A CD36-dependent non-canonical lipid metabolism program promotes immune escape and resistance to hypomethylating agent therapy in AML.

Environmental lipids are essential for fueling tumor energetics, but whether these exogenous lipids transported into cancer cells facilitate immune escape remains unclear. Here, we find that CD36, a transporter for exogenous lipids, promotes acute myeloid leukemia (AML) immune evasion. We show that, separately from its established role in lipid oxidation, CD36 on AML cells senses oxidized low-density lipoprotein (OxLDL) to prime the TLR4-LYN-MYD88-nuclear factor κB (NF-κB) pathway, and exogenous palmitate transfer via CD36 further potentiates this innate immune pathway by supporting ZDHHC6-mediated MYD88 palmitoylation. Subsequently, NF-κB drives the expression of immunosuppressive genes that inhibit anti-tumor T cell responses. Notably, high-fat-diet or hypomethylating agent decitabine treatment boosts the immunosuppressive potential of AML cells by hijacking CD36-dependent innate immune signaling, leading to a dampened therapeutic effect. This work is of translational interest because lipid restriction by US Food and Drug Administration (FDA)-approved lipid-lowering statin drugs improves the efficacy of decitabine therapy by weakening leukemic CD36-mediated immunosuppression.

Baseline circulating tumor DNA predicts long-term survival outcomes for patients with early breast cancer.

Background: Circulating tumor DNA (ctDNA) is a potential biomarker not only capable of monitoring the treatment response during neoadjuvant therapy (NAT) or rescue therapy, but also identifying minimal residual disease (MRD) and detecting early relapses after primary treatment. However, it remains uncertain whether the detection of ctDNA at diagnosis, before any treatment, can predict the prognosis for patients with early breast cancer. The objective of our study was to evaluate the predictive value of baseline ctDNA for prognosis in patients with early breast cancer. Methods: A total of 90 patients with early breast cancer and 24 healthy women were recruited between August 2016 and October 2016. Peripheral blood samples were collected from patients at diagnosis, before any treatment. Blood samples were processed and subjected to targeted deep sequencing with a next-generation sequencing (NGS) panel of 1,021 cancer-related genes. The recurrence-free survival (RFS) and invasive disease-free survival (iDFS) were reported. Results: The 90 patients with breast cancer included 6 patients with ductal carcinoma in situ (DCIS) and 84 patients with invasive breast cancer. Within the cohort of patients with invasive breast cancer, ctDNA were detected in 57 patients, with a ctDNA detection rate of 67.9%. Meanwhile, no ctDNA was detected in DCIS patients. Among 84 patients with invasive breast cancer, patients with high-level ctDNA had a significantly lower RFS compared to patients with low-level ctDNA (log-rank P=0.0036). Conclusions: Our study suggested that ctDNA at diagnosis, before any treatment, could potentially serve as a biomarker to predict the prognosis for patients with early breast cancer. However, further follow-up and more studies with large sample sizes are required to confirm these findings.

Recognition of autism spectrum disorder in children based on electroencephalogram network topology.

Although our knowledge of autism spectrum disorder (ASD) has been deepened, the accurate diagnosis of ASD from normal individuals is still left behind. In this study, we proposed to apply the spatial pattern of the network topology (SPN) to identify children with ASD from normal ones. Based on two independent batches of electroencephalogram datasets collected separately, the accurate recognition of ASD from normal children was achieved by applying the proposed SPN features. Since decreased long-range connectivity was identified for children with ASD, the SPN features extracted from the distinctive topological architecture between two groups in the first dataset were used to validate the capacity of SPN in classifying ASD, and the SPN features achieved the highest accuracy of 92.31%, which outperformed the other features e.g., power spectrum density (84.62%), network properties (76.92%), and sample entropy (73.08%). Moreover, within the second dataset, by using the model trained in the first dataset, the SPN also acquired the highest sensitivity in recognizing ASD, when compared to the other features. These results consistently illustrated that the functional brain network, especially the intrinsic spatial network topology, might be the potential biomarker for the diagnosis of ASD.

Decline in reproductive health and its transgenerational lag effect.

In the last two decades, there has been a fast-growing prevalence of infertility reported in China. Moreover, Chinese reproductive health has shown a clear decline. Thus, it is imperative to determine the precipitating causes and the root causes of this decline. Environmental and climate risks (ECRs) may be attributed to the decline in reproductive health. Experimental findings have shown that the impact of ECRs on reproductive health can be passed down from both males and females to their offspring, demonstrating an intergenerational and transgenerational lag effect. We perceive that the declined reproductive health may lead to negative demographic consequences in China; therefore, we suggest the following three regulations be implemented: (i) prevent Chinese of childbearing age from exposure to ECRs; (ii) further develop and promote assisted reproductive technology and set up sperm and ovum banks on a national scale; (iii) quantitatively establish the causality between fathers and mothers who suffer from ECRs and the impaired reproductive health in their progeny; and (iv) teach ECRs-health knowledge in psychotherapeutic training and continuing education.

Bioactivities of essential oil extracted from Elsholtzia densa Benth. And its main components against Tribolium castaneum eggs and pupae.

This study aimed to develop a relatively natural and safe botanical insecticide for controlling the storage pest Tribolium castaneum in the egg and pupal stages. It examined how Elsholtzia densa Benth. essential oil (EO) and its primary components, ß-caryophyllene and limonene, affected T. castaneum eggs and pupae through contact and fumigation. Among th, the contact activities of ß-caryophyllene against T. castaneum eggs and pupae are LD50 (median lethal dose, 50%) = 0.156 mg/cm2 and ED50 (median effective dose, 50%) = 16.35 mg/pupa respectively. The study also investigated the effect of ß-caryophyllene and limonene on T. castaneum eggs and pupae through synergistic contact and fumigation. When the mixing ratio of ß-caryophyllene and limonene was 7:1, the LD50 value of contact activity against T. castaneum eggs was reduced to 0.100 mg/cm2, displaying an obvious synergistic effect. Experiments were conducted to investigate the antitoxic effect of ß-caryophyllene on T. castaneum eggs and pupae, as well as its effects on the enzymatic activity of acetylcholinesterase, succinate dehydrogenase, glutathione S-transferase and carboxylesterase in T. castaneum pupae. Finally, the molecular docking techniques were employed to confirm the aforementioned effects on enzyme function. The findings of this study might help improve storage pest control with T. castaneum and create eco-friendly insecticides using E. densa EO, ß-caryophyllene, and limonene.

Nonplanar Aromaticity of Dinuclear Rare-Earth Metallacycles.

While the concept of metalla-aromaticity has well been extended to transition organometallic compounds in diverse geometries, aromatic rare-earth organometallic complexes are rare due to the special (n - 1)d0 configuration and high-lying (n - 1)d orbitals of rare-earth centers. In particular, nonplanar cases of rare-earth complexes have not been reported so far. Here, we disclose the nonplanar aromaticity of dinuclear scandium and samarium metallacycles characterized by various aromaticity indices (nucleus-independent chemical shift, isochemical shielding surface, anisotropy of induced current density, and isomerization stabilization energy). Bonding analyses (Kohn-Sham molecular orbital, adaptive natural density partitioning, multicenter bond indices, and principal interacting orbital) reveal that three delocalized π orbitals, predominantly contributed by the 2-butene tetraanion ligand, result in the formation of six-electron conjugated systems. Guided by these findings, we predicted that the lutetium and gadolinium analogues of dinuclear rare-earth metallacycles should be aromatic, which have been verified by the successful synthesis of real molecules. This work extends the concept of nonplanar aromaticity to the field of rare-earth metallacycles and illuminates the path for designing and synthesizing various rare-earth metalla-aromatics.

Panda-UV Unlocks Deeper Protein Characterization with Internal Fragments in Ultraviolet Photodissociation Mass Spectrometry.

Ultraviolet photodissociation (UVPD) mass spectrometry unlocks insights into the protein structure and sequence through fragmentation patterns. While N- and C-terminal fragments are traditionally relied upon, this work highlights the critical role of internal fragments in achieving near-complete sequencing of protein. Previous limitations of internal fragment utilization, owing to their abundance and potential for random matching, are addressed here with the development of Panda-UV, a novel software tool combining spectral calibration, and Pearson correlation coefficient scoring for confident fragment assignment. Panda-UV showcases its power through comprehensive benchmarks on three model proteins. The inclusion of internal fragments boosts identified fragment numbers by 26% and enhances average protein sequence coverage to a remarkable 93% for intact proteins, unlocking the hidden region of the largest protein carbonic anhydrase II in model proteins. Notably, an average of 65% of internal fragments can be identified in multiple replicates, demonstrating the high confidence of the fragments Panda-UV provided. Finally, the sequence coverages of mAb subunits can be increased up to 86% and the complementary determining regions (CDRs) are nearly completely sequenced in a single experiment. The source codes of Panda-UV are available at https://github.com/PHOENIXcenter/Panda-UV.

Microfluidic Immunosensor Platform for Sensitive Detection of Human Epidermal Growth Factor Receptor-2 Based on Enhanced Cathode Electrochemiluminescence of Bimetallic Nanoclusters.

In this work, a microfluidic immunosensor chip was developed by incorporating microfluidic technology with electrochemiluminescence (ECL) for sensitive detection of human epidermal growth factor receptor-2 (HER2). The immunosensor chip can achieve robust reproducibility in mass production by integrating multiple detection units in a series. Notably, nanoscale materials can be better adapted to microfluidic systems, greatly enhancing the accuracy of the immunosensor chip. Ag@Au NCs closed by glutathione (GSH) were introduced in the ECL microfluidic immunosensor system with excellent and stable ECL performance. The synthesized CeO2-Au was applied as a coreaction promoter in the ECL signal amplification system, which made the result of HER2 detection more reliable. In addition, the designed microfluidic immunosensor chip integrated the biosensing system into a microchip, realizing rapid and accurate detection of HER2 by its high throughput and low usage. The developed short peptide ligand NARKFKG (NRK) achieved an effective connection between the antibody and nanocarrier for improving the detection efficiency of the sensor. The immunosensor chip had better storage stability and sensitivity than traditional detection methods, with a wide detection range from 10 fg·mL-1 to 100 ng·mL-1 and a low detection limit (LOD) of 3.29 fg·mL-1. In general, a microfluidic immunosensor platform was successfully constructed, providing a new idea for breast cancer (BC) clinical detection.

High-Performance Liquid Chromatographic Quantification of the Plant Hormone Abscisic Acid at ppb Levels in Plant Samples after a Single Immunoaffinity Column Cleanup.

High-performance liquid chromatography with ultraviolet detection (HPLC-UV) is a common analysis technique due to its high versatility and simple operation. In the present study, HPLC-UV detection was integrated with immunoaffinity cleanup (IAC) of the sample extracts. The matrix effect was greatly reduced, and the limit of detection was as low as 1 ng/g of free abscisic acid (ABA) in fresh plant tissues. A monoclonal antibody 3F1 (mAb 3F1) was developed to specifically recognize free ABA but not ABA analogues. The mAb 3F1-immobilized immunoaffinity column exhibited a capacity of 850 ng/mL and an elution efficiency of 88.8-105% for standards. The extraction recoveries of the column for ABA ranged from 80.4 to 108.9%. ABA content was detected in various plant samples with IAC-HPLC-UV. The results were verified with ultraperformance liquid chromatography-electrospray tandem mass spectrometry. IAC-HPLC-UV can be a sensitive and cost-efficient method for plant hormone analysis.

Effectiveness of high-risk human papillomavirus genotyping for cervical cancer screening. A multicentre screening cohort study in rural China.

BACKGROUND: This study aimed to assess the effectiveness of high-risk human papillomavirus (HR-HPV) primary testing for cervical cancer screening in China's rural areas. METHODS: Women aged 21-64 years were recruited. Cervical cytology was diagnosed following the Bethesda 2001 classification system, HPV infection (HR-HPV, HPV-16, HPV-18, and other 12 genotypes) identified by Cobas-4800, and colposcopy and biopsy performed when required. Primary outcomes were defined as the cumulative incidence of cervical intraepithelial neoplasia grade 2/3/higher (CIN2/3+) and its relative risk at baseline and at the 36-month follow-up. RESULTS: The study included 9,218 women; mean age was 45.15 years (SD: 8.74); 81% completed the follow-up. The most frequent type of cytological lesions (12.4% ) were ASCUS (8.4%) and LSIL (2.2%). HR-HPV infection (16.3%) was more prevalent in HPV-16 than in HPV-18 (3 vs 1.5%); a positive relationship with the severity of the lesions, from 29.8% in ASCUS to 89.6% in HSIL was found. At baseline, 3.5% of the patients underwent colposcopy; 20% had a positive diagnosis. At the 36-month follow-up, the cumulative incidences of CIN2+ and CIN3+ were higher in women with HR-HPV infection (16.9 vs 0.5% and 8.2 vs 0.2%). The relative risk of CIN2/3+ was lower in HR-HPV-negative women compared to those with a negative cytology at baseline (0.4; 95%CI: 0.3-0.4). CONCLUSIONS: High-risk HPV-based screening may significantly reduce the risk of CIN2/3+ compared with cytology testing. This may be a new resource for public health demands in China's rural areas.

Accurate prediction of neurologic changes in critically ill infants using pose AI.

Infant alertness and neurologic changes can reflect life-threatening pathology but are assessed by exam, which can be intermittent and subjective. Reliable, continuous methods are needed. We hypothesized that our computer vision method to track movement, pose AI, could predict neurologic changes in the neonatal intensive care unit (NICU). We collected 4,705 hours of video linked to electroencephalograms (EEG) from 115 infants. We trained a deep learning pose algorithm that accurately predicted anatomic landmarks in three evaluation sets (ROC-AUCs 0.83-0.94), showing feasibility of applying pose AI in an ICU. We then trained classifiers on landmarks from pose AI and observed high performance for sedation (ROC-AUCs 0.87-0.91) and cerebral dysfunction (ROC-AUCs 0.76-0.91), demonstrating that an EEG diagnosis can be predicted from video data alone. Taken together, deep learning with pose AI may offer a scalable, minimally invasive method for neuro-telemetry in the NICU.

Menthol-Modified Quercetin Liposomes with Brain-Targeting Function for the Treatment of Senescent Alzheimer's Disease.

Oxidative stress and neuroinflammation in the aging brain are correlated with the development of neurodegenerative diseases, such as Alzheimer's disease (AD). The blood-brain barrier (BBB) poses a significant challenge to the effective delivery of therapeutics for AD. Prior research has demonstrated that menthol (Men) can augment the permeability of the BBB. Consequently, in the current study, we modified Men on the surface of liposomes to construct menthol-modified quercetin liposomes (Men-Qu-Lips), designed to cross the BBB and enhance quercetin (Qu) concentration in the brain for improved therapeutic efficacy. The experimental findings indicate that Men-Qu-Lips exhibited good encapsulation efficiency and stability, successfully crossed the BBB, improved oxidative stress and neuroinflammation in the brains of aged mice, protected neurons, and enhanced their learning and memory abilities.

Bioactivities and Synergistic Effect of Elsholtzia ciliata Essential Oil and Its Main Components against Lasioderma serricorne.

Investigations have shown that storage bugs seriously harm grains during storage. In the interim, essential oils (EOs) have been proven to be a good botanical pesticide. The anti-Lasioderma serricorne properties of Elsholtzia ciliata essential oil, which was obtained by steam distillation, were evaluated using DL-limonene, carvone, and their two optical isomer components using contact, repelling, and fumigation techniques. Simultaneously, the fumigation, contact, and repellent activities of carvone and its two optical isomers mixed with DL-limonene against L. serruricorne were evaluated. The results showed that E. ciliata, its main components (R-carvone, DL-limonene), and S-carvone exhibited both fumigations (LC50 = 14.47, 4.42, 20.9 and 3.78 mg/L) and contact (LD50 = 7.31, 4.03, 28.62 and 5.63 µg/adult) activity against L.serricorne. A binary mixture (1:1) of R-carvone and DL-limonene displayed an obvious synergistic effect. A binary mixture (1:1) of carvone and its two optical isomers exhibited an obvious synergistic effect, too. Furthermore, the repellent activity of the EO, carvone, and its two optical isomers, DL-limonene, and a combination of them varied. To stop insect damage during storage, E. ciliata and its components can be utilized as bio-insecticides.

Pharmacokinetics study of ginsenoside Rg1 liposome by pulmonary administration.

Ginsenoside Rg1 (Rg1), a monomer saponin component, is one of the components with the highest content in total saponins of Panaxnotoginseng. It had various pharmacological effects. The bioavailability of oral tablets is only 1-20 %, and it is eliminated quickly in the blood. The development of new dosage forms and new routes of administration of ginsenoside Rg1 with sustained release and high bioavailability has become a significant problem to be solved. The Rg1 liposomes study used a thin film dispersion ultrasound method for its preparation. This study focused the pharmacokinetic parameters of ginsenoside Rg1 liposomes in rats through the lung perfusion method. Ginsenoside Rg1 liposomes were round and uniform in shape, the particle size was 2-3 µm, and the encapsulation efficiency of ginsenoside Rg1 liposome was 51.2 %. Results showed that, after pulmonary administration of ginsenoside Rg1, the time of ginsenoside Rg1 detected by Rg1 liposomes was longer than that of Rg1 solution, the relative bioavailability of ginsenoside Rg1 liposome lung administration AUC liposome/AUC solution = 122.67 %. These results provided the scientific theoretical and experimental basis for further development of new dosage forms and new routes of administration of ginsenoside Rg1.

Study on fingerprint and quantitative analysis of Verbena officinalis water extract by LC-MS and HPLC.

Verbena officinalis L. as a medical plant has been used to treat many diseases. However, the quality control underlying V. officinalis remains to be studied. HPLC fingerprint analysis and the qualitative and quantitative analysis of water extract from V. officinalis were carried out, and it was found that the quality varies according to habitat and batch. Verbenalin could be a crucial component in the quality evaluation of V. officinalis. This study contributes to better understanding of quality control for V. officinalis.

Pulmonary Hypertension and Anastrozole (PHANTOM): A Randomized, Double-Blind, Placebo-Controlled Trial.

RATIONALE: Inhibition of aromatase with anastrozole reduces pulmonary hypertension in experimental models. OBJECTIVES: We aimed to determine whether anastrozole improved six-minute walk distance (6MWD) at six months in pulmonary arterial hypertension (PAH). METHODS: We performed a randomized, double-blind, placebo-controlled Phase II clinical trial of anastrozole in subjects with PAH at seven centers. Eighty-four post-menopausal women and men with PAH were randomized in a 1:1 ratio to receive anastrozole 1 mg or placebo by mouth daily, stratified by sex using permuted blocks of variable sizes. All subjects and study staff were masked. The primary outcome was the change from baseline in 6MWD at six months. Using intent-to-treat analysis, we estimated the treatment effect of anastrozole using linear regression models adjusted for sex and baseline 6MWD. Assuming 10% loss to follow-up, we anticipated having 80% power to detect a difference in the change in 6MWD of 22 meters. MEASUREMENTS AND MAIN RESULTS: Forty-one subjects were randomized to placebo and 43 to anastrozole and all received the allocated treatment. Three subjects in the placebo group and two in the anastrozole group discontinued study drug. There was no significant difference in the change in 6MWD at six months (placebo-corrected treatment effect -7.9 m, 95%CI -32.7 - 16.9, p = 0.53). There was no difference in adverse events between the groups. CONCLUSIONS: Anastrozole did not show a significant effect on 6MWD compared to placebo in post-menopausal women and men with PAH. Anastrozole was safe and did not show adverse effects. Clinical trial registration available at www. CLINICALTRIALS: gov, ID: NCT03229499.

Diet-omics in the Study of Urban and Rural Crohn disease Evolution (SOURCE) cohort.

Crohn disease (CD) burden has increased with globalization/urbanization, and the rapid rise is attributed to environmental changes rather than genetic drift. The Study Of Urban and Rural CD Evolution (SOURCE, n = 380) has considered diet-omics domains simultaneously to detect complex interactions and identify potential beneficial and pathogenic factors linked with rural-urban transition and CD. We characterize exposures, diet, ileal transcriptomics, metabolomics, and microbiome in newly diagnosed CD patients and controls in rural and urban China and Israel. We show that time spent by rural residents in urban environments is linked with changes in gut microbial composition and metabolomics, which mirror those seen in CD. Ileal transcriptomics highlights personal metabolic and immune gene expression modules, that are directly linked to potential protective dietary exposures (coffee, manganese, vitamin D), fecal metabolites, and the microbiome. Bacteria-associated metabolites are primarily linked with host immune modules, whereas diet-linked metabolites are associated with host epithelial metabolic functions.

Bioinformatics analysis and experimental validation of m6A and cuproptosis-related lncRNA NFE4 in clear cell renal cell carcinoma.

PURPOSE: This study aimed to construct an m6A and cuproptosis-related long non-coding RNAs (lncRNAs) signature to accurately predict the prognosis of kidney clear cell carcinoma (KIRC) patients using the information acquired from The Cancer Genome Atlas (TCGA) database. METHODS: First, the co-expression analysis was performed to identify lncRNAs linked with N6-methyladenosine (m6A) and cuproptosis in ccRCC. Then, a model encompassing four candidate lncRNAs was constructed via univariate, least absolute shrinkage together with selection operator (LASSO), and multivariate regression analyses. Furthermore, Kaplan-Meier, principal component, functional enrichment annotation, and nomogram analyses were performed to develop a risk model that could effectively assess medical outcomes for ccRCC cases. Moreover, the cellular function of NFE4 in Caki-1/OS-RC-2 cultures was elucidated through CCK-8/EdU assessments and Transwell experiments. Dataset outcomes indicated that NFE4 can have possible implications in m6A and cuproptosis, and may promote ccRCC progression. RESULTS: We constructed a panel of m6A and cuproptosis-related lncRNAs to construct a prognostic prediction model. The Kaplan-Meier and ROC curves showed that the feature had acceptable predictive validity in the TCGA training, test, and complete groups. Furthermore, the m6A and cuproptosis-related lncRNA model indicated higher diagnostic efficiency than other clinical features. Moreover, the NFE4 function analysis indicated a gene associated with m6A and cuproptosis-related lncRNAs in ccRCC. It was also revealed that the proliferation and migration of Caki-1 /OS-RC-2 cells were inhibited in the NFE4 knockdown group. CONCLUSION: Overall, this study indicated that NFE4 and our constructed risk signature could predict outcomes and have potential clinical value.

Simultaneous Screening of 172 Veterinary Drugs by Modified QuEChERS-LC-MS/MS in TCM Galli Gigerii Endothelium Corneum.

An analytical method was developed for the screening of 172 veterinary drugs in traditional Chinese medicine Galli Gigerii Endothelium Corneum by high-performance liquid chromatography tandem mass spectrometry. The samples were pretreated by a modified QuEChERS method. A Zorbax Eclipse plus C18 column (1.8 µm, 3.0 × 150 mm2, Agilent) was used for the separation of analytes by gradient elution. All analytes were detected by electrospray ionization mass spectrometry with multiple reaction monitoring mode. Good linearity with R ≥ 0.99 was exhibited for all analytes within the respective range. The recoveries of all monitored analytes ranged from 55.4 to 127.6% at three spiked levels (limit of quantitation-LOQ, 2-fold LOQ, 10-fold LOQ), with relative standard deviations <17.8%. The estimated LOQ levels were 0.2-20 µg/kg. The application of this method provides a reference for the safety control of traditional Chinese medicines.