deoxynortryptoquivaline (1), from the marine ascidian-derived fungus Aspergillus clavatus AS-107. The correct assignment of the relative configuration of 1 was accomplished using anisotropic NMR spectroscopy, while the absolute configuration was determined by comparing calculated and experimental ECD spectra. This case study highlights the effectiveness of anisotropic NMR parameters over isotropic NMR parameters in determining the relative configuration of complex natural products without the need for crystallization.

Disrupted network communication predicts mild cognitive impairment in end-stage renal disease: an individualized machine learning study based on resting-state fMRI.

End-Stage Renal Disease (ESRD) is known to be associated with a range of brain injuries, including cognitive decline. The purpose of this study is to investigate the functional connectivity (FC) of the resting-state networks (RSNs) through resting state functional magnetic resonance imaging (MRI), in order to gain insight into the neuropathological mechanism of ESRD. A total of 48 ESRD patients and 49 healthy controls underwent resting-state functional MRI and neuropsychological tests, for which Independent Components Analysis and graph-theory (GT) analysis were utilized. With the machine learning results, we examined the connections between RSNs abnormalities and neuropsychological test scores. Combining intra/inter network FC differences and GT results, ESRD was optimally distinguished in the testing dataset, with a balanced accuracy of 0.917 and area under curve (AUC) of 0.942. Shapley additive explanations results revealed that the increased functional network connectivity between DMN and left frontoparietal network (LFPN) was the most critical predictor for ESRD associated mild cognitive impairment diagnosis. Moreover, hypoSN (salience network) was positively correlated with Attention scores, while hyperLFPN was negatively correlated with Execution scores, indicating correlations between functional disruption and cognitive impairment measurements in ESRD patients. This study demonstrated that both the loss of FC within the SN and compensatory FC within the lateral frontoparietal network coexist in ESRD. This provides a network basis for understanding the individual brain circuits and offers additional noninvasive evidence to comprehend the brain networks in ESRD.

Functional Brain Network Alterations in Patients With Systemic Lupus Erythematosus With Different Cognitive Function States: A Graph Theory Analysis Study.

OBJECTIVE: The study aimed to investigate the characteristics of brain functional network disruption in patients with systemic lupus erythematosus (SLE) with different cognitive function states by using graph theory analysis and to explore their relationship with clinical data and neuropsychiatric scales. METHODS: Resting-state functional magnetic resonance imaging data were collected from 38 female SLE patients and 44 healthy controls. Based on Montreal Cognitive Assessment (MoCA) scores, SLE patients were divided into a high MoCA group (MoCA-H; MoCA score, ≥26) and a low MoCA group (MoCA-L; MoCA score, <26). The matrix of resting-state functional brain networks of subjects in the 3 groups was constructed by using the graph theory approach. The topological properties of the functional brain networks, including global and local metrics, in the 3 groups were calculated. The differences in the topological properties of networks between the 3 groups were compared. In addition, Spearman correlation analysis was used to explore the correlation between altered topological properties of brain networks and clinical indicators, as well as neuropsychiatric scales in SLE patients in the MoCA-L group. RESULTS: At the global level, in the sparsity threshold range of 0.10 to 0.34, the values of small-world properties were greater than 1 in all 3 groups, indicating that functional brain networks of both 3 groups had small-world properties. There were statistically significant differences in the characteristic path length, global, and local efficiency between 3 groups ( F = 3.825, P = 0.0260; F = 3.722, P = 0.0285; and F = 3.457, P = 0.0364, respectively). Systemic lupus erythematosus patients in the MoCA-L group showed increased characteristic path length ( t = 2.816, P = 0.00651), decreased global ( t = -2.729, P = 0.00826), and local efficiency ( t = -2.623, P = 0.0109) compared with healthy controls. No statistically significant differences in local metrics were found between the MoCA-H group and the healthy control, MoCA-L groups. At the local level, there was statistically significant difference in the node efficiency among the 3 groups ( P < 0.05 after Bonferroni correction). Compared with healthy controls, SLE patients in the MoCA-L group showed decreased node efficiency in left anterior cingulate paracingulate gyrus, bilateral putamen, bilateral pallidum, and left Heschl gyrus. No statistically significant differences in the local metrics were found between the MoCA-H, MoCA-L, and healthy control groups. Correlation analysis in SLE patients in the MoCA-L group showed that the characteristic path length was positively correlated with C4 levels ( r = 0.587, P = 0.007), the global and local efficiencies were negatively correlated with C4 levels ( r = -0.599, P = 0.005; r = -0.599, P = 0.005, respectively), and the node efficiency in the bilateral putamen was negatively correlated with C4 levels ( r = -0.611, P = 0.004; r = -0.570, P = 0.009). The node efficiency in the left pallidum was negatively correlated with disease duration ( r = -0.480, P = 0.032). The node efficiency in the left Heschl gyrus was negatively correlated with IgM levels ( r = -0.478, P = 0.033). No correlation was noted between other network metrics, clinical indicators, and neuropsychological scales. CONCLUSIONS: The topological properties of functional brain networks were disrupted in SLE patients with low MoCA scores, suggesting that altered topological properties of the brain networks were associated with cognitive function in SLE patients. Correlation between altered topological properties of the brain networks and clinical indicators was noted in SLE patients with low MoCA scores, suggesting that altered topological properties of brain networks in SLE patients may have clinical significance as imaging markers for monitoring disease changes in patients with SLE.

Engineering dendritic cell biomimetic membrane as a delivery system for tumor targeted therapy.

Targeted immunotherapies make substantial strides in clinical cancer care due to their ability to counteract the tumor's capacity to suppress immune responses. Advances in biomimetic technology with minimally immunogenic and highly targeted, are addressing issues of targeted drug delivery and disrupting the tumor's immunosuppressive environment to trigger immune activation. Specifically, the use of dendritic cell (DC) membranes to coat nanoparticles ensures targeted delivery due to DC's unique ability to activate naive T cells, spotlighting their role in immunotherapy aimed at disrupting the tumor microenvironment. The potential of DC's biomimetic membrane to mediate immune activation and target tumors is gaining momentum, enhancing the effectiveness of cancer treatments in conjunction with other immune responses. This review delves into the methodologies behind crafting DC membranes and the fusion of dendritic and tumor cell membranes for encapsulating therapeutic nanoparticles. It explores their applications and recent advancements in combating cancer, offering an all-encompassing perspective on DC biomimetic nanosystems, immunotherapy driven by antigen presentation, and the collaborative efforts of drug delivery in chemotherapy and photodynamic therapies. Current evidence shows promise in augmenting combined therapeutic approaches for cancer treatment and holds translational potential for various cancer treatments in a clinical setting.

5-Methyl-cytosine stabilizes DNA but hinders DNA hybridization revealed by magnetic tweezers and simulations.

5-Methyl-cytosine (5mC) is one of the most important DNA modifications and plays versatile biological roles. It is well known that 5mC stabilizes DNA duplexes. However, it remains unclear how 5mC affects the kinetics of DNA melting and hybridization. Here, we studied the kinetics of unzipping and rezipping using a 502-bp DNA hairpin by single-molecule magnetic tweezers. Under constant loading rates, 5mC increases the unzipping force but counterintuitively decreases the rezipping force at various salt and temperature conditions. Under constant forces, the non-methylated DNA hops between metastable states during unzipping and rezipping, which implies low energy barriers. Surprisingly, the 5mC DNA can't rezip after fully unzipping unless much lower forces are applied, where it rezips stochastically in a one-step manner, which implies 5mC kinetically hinders DNA hybridization and high energy barriers in DNA hybridization. All-atom molecular dynamics simulations reveal that the 5mC kinetically hinders DNA hybridization due to steric effects rather than electrostatic effects caused by the additional methyl groups of cytosines. Considering the possible high speed of DNA unzipping and zipping during replication and transcription, our findings provide new insights into the biological roles of 5mC.

Successful treatment of juvenile polyposis of infancy with sirolimus: a case report.

BACKGROUND: Infantile Juvenile polyposis of infantile (JPI) is a rare and aggressive form of juvenile polyposis syndrome (JPS) typically diagnosed in the first year of life. It often carries a poor prognosis due to chronic gastrointestinal bleeding, protein-losing enteropathy, malnutrition and immune deficiency. CASE PRESENTATION: We report a case of a girl initially presented with pallor at 7 months of age, which progressed to gastrointestinal bleeding and protein-losing enteropathy. Endoscopic examination, which included both upper gastrointestinal endoscopy and enteroscopy, showed diffuse polyposis. Histopathology results indicated the presence of juvenile polyps with no dysplasia in all removed polyps. Genetic testing identified a 2.1 Mb deletion on chromosome 10q23.2q23.31 involving the phosphatase and tensin homolog (PTEN) and bone morphogenetic protein receptor type IA (BMPR1A) genes. Treatment with sirolimus initiated at 10 months of age led to a reduction in the need for blood and albumin infusions, improved patient growth, and quality of life. While the frequency of endoscopic evaluations decreased with sirolimus, regular endoscopic polypectomy every 5 months remained necessary. However, discontinuation of sirolimus resulted in polyp recurrence after 2 months due to pneumonia. CONCLUSION: This case highlights sirolimus treatment can alleviate many complications of JPI, it does not eliminate the need for aggressive polypectomy.

Cadmium-induced fetal erythropoiesis disturbances in mice.

Maternal anemia has been identified as a contributing factor to adverse reproductive outcomes associated with cadmium (Cd) exposure, a common heavy metal. Our recent findings suggest that inhibited erythroid differentiation and enucleation also play significant roles in the direct embryonic toxicity resulting from maternal Cd exposure. However, the effects of Cd exposure on lipid metabolism remodeling, which is essential for physiological erythropoiesis, remain poorly understood. In the present study, pregnant mice were administered low doses of CdCl2 via oral exposure from early to late gestation to mitigate Cd-induced maternal anemia. Compared to vehicle-treated controls, embryos from Cd-treated mice exhibited a slight decrease in weight, though without signs of atrophy. Consistent with our previous observations, fetal livers from Cd-exposed embryos demonstrated a dose-dependent inhibition of erythroid differentiation, as confirmed by ex vivo analysis. Notably, an intrinsic decrease in lipid peroxidation during erythroid differentiation was observed in the bone marrow and fetal livers of vehicle-treated mice, attributed to diminished lipid content. In contrast, this decrease in lipid peroxidation was absent in fetal liver erythroblasts from Cd-treated mice, where an increase in lipid peroxidation was instead noted. These findings elucidate a potential mechanism, lipid peroxidation, underlying Cd-induced embryonic toxicity.