Extended Black Hole Thermodynamics from Extended Iyer-Wald Formalism.

In recent years, there has been significant interest in the field of extended black hole thermodynamics, where the cosmological constant and/or other coupling parameters are treated as thermodynamic variables. Drawing inspiration from the Iyer-Wald formalism, which reveals the intrinsic and universal structure of conventional black hole thermodynamics, we illustrate that a proper extension of this formalism also unveils the underlying theoretical structure of extended black hole thermodynamics. As a remarkable consequence, for any gravitational theory described by a diffeomorphism invariant action, it is always possible to construct a consistent extended thermodynamics using this extended formalism.

Black Hole Solutions as Topological Thermodynamic Defects.

In this Letter, employing the generalized off-shell free energy, we treat black hole solutions as defects in the thermodynamic parameter space. The results show that the positive and negative winding numbers corresponding to the defects indicate the local thermodynamical stable and unstable black hole solutions, respectively. The topological number defined as the sum of the winding numbers for all the black hole branches at an arbitrary given temperature is found to be a universal number independent of the black hole parameters. Moreover, this topological number only depends on the thermodynamic asymptotic behaviors of the black hole temperature at small and large black hole limits. Different black hole systems are characterized by three classes via this topological number. This number could help us in better understanding the black hole thermodynamics and, further, shed new light on the fundamental nature of quantum gravity.

[Biological functions of CREB/ATF bZIP transcription factor in metabolism and cell growth].

Nutrient overload-caused deregulation of glucose and lipid metabolism leads to insulin resistance and metabolic disorders, which increases the risk of several types of cancers. CREB/ATF bZIP transcription factor (CREBZF), a novel transcription factor of the ATF/CREB family, has emerged as a critical mechanism bridging the gap between metabolism and cell growth. CREBZF forms a heterodimer with other proteins and functions as a coregulator for gene expression. CREBZF deficiency in the liver attenuates hepatic steatosis in high fat diet-induced insulin-resistant mice, while the expression levels of CREBZF are increased in the livers of obese mice and humans with hepatic steatosis. Intriguingly, CREBZF also regulates cell proliferation and apoptosis via interaction with several transcription factors including STAT3, p53 and HCF-1. Knockout of CREBZF in hepatocytes results in enhanced cell cycle progression and proliferation capacity in mice. Here we highlight how the CREBZF signaling network contributes to the deregulation of metabolism and cell growth, and discuss the potential of targeting these molecules for the treatment of insulin resistance, diabetes, fatty liver disease and cancer.

Repulsive Interactions and Universal Properties of Charged Anti-de Sitter Black Hole Microstructures.

The Ruppeiner geometry of thermodynamic fluctuations provides a powerful diagnostic of black hole microstructures. We investigate this for charged anti-de Sitter black holes and find that, while an attractive microstructure interaction dominates for most parameter ranges, a weak repulsive interaction dominates for small black holes of high temperature. This unique property distinguishes the black hole system from that of a van der Waals fluid, where only attractive microstructure interactions are found. We also find two other novel universal properties for charged black holes. One is that the repulsive interaction is independent of the black hole charge and temperature. The other is that the behavior of the Ruppeiner curvature scalar near criticality is characterized by a dimensionless constant that is identical to that for a van der Waals fluid, providing us with new insight into black hole microstructures.

Highly efficient conversion of 1-cyanocycloalkaneacetonitrile using a "super nitrilase mutant".

Nitrilase is the member of carbon-nitrogen hydrogen hydrolase superfamily, which has been widely used for the hydrolysis of nitriles into corresponding carboxylic acids. But most nitrilases are plagued by product inhibition in the industrial application. In this study, a "super nitrilase mutant" of nitrilase with high activity, thermostability and improved product tolerance from Acidovorax facilis ZJB09122 was characterized. Then, an efficient process was developed by employing the whole cell of recombinant E. coli for the conversion of high concentration of 1-cyanocyclohexylacetonitrile-to-1-cyanocyclohexaneacetic acid, an important intermediate of gabapentin. Under the optimized conditions, the higher substrate concentrations such as 1.3 M, 1.5 M and 1.8 M could be hydrolyzed by 13.58 g DCW/L with outstanding productivity (> 740 g/L/day). This study developed a highly efficient bioprocess for the preparation of 1-cyanocyclohexaneacetic acid which has the great potential for industrial application.

Erratum: Insight into the Microscopic Structure of an AdS Black Hole from a Thermodynamical Phase Transition [Phys. Rev. Lett. 115, 111302 (2015)].

This corrects the article DOI: 10.1103/PhysRevLett.115.111302.

Insight into the microscopic structure of an AdS black hole from a thermodynamical phase transition.

Comparing with an ordinary thermodynamic system, we investigate the possible microscopic structure of a charged anti-de Sitter black hole completely from the thermodynamic viewpoint. The number density of the black hole molecules is introduced to measure the microscopic degrees of freedom of the black hole. We found that the number density suffers a sudden change accompanied by a latent heat when the black hole system crosses the small-large black hole coexistence curve, while when the system passes the critical point, it encounters a second-order phase transition with a vanishing latent heat due to the continuous change of the number density. Moreover, the thermodynamic scalar curvature suggests that there is a weak attractive interaction between two black hole molecules. These phenomena might cast new insight into the underlying microscopic structure of a charged anti-de Sitter black hole.

Exposure to 3G mobile phone signals does not affect the biological features of brain tumor cells.

BACKGROUND: The increase in mobile phone use has generated concerns about possible risks to human health, especially the development of brain tumors. Whether tumor patients should continue to use mobile telephones has remained unclear because of a paucity of information. Herein, we investigated whether electromagnetic fields from mobile phones could alter the biological features of human tumor cells and act as a tumor-promoting agent. METHODS: Human glioblastoma cell lines, U251-MG and U87-MG, were exposed to 1950-MHz time division-synchronous code division multiple access (TD-SCDMA) at a specific absorption rate (maximum SAR = 5.0 W/kg) for 12, 24, and 48 h. Cell morphologies and ultra-structures were observed by microscopy and the rates of apoptosis and cell cycle progression were monitored by flow cytometry. Additionally, cell growth was determined using the CKK-8 assay, and the expression levels of tumor and apoptosis-related genes and proteins were analyzed by real-time PCR and western blotting, respectively. Tumor formation and invasiveness were measured using a tumorigenicity assay in vivo and migration assays in vitro. RESULTS: No significant differences in either biological features or tumor formation ability were observed between unexposed and exposed glioblastoma cells. Our data showed that exposure to 1950-MHz TD-SCDMA electromagnetic fields for up to 48 h did not act as a cytotoxic or tumor-promoting agent to affect the proliferation or gene expression profile of glioblastoma cells. CONCLUSIONS: Our findings implied that exposing brain tumor cells in vitro for up to 48 h to 1950-MHz continuous TD-SCDMA electromagnetic fields did not elicit a general cell stress response.

Endogenous Retroviruses Unveiled: A Comprehensive Review of Inflammatory Signaling/Senescence-Related Pathways and Therapeutic Strategies.

Endogenous retroviruses (ERVs), a subset of genomic transposable elements (TEs) in a broader sense, have remained latent within mammalian genomes for tens of millions of years. These genetic elements are typically in a silenced state due to stringent regulatory mechanisms. However, under specific conditions, they can become activated, triggering inflammatory responses through diverse mechanisms. This activation has been shown to play a potential role in various neurological disorders, tumors, and cellular senescence. Consequently, the regulation of ERV expression through various methods holds promise for clinical applications in disease treatment. ERVs also engage in interactions with a variety of exogenous viruses, thereby influencing the outcomes of viral infectious diseases. This article comprehensively reviews the pathogenic cascade of ERVs, encompassing activation, inflammation, associated diseases, senescence, and interplay with viruses. Additionally, it outlines therapeutic strategies targeting ERVs with the aim of offering novel research directions for understanding the relationship between ERVs and diseases, along with corresponding treatment modalities.

Extracellular cold-inducible RNA-binding protein mediated neuroinflammation and neuronal apoptosis after traumatic brain injury.

Background: Extracellular cold-inducible RNA-binding protein (eCIRP) plays a vital role in the inflammatory response during cerebral ischaemia. However, the potential role and regulatory mechanism of eCIRP in traumatic brain injury (TBI) remain unclear. Here, we explored the effect of eCIRP on the development of TBI using a neural-specific CIRP knockout (KO) mouse model to determine the contribution of eCIRP to TBI-induced neuronal injury and to discover novel therapeutic targets for TBI. Methods: TBI animal models were generated in mice using the fluid percussion injury method. Microglia or neuron lines were subjected to different drug interventions. Histological and functional changes were observed by immunofluorescence and neurobehavioural testing. Apoptosis was examined by a TdT-mediated dUTP nick end labelling assay in vivo or by an annexin-V assay in vitro. Ultrastructural alterations in the cells were examined via electron microscopy. Tissue acetylation alterations were identified by non-labelled quantitative acetylation via proteomics. Protein or mRNA expression in cells and tissues was determined by western blot analysis or real-time quantitative polymerase chain reaction. The levels of inflammatory cytokines and mediators in the serum and supernatants were measured via enzyme-linked immunoassay. Results: There were closely positive correlations between eCIRP and inflammatory mediators, and between eCIRP and TBI markers in human and mouse serum. Neural-specific eCIRP KO decreased hemispheric volume loss and neuronal apoptosis and alleviated glial cell activation and neurological function damage after TBI. In contrast, eCIRP treatment resulted in endoplasmic reticulum disruption and ER stress (ERS)-related death of neurons and enhanced inflammatory mediators by glial cells. Mechanistically, we noted that eCIRP-induced neural apoptosis was associated with the activation of the protein kinase RNA-like ER kinase-activating transcription factor 4 (ATF4)-C/EBP homologous protein signalling pathway, and that eCIRP-induced microglial inflammation was associated with histone H3 acetylation and the α7 nicotinic acetylcholine receptor. Conclusions: These results suggest that TBI obviously enhances the secretion of eCIRP, thereby resulting in neural damage and inflammation in TBI. eCIRP may be a biomarker of TBI that can mediate the apoptosis of neuronal cells through the ERS apoptotic pathway and regulate the inflammatory response of microglia via histone modification.

The regrouping of Luminal B (HER2 negative), a better discriminator of outcome and recurrence score.

BACKGROUND: Breast cancer (BC) remains the leading cause of cancer-related deaths worldwide. High recurrence risk Luminal BC receives adjuvant chemotherapy in addition to standard hormone therapy. Considering the heterogeneity of Luminal B BC, a more accurate classification model is urgently needed. METHODS: In this study, we retrospectively reviewed the data of 1603 patients who were diagnosed with HER2-negative breast invasive ductal carcinoma. According to the expression level of PR and Ki-67 index, the Luminal B (HER2-negative) BCs were divided into three groups: ER+PR-Ki67low (ER-positive, PR-negative, and Ki-67 index <20%), ER+PR+Ki67high (ER-positive, PR-positive, and Ki-67 index ≥20%), and ER+PR-Ki67high (ER-positive, PR-negative, and Ki-67 index ≥20%). The cox proportional hazards regression model was used to evaluate the correlation between each variable and outcomes. Besides, discriminatory accuracy of the models was compared using the area under the receiver operating characteristic curve and log-rank χ2 value. RESULTS: The analysis results showed that there was a significant correlation between subtypes using this newly defined classification and overall survival (p < 0.001) and disease-free survival (DFS) (p < 0.001). Interestingly, patients in the ER+PR-Ki67high subgroup have the worst survival outcome in Luminal B (HER2-negative) subtype, similar to Triple-negative patients. Besides, the ER+PR+Ki67high has worse 5-year DFS compared with Luminal A group. There was a significant relationship between the regrouping subtype and the recurrence score index (RI) (p < 0.001). Moreover, the results showed that patients in ER+PR-Ki67high subtype were more likely to have high RI for distance recurrence (RI-DR) and local recurrence (RI-LRR). Our newly defined classification has a better discrimination ability to predict survival outcome and recurrence score of Luminal B (HER2-negative) BC patients, which may help in clinical decision-making for individual treatment.

Primary Exploration of the Clinical Application of 3D-Printed Complete Dentures.

PURPOSE: To explore the applications of 3D scanning and 3D printing techniques in the restorative treatment of edentulous patients. MATERIALS AND METHODS: A total of 30 edentulous patients (Atwood classes 1 to 4) who visited The 960th Hospital of the People's Liberation Army, Jinan, China, from March 1, 2018 to May 1, 2020 were selected, and the patients were randomly divided into two groups: a traditional complete denture group (group A) and a 3D-printed complete denture group (group B). Each group comprised 15 patients. In group A, the traditional method was used to fabricate complete dentures. In group B, 3D scanning, computer-aided design (CAD), 3D printing, and the duplicate denture technique were used to fabricate the dentures. A single-blinded method was used. Patient satisfaction was measured with a 0-10 visual analog scale (VAS) at four time points: immediately and 1 month, 3 months, and 6 months after denture delivery. SPSS version 22.0 software was used to analyze the data. RESULTS: The ability to speak, ability to chew, and comfort in the two groups gradually improved at the first three time points. VAS scores increased to a satisfactory level after 3 months. The esthetics and stability of the two groups were scored high after the initial delivery. The VAS scores of the two groups regarding esthetics, ability to speak, ability to chew, stability, and comfort were not significantly different (P > .05) at any time point. The number of visits in the 3D-printed complete denture group were significantly decreased in comparison to the traditional group. CONCLUSION: The use of 3D printing for manufacturing complete dentures can rapidly restore edentulous patients and meet patient demands regarding esthetics and function.

Cell Heterogeneity Uncovered by Single-Cell RNA Sequencing Offers Potential Therapeutic Targets for Ischemic Stroke.

Ischemic stroke is a detrimental neurological disease characterized by an irreversible infarct core surrounded by an ischemic penumbra, a salvageable region of brain tissue. Unique roles of distinct brain cell subpopulations within the neurovascular unit and peripheral immune cells during ischemic stroke remain elusive due to the heterogeneity of cells in the brain. Single-cell RNA sequencing (scRNA-seq) allows for an unbiased determination of cellular heterogeneity at high-resolution and identification of cell markers, thereby unveiling the principal brain clusters within the cell-type-specific gene expression patterns as well as cell-specific subclusters and their functions in different pathways underlying ischemic stroke. In this review, we have summarized the changes in differentiation trajectories of distinct cell types and highlighted the specific pathways and genes in brain cells that are impacted by stroke. This review is expected to inspire new research and provide directions for investigating the potential pathological mechanisms and novel treatment strategies for ischemic stroke at the level of a single cell.

Small RNA and Degradome Sequencing Reveal Important MicroRNA Function in Nicotiana tabacum Response to Bemisia tabaci.

MicroRNAs (miRNAs), a class of small non-coding regulatory RNAs, are key molecules in many biological and metabolic processes of plant growth, development and stress response via targeting mRNAs. The phloem-feeding insect whitefly Bemisia tabaci (Hemiptera, Aleyrodidae) is a serious pest that causes devastating harm to agricultural production worldwide. However, the function of host miRNAs in the response to whitefly infestation remains unclear. Here, we sequenced the small RNA and degradome of tobacco (Nicotiana tabacum L.), after and before infestation by B. tabaci. We identified 1291 miRNAs belonging to 138 miRNA families including 706 known miRNAs and 585 novel miRNAs. A total of 47 miRNAs were differentially expressed, of which 30 were upregulated and 17 were downregulated by whitefly exposure. Then, computational analysis showed that the target genes of differential miRNAs were involved in R gene regulation, plant innate immunity, plant pathogen defense, the plant hormone signal pathway and abiotic stress tolerance. Furthermore, degradome analysis demonstrated that 253 mRNAs were cleaved by 66 miRNAs. Among them, the targets cleaved by upregulated miR6025, miR160, miR171, miR166 and miR168 are consistent with our prediction, suggesting that pathogen-related miRNAs may function in plant defense against whitefly. Moreover, our results show that plant miRNA response and miRNA-mediated post-transcriptional regulation for phloem-feeding insect infestation are similar to pathogen invasion. Our study provides additional data to further elucidate how host plants respond and defend the phloem-feeding insects.

Neuroimmune Regulation in Sepsis-Associated Encephalopathy: The Interaction Between the Brain and Peripheral Immunity.

Sepsis-associated encephalopathy (SAE), the most popular cause of coma in the intensive care unit (ICU), is the diffuse cerebral damage caused by the septic challenge. SAE is closely related to high mortality and extended cognitive impairment in patients in septic shock. At present, many studies have demonstrated that SAE might be mainly associated with blood-brain barrier damage, abnormal neurotransmitter secretion, oxidative stress, and neuroimmune dysfunction. Nevertheless, the precise mechanism which initiates SAE and contributes to the long-term cognitive impairment remains largely unknown. Recently, a growing body of evidence has indicated that there is close crosstalk between SAE and peripheral immunity. The excessive migration of peripheral immune cells to the brain, the activation of glia, and resulting dysfunction of the central immune system are the main causes of septic nerve damage. This study reviews the update on the pathogenesis of septic encephalopathy, focusing on the over-activation of immune cells in the central nervous system (CNS) and the "neurocentral-endocrine-immune" networks in the development of SAE, aiming to further understand the potential mechanism of SAE and provide new targets for diagnosis and management of septic complications.

Worldwide productivity and research trend of publications concerning glioma-associated macrophage/microglia: A bibliometric study.

Glioma-associated macrophage/microglia (GAM) represents a key player in shaping a unique glioma ecosystem to facilitate tumor progression and therapeutic resistance. Numerous studies have been published concerning GAM, but no relevant bibliometric study has been performed yet. Our bibliometric study aimed to comprehensively summarize and analyze the global scientific output, research hotspots, and trendy topics of publications on GAM over time. Data on publications on GAM were collected using the Web of Science (WoS). The search date was 16 January 2022, and the publications were collected from 2002 to 2021. Totally, 1,224 articles and reviews were incorporated and analyzed in the current study. It showed that the annual publications concerning GAM kept increasing over the past 20 years. The United States had the largest number of publications and total citations. Holland, Kettenmann, and Gutmann were the top three authors in terms of citation frequency. Neuro-oncology represented the most influential journal in GAM studies, with the highest H-index, total citations, and publication numbers. The paper published by Hambardzumyan in 2016 had the highest local citations. Additionally, the analysis of keywords implied that "prognosis," "tumor microenvironment," and "immunotherapy" might become research hotspots. Furthermore, trendy topics in GAM studies suggested that "immune infiltration," "immune microenvironment," "bioinformatics," "prognosis," and "immunotherapy" deserved additional attention. In conclusion, this bibliometric study comprehensively analyzed the publication trend of GAM studies for the past 20 years, in which the research hotspots and trendy topics were also uncovered. This information offered scholars critical references for conducting in-depth studies on GAM in the future.

Lipid accumulation and novel insight into vascular smooth muscle cells in atherosclerosis.

Atherosclerosis is a chronic and progressive process. It is the most important pathological basis of cardiovascular disease and stroke. Vascular smooth muscle cells (VSMCs) are an essential cell type in atherosclerosis. Previous studies have revealed that VSMCs undergo phenotypic transformation in atherosclerosis to participate in the retention of atherogenic lipoproteins as well as the formation of the fibrous cap and the underlying necrotic core in plaques. The emergence of lineage-tracing studies indicates that the function and number of VSMCs in plaques have been greatly underestimated. In addition, recent studies have revealed that VSMCs make up at least 50% of the foam cell population in human and mouse atherosclerotic lesions. Therefore, understanding the formation of lipid-loaded VSMCs and their regulatory mechanisms is critical to elucidate the pathogenesis of atherosclerosis and to explore potential therapeutic targets. Moreover, combination of many complementary technologies such as lineage tracing, single-cell RNA sequencing (scRNA-seq), flow cytometry, and mass cytometry (CyTOF) with immunostaining has been performed to further understand the complex VSMC function. Correct identification of detrimental and beneficial processes may reveal successful therapeutic treatments targeting VSMCs and their derivatives during atherosclerosis. The purpose of this review is to summarize the process of lipid-loaded VSMC formation in atherosclerosis and to describe novel insight into VSMCs gained by using multiple advanced methods.

SCSit: A high-efficiency preprocessing tool for single-cell sequencing data from SPLiT-seq.

SPLiT-seq provides a low-cost platform to generate single-cell data by labeling the cellular origin of RNA through four rounds of combinatorial barcoding. However, an automatic and rapid method for preprocessing and classifying single-cell sequencing (SCS) data from SPLiT-seq, which directly identified and labeled combinatorial barcoding reads and distinguished special cell sequencing data, is currently lacking. Here, we develop a high-efficiency preprocessing tool for single-cell sequencing data from SPLiT-seq (SCSit), which can directly identify combinatorial barcodes and UMI of cell types and obtain more labeled reads, and remarkably enhance the retained data from SCS due to the exact alignment of insertion and deletion. Compared with the original method used in SPLiT-seq, the consistency of identified reads from SCSit increases to 97%, and mapped reads are twice than the original. Furthermore, the runtime of SCSit is less than 10% of the original. It can accurately and rapidly analyze SPLiT-seq raw data and obtain labeled reads, as well as effectively improve the single-cell data from SPLiT-seq platform. The data and source of SCSit are available on the GitHub website https://github.com/shang-qian/SCSit.

Production of erythriod cells from human embryonic stem cells by fetal liver cell extract treatment.

BACKGROUND: We recently developed a new method to induce human stem cells (hESCs) differentiation into hematopoietic progenitors by cell extract treatment. Here, we report an efficient strategy to generate erythroid progenitors from hESCs using cell extract from human fetal liver tissue (hFLT) with cytokines. Human embryoid bodies (hEBs) obtained of human H1 hESCs were treated with cell extract from hFLT and co-cultured with human fetal liver stromal cells (hFLSCs) feeder to induce hematopoietic cells. After the 11 days of treatment, hEBs were isolated and transplanted into liquid medium with hematopoietic cytokines for erythroid differentiation. Characteristics of the erythroid cells were analyzed by flow cytometry, Wright-Giemsa staining, real-time RT-PCR and related functional assays. RESULTS: The erythroid cells produced from hEBs could differentiate into enucleated cells and expressed globins in a time-dependent manner. They expressed not only embryonic globins but also the adult-globin with the maturation of the erythroid cells. In addition, our data showed that the hEBs-derived erythroid cells were able to act as oxygen carriers, indicating that hESCs could generate functional mature erythroid cells. CONCLUSION: Cell extract exposure with the addition of cytokines resulted in robust erythroid -like differentiation of hEBs and these hEBs-derived erythroid cells possessed functions similar to mature red blood cells.

Self-renewal and pluripotency is maintained in human embryonic stem cells by co-culture with human fetal liver stromal cells expressing hypoxia inducible factor 1alpha.

Human embryonic stem (hES) cells are typically maintained on mouse embryonic fibroblast (MEF) feeders or with MEF-conditioned medium. However, these xenosupport systems greatly limit the therapeutic applications of hES cells because of the risk of cross-transfer of animal pathogens. The stem cell niche is a unique tissue microenvironment that regulates the self-renewal and differentiation of stem cells. Recent evidence suggests that stem cells are localized in the microenvironment of low oxygen. We hypothesized that hypoxia could maintain the undifferentiated phenotype of embryonic stem cells. We have co-cultured a human embryonic cell line with human fetal liver stromal cells (hFLSCs) feeder cells stably expressing hypoxia-inducible factor-1 alpha (HIF-1alpha), which is known as the key transcription factor in hypoxia. The results suggested HIF-1alpha was critical for preventing differentiation of hES cells in culture. Consistent with this observation, hypoxia upregulated the expression of Nanog and Oct-4, the key factors expressed in undifferentiated stem cells. We further demonstrated that HIF-1alpha could upregulate the expression of some soluble factors including bFGF and SDF-1alpha, which are released into the microenvironment to maintain the undifferentiated status of hES cells. This suggests that the targets of HIF-1alpha are secreted soluble factors rather than a cell-cell contact mechanism, and defines an important mechanism for the inhibition of hESCs differentiation by hypoxia. Our findings developed a transgene feeder co-culture system and will provide a more reliable alternative for future therapeutic applications of hES cells.