Melatonin targets the paraventricular thalamus to promote non-rapid eye movement sleep in C3H/HeJ mice.

Melatonin (MLT) is an important circadian signal for sleep regulation, but the neural circuitries underlying the sleep-promoting effects of MLT are poorly understood. The paraventricular thalamus (PVT) is a critical thalamic area for wakefulness control and expresses MLT receptors, raising a possibility that PVT neurons may mediate the sleep-promoting effects of MLT. Here, we found that MLT receptors were densely expressed on PVT neurons and exhibited circadian-dependent variations in C3H/HeJ mice. Application of exogenous MLT decreased the excitability of PVT neurons, resulting in hyperpolarization of membrane potential and reduction of action potential firing. MLT also inhibited the spontaneous activity of PVT neurons at both population and single-neuron levels in freely behaving mice. Furthermore, pharmacological manipulations revealed that local infusion of exogeneous MLT into the PVT promoted non-rapid eye movement (NREM) sleep and increased NREM sleep duration, whereas MLT receptor antagonists decreased NREM sleep. Moreover, we found that selectively knocking down endogenous MLT receptors in the PVT decreased NREM sleep and correspondingly increased wakefulness, with particular changes shortly after the onset of the dark or light phase. Taken together, these results demonstrate that PVT is an important target of MLT for promoting NREM sleep.

Impact of childhood maltreatment on aging: a comprehensive Mendelian randomization analysis of multiple age-related biomarkers.

BACKGROUND: Childhood maltreatment (CM) is linked to long-term adverse health outcomes, including accelerated biological aging and cognitive decline. This study investigates the relationship between CM and various aging biomarkers: telomere length, facial aging, intrinsic epigenetic age acceleration (IEAA), GrimAge, HannumAge, PhenoAge, frailty index, and cognitive performance. METHODS: We conducted a Mendelian randomization (MR) study using published GWAS summary statistics. Aging biomarkers included telomere length (qPCR), facial aging (subjective evaluation), and epigenetic age markers (HannumAge, IEAA, GrimAge, PhenoAge). The frailty index was calculated from clinical assessments, and cognitive performance was evaluated with standardized tests. Analyses included Inverse-Variance Weighted (IVW), MR Egger, and Weighted Median (WM) methods, adjusted for multiple comparisons. RESULTS: CM was significantly associated with shorter telomere length (IVW: ß = - 0.1, 95% CI - 0.18 to - 0.02, pFDR = 0.032) and increased HannumAge (IVW: ß = 1.33, 95% CI 0.36 to 2.3, pFDR = 0.028), GrimAge (IVW: ß = 1.19, 95% CI 0.19 to 2.2, pFDR = 0.040), and PhenoAge (IVW: ß = 1.4, 95% CI 0.12 to 2.68, pFDR = 0.053). A significant association was also found with the frailty index (IVW: ß = 0.31, 95% CI 0.13 to 0.49, pFDR = 0.006). No significant associations were found with facial aging, IEAA, or cognitive performance. CONCLUSIONS: CM is linked to accelerated biological aging, shown by shorter telomere length and increased epigenetic aging markers. CM was also associated with increased frailty, highlighting the need for early interventions to mitigate long-term effects. Further research should explore mechanisms and prevention strategies.

Homeostatic Shrinkage of Dendritic Spines Requires Melatonin Type 3 Receptor Activation During Sleep.

High-frequency oscillatory activity in cognition-related neural circuits during wakefulness consistently induces the growth of dendritic spines and axonal terminals. Although these structural changes are essential for cognitive functions, it is hypothesized that if these newly expanded structures fail to establish functional connections, they may become superfluous. Sleep is believed to facilitate the reduction of such redundant structures to maintain neural homeostasis. However, the mechanisms underlying this pruning process during sleep remain poorly understood. In this study, that melatonin type 3 receptors (MT3Rs) are selectively expressed in the stellate neurons of the medial entorhinal cortex (MEC) is demonstrated, an area where high melatonin levels are detected during sleep. Activation of MT3Rs during sleep initiates the shrinkage of dendritic spines in stellate neurons by downregulating neural network activity and dephosphorylating synaptic proteins in the MEC. This process is disrupted when MT3R expression is knocked down or when MT3Rs are blocked during sleep. Notably, interference with MT3Rs in the MEC during sleep impairs the acquisition of spatial memory but does not affect object memory acquisition following sleep. These findings reveal novel molecular mechanisms involving melatonin and MT3Rs in the regulation of dendritic spine shrinkage during sleep, which is crucial for the acquisition and consolidation of spatial memory.

MR-Based Radiomics Predicts CDK6 Expression and Prognostic Value in High-grade Glioma.

RATIONALE AND OBJECTIVES: This study aims to assess the prognostic value of Cyclin-dependent kinases 6 (CDK6) expression levels and establish a machine learning-based radiomics model for predicting the expression levels of CDK6 in high-grade gliomas (HGG). MATERIALS AND METHODS: Clinical parameters and genomic data were extracted from 310 HGG patients in the Cancer Genome Atlas (TCGA) database and 27 patients in the Repository of Molecular Brain Neoplasia Data (REMBRANDT) database. Univariate and multivariate Cox regression, as well as Kaplan-Meier analysis, were performed for prognosis analysis. The correlation between immune cell Infiltration with CDK6 was assessed using spearman correlation analysis. Radiomic features were extracted from contrast-enhanced magnetic resonance imaging (CE-MRI) in the Cancer Imaging Archive (TCIA) database (n = 82) and REMBRANDT database (n = 27). Logistic regression (LR) and support vector machine (SVM) were employed to establish the radiomics model for predicting CDK6 expression. Receiver operating characteristic curve (ROC), calibration curve, and decision curve analysis (DCA) were utilized to assess the predictive performance of the radiomics model. Generate radiomic scores (RS) based on the LR model. An RS-based nomogram was constructed to predict the prognosis of HGG. RESULTS: CDK6 was significantly overexpressed in HGG tissues and was related to lower overall survival. A significant elevation in infiltrating M0 macrophages was observed in the CDK6 high group (P < 0.001). The LR radiomics model for the prediction of CDK6 expression levels (AUC=0.810 in the training cohort, AUC = 0.784 after cross-validation, AUC=0.750 in the testing cohort) was established utilizing three radiomic features. The predictive efficiencies of the RS-based nomogram, as measured by AUC, were 0.769 for 1-year, 0.815 for 3-year, and 0.780 for 5-year, respectively. CONCLUSION: The expression level of CDK6 can impact the prognosis of patients with HGG. The expression level of HGG can be noninvasively prognosticated utilizing a radiomics model.

Integrated multiomic analysis reveals disulfidptosis subtypes in glioblastoma: implications for immunotherapy, targeted therapy, and chemotherapy.

Introduction: Glioblastoma (GBM) presents significant challenges due to its malignancy and limited treatment options. Precision treatment requires subtyping patients based on prognosis. Disulfidptosis, a novel cell death mechanism, is linked to aberrant glucose metabolism and disulfide stress, particularly in tumors expressing high levels of SLC7A11. The exploration of disulfidptosis may provide a new perspective for precise diagnosis and treatment of glioblastoma. Methods: Transcriptome sequencing was conducted on samples from GBM patients treated at Tiantan Hospital (January 2022 - December 2023). Data from CGGA and TCGA databases were collected. Consensus clustering based on disulfidptosis features categorized GBM patients into two subtypes (DRGclusters). Tumor immune microenvironment, response to immunotherapy, and drug sensitivity were analyzed. An 8-gene disulfidptosis-based subtype predictor was developed using LASSO machine learning algorithm and validated on CGGA dataset. Results: Patients in DRGcluster A exhibited improved overall survival (OS) compared to DRGcluster B. DRGcluster subtypes showed differences in tumor immune microenvironment and response to immunotherapy. The predictor effectively stratified patients into high and low-risk groups. Significant differences in IC50 values for chemotherapy and targeted therapy were observed between risk groups. Discussion: Disulfidptosis-based classification offers promise as a prognostic predictor for GBM. It provides insights into tumor immune microenvironment and response to therapy. The predictor aids in patient stratification and personalized treatment selection, potentially improving outcomes for GBM patients.

A midbrain GABAergic circuit constrains wakefulness in a mouse model of stress.

Enhancement of wakefulness is a prerequisite for adaptive behaviors to cope with acute stress, but hyperarousal is associated with impaired behavioral performance. Although the neural circuitries promoting wakefulness in acute stress conditions have been extensively identified, less is known about the circuit mechanisms constraining wakefulness to prevent hyperarousal. Here, we found that chemogenetic or optogenetic activation of GAD2-positive GABAergic neurons in the midbrain dorsal raphe nucleus (DRNGAD2) decreased wakefulness, while inhibition or ablation of these neurons produced an increase in wakefulness along with hyperactivity. Surprisingly, DRNGAD2 neurons were paradoxically wakefulness-active and were further activated by acute stress. Bidirectional manipulations revealed that DRNGAD2 neurons constrained the increase of wakefulness and arousal level in a mouse model of stress. Circuit-specific investigations demonstrated that DRNGAD2 neurons constrained wakefulness via inhibition of the wakefulness-promoting paraventricular thalamus. Therefore, the present study identified a wakefulness-constraining role DRNGAD2 neurons in acute stress conditions.

Combined Nucleophilic and Electrophilic Functionalization to Optimize Blue Phosphorescence in Cyclometalated Platinum Complexes.

Ligand-based functionalization strategies have emerged as powerful approaches to tune and optimize blue phosphorescence, which can involve nucleophilic addition to coordinated ligands or electrophilic functionalization via the coordination of exogenous Lewis acids. Whereas both have been used separately to enhance the photophysical properties of organometallic compounds with high-energy triplet states, in this work, we show that these two strategies can be used together on the same platform. Isocyanide-supported cyclometalated platinum compounds undergo nucleophilic addition with diethylamine to form a strong σ-donor acyclic diaminocarbene-supporting ligand. In a subsequent step, a cyanide ancillary ligand is converted into a more strongly π-acidic isocyanoborate via the coordination of a borane Lewis acid. Importantly, both of these ligand-based functionalization steps improve the quantum yields and lifetimes of the blue-phosphorescent complexes. This synergy results in complexes with photoluminescence quantum yields up to 0.40 for deep blue and 0.75 for sky blue regions and PL lifetimes on the order of 10-5 s.

BTK Expression Level Prediction and the High-Grade Glioma Prognosis Using Radiomic Machine Learning Models.

We aimed to study whether the Bruton's tyrosine kinase (BTK) expression is correlated with the prognosis of patients with high-grade gliomas (HGGs) and predict its expression level prior to surgery, by constructing radiomic models. Clinical and gene expression data of 310 patients from The Cancer Genome Atlas (TCGA) were included for gene-based prognostic analysis. Among them, contrast-enhanced T1-weighted imaging (T1WI + C) from The Cancer Imaging Archive (TCIA) with genomic data was selected from 82 patients for radiomic models, including support vector machine (SVM) and logistic regression (LR) models. Furthermore, the nomogram incorporating radiomic signatures was constructed to evaluate its clinical efficacy. BTK was identified as an independent risk factor for HGGs through univariate and multivariate Cox regression analyses. Three radiomic features were selected to construct the SVM and LR models, and the validation set showed area under curve (AUCs) values of 0.711 (95% CI, 0.598-0.824) and 0.736 (95% CI, 0.627-0.844), respectively. The median survival times of the high Rad_score and low-Rad_score groups based on LR model were 15.53 and 23.03 months, respectively. In addition, the total risk score of each patient was used to construct a predictive nomogram, and the AUCs calculated from the corresponding time-dependent ROC curves were 0.533, 0.659, and 0.767 for 1, 3, and 5 years, respectively. BTK is an independent risk factor associated with poor prognosis in patients, and the radiomic model constructed in this study can effectively and non-invasively predict preoperative BTK expression levels and patient prognosis based on T1WI + C.

Spatial memory requires hypocretins to elevate medial entorhinal gamma oscillations.

The hypocretin (Hcrt) (also known as orexin) neuropeptidic wakefulness-promoting system is implicated in the regulation of spatial memory, but its specific role and mechanisms remain poorly understood. In this study, we revealed the innervation of the medial entorhinal cortex (MEC) by Hcrt neurons in mice. Using the genetically encoded G-protein-coupled receptor activation-based Hcrt sensor, we observed a significant increase in Hcrt levels in the MEC during novel object-place exploration. We identified the function of Hcrt at presynaptic glutamatergic terminals, where it recruits fast-spiking parvalbumin-positive neurons and promotes gamma oscillations. Bidirectional manipulations of Hcrt neurons' projections from the lateral hypothalamus (LHHcrt) to MEC revealed the essential role of this pathway in regulating object-place memory encoding, but not recall, through the modulation of gamma oscillations. Our findings highlight the significance of the LHHcrt-MEC circuitry in supporting spatial memory and reveal a unique neural basis for the hypothalamic regulation of spatial memory.

Luminescent Platinum Complexes with π-Extended Aryl Acetylide Ligands Supported by Isocyanides or Acyclic Diaminocarbenes.

In this work, we present a series of luminescent platinum acetylide complexes with acetylides that are electronically modified and/or π-extended. Six isocyanide-supported complexes with the general formula cis-[Pt(CNAr)2(C≡CR)2] and six acyclic diaminocarbene (ADC) complexes of the form trans-[Pt(ADC)2(C≡CR)2], all using the same five acetylide ligands, are described. The compounds are characterized by multinuclear NMR, FT-IR, and single-crystal X-ray diffraction. In most cases, the phosphorescence arises from an acetylide-centered 3(π → π*) excited state, although in one of the isocyanide compounds there is evidence for a charge-transfer excited state. The photoluminescence wavelength depends strongly on the substitution pattern and extent of the π conjugation on the acetylide, with maxima spanning the range of ca. 460-540 nm. Most photoluminescence lifetimes are long, beyond 50 µs, and quantum yields are low to moderate, 0.043-0.27. The photoluminescence quantum yields and lifetimes in these compounds do not systematically improve in the ADC complexes compared to the isocyanide versions, suggesting the neutral ligand σ-donor character does not play a large role in the excited-state dynamics when the triplet excited state is delocalized over a large π system.

Modular Imine Chelates with Variable Anionic Donors Promote Red Phosphorescence in Cyclometalated Iridium Complexes.

The lack of red and deep-red emitting molecular phosphors with high photoluminescence quantum yields remains a significant fundamental challenge and has implications in optoelectronic technologies for color displays and other consumer products. In this work, we introduce a series of seven new red or deep-red emitting heteroleptic bis-cyclometalated iridium(III) complexes, supported by five different ancillary ligands (L^X) from the salicylaldimine and 2-picolinamide families. Previous work had shown that electron-rich anionic chelating "L^X" ligands can be effective in supporting efficient red phosphorescence, and the complementary approach described here, in addition to being synthetically simpler, offers two key advantages over the previous designs. First, the "L" and "X" functionalities can be independently tuned, providing excellent control over the electronic energy levels and excited-state dynamics. Second, these classes of L^X ligands can have beneficial impacts on the excited-state dynamics but do not significantly perturb the emission color profile. Cyclic voltammetry experiments show that the substituents on the L^X ligand impact the HOMO energy but have a minimal effect on the LUMO energy. Photoluminescence measurements reveal that all the compounds luminesce in the red or deep-red region as a function of the cyclometalating ligand and exhibit exceptionally high photoluminescence quantum yields (ΦPL), comparable or superior to the best-performing red-emitting iridium complexes.

Ratiometric oxygen sensors of cyclometalated iridium(III) with enhanced quantum yields and variable dynamic ranges.

Four luminescent ratiometric oxygen sensors, pairing phosphorescent cyclometalated iridium with coumarin or BODIPY fluorophores, are presented here. These compounds realize three key improvements over our previous designs, namely higher phosphorescence quantum yields, the ability to access intermediate dynamic ranges better suited for typical atmospheric O2 levels, and the possibility of using visible excitation instead of UV. These ratiometric sensors are accessed via very simple, 1-step syntheses involving direct reaction of the chloro-bridged cyclometalated iridium dimer with the pyridyl-substituted fluorophore. They have phosphorescent quantum yields up to 29% with short to intermediate phosphoresence lifetimes ranging from 1.7 to 5.3 µs in three of the sensors, with the fourth having a long lifetime of 440 µs that is very responsive to oxygen. In one case, visible excitation of 430 nm is used to provide dual emission instead of UV excitation.

Substituent-Dependent Azide Addition to Isocyanides Generates Strongly Luminescent Iridium Complexes.

Ligand-centered functionalization reactions offer diverse strategies to prepare luminescent organometallic compounds. These compounds can have unique structures that are not accessible via traditional coordination chemistry and can possess enhanced or unusual photophysical properties. Here we show that bis-cyclometalated iridium bis-isocyanide complexes (1) react with azide (N3-) to form novel luminescent structures. The fate of the reaction with azide is determined primarily by the substituent on the aryl isocyanide. Those with electron-withdrawing substituents (CF3 or NO2) react with 1 equiv of azide followed by N2 extrusion, forming aryl cyanamido products (2). With electron-donating groups on the aryl isocyanide the reactivity is more diverse, and three outcomes are possible. In two cases, the isocyanide and azide undergo a [3 + 2] cycloaddition to form a C-bound tetrazolato structure (3). In three other cases, 2 equiv of azide are involved in the formation of a previously unobserved structure, where a tetrazolato and aryl cyanamido couple and rearrange to form a chelating ligand comprised of an N-bound tetrazolato and an acyclic diaminocarbene (4). Finally, a bimetallic aryl cyanamido complex (5) is isolated in one case. All compounds are luminescent, some with exceptional photoluminescence quantum yields as high as 0.81 in solution for sky-blue emission, and 0.87 for yellow emission and 0.65 for orange-red emission in polymer films.

A paraventricular thalamus to central amygdala neural circuit modulates acute stress-induced heightened wakefulness.

Heightened wakefulness in response to stressors is essential for survival but can also lead to sleep disorders like insomnia. The paraventricular thalamus (PVT) is both a critical thalamic area for wakefulness and a stress-sensitive brain region. However, whether the PVT and its neural circuitries are involved in controlling wakefulness in stress conditions remains unknown. Here, we find that PVT neurons projecting to the central amygdala (CeA) are activated by different stressors. These neurons are wakefulness-active and increase their activities upon sleep to wakefulness transitions. Optogenetic activation of the PVT-CeA circuit evokes transitions from sleep to wakefulness, whereas selectively silencing the activity of this circuit decreases time spent in wakefulness. Specifically, chemogenetic inhibition of CeA-projecting PVT neurons not only alleviates stress responses but also attenuates the acute stress-induced increase of wakefulness. Thus, our results demonstrate that the PVT-CeA circuit controls physiological wakefulness and modulates acute stress-induced heightened wakefulness.

Host Responses to Live-Attenuated ASFV (HLJ/18-7GD).

African swine fever (ASF) is a highly contagious and fatal disease caused by the African swine fever virus. Recently, the multigene family and CD2v gene-deleted ASF vaccine candidate HLJ/18-7GD was found to be safe and effective in laboratory and clinical trials. However, the immune-protective mechanisms underlying the effects of HLJ/18-7GD remain unclear. We assessed samples from pigs immunized with a single dose of 106 TCID50 HLJ/18-7GD. We found that pigs immunized with HLJ/18-7GD showed high levels of specific antibodies. T lymphocyte subsets (helper T cells (Th); cytotoxic T lymphocytes (CTL); double-positive T cells (DP-T cells)) were temporarily increased in peripheral blood mononuclear cells (PBMCs) after HLJ/18-7GD immunization. Once the HLJ/18-7GD-immunized pigs had been challenged with virulent HLJ/18, the percentage of Th, CTL, and DP-T cells increased significantly. PBMCs extracted from the pigs induced higher levels of CD8+ T cells after infection with the HLJ/18 strain in vitro. The levels of GM-CSF, IFN-γ, and TNF-α were upregulated at 7 days post-inoculation; this finding was contrary to the results obtained after HLJ/18 or HLJ/18ΔCD2v infection. The immune protection from HLJ/18-7GD resulted from many synergies, which could provide a theoretical basis for HLJ/18-7GD as a safe and effective ASF vaccine.

Trimetallic Iridium-Nickel-Iridium Bis(formazanate) Assemblies.

Formazans have attracted a lot of attention in coordination chemistry since the early 1940s because of their unique properties engendered by the nitrogen-rich conjugated backbone. Although many studies have been done using formazanates to chelate transition metals, research using formazanates as building blocks for polynuclear compounds and supramolecular chemistry remains rare. In this paper, we describe a synthetic strategy that uses a pyridyl-substituted bis(formazanato)nickel complex as a metalloligand to further assemble with two [Ir(C^N)2]+ centers (C^N is the cyclometalating ligand). The trimetallic complexes represent a new binding mode for flexidentate pyridyl-substituted formazanates and a new structural class of polynuclear formazanate complexes. This work expands the chemistry of polynuclear formazanate complexes, for the first time pairing 3d and 5d metals in the same assembly. The redox chemistry of these trimetallic complexes, evaluated via cyclic voltammetry, is described. The compounds described in this work are luminescent, and studies of bis-cyclometalated iridium model complexes lacking the formazanate bridge confirm that the phosphorescence arises from the iridium center.

Hyperthermic Intraperitoneal Chemotherapy (HIPEC) Combined with Surgery: A 12-Year Meta-Analysis of this Promising Treatment Strategy for Advanced Gastric Cancer at Different Stages.

BACKGROUND: This meta-analysis was designed to systematically assess the effectiveness and safety of hyperthermic intraperitoneal chemotherapy (HIPEC) combined with surgery for different stages of advanced gastric cancer (AGC) during the last 12 years. METHODS: The Cochrane Library, PubMed, Embase, Web of Science, and China National Knowledge Infrastructure (CNKI) were searched online, and papers were retrieved from other sources. Next, randomized controlled trials (RCTs) and high-quality nonrandomized controlled trials (NRCTs) were selected for this analysis. The meta-analysis was conducted with RevMan5.4 software. RESULT: The 10 RCTs and 13 NRCTs selected for the study included 1892 patients. The overall survival rates were higher in the HIPEC group at 1 year (risk ratio [RR], 0.52; P = 0.004) and 3 years (RR, 0.63; P < 0.00001) than in the control group for the patients without peritoneal cancer, and the HIPEC group had a significant reduction in the recurrence rate (RR, 0.60; p < 0.00001). Among the patients with peritoneal carcinomatosis (PC), the HIPEC group had significantly higher overall survival rates at 1 year (RR, 0.62; P = 0.00001), 2 years (RR, 0.85; P = 0.002), and 3 years (RR, 0.87; P = 0.0001), with an increase in the overall median survival time of 4.67 months. The two groups showed no statistically significant difference in terms of complications for patients with PC (RR, 1.03; P = 0.93) or without PC (RR, 1.15; P = 0.51). CONCLUSION: For local AGC without PC, standard surgery combined with prophylactic HIPEC could prolong survival and reduce the recurrence rate without more complications. The prognosis of this treatment strategy for patients with PC is closely related to patient selection. Complete cytoreduction combined with therapeutic HIPEC could prolong survival.

Prognosis and Biological Behavior of Gastric Signet-Ring Cell Carcinoma Better or Worse: A Meta-Analysis.

BACKGROUND: The clinical pathology of gastric signet-ring cell carcinoma (SRC) is still unclear. This meta-analysis was performed to evaluate the difference in biological behavior and prognosis between SRC and non-signet ring cell carcinoma (NSRC). METHODS: A total of 58 eligible studies were analyzed using RevMan and other auxiliary software. Biological behaviors were compared based on odds ratio (OR) and mean difference (MD). Hazards ratio (HR) was calculated for prognosis based on Kaplan-Meier curves. RESULTS: Totally, 28,946 SRC patients were compared with 81,917 NSRC patients. Compared with NSRC patients, lower male: female ratio (OR = 0.53, P < 0.01), younger age (MD = -4.89, P < 0.01), more middle location (OR = 1.64, P < 0.01), more depressed type at early stage (OR = 1.31, P < 0.05), higher incidence of Borrmann type IV (OR = 1.96, P < 0.01), less lymph node metastasis at early stage (OR = 0.78, P < 0.05), better prognosis at early stage (HR = 0.59, P < 0.01), and worse prognosis at advanced stage (HR = 1.19, P < 0.01) were associated with SRC patients. CONCLUSION: The prognosis of SRC at early stage is better than other types of gastric cancer, while that of SRC at advanced stage is relatively poorer.

Thermally induced transformation of a Cu4I4-based cluster to a Cu2I2-based cluster under mild conditions.

A reaction of 6,6'-bis((benzylthio)methyl)-2,2'-bipyridine (L) with CuI at room temperature led to one Cu4I4-based cluster, which could be thermally transformed to a Cu2I2-based one under mild conditions due to the formation of a Cu-S bond. Along with the structural transformation, remarkable changes in the color and luminescence have been triggered.