Targeting OXCT1-mediated ketone metabolism reprograms macrophages to promote antitumor immunity via CD8+ T cells in hepatocellular carcinoma.

BACKGROUND & AIMS: The liver is the main organ of ketogenesis, while ketones are mainly metabolized in peripheral tissues via the critical enzyme OXCT1. We previously found that ketolysis is reactivated in hepatocellular carcinoma (HCC) cells through OXCT1 expression to promote tumor progression; however, whether OXCT1 regulates antitumor immunity remains unclear. METHODS: To investigate the expression pattern of OXCT1 in hepatocellular carcinoma in vivo, we conducted multiplex immunohistochemistry (mIHC) experiments on human HCC specimens. To explore the role of OXCT1 in mouse hepatocellular carcinoma tumor-associated macrophages (TAMs), we generated LysMcreOXCT1f/f (OXCT1 conditional knockout in macrophages) mice. RESULTS: Here, we found that inhibiting OXCT1 expression in tumor-associated macrophages reduced CD8+ T-cell exhaustion through the succinate-H3K4me3-Arg1 axis. Initially, we found that OXCT1 was highly expressed in liver macrophages under steady state and that OXCT expression was further increased in TAMs. OXCT1 deficiency in macrophages suppressed tumor growth by reprogramming TAMs toward an antitumor phenotype, reducing CD8+ T-cell exhaustion and increasing CD8+ T-cell cytotoxicity. Mechanistically, high OXCT1 expression induced the accumulation of succinate, a byproduct of ketolysis, in TAMs, which promoted Arg1 transcription by increasing the H3K4 trimethylation (H3K4me3) level in the Arg1 promoter. In addition, Pimozide, an inhibitor of OXCT1, suppressed Arg1 expression as well as TAM polarization toward the protumor phenotype, leading to decreasing CD8+ T-cell exhaustion and deceleration of tumor growth. Finally, high expression of OXCT1 in macrophages was positively associated with poor survival in HCC patients. CONCLUSIONS: In conclusion, our results demonstrate that OXCT1 epigenetically suppresses antitumor immunity, suggesting that suppressing OXCT1 activity in TAMs is an effective approach for treating liver cancer. IMPACT AND IMPLICATIONS: The intricate metabolism of liver macrophages plays a critical role in shaping HCC progression and immune modulation. Targeting macrophage metabolism to counteract immune suppression presents a promising avenue for HCC. Here, we found that ketogenesis gene OXCT1 was highly expressed in tumor-associated macrophages and promoted tumor growth by reprogramming TAMs toward a protumor phenotype. And the strategic pharmacological intervention or genetic downregulation of OXCT1 in TAMs enhances the antitumor immunity and decelerated tumor growth. Our results suggest that suppressing OXCT1 activity in TAMs is an effective approach for treating liver cancer.

Evolution and Antigenic Differentiation of Avian Influenza A(H7N9) Virus, China.

We characterized the evolution and molecular characteristics of avian influenza A(H7N9) viruses isolated in China during 2021-2023. We systematically analyzed the 10-year evolution of the hemagglutinin gene to determine the evolutionary branch. Our results showed recent antigenic drift, providing crucial clues for updating the H7N9 vaccine and disease prevention and control.

Alzheimer's disease cerebrospinal fluid biomarkers and kidney function in normal and cognitively impaired older adults.

INTRODUCTION: Recent Alzheimer's disease (AD) clinical trials have used cerebrospinal fluid (CSF) biomarker levels for screening and enrollment. Preliminary evidence suggests that AD risk is related to impaired renal function. The impact of kidney function on commonly used AD biomarkers remains unknown. METHODS: Participants in studies conducted at the Goizueta Alzheimer's Disease Research Center (N = 973) had measurements of serum creatinine and CSF AD biomarkers. General linear models and individual data were used to assess the relationships between biomarkers and eGFR. RESULTS: Lower estimated glomerular filtration rate (eGFR) was associated with lower amyloid beta (Aß)42/tau ratio (p < 0.0001) and Aß42 (p = 0.002) and higher tau (p < 0.0001) and p-tau (p = 0.0002). The impact of eGFR on AD biomarker levels was more robust in individuals with cognitive impairment (all p-values were < 0.005). DISCUSSION: The association between eGFR and CSF AD biomarkers has a significant impact that varies by cognitive status. Future studies exploring this impact on the pathogenesis of AD and related biomarkers are needed. Highlights: There is a significant association between Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers and both estimated glomerular filtration rate (eGFR) and mild cognitive impairment (MCI).Kidney function influences CSF biomarker levels in individuals with normal cognitive function and those with MCI.The impact of kidney function on AD biomarker levels is more pronounced in individuals with cognitive impairment.The variation in CSF tau levels is independent of cardiovascular factors and is likely directly related to kidney function.Tau may have a possible role in both kidney and cognitive function.

Dermal FOXO3 activity in response to Wnt/ß-catenin signaling is required for feather follicle development of goose embryos (Anser cygnoides).

Feather is an important economic trait of poultry, and growth and development state of feathers plays an important role in the economic value of poultry. Dermal fibroblasts are required for structural integrity of the skin and for feather follicle development. How FOXO3 affects feather follicle development as skin tissues change during goose embryo (Anser cygnoides) development and growth is not well understood. Here, we demonstrate that in vitro culture of single feathers and skin tissue results in changes in feather morphological structure by adding drugs to the culture medium that affect FOXO3 expression. We used feather follicles to show that during growth, the root location of feathers, the dermis layer, affects cell proliferation and apoptosis and regulates the expression of major genes in the Wingless-types/beta-catenin (Wnt/ß-catenin) signaling pathway through the activity of FOXO3 in dermal fibroblasts. Feathers and dorsal skin tissues develop the correct structure, but feather length and width and feather follicle diameter change significantly (p < 0.05) without significant changes in feather follicle density (p > 0.05). Transfected dermal fibroblasts also showed that FOXO3 affected the formation and development of feather follicles in the embryonic stage by regulating the Wnt/ß-catenin signaling pathway. Therefore, this study reveals the critical role of dermal fibroblast-FOXO3-induced Wnt/ß-catenin signaling in promoting the formation and development of embryonic feather follicles.

Unlocking the Molecular Variations of a Micron-Scale Amyloid Plaque in an Early Stage Alzheimer's Disease by a Cellular-Resolution Mass Spectrometry Imaging Platform.

Uncovering the molecular changes at the site where Aß is deposited plays a critical role in advancing the diagnosis and treatment of Alzheimer's disease. However, there is currently a lack of a suitable label-free imaging method with a high spatial resolution for brain tissue analysis. In this study, we propose a modified desorption electrospray ionization (DESI) mass spectrometry imaging (MSI) method, called segmented temperature-controlled DESI (STC-DESI), to achieve high-resolution and high-sensitivity spatial metabolomics observation by precisely controlling desorption and ionization temperatures. By concentrating the spray plume and accelerating solvent evaporation at different temperatures, we achieved an impressive spatial resolution of 20 µm that enables direct observation of the heterogeneity around a single cell or an individual Aß plaque and an exciting sensitivity that allows a variety of low-abundance metabolites and less ionizable neutral lipids to be detected. We applied this STC-DESI method to analyze the brains of transgenic AD mice and identified molecular changes associated with individual Aß aggregates. More importantly, our study provides the first evidence that carnosine is significantly depleted and 5-caffeoylquinic acid (5-CQA) levels rise sharply around Aß deposits. These observations highlight the potential of carnosine as a sensitive molecular probe for clinical magnetic resonance imaging diagnosis and the potential of 5-CQA as an efficient therapeutic strategy for Aß clearance in the early AD stage. Overall, our findings demonstrate the effectiveness of our STC-DESI method and shed light on the potential roles of these molecules in AD pathology, specifically in cellular endocytosis, gray matter network disruption, and paravascular Aß clearance.

Protein Tyrosine Phosphatase SHP2 in Macrophages Acts as an Antiatherosclerotic Regulator in Mice.

BACKGROUND: Macrophages have versatile roles in atherosclerosis. SHP2 (Src homology 2 containing protein tyrosine phosphatase 2) has been demonstrated to play a critical role in regulating macrophage activation. However, the mechanism of SHP2 regulation of macrophage function in an atherosclerotic microenvironment remains unknown. METHODS: APOE (apolipoprotein E) or LDLR (low-density lipoprotein receptor) null mice treated with SHP099 were fed a Western diet for 8 weeks, while Shp2MKO:ApoE-/- or Shp2MKO:Ldlr-/- mice and exo-AAV8-SHP2E76K/ApoE-/- mice were fed a Western diet for 12 weeks. In vitro, levels of proinflammatory factors and phagocytic function were then studied in mouse peritoneal macrophages. RNA sequencing was used to identify PPARγ (peroxisome proliferative activated receptor γ) as the key downstream molecule. A PPARγ agonist was used to rescue the phenotypes observed in SHP2-deleted mice. RESULTS: Pharmacological inhibition and selective deletion in macrophages of SHP2 aggravated atherosclerosis in APOE and LDLR null mice with increased plaque macrophages and apoptotic cells. In vitro, SHP2 deficiency in APOE and LDLR null macrophages enhanced proinflammatory polarization and its efferocytosis was dramatically impaired. Conversely, the expression of gain-of-function mutation of SHP2 in mouse macrophages reduced atherosclerosis. The SHP2 agonist lovastatin repressesed macrophage inflammatory activation and enhanced efferocytosis. Mechanistically, RNA sequencing analysis identified PPARγ as a key downstream transcription factor. PPARγ was decreased in macrophages upon SHP2 deletion and inhibition. Importantly, PPARγ agonist decreased atherosclerosis in SHP2 knockout mice, restored efferocytotic defects, and reduced inflammatory activation in SHP2 deleted macrophages. PPARγ was decreased by the ubiquitin-mediated degradation upon SHP2 inhibition or deletion. Finally, we found that SHP2 was downregulated in atherosclerotic vessels. CONCLUSIONS: Overall, SHP2 in macrophages was found to act as an antiatherosclerotic regulator by stabilizing PPARγ in APOE/LDLR null mice.

Reactive Matrices for MALDI-MS of Cholesterol.

Cholesterol is a critical molecule whose dysregulation in certain brain regions is related to multiple neurological disorders. It is of pathological importance to map the distribution of cholesterol in brain. Matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) has been widely used in the molecular imaging of metabolites at a high spatial resolution. However, it is challenging to analyze cholesterol by MALDI-MS due to its difficulty in ionization. Herein, we present for the first time a type of reactive matrix for MALDI-MS of cholesterol. Methylpyridinium carboxaldehydes react with cholesterol and other hydroxyl-containing sterols, which greatly enhanced both desorption and ionization and improved the limits of detection to the low µg/mL range. Compared with previous methods, our reactive matrix requires only one step of chemical derivatization and avoids time-consuming enzymatic reaction, which simplified the sample pretreatment. The reactive matrix was successfully used in mapping the distribution of cholesterol in brain tissue sections using MALDI-MS imaging. In summary, this work has provided a sensitive and simple method for the MALDI-MS analysis of cholesterol, has proposed a novel solution to visualize the distribution of sterol metabolites, and has great potential for applications in neurological and pathological studies.

Determination of oxylipins and their precursors in breast milk by solid phase extraction-ultra high performance liquid chromatography-triple quadrupole tandem mass spectrometry.

Oxylipins and their precursors (long-chain polyunsaturated fatty acids, LCPUFAs) are key intercellular signaling molecules influencing the inflammatory response. Each oxylipin has pro- and/or anti-inflammatory effects, and the relative abundance of different oxylipins can alter the inflammatory balance, making it important to clarify the oxylipin profile of breast milk for optimal infant health. The extraction, identification, and simultaneous quantification of oxylipins in breast milk are challenging due to the structural similarity, limited stability, and the low endogenous concentration of oxylipins and the complex matrix of breast milk. This study aimed to develop a solid phase extraction-ultra high performance liquid chromatography-triple quadrupole tandem mass spectrometry (SPE-UPLC-MS/MS) method for the comprehensive and specific quantification of oxylipins and their precursors in breast milk. The LC conditions (including column, mobile phase, and gradient conditions) and SPE procedure (including SPE cartridges, elution solvent, and elution volume) were optimized to achieve accurate quantification and better analyte recovery. A single 18-minute chromatographic run allows for the quantification of 20 oxylipins and 5 PUFAs. The results showed good linearity (R2 > 0.99) over the concentration range of 2 to 100 ng/mL, with the instrument detection limits ranging from 0.01 to 0.90 ng/mL for oxylipins and 0.02 to 0.59 ng/mL for PUFAs. The method is rapid, sensitive, and reproducible (RSD ≤ 10%) and is suitable for the quantitative analysis of oxylipins and their precursors in infant formula samples.

Epidemiology and Association Rules Analysis for Pulmonary Tuberculosis Cases with Extrapulmonary Tuberculosis from Age and Gender Perspective: A Large-Scale Retrospective Multicenter Observational Study in China.

Background: Tuberculosis (TB), a multisystemic disease with protean presentation, remains a major global health problem. Although concurrent pulmonary tuberculosis (PTB) and extrapulmonary tuberculosis (EPTB) cases are commonly observed clinically, knowledge regarding concurrent PTB-EPTB is limited. Here, a large-scale multicenter observational study conducted in China aimed to study the epidemiology of concurrent PTB-EPTB cases by diagnostically defining TB types and then implementing association rules analysis. Methods: The retrospective study was conducted at 21 hospitals in 15 provinces in China and included all inpatients with confirmed TB diagnoses admitted from Jan 2011 to Dec 2017. Association rules analysis was conducted for cases with concurrent PTB and various types of EPTB using the Apriori algorithm. Results: Evaluation of 438,979TB inpatients indicated PTB was the most commonly diagnosed (82.05%) followed by tuberculous pleurisy (23.62%). Concurrent PTB-EPTB was found in 129,422 cases (29.48%) of which tuberculous pleurisy was the most common concurrent EPTB type observed. The multivariable logistic regression models demonstrated that odds ratios of concurrent PTB-EPTB cases varied by gender and age group. For PTB cases with concurrent EPTB, the strongest association was found between PTB and concurrent bronchial tuberculosis (lift = 1.09). For EPTB cases with concurrent PTB, the strongest association was found between pharyngeal/laryngeal tuberculosis and concurrent PTB (lift = 1.11). Confidence and lift values of concurrent PTB-EPTB cases varied with gender and age. Conclusions: Numerous concurrent PTB-EPTB case types were observed, with confidence and lift values varying with gender and age. Clinicians should screen for concurrent PTB-EPTB in order to improve treatment outcomes.

Subjective cognitive complaints in White and African American older adults: associations with demographic, mood, cognitive, and neuroimaging features.

Subjective cognitive complaints (SCC) in cognitively intact older adults have been investigated as a clinically important symptom that may portend the onset of a neurodegenerative disorder such as Alzheimer's disease. Few studies have concurrently incorporated demographic features, depressive symptoms, neuropsychological status, and neuroimaging correlates of SCC and evaluated whether these differ in White and African American older adults. In the current study, 131 (77 White, 54 African American) healthy participants ≥50 years old completed the Cognitive Function Instrument (CFI) to assess SCC, and they underwent objective cognitive testing, assessment of mood, and brain magnetic resonance imaging. Pearson Product Moment correlations were performed to evaluate associations of the CFI self-ratings with the above measures for the combined group and separately for White and African American participants. SCC were associated with greater depressive symptoms in both White and African American participants in adjusted models controlling for overall cognitive status, education, and hypertension. Greater white matter hyperintensities, lower cortical thickness, older age, and slower set shifting speed were associated with increased SCC in White participants. Although the correlations were not significant for African Americans, the strength of the associations were comparable to White participants. Hippocampal volume was not associated with either total SCC or items specific to memory functioning in the entire group. Longitudinal studies are needed to further evaluate the clinical significance of these associations with risk of conversion to mild cognitive impairment and dementia.

That H9N2 avian influenza viruses circulating in different regions gather in the same live-poultry market poses a potential threat to public health.

H9N2 avian influenza viruses are endemic and persistent in China, but those that are prevalent in different provinces are also causes of wide epidemics, related to the spread of wild birds and the cross-regional trade in live poultry. For the past 4 years, beginning in 2018, we have sampled a live-poultry market in Foshan, Guangdong, in this ongoing study. In addition to the prevalence of H9N2 avian influenza viruses in China during this period, we identified isolates from the same market belonging to clade A and clade B, which diverged in 2012-2013, and clade C, which diverged in 2014-2016, respectively. An analysis of population dynamics revealed that, after a critical divergence period from 2014 to 2016, the genetic diversity of H9N2 viruses peaked in 2017. Our spatiotemporal dynamics analysis found that clade A, B, and C, which maintain high rates of evolution, have different prevalence ranges and transmission paths. Clades A and B were mainly prevalent in East China in the early stage, and then spread to Southern China, becoming epidemic with clade C. Strains from different regions converge at the same live-poultry market to communicate, which may be one reasons the H9N2 viruses are difficult to eradicate and increasingly dominant throughout China. Selection pressure and molecular analysis have demonstrated that single amino acid polymorphisms at key receptor binding sites 156, 160, and 190 under positive selection pressure, suggesting that H9N2 viruses are undergoing mutations to adapt to new hosts. Live-poultry markets are important because people who visit them have frequent contact with poultry, H9N2 viruses from different regions converge at these markets and spread through contact between live birds and humans, generating increased risks of human exposure to these viruses and threatening public health safety. Thus, it is important to reducing the cross-regional trade of live poultry and strengthening the monitoring of avian influenza viruses in live-poultry markets to reduce the spread of avian influenza viruses.

Identification of Key Biomarkers and Candidate Molecules in Non-Small-Cell Lung Cancer by Integrated Bioinformatics Analysis.

Background: Non-small cell lung cancer (NSCLC) is the most prevalent malignant tumor of the lung cancer, for which the molecular mechanisms remain unknown. In this study, we identified novel biomarkers associated with the pathogenesis of NSCLC aiming to provide new diagnostic and therapeutic approaches for NSCLC by bioinformatics analysis. Methods: From the Gene Expression Omnibus database, GSE118370 and GSE10072 microarray datasets were obtained. Identifying the differentially expressed genes (DEGs) between lung adenocarcinoma and normal samples was done. By using bioinformatics tools, a protein-protein interaction (PPI) network was constructed, modules were analyzed, and enrichment analyses were performed. The expression and prognostic values of 14 hub genes were validated by the GEPIA database, and the correlation between hub genes and survival in lung adenocarcinoma was assessed by UALCAN, cBioPortal, String and Cytoscape, and Timer tools. Results: We found three genes (PIK3R1, SPP1, and PECAM1) that have a clear correlation with OS in the lung adenocarcinoma patient. It has been found that lung adenocarcinoma exhibits high expression of SPP1 and that this has been associated with poor prognosis, while low expression of PECAM1 and PIK3R1 is associated with poor prognosis (P < 0.05). We also found that the expression of SPP1 was associated with miR-146a-5p, while the high expression of miR-146a-5p was related to good prognosis (P < 0.05). On the contrary, the lower miR-21-5p on upstream of PIK3R1 is associated with a higher surviving rate in cancer patients (P < 0.05). Finally, we found that the immune checkpoint genes CD274(PD-L1) and PDCD1LG2(PD-1) were also related to SPP1 in lung adenocarcinoma. Conclusions: The results indicated that SPP1 is a cancer promoter (oncogene), while PECAM1 and PIK3R1 are cancer suppressor genes. These genes take part in the regulation of biological activities in lung adenocarcinoma, which provides a basis for improving detection and immunotherapeutic targets for lung adenocarcinoma.

Deep learning-assisted diagnosis of parotid gland tumors by using contrast-enhanced CT imaging.

OBJECTIVES: Imaging interpretation of the benignancy or malignancy of parotid gland tumors (PGTs) is a critical consideration prior to surgery in view of therapeutic and prognostic values of such discrimination. This study investigates the application of a deep learning-based method for preoperative stratification of PGTs. MATERIALS AND METHODS: Using the 3D DenseNet-121 architecture and a dataset consisting of 117 volumetric arterial-phase contrast-enhanced CT scans, we developed a binary classifier for PGT distinction and tested it. We compared the discriminative performance of the model on the test set to that of 12 junior and 12 senior head and neck clinicians. Besides, potential clinical utility of the model was evaluated by measuring changes in unassisted and model-assisted performance of junior clinicians. RESULTS: The model finally reached the sensitivity, specificity, PPV, NPV, F1-score of 0.955 (95% CI 0.751-0.998), 0.667 (95% CI 0.241-0.940), 0.913 (95% CI 0.705-0.985), 0.800 (95% CI 0.299-0.989) and 0.933, respectively, comparable to that of practicing clinicians. Furthermore, there were statistically significant increases in junior clinicians' specificity, PPV, NPV and F1-score in differentiating benign from malignant PGTs when unassisted and model-assisted performance of junior clinicians were compared. CONCLUSION: Our results provide evidence that deep learning-based method may offer assistance for PGT's binary distinction.

SHP2 inhibition mitigates adaptive resistance to MEK inhibitors in KRAS-mutant gastric cancer through the suppression of KSR1 activity.

Despite the promising antitumor activity of RAF/MEK inhibitors for RAS-driven cancers, not all patients respond to these therapies. Adaptive resistance has been reported as a major culprit in non-responders, which can be reversed by SHP2 inhibitors (SHP2is) in multiple cancer cells; however, the underlying mechanisms remain unknown. In this study, we found that KRAS-mutant gastric cancer cells respond to MEK inhibitors (MEKis) with adaptive resistance. Markedly, SHP2 activation accompanied by ERK signaling restoration in MEKi-treated cells, and a MEKi and SHP2i combination had a synergistic effect on downstream signaling blockade. In vivo, SHP099 combined with AZD6244 (selumetinib) was highly efficacious for the treatment of xenografts. Mechanistically, SHP2 was found to interact with the scaffold protein KSR1 through its protein tyrosine phosphatase domain. KSR1 knockdown sensitized cells to AZD6244, whereas a KSR1 activating mutation (S269A) diminished the synergistic anti-proliferative effect of SHP2i and MEKi. Interestingly, activated SHP2, during adaptive resistance to MEKis, impaired the interaction with KSR1, activating KSR1 to promote MAPK signaling. In conclusion, SHP2 promotes adaptive resistance to MEKis by activating KSR1; selumetinib combined with SHP099 might be an available therapeutic strategy for KRAS-mutant gastric cancers.

PFAS-induced lipidomic dysregulations and their associations with developmental toxicity in zebrafish embryos.

Per- and polyfluoroalkyl substances (PFASs) are persistent environmental contaminants, posing developmental toxicity to fish and human. PFAS-induced lipid metabolism disorders were demonstrated using the zebrafish (Danio rerio) embryo model, but the detailed changes of lipid compositions and the influence of these changes on the biological development are still unclear. Herein, lipidomics analysis was performed to reveal the dysregulations of lipid metabolism in zebrafish embryos exposed to perfluorooctanoic acid (PFOA) or perfluorooctane sulfonate (PFOS) through microinjection. Various abnormal phenotypes were observed, including heart bleeding, pericardium edema, spinal curvature and increased heart rate at 72 h after fertilization, especially in the PFOS exposure groups. Lipidomic profiling found downregulated phosphatidylethanolamines in the PFAS-exposed embryos, especially those containing a docosahexaenoyl (DHA) chain, indicating an excessive oxidative damage to the embryos. Glycerolipids were mainly upregulated in the PFOA groups but downregulated in the PFOS groups. These aberrations may reflect oxidative stress, energy metabolism malfunction and proinflammatory signals induced by PFASs. However, supplement of DHA may not be effective in recovering the lipidomic dysregulations and protecting from the developmental toxicity induced by PFASs, showing the complexity of the toxicological mechanisms. This work has revealed the associations between the abnormal phenotypes and dysregulations of lipid metabolism in zebrafish embryos induced by PFASs from the aspect of lipidomics, and discovered the underlying molecular mechanisms of the developmental toxicity of PFASs.

A Novel Domain Adversarial Networks Based on 3D-LSTM and Local Domain Discriminator for Hearing-Impaired Emotion Recognition.

Recent research on emotion recognition suggests that deep network-based adversarial learning has an ability to solve the cross-subject problem of emotion recognition. This study constructed a hearing-impaired electroencephalography (EEG) emotion dataset containing three emotions (positive, neutral, and negative) in 15 subjects. The emotional domain adversarial neural network (EDANN) was carried out to identify hearing-impaired subjects' emotions by learning hidden emotion information between the labeled data and the data with no-label. For the input data, we propose a spatial filter matrix to reduce the overfitting of the training data. A feature extraction network 3DLSTM-ConvNET was used to extract comprehensive emotional information from the time, frequency, and spatial dimensions. Moreover, emotion local domain discriminator and emotion film group local domain discriminator were added to reduce the distribution distance between the same kinds of emotions and different film groups, respectively. According to the experimental results, the average accuracy of subject-dependent is 0.984 (STD: 0.011), and that of subject-independent is 0.679 (STD: 0.140). In addition, by analyzing the discrimination characteristics, we found that the brain regions with emotional recognition in the hearing-impaired are distributed in the wider areas of the parietal and occipital lobes, which may be caused by visual processing.

Safety and biomarker effects of candesartan in non-hypertensive adults with prodromal Alzheimer's disease.

Observational studies suggest that angiotensin receptor blockers in hypertensive adults are associated with lower post-mortem indicators of Alzheimer's disease pathology. Candesartan, an angiotensin receptor blocker, has a positive cognitive effect in mild cognitive impairment with hypertension. However, its safety and effects in non-hypertensive individuals with Alzheimer's disease are unclear. This is the first double-blind randomized placebo-controlled trial aimed to assess safety and effects of 1-year therapy of candesartan on biomarkers and clinical indicators of Alzheimer's disease in non-hypertensive individuals with biomarker-confirmed prodromal Alzheimer's disease. Seventy-seven non-hypertensive participants 50 years or older (mean age: 68.1 years; 62% women; 20% African American) with mild cognitive impairment and biomarker confirmed Alzheimer's disease were randomized to escalating doses of once daily oral candesartan (up to 32 mg) or matched placebo. Main outcomes included safety and tolerability of candesartan, cerebrospinal fluid biomarkers (amyloid-ß42, amyloid-ß40, total tau and phospho-tau). Additional exploratory outcomes included PET imaging (Pittsburgh Compound-B (11C-PiB) and 18F-flortaucipir), brain MRI (structural and connectivity measures) and cognitive functioning. Analyses used intention-to-treat approach with group comparisons of safety measures using Chi-square test, and repeated measures mixed effects models were used to assess candesartan effects on main and exploratory outcomes (ClinicalTrials.gov, NCT02646982). Candesartan was found to be safe with no significant difference in safety measures: symptoms of hypotension, renal failure or hyperkalemia. Candesartan was also found to be associated with increases in cerebrospinal fluid Aß40 (between-group mean difference: 1211.95 pg/ml, 95% confidence interval: 313.27, 2110.63) and Aß42 (49.51 pg/ml, 95% confidence interval: -98.05, -0.98) reflecting lower brain amyloid accumulation. Candesartan was associated with decreased 11C-PiB in the parahippocampal region (-0.1104, 95% confidence interval: -0.19, -0.029) which remained significant after false discovery rate correction, and with an increase in functional network connectivity in the subcortical networks. Candesartan was further associated with improved executive function (Trail Making Test Part B) performance (-11.41 s, 95% confidence interval: -11.94, -10.89) and trended for an improved global cognitive functioning reflected by a composite cognitive score (0.002, 95% confidence interval: -0.0002, 0.005). We did not observe significant effects on tau levels, hippocampal volume or other cognitive measures (memory or clinical dementia rating scale-sum of boxes). In conclusion, among non-hypertensive prodromal Alzheimer's disease, candesartan is safe and likely decreases brain amyloid biomarkers, enhances subcortical brain connectivity and has favourable cognitive effects. These findings suggest that candesartan may have an important therapeutic role in Alzheimer's disease, and warrant further investigation given the lack of clear treatment options for this devastating illness.

Association of Plasma and Cerebrospinal Fluid Alzheimer Disease Biomarkers With Race and the Role of Genetic Ancestry, Vascular Comorbidities, and Neighborhood Factors.

Importance: Differences in cerebrospinal fluid (CSF) tau Alzheimer dementia (AD) biomarkers by self-identified race have been observed in prior studies. More recently, plasma biomarkers have been gaining recognition, but whether they exhibit similar differences is unclear. Furthermore, the underlying explanation for these differences in AD biomarkers is still unexplored. Objectives: To investigate differences in plasma biomarkers by race and genetic ancestry and explore potential underlying explanations for these differences. Design, Setting, and Participants: This cross-sectional study used participant data from the Brain, Stress, Hypertension, and Aging Research Program (B-SHARP), an observational study conducted in the greater Atlanta metropolitan area. Participants were enrolled from March 1, 2016, to January 1, 2020. Main Outcomes and Measures: Main outcomes were plasma and CSF amyloid-ß (Aß) 42, Aß40, phosphorylated tau181 (p-tau181), and neurofilament light. General linear models were used for key comparisons. Exposures: Main independent variables were self-identified race and genetic ancestry. Additional variables were cardiovascular factors, APOE4, educational attainment, Area Deprivation Index, and C-reactive protein (reflecting systemic inflammation state). Results: This analysis included 617 participants (mean [SD] age, 66 [7.9] years; 300 [49%] African American and 317 [51%] White; 429 [70%] with mild cognitive impairment). On the basis of self-reported race, plasma levels of Aß42 (adjusted mean difference, -1.20 pg/mL; 95% CI, -2.33 to -0.07 pg/mL), Aß40 (adjusted mean difference, -37.78 pg/mL; 95% CI, -60.16 to -15.39 pg/mL), p-tau181 (adjusted mean difference, -4.66 pg/mL; 95% CI, -7.05 to -1.90 pg/mL), and neurofilament light (adjusted mean difference, -1.58; 95% CI, -2.83 to -0.19 pg/mL) were consistently lower in African American individuals after adjusting for demographic characteristics, educational attainment, cognition, APOE4, and cardiovascular factors. A similar pattern was observed in the CSF biomarkers except for Aß42 and Aß40. Although unadjusted analyses revealed an association between these biomarkers and African ancestry, these associations were not significant after adjusting for the same covariates. Differences by self-reported race were not explained by varied cardiovascular risk factors, C-reactive protein, educational attainment, or Area Deprivation Index. Conclusions and Relevance: In this cross-sectional study of plasma biomarkers by race and genetic ancestry, the results indicated that plasma p-tau181, Aß40, and NFL were lower in African American individuals based on self-reported race but not genetic ancestry. These differences were not explained by cardiovascular risks or clinical stage differences. These racial differences should be considered in clinical interpretations and clinical trial screenings to avoid an additional increase in underrepresentation of African American individuals in AD trials.

Study on the cultivation of seedlings using buds of potato (Solanum tuberosum L.).

Background: Potato, a vegetable crop grown worldwide, has many uses, a short growth period, a large market demand and high economic benefits. The loss of potato seediness due to traditional potato growing methods is becoming increasingly evident, and research on new ways of growing potatoes is particularly important. Bud planting technology has the advantages of more reproduction, faster growth, and simplified maintenance of crop plants under cultivation. Methods: In this study, a bud planting method was adopted for the cultivation of potato seedlings. Specifically, we assessed different types of treatments for the production of high-quality buds and seedlings of potato. A total of four disease-free potato varieties (Fujin, Youjin, Zhongshu 4, and Feiwuruita) were selected, potato buds with three different lengths (3 cm, 5 cm, and 7 cm) were considered the T1, T2, and T3 treatments, and terminal buds, middle buds, and tail buds were used as the T4, T5, and T6 treatments. A nutrient pot experiment was performed following a randomized complete block design (RCBD) with three replicates and a natural control (CK) treatment. Cultivation was performed with the common horticultural practices of weeding and hoeing applied as needed. The photosynthetic indices, physiological indices, growth indices and quality of potato seedlings and quality of potato buds were measured at two-week intervals, and yield indices were measured when the final crop was harvested 14 weeks after planting. Results and Conclusions: Cultivation of seedlings from potato buds of different lengths increased the reproduction coefficient and reduced the number of seed potatoes needed for cultivation. All morphological, physiological, and yield indices showed positive trends. A potato bud length of 7 cm was optimal for raising seedlings. Moreover, buds located at the terminal of the potato yielded seedlings with the best quality. In conclusion, we recommend that our proven bud planting technique be adopted at the commercial level, which could support good crop production with maximum yield.

Serum metabolomic abnormalities in survivors of non-severe COVID-19.

Metabolic reprogramming is a distinctive characteristic of SARS-CoV-2 infection, which refers to metabolic changes in hosts triggered by viruses for their survival and spread. It is current urgent to understand the metabolic health status of COVID-19 survivors and its association with long-term health consequences of infection, especially for the predominant non-severe patients. Herein, we show systemic metabolic signatures of survivors of non-severe COVID-19 from Wuhan, China at six months after discharge using metabolomics approaches. The serum amino acids, organic acids, purine, fatty acids and lipid metabolism were still abnormal in the survivors, but the kynurenine pathway and the level of itaconic acid have returned to normal. These metabolic abnormalities are associated with liver injury, mental health, energy production, and inflammatory responses. Our findings identify and highlight the metabolic abnormalities in survivors of non-severe COVID-19, which provide information on biomarkers and therapeutic targets of infection and cues for post-hospital care and intervention strategies centered on metabolism reprogramming.