A thalamic nucleus reuniens-lateral septum-lateral hypothalamus circuit for comorbid anxiety-like behaviors in chronic itch.

Chronic itch often clinically coexists with anxiety symptoms, creating a vicious cycle of itch-anxiety comorbidities that are difficult to treat. However, the neuronal circuit mechanisms underlying the comorbidity of anxiety in chronic itch remain elusive. Here, we report anxiety-like behaviors in mouse models of chronic itch and identify γ-aminobutyric acid-releasing (GABAergic) neurons in the lateral septum (LS) as the key player in chronic itch-induced anxiety. In addition, chronic itch is accompanied with enhanced activity and synaptic plasticity of excitatory projections from the thalamic nucleus reuniens (Re) onto LS GABAergic neurons. Selective chemogenetic inhibition of the Re → LS circuit notably alleviated chronic itch-induced anxiety, with no impact on anxiety induced by restraint stress. Last, GABAergic neurons in lateral hypothalamus (LH) receive monosynaptic inhibition from LS GABAergic neurons to mediate chronic itch-induced anxiety. These findings underscore the potential significance of the Re → LS → LH pathway in regulating anxiety-like comorbid symptoms associated with chronic itch.

The role of serine/threonine protein kinases in cardiovascular disease and potential therapeutic methods.

Protein phosphorylation is an important link in a variety of signaling pathways, and most of the important life processes in cells involve protein phosphorylation. Based on the amino acid residues of phosphorylated proteins, protein kinases can be categorized into the following families: serine/threonine protein kinases, tyrosine-specific protein kinases, histidine-specific protein kinases, tryptophan kinases, and aspartate/glutamyl protein kinases. Of all the protein kinases, most are serine/threonine kinases, where serine/threonine protein kinases are protein kinases that catalyze the phosphorylation of serine or threonine residues on target proteins using ATP as a phosphate donor. The current socially accepted classification of serine/threonine kinases is to divide them into seven major groups: protein kinase A, G, C (AGC), CMGC, Calmodulin-dependent protein kinase (CAMK), Casein kinase (CK1), STE, Tyrosine kinase (TKL) and others. After decades of research, a preliminary understanding of the specific classification and respective functions of serine/threonine kinases has entered a new period of exploration. In this paper, we review the literature of the previous years and introduce the specific signaling pathways and related therapeutic modalities played by each of the small protein kinases in the serine/threonine protein kinase family, respectively, in some common cardiovascular system diseases such as heart failure, myocardial infarction, ischemia-reperfusion injury, and diabetic cardiomyopathy. To a certain extent, the current research results, including molecular mechanisms and therapeutic methods, are fully summarized and a systematic report is made for the prevention and treatment of cardiovascular diseases in the future.

Programmed death of cardiomyocytes in cardiovascular disease and new therapeutic approaches.

Cardiovascular diseases (CVDs) have a complex pathogenesis and pose a major threat to human health. Cardiomyocytes have a low regenerative capacity, and their death is a key factor in the morbidity and mortality of many CVDs. Cardiomyocyte death can be regulated by specific signaling pathways known as programmed cell death (PCD), including apoptosis, necroptosis, autophagy, pyroptosis, and ferroptosis, etc. Abnormalities in PCD can lead to the development of a variety of cardiovascular diseases, and there are also molecular-level interconnections between different PCD pathways under the same cardiovascular disease model. Currently, the link between programmed cell death in cardiomyocytes and cardiovascular disease is not fully understood. This review describes the molecular mechanisms of programmed death and the impact of cardiomyocyte death on cardiovascular disease development. Emphasis is placed on a summary of drugs and potential therapeutic approaches that can be used to treat cardiovascular disease by targeting and blocking programmed cell death in cardiomyocytes.

An ultra-short-acting benzodiazepine in thalamic nucleus reuniens undermines fear extinction via intermediation of hippocamposeptal circuits.

Benzodiazepines, commonly used for anxiolytics, hinder conditioned fear extinction, and the underlying circuit mechanisms are unclear. Utilizing remimazolam, an ultra-short-acting benzodiazepine, here we reveal its impact on the thalamic nucleus reuniens (RE) and interconnected hippocamposeptal circuits during fear extinction. Systemic or RE-specific administration of remimazolam impedes fear extinction by reducing RE activation through A type GABA receptors. Remimazolam enhances long-range GABAergic inhibition from lateral septum (LS) to RE, underlying the compromised fear extinction. RE projects to ventral hippocampus (vHPC), which in turn sends projections characterized by feed-forward inhibition to the GABAergic neurons of the LS. This is coupled with long-range GABAergic projections from the LS to RE, collectively constituting an overall positive feedback circuit construct that promotes fear extinction. RE-specific remimazolam negates the facilitation of fear extinction by disrupting this circuit. Thus, remimazolam in RE disrupts fear extinction caused by hippocamposeptal intermediation, offering mechanistic insights for the dilemma of combining anxiolytics with extinction-based exposure therapy.

Regulation of lipid metabolism by E3 ubiquitin ligases in lipid-associated metabolic diseases.

Previous studies have progressively elucidated the involvement of E3 ubiquitin (Ub) ligases in regulating lipid metabolism. Ubiquitination, facilitated by E3 Ub ligases, modifies critical enzymes in lipid metabolism, enabling them to respond to specific signals. In this review, we aim to present a comprehensive analysis of the role of E3 Ub ligases in lipid metabolism, which includes lipid synthesis and lipolysis, and their influence on cellular lipid homeostasis through the modulation of lipid uptake and efflux. Furthermore, it explores how the ubiquitination process governs the degradation or activation of pivotal enzymes, thereby regulating lipid metabolism at the transcriptional level. Perturbations in lipid metabolism have been implicated in various diseases, including hepatic lipid metabolism disorders, atherosclerosis, diabetes, and cancer. Therefore, this review focuses on the association between E3 Ub ligases and lipid metabolism in lipid-related diseases, highlighting enzymes critically involved in lipid synthesis and catabolism, transcriptional regulators, lipid uptake translocators, and transporters. Overall, this review aims to identify gaps in current knowledge, highlight areas requiring further research, offer potential targeted therapeutic approaches, and provide a comprehensive outlook on clinical conditions associated with lipid metabolic diseases.

Advances in the study of exosomes in cardiovascular diseases.

BACKGROUND: Cardiovascular disease (CVD) has been the leading cause of death worldwide for many years. In recent years, exosomes have gained extensive attention in the cardiovascular system due to their excellent biocompatibility. Studies have extensively researched miRNAs in exosomes and found that they play critical roles in various physiological and pathological processes in the cardiovascular system. These processes include promoting or inhibiting inflammatory responses, promoting angiogenesis, participating in cell proliferation and migration, and promoting pathological progression such as fibrosis. AIM OF REVIEW: This systematic review examines the role of exosomes in various cardiovascular diseases such as atherosclerosis, myocardial infarction, ischemia-reperfusion injury, heart failure and cardiomyopathy. It also presents the latest treatment and prevention methods utilizing exosomes. The study aims to provide new insights and approaches for preventing and treating cardiovascular diseases by exploring the relationship between exosomes and these conditions. Furthermore, the review emphasizes the potential clinical use of exosomes as biomarkers for diagnosing cardiovascular diseases. KEY SCIENTIFIC CONCEPTS OF REVIEW: Exosomes are nanoscale vesicles surrounded by lipid bilayers that are secreted by most cells in the body. They are heterogeneous, varying in size and composition, with a diameter typically ranging from 40 to 160 nm. Exosomes serve as a means of information communication between cells, carrying various biologically active substances, including lipids, proteins, and small RNAs such as miRNAs and lncRNAs. As a result, they participate in both physiological and pathological processes within the body.

The role of glycolytic metabolic pathways in cardiovascular disease and potential therapeutic approaches.

Cardiovascular disease (CVD) is a major threat to human health, accounting for 46% of non-communicable disease deaths. Glycolysis is a conserved and rigorous biological process that breaks down glucose into pyruvate, and its primary function is to provide the body with the energy and intermediate products needed for life activities. The non-glycolytic actions of enzymes associated with the glycolytic pathway have long been found to be associated with the development of CVD, typically exemplified by metabolic remodeling in heart failure, which is a condition in which the heart exhibits a rapid adaptive response to hypoxic and hypoxic conditions, occurring early in the course of heart failure. It is mainly characterized by a decrease in oxidative phosphorylation and a rise in the glycolytic pathway, and the rise in glycolysis is considered a hallmark of metabolic remodeling. In addition to this, the glycolytic metabolic pathway is the main source of energy for cardiomyocytes during ischemia-reperfusion. Not only that, the auxiliary pathways of glycolysis, such as the polyol pathway, hexosamine pathway, and pentose phosphate pathway, are also closely related to CVD. Therefore, targeting glycolysis is very attractive for therapeutic intervention in CVD. However, the relationship between glycolytic pathway and CVD is very complex, and some preclinical studies have confirmed that targeting glycolysis does have a certain degree of efficacy, but its specific role in the development of CVD has yet to be explored. This article aims to summarize the current knowledge regarding the glycolytic pathway and its key enzymes (including hexokinase (HK), phosphoglucose isomerase (PGI), phosphofructokinase-1 (PFK1), aldolase (Aldolase), phosphoglycerate metatase (PGAM), enolase (ENO) pyruvate kinase (PKM) lactate dehydrogenase (LDH)) for their role in cardiovascular diseases (e.g., heart failure, myocardial infarction, atherosclerosis) and possible emerging therapeutic targets.

Dry Friction Properties of Diamond-Coated Silicon Carbide.

Dry friction between seal faces, caused by unstable or extreme operating conditions, significantly affects the running stability and service life of mechanical seals. Therefore, in this work, nanocrystalline diamond (NCD) coatings were prepared on the surface of silicon carbide (SiC) seal rings by hot filament chemical vapor deposition (HFCVD). The friction test results under dry environment reveals that the coefficient of friction (COF) of SiC-NCD seal pairs is about 0.07-0.09, which were reduced by 83-86% compared to SiC-SiC seal pairs. The wear rate of SiC-NCD seal pairs is relatively low, ranging from 1.13 × 10-7 mm3/N·m to 3.26 × 10-7 mm3/N·m under different test conditions, which is due to the fact that the NCD coatings prevent adhesive and abrasive wear between the SiC seal rings. The analysis and observation of the wear tracks illustrate that the excellent tribological performance of the SiC-NCD seal pairs is due to a self-lubricating amorphous layer formed on the worn surface. In conclusion, this work highlights a pathway to enable mechanical seals to satisfy the high application requirements under highly parametric working conditions.

Synaptic scaling of corticostriatal circuits underlies hyperactivity in GABA Transporter-1 deficient mice.

Homeostatic synaptic scaling entails adjustment of synaptic strength on a cell to prolonged changes of neuronal activity, which is postulated to participate in neuropsychiatric disorders in vivo. Here, we find that sustained elevation in ambient GABA levels, by either genetic deletion or pharmacological blockade of GABA transporter-1 (GAT1), leads to synaptic scaling up of corticostriatal pathways, which underlies locomotor hyperactivity. Meanwhile, medium spiny neurons of the dorsal striatum exhibit an aberrant increase in excitatory synaptic transmission and corresponding structural changes in dendritic spines. Mechanistically, GAT1 deficiency dampens the expression and function of metabotropic glutamate receptors (mGluRs) and endocannabinoid (eCB)-dependent long-term depression of excitatory transmission. Conversely, restoring mGluR function in GAT1 deficient mice rescues excitatory transmission. Lastly, pharmacological potentiation of mGluR-eCB signaling or inhibition of homomeric-GluA1 AMPA receptors eliminates locomotor hyperactivity in the GAT1 deficient mice. Together, these results reveal a synaptic scaling mechanism in corticostriatal pathways that regulate locomotor activity.

Nucleus pulposus related lncRNA and mRNA expression profiles in intervertebral disc degeneration.

In the present study, we aimed to have a comprehensive understanding of nucleus pulposus related long noncoding RNA (lncRNA) and mRNA expression profiles in intervertebral disc degeneration (IDD). In total, 2418 mRNAs and 528 lncRNAs were found to be differentially expressed in the IDD group compared with the Control group. Combining microarray datasets and sequencing data, 5 overlapping DEMs and 7 overlapping DELs were identified. NF-κB signaling pathway, PI3K-Akt signaling pathway and Wnt/ß-catenin signaling pathway were strongly linked with enriched GO terms and KEGG pathways. The ceRNA network suggested that lnc-TMEM44-AS1-hsa-miR-206-HDAC4 may be one crucial axis in IDD. PPI network analysis was constructed with 309 nodes and 129 edges. And the highest connectivity degrees were ALB, APOB and CCL2. This study suggested that specific lncRNAs and ceRNA axes may be crucial in the development of IDD. It provides a new perspective for delaying IDD process and enhancing intervertebral disc repair.

Insular cortical circuits as an executive gateway to decipher threat or extinction memory via distinct subcortical pathways.

Threat and extinction memories are crucial for organisms' survival in changing environments. These memories are believed to be encoded by separate ensembles of neurons in the brain, but their whereabouts remain elusive. Using an auditory fear-conditioning and extinction paradigm in male mice, here we discovered that two distinct projection neuron subpopulations in physical proximity within the insular cortex (IC), targeting the central amygdala (CeA) and nucleus accumbens (NAc), respectively, to encode fear and extinction memories. Reciprocal intracortical inhibition of these two IC subpopulations gates the emergence of either fear or extinction memory. Using rabies-virus-assisted tracing, we found IC-NAc projection neurons to be preferentially innervated by intercortical inputs from the orbitofrontal cortex (OFC), specifically enhancing extinction to override fear memory. These results demonstrate that IC serves as an operation node harboring distinct projection neurons that decipher fear or extinction memory under the top-down executive control from OFC.

Dynamic tripartite construct of interregional engram circuits underlies forgetting of extinction memory.

Fear extinction allows for adaptive control of learned fear responses but often fails, resulting in a renewal or spontaneous recovery of the extinguished fear, i.e., forgetting of the extinction memory readily occurs. Using an activity-dependent neuronal labeling strategy, we demonstrate that engram neurons for fear extinction memory are dynamically positioned in the medial prefrontal cortex (mPFC), basolateral amygdala (BLA), and ventral hippocampus (vHPC), which constitute an engram construct in the term of directional engram synaptic connectivity from the BLA or vHPC to mPFC, but not that in the opposite direction, for retrieval of extinction memory. Fear renewal or spontaneous recovery switches the extinction engram construct from an accessible to inaccessible state, whereas additional extinction learning or optogenetic induction of long-term potentiation restores the directional engram connectivity and prevents the return of fear. Thus, the plasticity of engram construct underlies forgetting of extinction memory.

The role of m6A methylation in osteosarcoma biological processes and its potential clinical value.

Osteosarcoma (OS) is the most common primary malignant bone tumor in children and young adults and has a poor prognosis. Recent developments in the field of high-throughput sequencing technology, particularly in methylated RNA immunoprecipitation sequencing (MeRIP-seq), have led to renewed interest in RNA methylation. Among the various RNA modifications, N6-methyladenosine (m6A) modifications are the most common. Emerging evidence suggests that m6A methylation can affect the complexity of cancer progression by regulating biological functions related to cancer. In this review, we will shed light on recent findings regarding the biological function of m6A methylation in OS and discuss future research directions and potential clinical applications of RNA methyltransferases in OS.

Study on Appropriate Rectal Volume for External Irradiation in Patients With Cervical Cancer.

Objective: To investigate the appropriate rectal volume for external irradiation of cervical cancer. Methods: A retrospective study of 143 patients with cervical cancer who underwent external radiotherapy from January 2017 to September 2020 was conducted. Average rectum volumes and the cumulative dose (V30, V40, V50, D2cc) to organs at risk (bladder, rectum, and small bowel) during radiotherapy were evaluated using the treatment planning system. Rates of radiation cystitis and radiation proctitis were assessed. Results: The median follow-up was 48 months, and the included patients had a median age of 53 years. Patients were divided into 3 groups based on their average rectum volume: Group A: <40 ml; Group B: 40-70 ml; and Group C: ≥70 ml. V30 and V40 in the rectum bladder and small bowel were highest in Group A (mean ± SD standard deviation), but V50 and D2cc in the rectum and bladder were highest in Group C (mean ± SD). Patients in Group B had the lower incidence of both radiation cystitis and radiation proctitis. (p<0.05). Conclusions: For external irradiation in patients with cervical cancer, a rectum volume of 40-70 ml seems most appropriate, whereas >70 ml increases the risk of severe radiation cystitis and radiation proctitis, and <40 ml increases the risk of mild radiation cystitis and mild radiation proctitis.

Narrative review of gene modification: applications in three-dimensional (3D) bioprinting.

OBJECTIVE: This article focused on the application scenarios of three-dimensional (3D) bioprinting and gene-editing technology in various medical fields, including gene therapy, tissue engineering, tumor microenvironment simulation, tumor model construction, cancer regulation and expression, osteogenesis, and skin and vascular regeneration, and summarizing its development prospects and shortcomings. BACKGROUND: 3D bioprinting is a process based on additive manufacturing that uses biological materials as the microenvironment living cells. The scaffolds and carriers manufactured by 3D bioprinting technology provide a safe, efficient, and economical platform for genes, cells, and biomolecules. Gene modification refers to replacing, splicing, silencing, editing, controlling or inactivating genes and delivering new genes. The combination of this technology that changes cell function or cell fate or corrects endogenous mutations and 3D bioprinting technology has been widely used in various medical field. METHODS: We conducted a literature search for papers published up to March 2021 on the gene modification combined with 3D bioprinting in various medical fields via PubMed, Web of Science, China National Knowledge Infrastructure (CNKI). The following medical subject heading terms were included for a MEDLINE search: "3D printing/gene editing", "3D printing/genetic modification", "3D printing/seed cell", "bioprinting/gene editing", "bioprinting/genetic modification", "bioprinting/seed cell", "scaffold/gene editing", "scaffold/genetic modification", "scaffold/seed cell", "gene/scaffold", "gene/bioprinting", "gene/3D printing". Quantitative and qualitative data was extracted through interpretation of each article. CONCLUSIONS: We have reviewed the application scenarios of 3D bioprinting and gene-editing technology in various medical fields, it provides an efficient and accurate delivery system for personalized tumor therapy, enhancing the targeting effect while maintaining the integrity of the fabricated structure. It exhibits significant application potential in developing tumor drugs. In addition, scaffolds obtained via 3D bioprinting provide gene therapy applications for skin and bone healing and repair and inducing stem cell differentiation. It also considers the future development direction in this field, such as the emergence and development of gene printing, 4D printing. The combination of nanotechnology and gene printing may provide a new way for future disease research and treatment.

Input associativity underlies fear memory renewal.

Synaptic associativity, a feature of Hebbian plasticity wherein coactivation of two inputs onto the same neuron produces synergistic actions on postsynaptic activity, is a primary cellular correlate of associative learning. However, whether and how synaptic associativity are implemented into context-dependent relapse of extinguished memory (i.e. fear renewal) is unknown. Here, using an auditory fear conditioning paradigm in mice, we show that fear renewal is determined by the associativity between convergent inputs from the auditory cortex (ACx) and ventral hippocampus (vHPC) onto the lateral amygdala (LA) that reactivate ensembles engaged during learning. Fear renewal enhances synaptic strengths of both ACx to LA and the previously unknown vHPC to LA monosynaptic inputs. While inactivating either of the afferents abolishes fear renewal, optogenetic activation of their input associativity in the LA recapitulates fear renewal. Thus, input associativity underlies fear memory renewal.

E3 Ubiquitin Ligase-Mediated Regulation of Osteoblast Differentiation and Bone Formation.

The ubiquitin-proteasome system (UPS) is an essential pathway that regulates the homeostasis and function of intracellular proteins and is a crucial protein-degradation system in osteoblast differentiation and bone formation. Abnormal regulation of ubiquitination leads to osteoblast differentiation disorders, interfering with bone formation and ultimately leading to osteoporosis. E3 ubiquitin ligases (E3) promote addition of a ubiquitin moiety to substrate proteins, specifically recognizing the substrate and modulating tyrosine kinase receptors, signaling proteins, and transcription factors involved in the regulation of osteoblast proliferation, differentiation, survival, and bone formation. In this review, we summarize current progress in the understanding of the function and regulatory effects of E3 ligases on the transcription factors and signaling pathways that regulate osteoblast differentiation and bone formation. A deep understanding of E3 ligase-mediated regulation of osteoblast differentiation provides a scientific rationale for the discovery and development of novel E3-targeting therapeutic strategies for osteoporosis.

The role of non­coding RNAs in the regulation, diagnosis, prognosis and treatment of osteosarcoma (Review).

Osteosarcoma (OS) is the most common primary bone tumor worldwide. OS exhibits a range of aggressive behaviors, including early metastasis potential, rapid progression, poor clinical prognosis and insensitivity to chemoradiotherapy. Non­coding RNAs are transcripts that do not encode proteins. A significant number of studies published on OS have been focused on the aberrant expression of non­coding RNAs and their involvement in tumor initiation and progression. It has been confirmed that non­coding RNAs exert their regulatory functions at both the transcriptional and post­transcriptional level, which leads to tumor initiation or progression in OS. According to present knowledge, this review provides a state­of­the­art overview of the functions and mechanisms of microRNAs, long non­coding RNAs and circular RNAs in terms of their involvement with OS. The review also covers their potential clinical application in the diagnosis, prognosis and treatment of OS. It is hoped that the information presented in this review on the involvement of non­coding RNAs in OS will lead to a more comprehensive understanding of OS and provide a useful perspective on the potential diagnostic and therapeutic applications of non­coding RNAs for patients with OS.

Mechanisms linking mitochondrial mechanotransduction and chondrocyte biology in the pathogenesis of osteoarthritis.

Mechanical loading is essential for chondrocyte health. Chondrocytes can sense and respond to various extracellular mechanical signals through an integrated set of mechanisms. Recently, it has been found that mitochondria, acting as critical mechanotransducers, are at the intersection between extracellular mechanical signals and chondrocyte biology. Much attention has been focused on identifying how mechanical loading-induced mitochondrial dysfunction contributes to the pathogenesis of osteoarthritis. In contrast, little is known regarding the mechanisms underlying functional alterations in mitochondria induced by mechanical stimulation. In this review, we describe how chondrocytes perceive environmental mechanical signals. We discuss how mechanical load induces mitochondrial functional alterations and highlight the major unanswered questions in this field. We speculate that AMP-activated protein kinase (AMPK), a master regulator of energy homeostasis, may play an important role in coupling force transmission to mitochondrial health and intracellular biological responses.

Large-Volume Lateral Lymph Node Metastasis Predicts Worse Prognosis in Papillary Thyroid Carcinoma Patients With N1b.

We aimed to evaluate the relevance of large-volume lateral lymph node metastases (LLNMs) at risk of recurrence/persistence in papillary thyroid carcinoma (PTC) with LLNMs (N1b). This retrospective study included 448 PTC patients, who had positive LLNMs confirmed by histology and suspected of LLNMs by preoperative ultrasound. According to the number of pathological LLNMs, patients were divided into large-volume LLNM (number of LLNMs >5) and low-volume LLNM (number of LLNMs ≤5). Risk factors of recurrence/persistence in PTC patients with N1b were analyzed. Preoperative ultrasound features of PTC with large-volume LLNM were analyzed. For the patients with a mean follow-up of 44.0 months, the risk of recurrence/persistence was 25.1% in PTC patients with N1b. The recurrence/persistence rate was significantly higher in patients with large-volume LLNM than in patients with low-volume LLNM by multivariate analysis (37.3% vs. 17.1%; HR = 2.451, 95% CI 1.41-4.261, p = 0.001). The 3-year and 5-year recurrence/persistence-free survival for those with large-volume LLNM were 93.2% and 47.2%, respectively. Moreover, we found that multilevel suspected LLNMs and loss of fatty hilum were independent preoperative indicative factors of large-volume LLNM (OR = 6.239, 95% CI 3.547-10.977, p < 0.001; OR = 5.149, 95% CI 1.859-14.261, p = 0.002). In conclusion, multilevel suspected LLNM and loss of fatty hilum on ultrasound tended to be more common in patients with large-volume LLNM. PTC patients with large-volume LLNM are at a higher recurrent/persistent risk than those with low-volume LLNM. Large-volume LLNM may be used to stratify the risk of recurrence/persistence in PTC.