Prevalence and outcomes of atrial fibrillation in patients suffering prostate cancer: a national analysis in the United States.

Purpose: Although the adverse effects of atrial fibrillation (AF) on cancers have been well reported, the relationship between the AF and the adverse outcomes in prostate cancer (PC) remains inconclusive. This study aimed to explore the prevalence of AF and evaluate the relationship between AF and clinical outcomes in PC patients. Methods: Patients diagnosed with PC between 2008 and 2017 were identified from the National Inpatient Sample database. The trends in AF prevalence were compared among PC patients and their subgroups. Multivariable regression models were used to assess the associations between AF and in-hospital mortality, length of hospital stay, total cost, and other clinical outcomes. Results: 256,239 PC hospitalizations were identified; 41,356 (83.8%) had no AF and 214,883 (16.2%) had AF. AF prevalence increased from 14.0% in 2008 to 20.1% in 2017 (P < .001). In-hospital mortality in PC inpatients with AF increased from 5.1% in 2008 to 8.1% in 2017 (P < .001). AF was associated with adverse clinical outcomes, such as in-hospital mortality, congestive heart failure, pulmonary circulation disorders, renal failure, fluid and electrolyte disorders, cardiogenic shock, higher total cost, and longer length of hospital stay. Conclusions: The prevalence of AF among inpatients with PC increased from 2008 to 2017. AF was associated with poor prognosis and higher health resource utilization. Better management strategies for patients with comorbid PC and AF, particularly in older individuals, are required.

Successful management of Mycobacterium abscessus pneumonia in a 53-day-old immunocompetent infant.

Pulmonary infection due to Mycobacterium abscessus complex (MABC) usually occurs in children with underlying risk factors including cystic fibrosis (CF), chronic lung disease, and immunocompromised status, but rarely in immunocompetent children without underlying lung disease, especially in infants. We present a case of MABC pulmonary disease (MABC-PD) in an otherwise healthy 53-day-old male infant with one week of cough and respiratory distress. Computed tomography showed multiple masses across both lungs. Isolated mycobacteria from his bronchoalveolar lavage fluid were identified as MABC. We describe our complete evaluation, including immunodeficiency evaluation incorporating whole exome sequencing and our therapeutic process given complicated susceptibility pattern of the M. abscessus isolate, and review literature for MABC-PD in immunocompetent children. The infant was successfully treated through prolonged treatment with parenteral Amikacin, Cefoxitin, Linezolid, and Clarithromycin, combined with inhaled Amikacin.

Dysregulated Ribosome Biogenesis Is a Targetable Vulnerability in Triple-Negative Breast Cancer: MRPS27 as a Key Mediator of the Stemness-inhibitory Effect of Lovastatin.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with limited effective therapeutic options readily available. We have previously demonstrated that lovastatin, an FDA-approved lipid-lowering drug, selectively inhibits the stemness properties of TNBC. However, the intracellular targets of lovastatin in TNBC remain largely unknown. Here, we unexpectedly uncovered ribosome biogenesis as the predominant pathway targeted by lovastatin in TNBC. Lovastatin induced the translocation of ribosome biogenesis-related proteins including nucleophosmin (NPM), nucleolar and coiled-body phosphoprotein 1 (NOLC1), and the ribosomal protein RPL3. Lovastatin also suppressed the transcript levels of rRNAs and increased the nuclear protein level and transcriptional activity of p53, a master mediator of nucleolar stress. A prognostic model generated from 10 ribosome biogenesis-related genes showed outstanding performance in predicting the survival of TNBC patients. Mitochondrial ribosomal protein S27 (MRPS27), the top-ranked risky model gene, was highly expressed and correlated with tumor stage and lymph node involvement in TNBC. Mechanistically, MRPS27 knockdown inhibited the stemness properties and the malignant phenotypes of TNBC. Overexpression of MRPS27 attenuated the stemness-inhibitory effect of lovastatin in TNBC cells. Our findings reveal that dysregulated ribosome biogenesis is a targetable vulnerability and targeting MRPS27 could be a novel therapeutic strategy for TNBC patients.

Discovery of Highly Potent Solute Carrier 13 Member 5 (SLC13A5) Inhibitors for the Treatment of Hyperlipidemia.

In the face of escalating metabolic disease prevalence, largely driven by modern lifestyle factors, this study addresses the critical need for novel therapeutic approaches. We have identified the sodium-coupled citrate transporter (NaCT or SLC13A5) as a target for intervention. Utilizing rational drug design, we developed a new class of SLC13A5 inhibitors, anchored by the hydroxysuccinic acid scaffold, refining the structure of PF-06649298. Among these, LBA-3 emerged as a standout compound, exhibiting remarkable potency with an IC50 value of 67 nM, significantly improving upon PF-06649298. In vitro assays demonstrated LBA-3's efficacy in reducing triglyceride levels in OPA-induced HepG2 cells. Moreover, LBA-3 displayed superior pharmacokinetic properties and effectively lowered triglyceride and total cholesterol levels in diverse mouse models (PCN-stimulated and starvation-induced), without detectable toxicity. These findings not only spotlight LBA-3 as a promising candidate for hyperlipidemia treatment but also exemplify the potential of targeted molecular design in advancing metabolic disorder therapeutics.

Combined therapy of dabrafenib and an anti-HER2 antibody-drug conjugate for advanced BRAF-mutant melanoma.

BACKGROUND: Melanoma is the most lethal skin cancer characterized by its high metastatic potential. In the past decade, targeted and immunotherapy have brought revolutionary survival benefits to patients with advanced and metastatic melanoma, but these treatment responses are also heterogeneous and/or do not achieve durable responses. Therefore, novel therapeutic strategies for improving outcomes remain an unmet clinical need. The aim of this study was to evaluate the therapeutic potential and underlying molecular mechanisms of RC48, a novel HER2-target antibody drug conjugate, either alone or in combination with dabrafenib, a V600-mutant BRAF inhibitor, for the treatment of advanced BRAF-mutant cutaneous melanoma. METHODS: We evaluated the therapeutic efficacy of RC48, alone or in combination with dabrafenib, in BRAF-mutant cutaneous melanoma cell lines and cell-derived xenograft (CDX) models. We also conducted signaling pathways analysis and global mRNA sequencing to explore mechanisms underlying the synergistic effect of the combination therapy. RESULTS: Our results revealed the expression of membrane-localized HER2 in melanoma cells. RC48 effectively targeted and inhibited the growth of HER2-positive human melanoma cell lines and corresponding CDX models. When used RC48 and dabrafenib synergically induced tumor regression together in human BRAF-mutant melanoma cell lines and CDX models. Mechanically, our results demonstrated that the combination therapy induced apoptosis and cell cycle arrest while suppressing cell motility in vitro. Furthermore, global RNA sequencing analysis demonstrated that the combination treatment led to the downregulation of several key signaling pathways, including the PI3K-AKT pathway, MAPK pathway, AMPK pathway, and FOXO pathway. CONCLUSION: These findings establish a preclinical foundation for the combined use of an anti-HER2 drug conjugate and a BRAF inhibitor in the treatment of BRAF-mutant cutaneous melanoma.

Gestational diabetes mellitus enhances cobalt placental transfer efficiency between mother and infant.

Background: The fetal stage is pivotal for growth and development, making it susceptible to the adverse effects of prenatal metal(loid)s exposure. This study evaluated the influence of gestational diabetes mellitus (GDM) on the placental transfer efficiency (PTE) of metal(loid)s and thus assessed the associated risks of prenatal metal(loid)s exposure.Materials and method: Designed as a case-control study, it incorporated 114 pregnant participants: 65 without complications and 49 diagnosed with GDM. We utilized inductively coupled plasma mass spectrometry to quantify seven metal(loid)s - manganese (Mn), cobalt (Co), nickel (Ni), copper (Cu), gallium (Ga), arsenic (As), and cadmium (Cd) - in both maternal venous blood and umbilical cord blood.Result: We compared metal(loid)s concentrations and their PTE in the maternal and cord blood between the two groups. Notably, Cu, Ga, As, and Co levels in the umbilical cord blood of the GDM group (657.9 ± 167.2 µg/L, 1.23 ± 0.34 µg/L, 5.19 ± 2.58 µg/L, 1.09 ± 2.03 µg/L) surpassed those of the control group, with PTE of Co showing a marked increase in GDM group (568.8 ± 150.4 µg/L, 1.05 ± 0.31 µg/L, 4.09 ± 2.54 µg/L, 0.47 ± 0.91 µg/L), with PTE of Co showing a marked increase in GDM group (p < 0.05). The PTE of Ni exhibited a reduction in the GDM group relative to the control group, yet this decrease did not reach statistical significance.Conclusion: This study indicates that GDM can influence the placental transfer efficiency of certain metal(loid)s, leading to higher concentrations of Co, Cu, Ga, and As in the umbilical cord blood of the GDM group. The marked increase in the PTE of Co suggests a potential link to placental abnormal angiogenesis due to GDM.

The Causal Relationship between Plasma Myeloperoxidase Levels and Respiratory Tract Infections: A Bidirectional Mendelian Randomization Study.

Background: Observational researches reported the underlying correlation of plasma myeloperoxidase (MPO) concentration with respiratory tract infections (RTIs), but their causality remained unclear. Here, we examined the cause-effect relation between plasma MPO levels and RTIs. Materials and Methods: Datasets of plasma MPO levels were from the Folkersen et al. study (n = 21,758) and INTERVAL study (n = 3,301). Summarized data for upper respiratory tract infection (URTI) (2,795 cases and 483,689 controls) and lower respiratory tract infection (LRTI) in the intensive care unit (ICU) (585 cases and 430,780 controls) were from the UK Biobank database. The primary method for Mendelian randomization (MR) analysis was the inverse variance weighted approach, with MR-Egger and weighted median methods as supplements. Cochrane's Q test, MR-Egger intercept test, MR pleiotropy residual sum and outliers global test, funnel plots, and leave-one-out analysis were used for sensitivity analysis. Results: We found that plasma MPO levels were positively associated with URTI (odds ratio (OR) = 1.135; 95% confidence interval (CI) = 1.011-1.274; P=0.032) and LRTI (ICU) (OR = 1.323; 95% CI = 1.006-1.739; P=0.045). The consistent impact direction is shown when additional plasma MPO level genome-wide association study datasets are used (URTI: OR = 1.158; 95% CI = 1.072-1.251; P < 0.001; LRTI (ICU): OR = 1.216; 95% CI = 1.020-1.450; P=0.030). There was no evidence of a causal effect of URTI and LRTI (ICU) on plasma MPO concentration in the reverse analysis (P > 0.050). The sensitivity analysis revealed no violations of MR presumptions. Conclusions: Plasma MPO levels may causally affect the risks of URTI and LRTI (ICU). In contrast, the causal role of URTI and LRTI (ICU) on plasma MPO concentration was not supported in our MR analysis. Further studies are needed to identify the relationship between RTIs and plasma MPO levels.

A Two-Stage Generative Model with CycleGAN and Joint Diffusion for MRI-based Brain Tumor Detection.

Accurate detection and segmentation of brain tumors is critical for medical diagnosis. However, current supervised learning methods require extensively annotated images and the state-of-the-art generative models used in unsupervised methods often have limitations in covering the whole data distribution. In this paper, we propose a novel framework Two-Stage Generative Model (TSGM) that combines Cycle Generative Adversarial Network (CycleGAN) and Variance Exploding stochastic differential equation using joint probability (VE-JP) to improve brain tumor detection and segmentation. The CycleGAN is trained on unpaired data to generate abnormal images from healthy images as data prior. Then VE-JP is implemented to reconstruct healthy images using synthetic paired abnormal images as a guide, which alters only pathological regions but not regions of healthy. Notably, our method directly learned the joint probability distribution for conditional generation. The residual between input and reconstructed images suggests the abnormalities and a thresholding method is subsequently applied to obtain segmentation results. Furthermore, the multimodal results are weighted with different weights to improve the segmentation accuracy further. We validated our method on three datasets, and compared with other unsupervised methods for anomaly detection and segmentation. The DSC score of 0.8590 in BraTs2020 dataset, 0.6226 in ITCS dataset and 0.7403 in In-house dataset show that our method achieves better segmentation performance and has better generalization.

[Distribution Prediction of Soil Heavy Metals Based on Remote Sensing Temporal-Spatial-Spectral Features and Random Forest Model].

Obtaining soil heavy metal content characteristics and spatial distribution is crucial for preventing soil pollution and formulating environmental protection policies. We collected 304 surface soil samples (0-20 cm) in the Changqing district. At the same time, the spectral, temporal, and spatial features of soil heavy metals were derived from multi-remote sensing data; the temporal-spatial-spectral features closely related to soil heavy metals were selected via correlation analysis and used as input independent variables. The measured soil arsenic (As) content was used as the dependent variable to establish a spatial prediction model based on the random forest (RF) algorithm. The results showed the following:the As content in the soils exceeded the background value by 43.17% but did not exceed the risk screening values and intervention values, indicating slight heavy metal pollution in the soil. The accuracy ranking of the spatial prediction models with one feature type from high to low was spatial features (ratio of performance to inter-quartile range (RPIQ)=3.87)>temporal features (RPIQ=2.57)>spectral features (RPIQ=2.50). The spatial features were the most informative for predicting soil heavy metals. The models using temporal-spatial, temporal-spectral, and spatial-spectral features were superior to those using only one feature type, and the RPIQ values were 4.81, 4.21, and 4.70, respectively. The RF model with temporal-spatial-spectral features achieved the highest spatial prediction accuracy (R2=0.90; root mean square error (RMSE)=0.77; RPIQ=5.68). The As content decreased from the northwest to the southeast due to Yellow River erosion and industrial activities. The spatial prediction of soil heavy metals incorporating remote sensing temporal-spatial-spectral features and the random forest model provides effective support for soil pollution prevention and environmental risk control.

Synergistic antitumor activity between HER2 antibody-drug conjugate and chemotherapy for treating advanced colorectal cancer.

Colorectal cancer (CRC) is the third most common cancer associated with a poor prognosis. Effective targeted therapy alone or in combination for treating advanced CRC remains to be a major clinical challenge. Here, we propose the therapeutic efficacy and molecular mechanism underlying RC48, a FDA-approved anti-HER2 antibody conjugate via a cleavable linker to the microtubule inhibitor monomethyl auristatin E (MMAE), either alone or in combination with gemcitabine (GEM) in various models of HER2-positive advanced CRC. Our findings demonstrated that HER2 was widely expressed and located on the plasma membrane of CRC patient specimens, PDX xenograft tumors and cell lines. It confirmed that RC48 alone significantly targeted and eradicated HER2 positive CRC tumor in these models. Moreover, we screened a panel of FDA-approved first-line chemotherapy drugs in vitro. We found that GEM exhibited stronger antiproliferative activity compared to the other first-line anti-cancer agents. Furthermore, combination therapy of RC48 and GEM significantly showed synergetic antitumor activity in vitro and in vivo. To gain further mechanistic insights into the combination therapy, we performed RNA-seq analysis. The results revealed that combination treatment of RC48 and GEM regulated multiple signaling pathways, such as PI3K-AKT, MAPK, p53, Foxo, apoptosis, cell cycle and cell senescence, etc., to exert its antitumor activity in CRC cells. Collectively, these preclinical findings demonstrated that RC48 alone or combinational therapy exerted promising antitumor activity, and meriting the preclinical framework for combinational therapy of anti-HER2 drug conjugate drug and chemotherapy drugs for HER2-positive patients with advanced CRC.

A Comprehensive Review on Synergy of Multi-Modal Data and AI Technologies in Medical Diagnosis.

Disease diagnosis represents a critical and arduous endeavor within the medical field. Artificial intelligence (AI) techniques, spanning from machine learning and deep learning to large model paradigms, stand poised to significantly augment physicians in rendering more evidence-based decisions, thus presenting a pioneering solution for clinical practice. Traditionally, the amalgamation of diverse medical data modalities (e.g., image, text, speech, genetic data, physiological signals) is imperative to facilitate a comprehensive disease analysis, a topic of burgeoning interest among both researchers and clinicians in recent times. Hence, there exists a pressing need to synthesize the latest strides in multi-modal data and AI technologies in the realm of medical diagnosis. In this paper, we narrow our focus to five specific disorders (Alzheimer's disease, breast cancer, depression, heart disease, epilepsy), elucidating advanced endeavors in their diagnosis and treatment through the lens of artificial intelligence. Our survey not only delineates detailed diagnostic methodologies across varying modalities but also underscores commonly utilized public datasets, the intricacies of feature engineering, prevalent classification models, and envisaged challenges for future endeavors. In essence, our research endeavors to contribute to the advancement of diagnostic methodologies, furnishing invaluable insights for clinical decision making.

Identification and effective regulation of scarb1 gene involved in pigmentation change in autotetraploid Carassius auratus.

The autotetraploid Carassius auratus (4nRR, 4 n=200, RRRR) is derived from whole-genome duplication of Carassius auratus red var. (RCC, 2 n=100, RR). In the current study, we demonstrated that chromatophores and pigment changes directly caused the coloration and variation of 4nRR skin (red in RCC, brownish-yellow in 4nRR). To further explore the molecular mechanisms underlying coloration formation and variation in 4nRR, we performed transcriptome profiling and molecular functional verification in RCC and 4nRR. Results revealed that scarb1, associated with carotenoid metabolism, underwent significant down-regulation in 4nRR. Efficient editing of this candidate pigment gene provided clear evidence of its significant role in RCC coloration. Subsequently, we identified four divergent scarb1 homeologs in 4nRR: two original scarb1 homeologs from RCC and two duplicated ones. Notably, three of these homeologs possessed two highly conserved alleles, exhibiting biased and allele-specific expression in the skin. Remarkably, after precise editing of both the original and duplicated scarb1 homeologs and/or alleles, 4nRR individuals, whether singly or multiply mutated, displayed a transition from brownish-yellow skin to a cyan-gray phenotype. Concurrently, the proportional areas of the cyan-gray regions displayed a gene-dose correlation. These findings illustrate the subfunctionalization of duplicated scarb1, with all scarb1 genes synergistically and equally contributing to the pigmentation of 4nRR. This is the first report concerning the functional differentiation of duplicated homeologs in an autopolyploid fish, substantially enriching our understanding of coloration formation and change within this group of organisms.

Study on dynamic characteristics of salinized silt under cyclic loading.

Under the repeated action of aircraft taxiing load, the subgrade plastic deformation becomes the key factor affecting the service performance of the airfields when salinized silt is used to fill the subgrade. In this study, the dynamic triaxial tests were carried out on a region in the northern part of China to study the effects of different salt contents on the dynamic characteristics of silt under cyclic loading. A prediction model for the salinized silt dynamic strength with a plastic strain of 4% as the failure criterion for the subgrade was thus proposed. It is found that with the increase of dynamic stress amplitude, the salinized silt plastic deformation transforms gradually from plastic deformation to incremental failure. The salt contents significantly influence the plastic strain and critical dynamic stress of silt. The strength of the salinized silt specimen is related to the ion concentration in the soil pores and the arrangement pattern of soil particles, as indicated by the progressive strength increase of the salinized silt at the low salt content of 1% and a further gradual decrease at high salt content.

Magnetic resonance imaging-based approaches for detecting the efficacy of combining therapy following VEGFR-2 and PD-1 blockade in a colon cancer model.

BACKGROUND: Angiogenesis inhibitors have been identified to improve the efficacy of immunotherapy in recent studies. However, the delayed therapeutic effect of immunotherapy poses challenges in treatment planning. Therefore, this study aims to explore the potential of non-invasive imaging techniques, specifically intravoxel-incoherent-motion diffusion-weighted imaging (IVIM-DWI) and blood oxygenation level-dependent magnetic resonance imaging (BOLD-MRI), in detecting the anti-tumor response to the combination therapy involving immune checkpoint blockade therapy and anti-angiogenesis therapy in a tumor-bearing animal model. METHODS: The C57BL/6 mice were implanted with murine MC-38 cells to establish colon cancer xenograft model, and randomly divided into the control group, anti-PD-1 therapy group, and combination therapy group (VEGFR-2 inhibitor combined with anti-PD-1 antibody treatment). All mice were imaged before and, on the 3rd, 6th, 9th, and 12th day after administration, and pathological examinations were conducted at the same time points. RESULTS: The combination therapy group effectively suppressed tumor growth, exhibiting a significantly higher tumor inhibition rate of 69.96% compared to the anti-PD-1 group (56.71%). The f value and D* value of IVIM-DWI exhibit advantages in reflecting tumor angiogenesis. The D* value showed the highest correlation with CD31 (r = 0.702, P = 0.001), and the f value demonstrated the closest correlation with vessel maturity (r = 0.693, P = 0.001). While the BOLD-MRI parameter, R2* value, shows the highest correlation with Hif-1α(r = 0.778, P < 0.001), indicating the capability of BOLD-MRI to evaluate tumor hypoxia. In addition, the D value of IVIM-DWI is closely related to tumor cell proliferation, apoptosis, and infiltration of lymphocytes. The D value was highly correlated with Ki-67 (r = - 0.792, P < 0.001), TUNEL (r = 0.910, P < 0.001) and CD8a (r = 0.918, P < 0.001). CONCLUSIONS: The combination of VEGFR-2 inhibitors with PD-1 immunotherapy shows a synergistic anti-tumor effect on the mouse colon cancer model. IVIM-DWI and BOLD-MRI are expected to be used as non-invasive approaches to provide imaging-based evidence for tumor response detection and efficacy evaluation.

Development and therapeutic potential of GSPT1 molecular glue degraders: A medicinal chemistry perspective.

Unprecedented therapeutic targeting of previously undruggable proteins has now been achieved by molecular-glue-mediated proximity-induced degradation. As a small GTPase, G1 to S phase transition 1 (GSPT1) interacts with eRF1, the translation termination factor, to facilitate the process of translation termination. Studied demonstrated that GSPT1 plays a vital role in the acute myeloid leukemia (AML) and MYC-driven lung cancer. Thus, molecular glue (MG) degraders targeting GSPT1 is a novel and promising approach for treating AML and MYC-driven cancers. In this Perspective, we briefly summarize the structural and functional aspects of GSPT1, highlighting the latest advances and challenges in MG degraders, as well as some representative patents. The structure-activity relationships, mechanism of action and pharmacokinetic features of MG degraders are emphasized to provide a comprehensive compendium on the rational design of GSPT1 MG degraders. We hope to provide an updated overview, and design guide for strategies targeting GSPT1 for the treatment of cancer.

Glycomyces niveus sp. nov., a novel actinomycete isolated from sandy soil.

A novel mycelium-forming actinomycete, designated strain NEAU-S30T, was isolated from the sandy soil of a sea beach in Shouguang city, Shandong province, PR China. The strain developed long chains of non-motile cylindrical spores with smooth surfaces on aerial mycelia. The results of a polyphasic taxonomic study indicated that NEAU-S30T represented a member of the genus Glycomyces. The results of 16S rRNA gene sequence analysis indicated that NEAU-S30T was closely related to 'Glycomycesluteolus' (98.97 % sequence similarity), Glycomycesalgeriensis (98.90 %), 'Glycomyces tritici' (98.83 %) and Glycomyces lechevalierae (98.76 %). The average nucleotide identity (ANI) values between NEAU-S30T and 'G. luteolus' NEAU-A15, G. algeriensis DSM 44727T, 'G. tritici' NEAU-C2 and G. lechevalierae DSM 44724T were 87.77, 87.53, 87.41 and 87.80 %, respectively. The digital DNA G+C content of the genomic DNA was 70.5 %. The whole-cell sugars contained ribose and xylose. The predominant menaquinones were MK-10(H2), MK-10(H4) and MK-10(H6). The predominant fatty acids were anteiso-C15 : 0, iso-C16 : 0, anteiso-C17 : 0 and iso-C15 : 0. The polar lipid profile consisted of diphosphatidylglycerol, phosphatidylglycerol, phosphoglycolipid, phosphatidylinositol, phosphatidylinositol mannoside and an unidentified glycolipid. On the basis of the results of comparative analysis of genotypic, phenotypic and chemotaxonomic data, the novel actinomycete strain NEAU-S30T (=JCM 33975T=CGMCC 4.7890T) represents the type strain of a novel species within the genus Glycomyces, for which the name Glycomyces niveus sp. nov. is proposed.

New phenylbutenoids and terpene glycosides from Ginkgo biloba leaves.

Our continued works on the chemical constituents of Ginkgo biloba (G. biloba) leaves has led to the isolation of two novel phenylbutenoids (1, 2), along with five previously unidentified terpene glycosides (3-7). Among them, compounds 1 and 2 represent unique (Z)-phenylbutenoids, 3-6 are megastigmane glycosides, and 7 is identified as a rare bilobanone glycoside (Fig. 1). This study marks the first reported isolation of phenylbutenoid and bilobanone glycoside from G. biloba. The chemical structures of these compounds were elucidated through extensive spectroscopic analysis, including HR-ESI-MS and various 1D and 2D NMR experiments. Furthermore, the absolute configurations of these molecules were determined using Mosher's method, ECD experiments, and Cu-Kα X-ray crystallographic analyses.

40 Hz light flickering promotes sleep through cortical adenosine signaling.

Flickering light stimulation has emerged as a promising non-invasive neuromodulation strategy to alleviate neuropsychiatric disorders. However, the lack of a neurochemical underpinning has hampered its therapeutic development. Here, we demonstrate that light flickering triggered an immediate and sustained increase (up to 3 h after flickering) in extracellular adenosine levels in the primary visual cortex (V1) and other brain regions, as a function of light frequency and intensity, with maximal effects observed at 40 Hz frequency and 4000 lux. We uncovered cortical (glutamatergic and GABAergic) neurons, rather than astrocytes, as the cellular source, the intracellular adenosine generation from AMPK-associated energy metabolism pathways (but not SAM-transmethylation or salvage purine pathways), and adenosine efflux mediated by equilibrative nucleoside transporter-2 (ENT2) as the molecular pathway responsible for extracellular adenosine generation. Importantly, 40 Hz (but not 20 and 80 Hz) light flickering for 30 min enhanced non-rapid eye movement (non-REM) and REM sleep for 2-3 h in mice. This somnogenic effect was abolished by ablation of V1 (but not superior colliculus) neurons and by genetic deletion of the gene encoding ENT2 (but not ENT1), but recaptured by chemogenetic inhibition of V1 neurons and by focal infusion of adenosine into V1 in a dose-dependent manner. Lastly, 40 Hz light flickering for 30 min also promoted sleep in children with insomnia by decreasing sleep onset latency, increasing total sleep time, and reducing waking after sleep onset. Collectively, our findings establish the ENT2-mediated adenosine signaling in V1 as the neurochemical basis for 40 Hz flickering-induced sleep and unravel a novel and non-invasive treatment for insomnia, a condition that affects 20% of the world population.

The Use of Eye-Tracking Technology in Dento-Maxillofacial Esthetics: A Systematic Review.

The use of eye-tracking technology in dental esthetics has gained popularity over the past decade because of its ability to assess observers' visual preferences in an objective manner. The goal of this study was to provide a comprehensive review of eye-tracking studies in dentistry, which could provide a reference for the rational and effective application of eye-tracking technology by dentists in the future. A comprehensive search of articles on eye tracking, published from January 1946 to June 2023, was conducted across several databases using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The major criterion for inclusion was that the study evaluated the use of eye-tracking technology in the field of dentistry. Two independent reviewers screened the eligible studies. A total of 67 articles were identified, 41 of which met our inclusion criteria. The most common application of eye tracking was the assessment of perceptions of changes in specific dental conditions among different classes of observers. Overall differences between groups (different classes of observers, different types of conditions) among different areas or regions of interest were analyzed. This systematic review demonstrated the utility of eye-tracking technology as a quantifiable objective assessment and emerging research tool for evaluating outcomes in several domains of dentistry.