Batf-Dependent Th17 cells act through IL23R pathway to promote prostate adenocarcinoma initiation and progression.

BACKGROUND: The role of Th17 cells in prostate cancer (PCa) is not fully understood. The transcription factor BATF controls the differentiation of Th17 cells. Mice deficient in Batf do not produce Th17 cells. METHODS: In this study, we aimed to characterize the role of Batf-dependent Th17 cells in PCa by crossbreeding Batf knockout (Batf-/-) mice with mice conditionally mutant for Pten. We found that Batf-/- mice had changes in the morphology of prostate epithelial cells compared to normal mice, and Batf-/- mice deficient in Pten (named Batf-) had smaller prostate size and developed fewer invasive prostate adenocarcinomas than Pten-deficient mice with Batf expression (named Batf+). The prostate tumors in Batf- mice showed reduced proliferation, increased apoptosis, decreased angiogenesis and inflammatory cell infiltration, and activation of NF-κB signaling. Moreover, Batf- mice showed significantly reduced IL-23/IL-23R signaling. In the prostate stroma of Batf- mice, IL-23R-positive cells were decreased considerably compared to Batf+ mice. Splenocytes and prostate tissues from Batf- mice cultured under Th17 differentiation conditions expressed reduced IL-23/IL-23R than cultured cells from Batf+ mice. Anti-IL23p19 antibody treatment of Pten-deficient mice reduced prostate tumors and angiogenesis compared to control IgG-treated mice. In human prostate tumors, BATF mRNA level was positively correlated with IL23A and IL-23R but not RORC. CONCLUSION: Our novel findings underscore the crucial role of IL-23/IL23R signaling in mediating the function of Batf-dependent Th17 cells, thereby promoting PCa initiation and progression. This highlights the Batf-IL-23R axis as a promising target for the development of innovative strategies for PCa prevention and treatment.

Influence of land use change on habitat quality: a case study of coal mining subsidence areas.

Revealing the spatiotemporal evolution characteristics and key driving processes behind the habitat quality is of great significance for the scientific management of production, living, and ecological spaces in resource-based cities, as well as for the efficient allocation of resources. Focusing on the largest coal-mining subsidence area in Jiangsu Province of China, this study examines the spatiotemporal evolution of land use intensity, morphology, and functionality across different time periods. It evaluates the habitat quality characteristics of the Pan'an Lake area by utilizing the InVEST model, spatial autocorrelation, and hotspot analysis techniques. Subsequently, by employing the GTWR model, it quantifies the influence of key factors, unveiling the spatially varying characteristics of their impact on habitat quality. The findings reveal a notable surge in construction activity within the Pan'an Lake area, indicative of pronounced human intervention. Concurrently, habitat degradation intensifies, alongside an expanding spatial heterogeneity in degradation levels. The worst habitat quality occurs during the periods of coal mining and large-scale urban construction. The escalation in land use intensity emerges as the primary catalyst for habitat quality decline in the Pan'an Lake area, with other factors exhibiting spatial variability in their effects and intensities across different stages.

Influence of social mindfulness and Zhongyong thinking style on cooperative financial decision making in a Western sample.

Social mindfulness and Zhongyong thinking style are of high importance when evaluating relevant co-actors in the social world. The current study investigates the influence of social mindfulness and Zhongyong thinking style on cooperative financial decision making in a public goods game among a Canadian sample. We hypothesize that higher perceived social mindfulness and higher perceived Zhongyong thinking style will increase the amount of money contributed to a joint project in a public goods game. The sample was a prolific-based online recruited sample of n = 125 Canadians. We observed a significant main effect of Zhongyong thinking style on the amount of contributed money in the public goods game. Social mindfulness did not reach significance. The influence of Zhongyong thinking style was qualified by a significant Zhongyong by gender interaction, indicating that females but not males reduced their contributions if the Zhongyong thinking style of the co-actor was manipulated as being low. It is shown that Zhongyong thinking style is also relevant in a Western cultural setting. Future research is needed, however, to investigate further the reasons for the differences between females and males.

A high-quality haplotype genome of Michelia alba DC reveals differences in methylation patterns and flower characteristics.

Michelia alba DC is a highly valuable ornamental plant of the Magnoliaceae family. This evergreen tropical tree commonly grows in Southeast Asia and is adored for its delightful fragrance. Our study assembled the M. alba haplotype genome MC and MM by utilizing Nanopore ultralong reads, Pacbio Hifi long reads and parental second-generation data. Moreover, the first methylation map of Magnoliaceae was constructed based on the methylation site data obtained using Nanopore data. Metabolomic datasets were generated from the flowers of three different species to assess variations in pigment and volatile compound accumulation. Finally, transcriptome data were generated to link genomic, methylation, and morphological patterns to reveal the reasons underlying the differences between M. alba and its parental lines in petal color, flower shape, and fragrance. We found that the AP1 and AP2 genes are crucial in M. alba petal formation, while the 4CL, PAL, and C4H genes control petal color. The data generated in this study serve as a foundation for future physiological and biochemical research on M. alba, facilitate the targeted improvement of M. alba varieties, and offer a theoretical basis for molecular research on Michelia L.

Black Phosphorus Quantum Dot Loaded Bioinspired Nanoplatform Synergized with aPD-L1 for Multimode Cancer Immunotherapy.

Efforts to prolong the blood circulation time and bypass immune clearance play vital roles in improving the therapeutic efficacy of nanoparticles (NPs). Herein, a multifunctional nanoplatform (BPP@RTL) that precisely targets tumor cells is fabricated by encapsulating ultrasmall phototherapeutic agent black phosphorus quantum dot (BPQD), chemotherapeutic drug paclitaxel (PTX), and immunomodulator PolyMetformin (PM) in hybrid membrane-camouflaged liposomes. Specifically, the hybrid cell membrane coating derived from the fusion of cancer cell membrane and red blood cell membrane displays excellent tumor targeting efficiency and long blood circulation property due to the innate features of both membranes. After collaboration with aPD-L1-based immune checkpoint blockade therapy, a boosted immunotherapeutic effect is obtained due to elevated dendritic cell maturation and T cell activation. Significantly, laser-irradiated BPP@RTL combined with aPD-L1 effectively eliminates primary tumors and inhibits lung metastasis in 4T1 breast tumor model, offering a promising treatment plan to develop personalized antitumor strategy.

Characterization of human skin under tension using terahertz time domain spectroscopy.

This paper introduces a spectral analysis method for monitoring the human skin in vivo based on a combination of terahertz time-domain spectroscopy (THz-TDS) and optical coherence tomography (OCT). The method can quantitatively measure the refractive index, thickness and transmission coefficient of epidermis, and the refractive index of dermis in natural, as well as the tension condition of the skin. An optically reflective model for the multilayer structure of the skin is first established. The initial thickness of the epidermis is then measured by OCT as a known quantity for the established model. By fitting the established model to the experimentally obtained THz-TDS signals, the above parameters of the skin can be calibrated. Furthermore, the dependence of these skin parameters on the tension status are investigated. This study provides a means for terahertz technology to measure the skin in vivo.

Pyridine-Based Covalent Organic Frameworks with Pyridyl-Imine Structures for Boosting Photocatalytic H2O2 Production via One-Step 2e- Oxygen Reduction.

Bipyridine-based covalent organic frameworks (COFs) have emerged as promising contenders for the photocatalytic generation of hydrogen peroxide (H2O2). However, the presence of imine nitrogen alters the mode of H2O2 generation from an efficient one-step two-electron (2e-) route to a two-step 2e- oxygen reduction pathway. In this work, we introduce 3,3'-bipyridine units into imine-based COF skeletons, creating a pyridyl-imine structure with two adjacent nitrogen atoms between the pyridine ring and imine linkage. This unique bipyridine-like architecture can effectively suppress the two-step 2e- ORR process at the single imine-nitrogen site, facilitating a more efficient one-step 2e- pathway. Consequently, the optimized pyridyl-imine COF (PyIm-COF) exhibits a remarkable H2O2 production rate of up to 5850 µmol h-1 g-1, nearly double that of pristine bipyridine COFs. This work provides valuable insight into the rational design of functionalized COFs for enhanced H2O2 production in photocatalysis.

Glycogen synthesis is required for adaptive thermogenesis in beige adipose tissue and affects diet-induced obesity.

Glycogen is a form of energy storage for glucose in different tissues such as liver and skeletal muscle. It remains incompletely understood how glycogen impacts on adipose tissue functionality. Cold exposure elevated the expression of Gys1 that encodes glycogen synthase 1 in brown adipose tissue (BAT) and inguinal white adipose tissue (iWAT). The in vivo function of Gys1 was analyzed using a mouse model in which Gys1 was deleted specifically in adipose tissues. Under normal chow conditions, Gys1 deletion caused little changes to body weight and glucose metabolism. Deletion of Gys1 abrogated upregulation of UCP1 and other thermogenesis-related genes in iWAT upon prolonged cold exposure or treatment with ß3-adrenergic receptor agonist CL-316,243. Stimulation of UCP1 by CL-316,243 in adipose-derived stromal cells (stromal vascular fractions, SVFs) was also reduced by Gys1 deletion. Both the basal glycogen content and CL-316,243-stimulated glycogen accumulation in adipose tissues were reduced by Gys1 deletion. High-fat diet-induced obesity and insulin resistance were aggravated in Gys1-deleted mice. The loss of body weight upon CL-316,243 treatment was also abrogated by the loss of Gys1. In conclusion, our results underscore the pivotal role of glycogen synthesis in adaptive thermogenesis in beige adipose tissue and its impact on diet-induced obesity in mice.NEW & NOTEWORTHY Glycogen is one of major types of fuel reserve in the body and its classical function is to maintain blood glucose level. This study uncovers that glycogen synthesis is required for beige fat tissue to generate heat upon cold exposure. Such a function of glycogen is linked to development of high-fat diet-induced obesity, thus extending our understanding about the physiological functions of glycogen.

AMPA receptor inhibition alleviates inflammatory response and myocardial apoptosis after myocardial infarction by inhibiting TLR4/NF-κB signaling pathway.

Myocardial infarction leads to myocardial inflammation and apoptosis, which are crucial factors leading to heart failure and cardiovascular dysfunction, eventually resulting in death. While the inhibition of AMPA receptors mitigates inflammation and tissue apoptosis, the effectiveness of this inhibition in the pathophysiological processes of myocardial infarction remains unclear. This study investigated the role of AMPA receptor inhibition in myocardial infarction and elucidated the underlying mechanisms. This study established a myocardial infarction model by ligating the left anterior descending branch of the coronary artery in Sprague-Dawley rats. The findings suggested that injecting the AMPA receptor antagonist NBQX into myocardial infarction rats effectively alleviated cardiac inflammation, myocardial necrosis, and apoptosis and improved their cardiac contractile function. Conversely, injecting the AMPA receptor agonist CX546 into infarcted rats exacerbated the symptoms and tissue damage, as reflected by histopathology. This agonist also stimulated the TLR4/NF-κB pathway, further deteriorating cardiac function. Furthermore, the investigations revealed that AMPA receptor inhibition hindered the nuclear translocation of P65, blocking its downstream signaling pathway and attenuating tissue inflammation. In summary, this study affirmed the potential of AMPA receptor inhibition in countering inflammation and tissue apoptosis after myocardial infarction, making it a promising therapeutic target for mitigating myocardial infarction.

Characterization of radial artery perforation patterns using optical coherence tomography.

BACKGROUND: The characterization of radial artery perforation (RAP) patterns using optical coherence tomography (OCT) has not been well established. This study aimed to identify the characteristic RAP patterns in patients diagnosed through post-procedural OCT examination. METHODS: This retrospective study included 1936 consecutive patients who underwent radial artery (RA) OCT following OCT-guided transradial coronary intervention (TRI) from January 2016 to July 2022. Data regarding RAP characteristics were collected through OCT, including the perforation site as well as dimensions such as the length, width, and arc. Furthermore, RAP types were classified as small or large perforations, with a cut-off arc value of ≤90°. RESULTS: RAP, as identified by RA angiography (RAA) during TRI and on post-procedural OCT, was found in 16 out of 1936 patients (0.83 %). RA OCT imaging showed that the median distance between the RA ostium and the perforation site, the perforation length, width, and arc were 30.6 (14.4-42.2) mm, 1.55 (1.03-1.92) mm, 0.74 (0.60-1.14) mm, and 42.5 (25.0-58.1) °, respectively. Small perforations (arc ≤90°) were observed in 14 out of the 16 (87.5 %) patients with RAP. Post-procedural RAA revealed that 15 out of the 16 (93.7 %) patients with RAP had sealed perforations, with the remaining patient requiring external compression. CONCLUSIONS: Our findings demonstrated that RAP is uncommon during TRI, with clearly defined characteristic patterns on OCT. Most RAPs are small and tend to spontaneous seal through catheter tamponade.

Visible Light-Regulated Ring-Opening Polymerization of Lactones by Employing Indigo as a Photoacid Catalyst.

The development of visible light-regulated polymerizations for precision synthesis of polymers has drawn considerable attention in the past years. In this study, an ancient dye, indigo, is successfully identified as a new and efficient photoacid catalyst, which can readily promote the ring-opening polymerization of lactones under visible light irradiation in a well-controlled manner, affording the desired polyester products with predictable molecular weights and narrow dispersity. The enhanced acidity of indigos by excitation is crucial to the H-bonding activation of the lactone monomers. Chain extension and block copolymer synthesis are also demonstrated with this method.

Mitigating phospholipid peroxidation of macrophages in stress-induced tumor microenvironment by natural ALOX15/PEBP1 complex inhibitors.

BACKGROUND: The intricate interactions between chronic psychological stress and susceptibility to breast cancer have been recognized, yet the underlying mechanisms remain unexplored. Danzhi Xiaoyao Powder (DZXY), a traditional Chinese medicine (TCM) formula, has found clinical utility in the treatment of breast cancer. Macrophages, as the predominant immune cell population within the tumor microenvironment (TME), play a pivotal role in orchestrating tumor immunosurveillance. Emerging evidence suggests that lipid oxidation accumulation in TME macrophages, plays a critical role in breast cancer development and progression. However, a comprehensive understanding of the pharmacological mechanisms and active components of DZXY related to its clinical application in the treatment of stress-aggravated breast cancer remains elusive. PURPOSE: This study sought to explore the plausible regulatory mechanisms and identify the key active components of DZXY contributing to its therapeutic efficacy in the context of breast cancer. METHODS: Initially, we conducted an investigation into the relationship between the phagocytic capacity of macrophages damaged by psychological stress and phospholipid peroxidation using flow cytometry and LC-MS/MS-based phospholipomics. Subsequently, we evaluated the therapeutic efficacy of DZXY based on the results of the tumor size, tumor weight, the phospholipid peroxidation pathway and phagocytosis of macrophage. Additionally, the target-mediated characterization strategy based on binding of arachidonate 15-lipoxygenase (ALOX15) to phosphatidylethanolamine-binding protein-1 (PEBP1), including molecular docking analysis, microscale thermophoresis (MST) assay, co-immunoprecipitation analysis and activity verification, has been further implemented to reveal the key bio-active components in DZXY. Finally, we evaluated the therapeutic efficacy of isochlorogenic acid C (ICAC) based on the results of tumor size, tumor weight, the phospholipid peroxidation pathway, and macrophage phagocytosis in vivo. RESULTS: The present study demonstrated that phospholipid peroxides, as determined by LC-MS/MS-based phospholipidomics, triggered in macrophages, which in turn compromised their capacity to eliminate tumor cells through phagocytosis. Furthermore, we elucidate the mechanism behind stress-induced PEBP1 to form a complex with ALOX15, thereby mediating membrane phospholipid peroxidation in macrophages. DZXY, demonstrates potent anti-breast cancer therapeutic effects by disrupting the ALOX15/PEBP1 interaction and inhibiting phospholipid peroxidation, ultimately enhancing macrophages' phagocytic capability towards tumor cells. Notably, ICAC emerged as a promising active component in DZXY, which can inhibit the ALOX15/PEBP1 interaction, thereby mitigating phospholipid peroxidation in macrophages. CONCLUSION: Collectively, our findings elucidate stress increases the susceptibility of breast cancer by driving lipid peroxidation of macrophages and suggest the ALOX15/PEBP1 complex as a promising intervention target for DZXY.

CDKL1 potentiates the antitumor efficacy of radioimmunotherapy by binding to transcription factor YBX1 and blocking PD-L1 expression in lung cancer.

BACKGROUND: The evasion of the immune response by tumor cells through programmed death-ligand 1 (PD-L1) has been identified as a factor contributing to resistance to radioimmunotherapy in lung cancer patients. However, the precise molecular mechanisms underlying the regulation of PD-L1 remain incompletely understood. This study aimed to investigate the role of cyclin-dependent kinase-like 1 (CDKL1) in the modulation of PD-L1 expression and the response to radioimmunotherapy in lung cancer. METHODS: The tumorigenic roles of CDKL1 were assessed via cell growth, colony formation, and EdU assays and an in vivo nude mouse xenograft model. The in vitro radiosensitization effect of CDKL1 was evaluated using a neutral comet assay, γH2AX foci formation analysis, and a clonogenic cell survival assay. The protein‒protein interactions were confirmed via coimmunoprecipitation and GST pulldown assays. The regulation of PD-L1 by CDKL1 was evaluated via chromatin immunoprecipitation (ChIP), real-time quantitative PCR, and flow cytometry analysis. An in vitro conditioned culture model and an in vivo C57BL/6J mouse xenograft model were developed to detect the activation markers of CD8+ T cells and evaluate the efficacy of CDKL1 overexpression combined with radiotherapy (RT) and an anti-PD-L1 antibody in treating lung cancer. RESULTS: CDKL1 was downregulated and suppressed the growth and proliferation of lung cancer cells and increased radiosensitivity in vitro and in vivo. Mechanistically, CDKL1 interacted with the transcription factor YBX1 and decreased the binding affinity of YBX1 for the PD-L1 gene promoter, which consequently inhibits the expression of PD-L1, ultimately leading to the activation of CD8+ T cells and the inhibition of immune evasion in lung cancer. Moreover, the combination of CDKL1 overexpression, RT, and anti-PD-L1 antibody therapy exhibited the most potent antitumor efficacy against lung cancer. CONCLUSIONS: Our findings demonstrate that CDKL1 plays a crucial role in regulating PD-L1 expression, thereby enhancing the antitumor effects of radioimmunotherapy. These results suggest that CDKL1 may be a promising therapeutic target for the treatment of lung cancer.

Exploration of surface tension measurement methods for pharmaceutical excipients.

Surface tension is a crucial functional indicator for various classes of pharmaceutical excipients, as highlighted in both the Pharmacopoeia of the People's Republic of China (ChP) < 9601 Guidelines for Functionality-related Characteristics of Pharmaceutical Excipients > and the United States Pharmacopoeia (USP) < 1059 Excipient Performance >. However, there are few systematic studies on surface tension measurement of pharmaceutical excipients, resulting in a lack of stable parameter support in practical applications. In this study, we aim to fill this gap by exploring three different methods for measuring surface tension. These methods were carefully developed taking into account the actual measurement process and statistical theory, thus ensuring their applicability and reliability. Through comparative analyses, we have identified the most suitable measurement methods for different classes of pharmaceutical excipients. In addition, this paper describes the surface adsorption behavior of various excipients. Therefore, this study provides valuable guidance for the determination of surface tension and the study of surface adsorption behavior, which lays the foundation for further comprehensive research in the field of surface tension of pharmaceutical excipients and the improvement of general pharmacopoeia specification.

Multiple plaque ruptures healing assessed by serial optical coherence tomography.

A 30-year-old man with hypertension presented to the emergency department with a 30-minute episode of diaphoresis and chest pain, acute inferior myocardial infarction was diagnosed on electrocardiogram.

Blood-Brain Barrier-Penetrating and Lesion-Targeting Nanoplatforms Inspired by the Pathophysiological Features for Synergistic Ischemic Stroke Therapy.

Ischemic stroke is a dreadful vascular disorder that poses enormous threats to the public health. Due to its complicated pathophysiological features, current treatment options after ischemic stroke attack remains unsatisfactory. Insufficient drug delivery to ischemic lesions impeded by the blood-brain barrier (BBB) largely limits the therapeutic efficacy of most anti-stroke agents. Herein, inspired by the rapid BBB penetrability of 4T1 tumor cells upon their brain metastasis and natural roles of platelet in targeting injured vasculatures, a bio-derived nanojacket is developed by fusing 4T1 tumor cell membrane with platelet membrane, which further clothes on the surface of paeonol and polymetformin-loaded liposome to obtain biomimetic nanoplatforms (PP@PCL) for ischemic stroke treatment. The designed PP@PCL could remarkably alleviate ischemia-reperfusion injury by efficiently targeting ischemic lesion, preventing neuroinflammation, scavenging excess reactive oxygen species (ROS), reprogramming microglia phenotypes, and promoting angiogenesis due to the synergistic therapeutic mechanisms that anchor the pathophysiological characteristics of ischemic stroke. As a result, PP@PCL exerts desirable therapeutic efficacy in injured PC12 neuronal cells and rat model of ischemic stroke, which significantly attenuates neuronal apoptosis, reduces infarct volume, and recovers neurological functions, bringing new insights into exploiting promising treatment strategies for cerebral ischemic stroke management.

Salmonella-mediated methionine deprivation drives immune activation and enhances immune checkpoint blockade therapy in melanoma.

BACKGROUND: Although immune checkpoint inhibitor (ICI)-based therapy is advantageous for patients with advanced melanoma, resistance and relapse are frequent. Thus, it is crucial to identify effective drug combinations and develop new therapies for the treatment of melanoma. SGN1, a genetically modified Salmonella typhimurium species that causes the targeted deprivation of methionine in tumor tissues, is currently under investigation in clinical trials. However, the inhibitory effect of SGN1 on melanoma and the benefits of SGN1 in combination with ICIs remain largely unexplored. Therefore, this study aims to investigate the antitumor potential of SGN1, and its ability to enhance the efficacy of antibody-based programmed cell death-ligand 1 (PD-L1) inhibitors in the treatment of murine melanoma. METHODS: The antitumor activity of SGN1 and the effect of SGN1 on the efficacy of PD-L1 inhibitors was studied through murine melanoma models. Further, The Cancer Genome Atlas-melanoma cohort was clustered using ConsensusClusterPlus based on the methionine deprivation-related genes, and immune characterization was performed using xCell, Microenvironment Cell Populations-counter, Estimation of Stromal and Immune cells in MAlignant Tumor tissues using Expression data, and immunophenoscore (IPS) analyses. The messenger RNA data on programmed death-1 (PD-1) immunotherapy response were obtained from the Gene Expression Omnibus database. Gene Set Enrichment Analysis of methionine deprivation-up gene set was performed to determine the differences between pretreatment responders and non-responders. RESULTS: This study showed that both, the intratumoral and the intravenous administration of SGN1 in subcutaneous B16-F10 melanomas, suppress tumor growth, which was associated with an activated CD8+T-cell response in the tumor microenvironment. Combination therapy of SGN1 with systemic anti-PD-L1 therapy resulted in better antitumor activity than the individual monotherapies, respectively, and the high therapeutic efficacy of the combination was associated with an increase in the systemic level of tumor-specific CD8+ T cells. Two clusters consisting of methionine deprivation-related genes were identified. Patients in cluster 2 had higher expression of methionine_deprivation_up genes, better clinical outcomes, and higher immune infiltration levels compared with patients in cluster 1. Western blot, IPS analysis, and immunotherapy cohort study revealed that methionine deficiency may show a better response to ICI therapy CONCLUSIONS：: This study reports Salmonella-based SGN1 as a potent anticancer agent against melanoma, and lays the groundwork for the potential synergistic effect of ICIs and SGN1 brought about by improving the immune microenvironment in melanomas.

Impact of Exposure to a Mixture of Organophosphate Esters on Adrenal Cell Phenotype, Lipidome, and Function.

Organophosphate esters (OPEs) are used primarily as flame retardants and plasticizers. Previously, we reported that adrenal cells are important targets of individual OPEs. However, real-life exposures are to complex mixtures of these chemicals. To address this, we exposed H295R human adrenal cells to varying dilutions (1/1000K to 1/3K) of a Canadian household dust-based OPE mixture for 48 hours and evaluated effects on phenotypic, lipidomic, and functional parameters. Using a high-content screening approach, we assessed phenotypic markers at mixture concentrations at which there was greater than 70% cell survival; the most striking effect of the OPE mixture was a 2.5-fold increase in the total area of lipid droplets. We then determined the response of specific lipid species to OPE exposures with novel, nontargeted lipidomic analysis of isolated lipid droplets. These data revealed that house dust OPEs induced concentration-dependent alterations in the composition of lipid droplets, particularly affecting the triglyceride, diglyceride, phosphatidylcholine, and cholesterol ester subclasses. The steroid-producing function of adrenal cells in the presence or absence of a steroidogenic stimulus, forskolin, was determined. While the production of 17ß-estradiol remained unaffected, a slight decrease in testosterone production was observed after stimulation. Conversely, a 2-fold increase in both basal and stimulated cortisol and aldosterone production was observed. Thus, exposure to a house dust-based mixture of OPEs exerts endocrine-disrupting effects on adrenal cells, highlighting the importance of assessing the effects of environmentally relevant mixtures.

Association between low-normal thyroid function and advanced liver fibrosis in metabolic dysfunction-associated fatty liver disease patients: a retrospective cohort study.

Background: Recent studies have found that thyroid function may be associated with the occurrence and development of advanced liver fibrosis in patients with metabolic dysfunction-associated fatty liver disease (MAFLD). However, the majority of such research has consisted of cross-sectional studies. This retrospective cohort study aimed to investigate the effect of low-normal thyroid function on advanced liver fibrosis in MAFLD patients over a 5-year period. Methods: This retrospective cohort study enrolled 825 outpatients and inpatients with MAFLD who attended the Third Affiliated Hospital of Sun Yat-sen University (Guangzhou, China) between January 2011 and December 2018. Based on plasma thyroid hormone and thyroid-stimulating hormone levels, these patients were divided into two groups, namely a low-normal thyroid function group and a strict-normal thyroid function group. The fibrosis-4 score was used to assess advanced liver fibrosis. A chi-square test was conducted to compare the occurrence of advanced fibrosis between the groups. Results: Among the 825 MAFLD patients, 117 and 708 were defined as having low-normal thyroid function and strict-normal thyroid function, respectively. Follow-up data were available for 767 patients (93.0%) during a 5-year period. Eight (7.5%) MAFLD patients with low-normal thyroid function and 26 (3.9%) with strict-normal thyroid function developed advanced liver fibrosis and the cumulative incidence was not significantly different (P = 0.163). Stratification analysis showed that the lean MAFLD patients (body mass index ≤ 23 kg/m2) with low-normal thyroid function had a higher risk of advanced liver fibrosis than the lean MAFLD patients with strict-normal thyroid function (P < 0.05). Conclusion: Low-normal thyroid function is associated with advanced liver fibrosis among lean MAFLD patients.

Hypothalamic CRF neurons facilitate brain reward function.

Aversive stimuli activate corticotropin-releasing factor (CRF)-expressing neurons in the paraventricular nucleus of hypothalamus (PVNCRF neurons) and other brain stress systems to facilitate avoidance behaviors. Appetitive stimuli also engage the brain stress systems, but their contributions to reward-related behaviors are less well understood. Here, we show that mice work vigorously to optically activate PVNCRF neurons in an operant chamber, indicating a reinforcing nature of these neurons. The reinforcing property of these neurons is not mediated by activation of the hypothalamic-pituitary-adrenal (HPA) axis. We found that PVNCRF neurons send direct projections to the ventral tegmental area (VTA), and selective activation of these projections induced robust self-stimulation behaviors, without activation of the HPA axis. Similar to the PVNCRF cell bodies, self-stimulation of PVNCRF-VTA projection was dramatically attenuated by systemic pretreatment of CRF receptor 1 or dopamine D1 receptor (D1R) antagonist and augmented by corticosterone synthesis inhibitor metyrapone, but not altered by dopamine D2 receptor (D2R) antagonist. Furthermore, we found that activation of PVNCRF-VTA projections increased c-Fos expression in the VTA dopamine neurons and rapidly triggered dopamine release in the nucleus accumbens (NAc), and microinfusion of D1R or D2R antagonist into the NAc decreased the self-stimulation of these projections. Together, our findings reveal an unappreciated role of PVNCRF neurons and their VTA projections in driving reward-related behaviors, independent of their core neuroendocrine functions. As activation of PVNCRF neurons is the final common path for many stress systems, our study suggests a novel mechanism underlying the positive reinforcing effect of stressful stimuli.