Morphometric brain organization across the human lifespan reveals increased dispersion linked to cognitive performance.

The human brain is organized as segregation and integration units and follows complex developmental trajectories throughout life. The cortical manifold provides a new means of studying the brain's organization in a multidimensional connectivity gradient space. However, how the brain's morphometric organization changes across the human lifespan remains unclear. Here, leveraging structural magnetic resonance imaging scans from 1,790 healthy individuals aged 8 to 89 years, we investigated age-related global, within- and between-network dispersions to reveal the segregation and integration of brain networks from 3D manifolds based on morphometric similarity network (MSN), combining multiple features conceptualized as a "fingerprint" of an individual's brain. Developmental trajectories of global dispersion unfolded along patterns of molecular brain organization, such as acetylcholine receptor. Communities were increasingly dispersed with age, reflecting more disassortative morphometric similarity profiles within a community. Increasing within-network dispersion of primary motor and association cortices mediated the influence of age on the cognitive flexibility of executive functions. We also found that the secondary sensory cortices were decreasingly dispersed with the rest of the cortices during aging, possibly indicating a shift of secondary sensory cortices across the human lifespan from an extreme to a more central position in 3D manifolds. Together, our results reveal the age-related segregation and integration of MSN from the perspective of a multidimensional gradient space, providing new insights into lifespan changes in multiple morphometric features of the brain, as well as the influence of such changes on cognitive performance.

Exosomal long non-coding RNA TRPM2-AS promotes angiogenesis in gallbladder cancer through interacting with PABPC1 to activate NOTCH1 signaling pathway.

BACKGROUND: Abnormal angiogenesis is crucial for gallbladder cancer (GBC) tumor growth and invasion, highlighting the importance of elucidating the mechanisms underlying this process. LncRNA (long non-coding RNA) is widely involved in the malignancy of GBC. However, conclusive evidence confirming the correlation between lncRNAs and angiogenesis in GBC is lacking. METHODS: LncRNA sequencing was performed to identify the differentially expressed lncRNAs. RT-qPCR, western blot, FISH, and immunofluorescence were used to measure TRPM2-AS and NOTCH1 signaling pathway expression in vitro. Mouse xenograft and lung metastasis models were used to evaluate the biological function of TRPM2-AS during angiogenesis in vivo. EDU, transwell, and tube formation assays were used to detect the angiogenic ability of HUVECs. RIP, RAP, RNA pull-down, dual-luciferase reporter system, and mass spectrometry were used to confirm the interaction between TRPM2-AS, IGF2BP2, NUMB, and PABPC1. RESULTS: TRPM2-AS was upregulated in GBC tissues and was closely related to angiogenesis and poor prognosis in patients with GBC. The high expression level and stability of TRPM2-AS benefited from m6A modification, which is recognized by IGF2BP2. In terms of exerting pro-angiogenic effects, TRPM2-AS loaded with exosomes transported from GBC cells to HUVECs enhanced PABPC1-mediated NUMB expression inhibition, ultimately promoting the activation of the NOTCH1 signaling pathway. PABPC1 inhibited NUMB mRNA expression through interacting with AGO2 and promoted miR-31-5p and miR-146a-5p-mediated the degradation of NUMB mRNA. The NOTCH signaling pathway inhibitor DAPT inhibited GBC tumor angiogenesis, and TRPM2-AS knockdown enhanced this effect. CONCLUSIONS: TRPM2-AS is a novel and promising biomarker for GBC angiogenesis that promotes angiogenesis by facilitating the activation of the NOTCH1 signaling pathway. Targeting TRPM2-AS opens further opportunities for future GBC treatments.

Role of soluble epoxide hydrolase in pain and depression comorbidity.

The coexistence of chronic pain and depression in clinical practice places a substantial social burden and profoundly impacts in patients. Although a clear correlation exists, the underlying mechanism of comorbidity between chronic pain and depression remains elusive. Research conducted in recent decades has uncovered that soluble epoxide hydrolase, a pivotal enzyme in the metabolism of polyunsaturated fatty acids, plays a crucial role in inflammation. Interestingly, this enzyme is intricately linked to the development of both pain and depression. With this understanding, this review aims to summarize the roles of soluble epoxide hydrolase in pain, depression, and their comorbidity. Simultaneously, we will also explore the underlying mechanisms, providing guidance for future research and drug development.

Integrative analyses of bulk and single-cell transcriptomics reveals the infiltration and crosstalk of cancer-associated fibroblasts as a novel predictor for prognosis and microenvironment remodeling in intrahepatic cholangiocarcinoma.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is a highly malignant neoplasm and characterized by desmoplastic matrix. The heterogeneity and crosstalk of tumor microenvironment remain incompletely understood. METHODS: To address this gap, we performed Weighted Gene Co-expression Network Analysis (WGCNA) to identify and construct a cancer associated fibroblasts (CAFs) infiltration biomarker. We also depicted the intercellular communication network and important receptor-ligand complexes using the single-cell transcriptomics analysis of tumor and Adjacent normal tissue. RESULTS: Through the intersection of TCGA DEGs and WGCNA module genes, 784 differential genes related to CAFs infiltration were obtained. After a series of regression analyses, the CAFs score was generated by integrating the expressions of EVA1A, APBA2, LRRTM4, GOLGA8M, BPIFB2, and their corresponding coefficients. In the TCGA-CHOL, GSE89748, and 107,943 cohorts, the high CAFs score group showed unfavorable survival prognosis (p < 0.001, p = 0.0074, p = 0.028, respectively). Additionally, a series of drugs have been predicted to be more sensitive to the high-risk group (p < 0.05). Subsequent to dimension reduction and clustering, thirteen clusters were identified to construct the single-cell atlas. Cell-cell interaction analysis unveiled significant enhancement of signal transduction in tumor tissues, particularly from fibroblasts to malignant cells via diverse pathways. Moreover, SCENIC analysis indicated that HOXA5, WT1, and LHX2 are fibroblast specific motifs. CONCLUSIONS: This study reveals the key role of fibroblasts - oncocytes interaction in the remodeling of the immunosuppressive microenvironment in intrahepatic cholangiocarcinoma. Subsequently, it may trigger cascade activation of downstream signaling pathways such as PI3K-AKT and Notch in tumor, thus initiating tumorigenesis. Targeted drugs aimed at disrupting fibroblasts-tumor cell interaction, along with associated enrichment pathways, show potential in mitigating the immunosuppressive microenvironment that facilitates tumor progression.

Prognostic Significance of Tumor Necrosis in Patients with Gallbladder Carcinoma Undergoing Curative-Intent Resection.

BACKGROUND: Tumor necrosis has been indicated to correlate with dismal survival outcomes of a variety of solid tumors. However, the significance and prognostic value of tumor necrosis remain unclear in gallbladder carcinoma. The aim of this research is to explore the relationships between necrosis with long-term survival and tumor-related biological characteristics of patients with gallbladder carcinoma. PATIENTS AND METHODS: Patients with gallbladder carcinoma who accepted curative-intent resection in West China Hospital of Sichuan University (China) between January 2010 and December 2021 were retrospectively analyzed. Tumor necrosis was determined by staining the patient's original tissue sections with hematoxylin and eosin. Based on the presence of tumor necrosis, the pathologic features and survival outcomes were compared. RESULTS: This study enrolled 213 patients with gallbladder carcinoma who underwent curative-intent surgery, of whom 89 had tumor necrosis. Comparative analyses indicated that patients with tumor necrosis had more aggressive clinicopathological features, such as larger tumor size (p = 0.002), poorer tumor differentiation (p = 0.029), more frequent vascular invasion (p < 0.001), presence of lymph node metastasis (p = 0.014), and higher tumor status (p = 0.01), and experienced poorer survival. Univariate and multivariate analyses revealed that tumor necrosis was an independent prognostic factor for overall survival (multivariate: HR 1.651, p = 0.026) and disease-free survival (multivariate: HR 1.589, p = 0.040). CONCLUSIONS: Tumor necrosis can be considered as an independent predictive factor for overall survival and disease-free survival among individuals with gallbladder carcinoma, which was a valuable pathologic parameter.

Designing a structure-function alphabet of helix based on reduced amino acid clusters.

Several simple secondary structures could form complex and diverse functional proteins, meaning that secondary structures may contain a lot of hidden information and are arranged according to certain principles, to carry enough information of functional specificity and diversity. However, these inner information and principles have not been understood systematically. In our study, we designed a structure-function alphabet of helix based on reduced amino acid clusters to describe the typical features of helices and delve into the information. Firstly, we selected 480 typical helices from membrane proteins, zymoproteins, transcription factors, and other proteins to define and calculate the interval range, and the helices are classified in terms of hydrophilicity, charge and length: (1) hydrophobic helix (≤43%), amphiphilic helix (43%∼71%), and hydrophilic helix (≥71%). (2) positive helix, negative helix, electrically neutral helix and uncharged helix. (3) short helix (≤8 aa), medium-length helix (9-28 aa), and long helix (≥29 aa). Then, we designed an alphabet containing 36 triplet codes according to the above classification, so that the main features of each helix can be represented by only three letters. This alphabet not only preliminarily defined the helix characteristics, but also greatly reduced the informational dimension of protein structure. Finally, we present an application example to demonstrate the value of the structure-function alphabet in protein functional determination and differentiation.

The role of CD38 in inflammation-induced depression-like behavior and the antidepressant effect of (R)-ketamine.

CD38 is involved in immune responses, cell proliferation, and has been identified in the brain, where it is implicated in inflammation processes and psychiatric disorders. We hypothesized that dysfunctional CD38 activity in the brain may contribute to the pathogenesis of depression. To investigate the underlying mechanisms, we used a lipopolysaccharide (LPS)-induced depression-like model and conducted behavioral tests, molecular and morphological methods, along with optogenetic techniques. We microinjected adeno-associated virus into the hippocampal CA3 region with stereotaxic instrumentation. Our results showed a marked increase in CD38 expression in both the hippocampus and cortex of LPS-treated mice. Additionally, pharmacological inhibition and genetic knockout of CD38 effectively alleviated neuroinflammation, microglia activation, synaptic defects, and Sirt1/STAT3 signaling, subsequently improving depression-like behaviors. Moreover, optogenetic activation of glutamatergic neurons of hippocampal CA3 reduced the susceptibility of mice to depression-like behaviors, accompanied by reduced CD38 expression. We also found that (R)-ketamine, which displayed antidepressant effects, was linked to its anti-inflammatory properties by suppressing increased CD38 expression and reversing synaptic defects. In conclusion, hippocampal CD38 is closely linked to depression-like behaviors in an inflammation model, highlighting its potential as a therapeutic target for antidepressant development.

Hydrophobic Solid Photothermal Slippery Surfaces with Rapid Self-repairing, Dual Anti-icing/Deicing, and Excellent Stability Based on Paraffin and Etching.

Ice and snow disasters have greatly affected both the global economy and human life, and the search for efficient and stable anti-icing/deicing coatings has become the main goal of much research. Currently, the development and application of anti-icing/deicing coatings are severely limited due to their complex preparation, structural fragility, and low stability. This work presents a method for preparing hydrophobic solid photothermal slippery surfaces (SPSS) that exhibit rapid self-repairing, dual anti-icing/deicing properties, and remarkable stability. A photothermal layer of copper oxide (CuO) was prepared by using chemical deposition and etching techniques. The layer was then impregnated with stearic acid and solid paraffin wax to create a hydrophobic solid photothermal slippery surface. This solves the issue of low stability on superhydrophobic surfaces caused by fragile and irretrievable micro/nanostructures. In addition, the underlying photothermal superhydrophobic surface provides good anti-icing/deicing properties even if the paraffin on the surface evaporates or is lost during operation. The findings indicate that when subjected to simulated light irradiation, the coating's surface temperature increases to 80 °C within 12 min. The self-repair process is completed rapidly in 170 s, and at -15 °C, it takes only 201 s for the ice on the surface to melt completely. The surface underneath the paraffin exhibited good superhydrophobic properties, with a contact angle (CA) of 154.1° and a sliding angle (SA) of 6.8° after the loss of paraffin. Simultaneously, the surface's mechanical stability and durability, along with its self-cleaning and antifouling properties, enhance its service life. These characteristics provide promising opportunities for practical applications that require long-term anti-icing/deicing surfaces.

FOXO1 induced fatty acid oxidation in hepatic cells by targeting ALDH1L2.

BACKGROUND AND AIM: Lipid metabolism disorder is the primary feature of numerous refractory chronic diseases. Fatty acid oxidation, an essential aerobic biological process, is closely related to the progression of NAFLD. The forkhead transcription factor FOXO1 has been reported to play an important role in lipid metabolism. However, the molecular mechanism through which FOXO1 regulates fatty acid oxidation remains unclear. METHODS: Transcriptomic analysis was performed to examine the cellular expression profile to determine the functional role of FOXO1 in HepG2 cells with palmitic acid (PA)-induced lipid accumulation. FOXO1-binding motifs at the promoter region of aldehyde dehydrogenase 1 family member L2 (ALDH1L2) were predicted via bioinformatic analysis and confirmed via luciferase reporter assay. Overexpression of ALDH1L2 was induced to recover the impaired fatty acid oxidation in FOXO1-knockout cells. RESULTS: Knockout of FOXO1 aggravated lipid deposition in hepatic cells. Transcriptomic profiling revealed that knockout of FOXO1 increased the expression of genes associated with fatty acid synthesis but decreased the expression of carnitine palmitoyltransferase1a (CPT1α) and adipose triglyceride lipase (ATGL), which contribute to fatty acid oxidation. Mechanistically, FOXO1 was identified as a transcription factor of ALDH1L2. Knockout of FOXO1 significantly decreased the protein expression of ALDH1L2 and CPT1α in vitro and in vivo. Furthermore, overexpression of ALDH1L2 restored fatty acid oxidation in FOXO1-knockout cells. CONCLUSION: The findings of this study indicate that FOXO1 modulates fatty acid oxidation by targeting ALDH1L2.

Spatiotemporal topological correspondence between blood oxygenation and glucose metabolism revealed by simultaneous fPET-fMRI in brain's white matter.

White matter (WM) makes up half of the human brain. Compelling functional MRI evidence indicates that white matter exhibits neural activation and synchronization via a hemodynamic window. However, the neurometabolic underpinnings of white matter temporal synchronization and spatial topology remain unknown. By leveraging concurrent [18F]FDG-fPET and blood-oxygenation-level-dependent-fMRI, we demonstrated the temporal and spatial correspondences between blood oxygenation and glucose metabolism in the human brain white matter. In the temporal scale, we found that blood-oxygenation-level-dependent signals shared mutual information with FDG signals in the default-mode, visual, and sensorimotor-auditory networks. For spatial distribution, the blood-oxygenation-level-dependent functional networks in white matter were accompanied by substantial correspondence of FDG functional connectivity at different topological scales, including degree centrality and global gradients. Furthermore, the content of blood-oxygenation-level-dependent fluctuations in the white matter default-mode network was aligned and liberal with the FDG graph, suggesting the freedom of default-mode network neuro-dynamics, but the constraint by metabolic dynamics. Moreover, the dissociation of the functional gradient between blood-oxygenation-level-dependent and FDG connectivity specific to the white matter default-mode network revealed functional heterogeneities. Together, the results showed that brain energy metabolism was closely coupled with blood oxygenation in white matter. Comprehensive and complementary information from fMRI and fPET might therefore help decode brain white matter functions.

Systematically mapping gray matter abnormal patterns in drug-naïve first-episode schizophrenia from childhood to adolescence.

BACKGROUND: Schizophrenia originates early in neurodevelopment, underscoring the need to elaborate on anomalies in the still maturing brain of early-onset schizophrenia (EOS). METHODS: Gray matter (GM) volumes were evaluated in 94 antipsychotic-naïve first-episode EOS patients and 100 typically developing (TD) controls. The anatomical profiles of changing GM deficits in EOS were detected using 2-way analyses of variance with diagnosis and age as factors, and its timing was further charted using stage-specific group comparisons. Interregional relationships of GM alterations were established using structural covariance network analyses. RESULTS: Antagonistic interaction results suggested dynamic GM abnormalities of the left fusiform gyrus, inferior occipital gyrus, and lingual gyrus in EOS. These regions comprise a dominating part of the ventral stream, a ventral occipitotemporal (vOT) network engaged in early social information processing. GM abnormalities were mainly located in the vOT regions in childhood-onset patients, whereas in the rostral prefrontal cortex (rPFC) in adolescent-onset patients. Moreover, compared with TD controls, patients' GM synchronization with the ventral stream was disrupted in widespread high-order social perception regions including the rPFC and salience network. CONCLUSIONS: The current findings reveal age-related anatomical abnormalities of the social perception system in pediatric patients with schizophrenia.

RaacFold: a webserver for 3D visualization and analysis of protein structure by using reduced amino acid alphabets.

Protein structure exhibits greater complexity and diversity than DNA structure, and usually affects the interpretation of the function, interactions and biological annotations. Reduced amino acid alphabets (Raaa) exhibit a powerful ability to decrease protein complexity and identify functional conserved regions, which motivated us to create RaacFold. The RaacFold provides 687 reduced amino acid clusters (Raac) based on 58 reduction methods and offers three analysis tools: Protein Analysis, Align Analysis, and Multi Analysis. The Protein Analysis and Align Analysis provide reduced representations of sequence-structure according to physicochemical similarities and computational biology strategies. With the simplified representations, the protein structure can be viewed more concise and clearer to capture biological insight than the unreduced structure. Thus, the design of artificial protein will be more convenient, and redundant interference is avoided. In addition, Multi Analysis allows users to explore biophysical variation and conservation in the evolution of protein structure and function. This supplies important information for the identification and exploration of the nonhomologous functions of paralogs. Simultaneously, RaacFold provides powerful 2D and 3D rendering performance with advanced parameters for sequences, structures, and related annotations. RaacFold is freely available at http://bioinfor.imu.edu.cn/raacfold.

CSCD2: an integrated interactional database of cancer-specific circular RNAs.

The significant function of circRNAs in cancer was recognized in recent work, so a well-organized resource is required for characterizing the interactions between circRNAs and other functional molecules (such as microRNA and RNA-binding protein) in cancer. We previously developed cancer-specific circRNA database (CSCD), a comprehensive database for cancer-specific circRNAs, which is widely used in circRNA research. Here, we updated CSCD to CSCD2 (http://geneyun.net/CSCD2 or http://gb.whu.edu.cn/CSCD2), which includes significantly more cancer-specific circRNAs identified from a large number of human cancer and normal tissues/cell lines. CSCD2 contains >1000 samples (825 tissues and 288 cell lines) and identifies a large number of circRNAs: 1 013 461 cancer-specific circRNAs, 1 533 704 circRNAs from only normal samples and 354 422 circRNAs from both cancer and normal samples. In addition, CSCD2 predicts potential miRNA-circRNA and RBP-circRNA interactions using binding motifs from >200 RBPs and 2000 microRNAs. Furthermore, the potential full-length and open reading frame sequence of these circRNAs were also predicted. Collectively, CSCD2 provides a significantly enhanced resource for exploring the function and regulation of circRNAs in cancer.

Molecular Regulation of Thermogenic Mechanisms in Beige Adipocytes.

Adipose tissue is conventionally recognized as a metabolic organ responsible for storing energy. However, a proportion of adipose tissue also functions as a thermogenic organ, contributing to the inhibition of weight gain and prevention of metabolic diseases. In recent years, there has been significant progress in the study of thermogenic fats, particularly brown adipose tissue (BAT). Despite this progress, the mechanism underlying thermogenesis in beige adipose tissue remains highly controversial. It is widely acknowledged that beige adipose tissue has three additional thermogenic mechanisms in addition to the conventional UCP1-dependent thermogenesis: Ca2+ cycling thermogenesis, creatine substrate cycling thermogenesis, and triacylglycerol/fatty acid cycling thermogenesis. This paper delves into these three mechanisms and reviews the latest advancements in the molecular regulation of thermogenesis from the molecular genetic perspective. The objective of this review is to provide readers with a foundation of knowledge regarding the beige fats and a foundation for future research into the mechanisms of this process, which may lead to the development of new strategies for maintaining human health.

Birinapant Reshapes the Tumor Immunopeptidome and Enhances Antigen Presentation.

Birinapant, an antagonist of the inhibitor of apoptosis proteins, upregulates MHCs in tumor cells and displays a better tumoricidal effect when used in combination with immune checkpoint inhibitors, indicating that Birinapant may affect the antigen presentation pathway; however, the mechanism remains elusive. Based on high-resolution mass spectrometry and in vitro and in vivo models, we adopted integrated genomics, proteomics, and immunopeptidomics strategies to study the mechanism underlying the regulation of tumor immunity by Birinapant from the perspective of antigen presentation. Firstly, in HT29 and MCF7 cells, Birinapant increased the number and abundance of immunopeptides and source proteins. Secondly, a greater number of cancer/testis antigen peptides with increased abundance and more neoantigens were identified following Birinapant treatment. Moreover, we demonstrate the existence and immunogenicity of a neoantigen derived from insertion/deletion mutation. Thirdly, in HT29 cell-derived xenograft models, Birinapant administration also reshaped the immunopeptidome, and the tumor exhibited better immunogenicity. These data suggest that Birinapant can reshape the tumor immunopeptidome with respect to quality and quantity, which improves the presentation of CTA peptides and neoantigens, thus enhancing the immunogenicity of tumor cells. Such changes may be vital to the effectiveness of combination therapy, which can be further transferred to the clinic or aid in the development of new immunotherapeutic strategies to improve the anti-tumor immune response.

Investigation the nutritional properties of Auricularia auricula pulp fermented with Lactobacillus strains and their effects on gut microbiota.

BACKGROUND: Auricularia auricula is rich in bioactive components, and microbial fermentation can further dramatically increase its content and bioavailability. However, there are few studies on the relationship between fermented A. auricula pulp (FAAP) and gut microbiota. In this study, standard strains Lactobacillus plantarum 21801 and 21805 purchased from the China Center of Industrial Culture Collection were used to ferment A. auricula pulp at a ratio of 2:1, with an inoculum of 5%, a fermentation temperature of 31 °C, and a fermentation time of 22 h. The nutritional properties, aroma, and color of FAAP and their effects on the body characteristics of mice and the structure and abundance of gut microbiota are discussed. RESULTS: The results showed that, compared with A. auricula pulp, FAAP significantly increased the nutritional properties while maintaining favorable sensory quality and flavor profiles. Among them, the content of total polyphenols and total flavonoids reached 22.04 µg mL-1 and 20.56 µg mL-1 respectively, and the 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid free-radical scavenging rate increased to 73.21%. The consumption of FAAP had no negative effects on weight or liver and kidney function in mice and dramatically enhanced the antioxidant capacity in the liver and serum. The production of short-chain fatty acids in the gut was promoted, the relative abundance of beneficial bacteria (Lactobacillus, Bifidobacterium, norank_f__Muribaculaceae and unclassified_f__Lachnospiraceae) increased, and the growth of some pathogenic bacteria (Helicobacter, Mucispirillum, and Alloprevotella) was inhibited. CONCLUSION: These findings demonstrate that FAAP is rich in nutrients and has unique functional properties that promote host health and regulate the gut microbiota. © 2023 Society of Chemical Industry.

[Effects of 4-hydroxy-2(3H)-benzoxazolone on proliferation and apoptosis of pancreatic cancer L3.6 cells].

This study explored the effects of 4-hydroxy-2(3H)-benzoxazolone(HBOA) on the proliferation and apoptosis of pancreatic cancer cells and its molecular mechanism. The L3.6 cells cultured in vitro were treated with HBOA of 0-1.0 mmol·L~(-1). The cell viability was detected by the cell counting kit-8(CCK-8) method, and the half inhibitory concentration(IC_(50)) was analyzed to determine the drug concentration and time. The cell morphology was observed under an inverted microscope and by acridine orange(AO) staining. The ability of proliferation and self-renewal were evaluated through live cell counting and colony formation experiments. The cell cycle progression and cell apoptosis rate were detected by flow cytometry. The morphology of cell apoptosis was observed by scanning electron microscopy. The mRNA expression of proliferating cell nuclear antigen(PCNA), cyclinA1, cyclinA2, cyclin dependent kinase 2(CDK2), and cyclin dependent kinase inhibitor 1A(P21) were determined by qPCR. The level of reactive oxygen species(ROS), lipid peroxide, and mitochondrial membrane potential were measured by flow cytometry. The activity of protein kinase B(Akt)/mammalian target of rapamycin(mTOR) signaling pathway was detected by Western blot. Compared with the control group, the cells treated with HBOA exhibited a significant decrease in viability. Then the optimal concentration and intervention time of HBOA were determined to be 0.4 mmol·L~(-1), 0.6 mmol·L~(-1), and 48 h. Compared with the control group, groups with HBOA of 0.4 mmol·L~(-1 )and 0.6 mmol·L~(-1) showed a significant suppression in cell proliferation and colony formation ability, down-regulated mRNA of PCNA, cyclinA1, cyclinA2, and CDK2, up-regulated P21 mRNA, S-phase cell cycle arrest, and increased cell apoptosis rate. There was an appearance of apoptotic bodies, increased ROS and lipid peroxide, decreased mitochondrial membrane potential(with a significant decrease in 0.6 mmol·L~(-1) group), and down-regulated p-Akt and p-mTOR proteins. The results show that HBOA inhibits the proliferation of pancreatic cancer L3.6 cells and induces cell apoptosis, which may be related to the increase in reactive oxygen species and the inhibition of the Akt/mTOR pathway.

ADEIP: an integrated platform of age-dependent expression and immune profiles across human tissues.

Gene expression and immune status in human tissues are changed with aging. There is a need to develop a comprehensive platform to explore the dynamics of age-related gene expression and immune profiles across tissues in genome-wide studies. Here, we collected RNA-Seq datasets from GTEx project, containing 16 704 samples from 30 major tissues in six age groups ranging from 20 to 79 years old. Dynamic gene expression along with aging were depicted and gene set enrichment analysis was performed among those age groups. Genes from 34 known immune function categories and immune cell compositions were investigated and compared among different age groups. Finally, we integrated all the results and developed a platform named ADEIP (http://gb.whu.edu.cn/ADEIP or http://geneyun.net/ADEIP), integrating the age-dependent gene expression and immune profiles across tissues. To demonstrate the usage of ADEIP, we applied two datasets: severe acute respiratory syndrome coronavirus 2 and human mesenchymal stem cells-assoicated genes. We also included the expression and immune dynamics of these genes in the platform. Collectively, ADEIP is a powerful platform for studying age-related immune regulation in organogenesis and other infectious or genetic diseases.

Cortical morphometric vulnerability to generalised epilepsy reflects chromosome- and cell type-specific transcriptomic signatures.

AIMS: Generalised epilepsy is thought to involve distributed brain networks. However, the molecular and cellular factors that render different brain regions more vulnerable to epileptogenesis remain largely unknown. We aimed to investigate epilepsy-related morphometric similarity network (MSN) abnormalities at the macroscale level and their relationships with microscale gene expressions at the microscale level. METHODS: We compared the MSN of genetic generalised epilepsy with generalised tonic-clonic seizure patients (GGE-GTCS, n = 101) to demographically matched healthy controls (HC, n = 150). Cortical MSNs were estimated by combining seven morphometric features derived from structural magnetic resonance imaging for each individual. Regional gene expression profiles were derived from brain-wide microarray measurements provided by the Allen Human Brain Atlas. RESULTS: GGE-GTCS patients exhibited decreased regional MSNs in primary motor, prefrontal and temporal regions and increases in occipital, insular and posterior cingulate cortices, when compared with the HC. These case-control neuroimaging differences were validated using split-half analyses and were not affected by medication or drug response effects. When assessing associations with gene expression, genes associated with GGE-GTCS-related MSN differences were enriched in several biological processes, including 'synapse organisation', 'neurotransmitter transport' pathways and excitatory/inhibitory neuronal cell types. Collectively, the GGE-GTCS-related cortical vulnerabilities were associated with chromosomes 4, 5, 11 and 16 and were dispersed bottom-up at the cellular, pathway and disease levels, which contributed to epileptogenesis, suggesting diverse neurobiologically relevant enrichments in GGE-GTCS. CONCLUSIONS: By bridging the gaps between transcriptional signatures and in vivo neuroimaging, we highlighted the importance of using MSN abnormalities of the human brain in GGE-GTCS patients to investigate disease-relevant genes and biological processes.

Triglyceride-glucose index is associated with recurrent revascularization in patients with type 2 diabetes mellitus after percutaneous coronary intervention.

BACKGROUND: The Triglyceride-glucose (TyG) index, as a surrogate marker of insulin resistance, is independently associated with the severity of coronary artery lesions and the prognosis of coronary heart disease. The investigation aimed to explore the relationship between the TyG index and recurrent revascularization in individuals with type 2 diabetes mellitus (T2DM) resulting from the progression of lesions or in-stent restenosis (ISR) after percutaneous coronary intervention (PCI). METHOD: A total of 633 patients who met the inclusion and exclusion criteria were enrolled and divided into three groups based on the tertiles of the TyG index. The primary endpoint was recurrent revascularization resulting from the progression of lesions or ISR. All-cause death was considered as the competing risk event. Competing risk analysis and Cox regression analysis for predicting recurrent revascularization after PCI were conducted stepwise. Variables were standardized to make the hazard ratio (HR), subdistribution hazard ratio (SHR) and corresponding 95% CI more consistent prior to being used for fitting the multivariate risk model. The predictive ability of the TyG index was evaluated using several measures, including the ROC curve, likelihood ratio test, Akaike's information criteria, category-free continuous net reclassification improvement (cNRI > 0), and integrated discrimination improvement (IDI). Internal validation was conducted through bootstrapping with 1000 resamples. RESULTS: During a median follow-up period of 18.33 months, a total of 64 (10.11%) patients experienced recurrent revascularization, including 55 cases of lesion progression and 9 cases of in-stent restenosis. After controlling for competitive risk events, the TyG index was independently associated with a higher risk of recurrent revascularization [SHR:1.4345, (95% CI 1.1458-1.7959), P = 0.002]. The likelihood ratio test and Akaike's information criteria showed that the TyG index significantly improves the prognostic ability. Additionally, adding the TyG index improved the ability of the established risk model in predicting recurrent revascularization, indicated by a C-index of 0.759 (95% CI 0.724-0.792, P < 0.01), with a cNRI > 0 of 0.170 (95% CI 0.023-0.287, P < 0.05), and an IDI of 0.024 (95% CI 0.009-0.039, P = 0.002). These results remained consistent when the models containing TyG index were confirmed using an internal bootstrap validation method. CONCLUSION: The findings highlight the potential of the TyG index as a predictor of recurrent revascularization. Lesion progression emerged as the primary contributor to recurrent revascularization instead of in-stent restenosis. The incorporation of the TyG index into risk prediction models is likely to be beneficial for accurate risk stratification in order to improve prognosis.