Indoleamine 2,3-dioxygenase-1 involves in CD8+T cell exhaustion in glioblastoma via regulating tryptophan levels.

Indoleamine 2,3-dioxygenase-1 (IDO-1) is an enzyme that catalyzes the metabolism of tryptophan (Trp). It is expressed in limited amounts in normal tissues but significantly upregulated during inflammation and infection. Various inflammatory factors, especially IFN-γ, can induce the expression of IDO-1. While extensive research has been conducted on the role of IDO-1 in tumors, its specific role in complex central nervous system tumors such as glioblastoma (GBM) remains unclear. This study aims to explore the role of IDO-1 in the development of GBM and analyze its association with tryptophan levels and CD8+T cell exhaustion in the tumor region. To achieve this, we constructed an orthotopic mouse glioblastoma tumor model to investigate the specific mechanisms between IDO-1, GBM, and CD8+T cell exhaustion. Our results showed that IDO-1 can promote CD8+T cell exhaustion by reducing tryptophan levels. When IDO-1 was knocked down in glioblastoma cells, other cells within the tumor microenvironment upregulated IDO-1 expression to compensate for the loss and enhance immunosuppressive effects. Therefore, the data suggest that the GBM microenvironment controls tryptophan levels by regulating IDO-1 expression, which plays a critical role in immune suppression. These findings support the use of immune therapy in combination with IDO-1 inhibitors or tryptophan supplementation as a potential treatment strategy.

An Investigation of Volatile Flavor Compounds and Lipolysis-Oxidation in Coppa as Affected by the Inoculation of Coagulase-Negative Staphylococcus during the Air-Drying Stage.

This study aimed to explore the effects of coagulase-negative Staphylococcus inoculation on flavor generation and lipolysis-oxidation in Coppa. Acid lipase, neutral lipase, phospholipase, and lipoxygenase (LOX) activities, as well as free fatty acids, volatile compounds, and sensory evaluation, were determined during the fermentation and air-drying processes of Coppa over 40 days. Staphylococcus carnosus and Staphylococcus xylosus or a combination of both strains were selected for this study, and natural fermentation was treated as a control. The results showed that Staphylococcus inoculation significantly enhanced lipase and LOX activities, and mixed strains had a superior effect. Palmitic acid, stearic acid, linoleic acid, and oleic acid were identified as the predominant free fatty acids in Coppa, with the mixed fermentation group exhibiting the highest contents. Acids, aldehydes, alcohols, ketones, esters, and phenols were found for the volatile compounds in Coppa. These findings thus suggested a positive role of Staphylococcus inoculation in activating lipolysis-oxidation and contributing to the flavor formation of Coppa during the air-drying stage.

CamoFormer: Masked Separable Attention for Camouflaged Object Detection.

How to identify and segment camouflaged objects from the background is challenging. Inspired by the multi-head self-attention in Transformers, we present a simple masked separable attention (MSA) for camouflaged object detection. We first separate the multi-head self-attention into three parts, which are responsible for distinguishing the camouflaged objects from the background using different mask strategies. Furthermore, we propose to capture high-resolution semantic representations progressively based on a simple top-down decoder with the proposed MSA to attain precise segmentation results. These structures plus a backbone encoder form a new model, dubbed CamoFormer. Extensive experiments show that CamoFormer achieves new state-of-the-art performance on three widely-used camouflaged object detection benchmarks. To better evaluate the performance of the proposed CamoFormer around the border regions, we propose to use two new metrics, i.e. BR-M and BR-F. There are on average  âˆ¼ 5% relative improvements over previous methods in terms of S-measure and weighted F-measure. Our code is available at https://github.com/HVision-NKU/CamoFormer.

Glioblastoma-derived exosomes promote lipid accumulation and induce ferroptosis in dendritic cells via the NRF2/GPX4 pathway.

Glioblastoma-derived exosomes (GDEs), containing nucleic acids, proteins, fatty acids and other substances, perform multiple important functions in glioblastoma microenvironment. Tumor-derived exosomes serve as carriers of fatty acids and induce a shift in metabolism towards oxidative phosphorylation, thus driving immune dysfunction of dendritic cells (DCs). Lipid peroxidation is an important characteristic of ferroptosis. Nevertheless, it remains unclear whether GDEs can induce lipid accumulation and lipid oxidation to trigger ferroptosis in DCs. In our study, we investigate the impact of GDEs on lipid accumulation and oxidation in DCs by inhibiting GDEs secretion through knocking down the expression of Rab27a using a rat orthotopic glioblastoma model. The results show that inhibiting the secretion of GDEs can reduce lipid accumulation in infiltrating DCs in the brain and decrease mature dendritic cells (mDCs) lipid peroxidation levels, thereby suppressing glioblastoma growth. Mechanistically, we employed in vitro treatments of bone marrow-derived dendritic cells (BMDCs) with GDEs. The results indicate that GDEs decrease the viability of mDCs compared to immature dendritic cells (imDCs) and trigger ferroptosis in mDCs via the NRF2/GPX4 pathway. Overall, these findings provide new insights into the development of immune-suppressive glioblastoma microenvironment through the interaction of GDEs with DCs.

Alcohol Exposure and Disease Associations: A Mendelian Randomization and Meta-Analysis on Weekly Consumption and Problematic Drinking.

Alcohol consumption significantly impacts disease burden and has been linked to various diseases in observational studies. However, comprehensive meta-analyses using Mendelian randomization (MR) to examine drinking patterns are limited. We aimed to evaluate the health risks of alcohol use by integrating findings from MR studies. A thorough search was conducted for MR studies focused on alcohol exposure. We utilized two sets of instrumental variables-alcohol consumption and problematic alcohol use-and summary statistics from the FinnGen consortium R9 release to perform de novo MR analyses. Our meta-analysis encompassed 64 published and 151 de novo MR analyses across 76 distinct primary outcomes. Results show that a genetic predisposition to alcohol consumption, independent of smoking, significantly correlates with a decreased risk of Parkinson's disease, prostate hyperplasia, and rheumatoid arthritis. It was also associated with an increased risk of chronic pancreatitis, colorectal cancer, and head and neck cancers. Additionally, a genetic predisposition to problematic alcohol use is strongly associated with increased risks of alcoholic liver disease, cirrhosis, both acute and chronic pancreatitis, and pneumonia. Evidence from our MR study supports the notion that alcohol consumption and problematic alcohol use are causally associated with a range of diseases, predominantly by increasing the risk.

Effects of warming and drought on growth and development of soybean in Hailun region.

As a result of global warming, drought, flooding, change in the rainfall pattern, etc. occur frequently. All these natural disasters could cause serious damage to the food security. Soybean is one of the most important oil crops in China. In recent years, the changing climate has brought many uncertain risks to the growth and production of soybean. In this study, based on the local meteorological, soil, and soybean growth-related experimental data, the effects of high temperature and drought stress on soybean were tested. The test parameters were leaf area index (LAI) and dry matter weight, while the analytical tool used was World Food Studies Model crop model. The research was carried out in Hailun City, Heilongjiang Province, China. The results showed that warming stress shortened the growth period of soybean and reduced the LAI and dry matter accumulation. On the other hand, drought stress also showed a significant impact on the growth period as well as reduced LAI and dry matter accumulation. Comparing the whole growth as well as the flowering-stage to seed-filling-stage treatments of soybean, the results were found very similar. It indicated that the soybean growth from flowering to seed-filling stage was strongly affected by the external environmental factors. The high temperature and drought disasters in the fruiting stages would have a greater impact on the growth and production of soybean crop.

Rising trend of childlessness in China: analysis of social and regional disparities with 2010 and 2020 census data.

INTRODUCTION: In recent decades, there has been a significant increase in childlessness. This paper analysed childlessness in China, specifically examining its socio and regional disparities. METHODS: With data from China's 2020 population census, supplemented with data from China's 2010 population census and 2015 inter-censual 1% population sample survey, we used a basic indicator of age-specific childlessness proportion, a decomposition method, and probability distribution models to analyse, fit and project childlessness. RESULTS: We presented age-specific childlessness proportions for women as a whole and by socioeconomic features, decomposition and projection results. The childlessness proportion increased markedly from 2010 to 2020, reaching 5.16% for women aged 49. The proportion is highest for city women, followed by township women, and is lowest among village women, at 6.29%, 5.50% and 3.72 % for women aged 49, respectively. The proportion for women aged 49 with high college education or above was 7.98%, and only 4.42% for women with junior high school education. The proportion also exhibits marked provincial discrepancies, and the total fertility rate is negatively correlated with childlessness at the province level. The decomposition results distinguished the different contribution of change in educational structure and change in childlessness proportion for subgroups to the total childlessness proportion change. It is projected that city women, women with high education will have higher childlessness proportion, and the proportion will further increase with the rapid increase in education level and urbanisation. CONCLUSIONS: Childlessness has risen to a relatively high level, and varies among women with different characteristics. This should be taken into consideration in China's countermeasures to reduce childlessness and curtail further fertility decline accordingly.

COMBINe enables automated detection and classification of neurons and astrocytes in tissue-cleared mouse brains.

Tissue clearing renders entire organs transparent to accelerate whole-tissue imaging; for example, with light-sheet fluorescence microscopy. Yet, challenges remain in analyzing the large resulting 3D datasets that consist of terabytes of images and information on millions of labeled cells. Previous work has established pipelines for automated analysis of tissue-cleared mouse brains, but the focus there was on single-color channels and/or detection of nuclear localized signals in relatively low-resolution images. Here, we present an automated workflow (COMBINe, Cell detectiOn in Mouse BraIN) to map sparsely labeled neurons and astrocytes in genetically distinct mouse forebrains using mosaic analysis with double markers (MADM). COMBINe blends modules from multiple pipelines with RetinaNet at its core. We quantitatively analyzed the regional and subregional effects of MADM-based deletion of the epidermal growth factor receptor (EGFR) on neuronal and astrocyte populations in the mouse forebrain.

Bulk and mosaic deletions of Egfr reveal regionally defined gliogenesis in the developing mouse forebrain.

The epidermal growth factor receptor (EGFR) plays a role in cell proliferation and differentiation during healthy development and tumor growth; however, its requirement for brain development remains unclear. Here we used a conditional mouse allele for Egfr to examine its contributions to perinatal forebrain development at the tissue level. Subtractive bulk ventral and dorsal forebrain deletions of Egfr uncovered significant and permanent decreases in oligodendrogenesis and myelination in the cortex and corpus callosum. Additionally, an increase in astrogenesis or reactive astrocytes in effected regions was evident in response to cortical scarring. Sparse deletion using mosaic analysis with double markers (MADM) surprisingly revealed a regional requirement for EGFR in rostrodorsal, but not ventrocaudal glial lineages including both astrocytes and oligodendrocytes. The EGFR-independent ventral glial progenitors may compensate for the missing EGFR-dependent dorsal glia in the bulk Egfr-deleted forebrain, potentially exposing a regenerative population of gliogenic progenitors in the mouse forebrain.

Development of CRISPR-Mediated Nucleic Acid Detection Technologies and Their Applications in the Livestock Industry.

The rapid rate of virus transmission and pathogen mutation and evolution highlight the necessity for innovative approaches to the diagnosis and prevention of infectious diseases. Traditional technologies for pathogen detection, mostly PCR-based, involve costly/advanced equipment and skilled personnel and are therefore not feasible in resource-limited areas. Over the years, many promising methods based on clustered regularly interspaced short palindromic repeats and the associated protein systems (CRISPR/Cas), i.e., orthologues of Cas9, Cas12, Cas13 and Cas14, have been reported for nucleic acid detection. CRISPR/Cas effectors can provide one-tube reaction systems, amplification-free strategies, simultaneous multiplex pathogen detection, visual colorimetric detection, and quantitative identification as alternatives to quantitative PCR (qPCR). This review summarizes the current development of CRISPR/Cas-mediated molecular diagnostics, as well as their design software and readout methods, highlighting technical improvements for integrating CRISPR/Cas technologies into on-site applications. It further highlights recent applications of CRISPR/Cas-based nucleic acid detection in livestock industry, including emerging infectious diseases, authenticity and composition of meat/milk products, as well as sex determination of early embryos.

Tracking footprints of artificial and natural selection signatures in breeding and non-breeding cats.

Stray non-breeding cats (stray) represent the largest heterogeneous cat population subject to natural selection, while populations of the Siamese (SIAM) and Oriental Shorthair (OSH) breeds developed through intensive artificial selection for aesthetic traits. Runs of homozygosity (ROH) and demographic measures are useful tools to discover chromosomal regions of recent selection and to characterize genetic diversity in domestic cat populations. To achieve this, we genotyped 150 stray and 26 household non-breeding cats (household) on the Illumina feline 63 K SNP BeadChip and compared them to SIAM and OSH. The 50% decay value of squared correlation coefficients (r2) in stray (0.23), household (0.25), OSH (0.24) and SIAM (0.25) corresponded to a mean marker distance of 1.12 Kb, 4.55 Kb, 62.50 Kb and 175.07 Kb, respectively. The effective population size (Ne) decreased in the current generation to 55 in stray, 11 in household, 9 in OSH and 7 in SIAM. In the recent generation, the increase in inbreeding per generation (ΔF) reached its maximum values of 0.0090, 0.0443, 0.0561 and 0.0710 in stray, household, OSH and SIAM, respectively. The genomic inbreeding coefficient (FROH) based on ROH was calculated for three length categories. The FROH was between 0.014 (FROH60) and 0.020 (FROH5) for stray, between 0.018 (FROH60) and 0.024 (FROH5) for household, between 0.048 (FROH60) and 0.069 (FROH5) for OSH and between 0.053 (FROH60) and 0.073 (FROH5) for SIAM. We identified nine unique selective regions for stray through genome-wide analyses for regions with reduced heterozygosity based on FST statistics. Genes in these regions have previously been associated with reproduction (BUB1B), motor/neurological behavior (GPHN, GABRB3), cold-induced thermogenesis (DIO2, TSHR), immune system development (TSHR), viral carcinogenesis (GTF2A1), host immune response against bacteria, viruses, chemoattractant and cancer cells (PLCB2, BAHD1, TIGAR), and lifespan and aging (BUB1B, FGF23). In addition, we identified twelve unique selective regions for OSH containing candidate genes for a wide range of coat colors and patterns (ADAMTS20, KITLG, TYR, TYRO3-a MITF regulator, GPNMB, FGF7, RAB38) as well as congenital heart defects (PDE4D, PKP2) and gastrointestinal disorders (NLGN1, ALDH1B1). Genes in stray that represent unique selective events indicate, at least in part, natural selection for environmental adaptation and resistance to infectious disease, and should be the subject of future research. Stray cats represent an important genetic resource and have the potential to become a research model for disease resistance and longevity, which is why we recommend preserving semen before neutering.

A one-tube rapid visual CRISPR assay for the field detection of Japanese encephalitis virus.

Early and rapid detection of Japanese encephalitis virus (JEV) is necessary for timely preventive and control measures. However, JEV RNA detection remains challenging due to the low level of viremia. In this study, a RApid VIsual CRISPR (RAVI-CRISPR) assay based on reverse transcription loop-mediated isothermal amplification (RT-LAMP) and CRISPR/Cas12a targeting was developed for easy detection of JEV in the field. We showed successful detection of 8.97 or more copies of the C gene sequence of JEV RNA within approximately 60 min. This assay also displayed no cross-reactivity with other porcine pathogens. We applied our one-tube RAVI-CRISPR assay to 18 brain tissue sample for JE diagnosis. The results from both fluorescence intensity measurements and directly naked-eye visualization were consistent with those from real-time PCR analysis. Taken together, our results showed that one-tube RAVI-CRISPR assay is robust, convenient, sensitive, specific, affordable, and potentially adaptable to on-site detection or surveillance of JEV in clinical and vector samples.

Safety and immunogenicity of COVID-19 vaccination in patients with hepatocellular carcinoma (CHESS-NMCID 2101): A multicenter prospective study.

Data on safety and immunogenicity of coronavirus disease 2019 (COVID-19) vaccinations in hepatocellular carcinoma (HCC) patients are limited. In this multicenter prospective study, HCC patients received two doses of inactivated whole-virion COVID-19 vaccines. The safety and neutralizing antibody were monitored. Totally, 74 patients were enrolled from 10 centers in China, and 37 (50.0%), 25 (33.8%), and 12 (16.2%) received the CoronaVac, BBIBP-CorV, and WIBP-CorV, respectively. The vaccines were well tolerated, where pain at the injection site (6.8% [5/74]) and anorexia (2.7% [2/74]) were the most frequent local and systemic adverse events. The median level of neutralizing antibody was 13.5 (interquartile range [IQR]: 6.9-23.2) AU/ml at 45 (IQR: 19-72) days after the second dose of vaccinations, and 60.8% (45/74) of patients had positive neutralizing antibody. Additionally, lower γ-glutamyl transpeptidase level was related to positive neutralizing antibody (odds ratio = 1.022 [1.003-1.049], p = 0.049). In conclusion, this study found that inactivated COVID-19 vaccinations are safe and the immunogenicity is acceptable or hyporesponsive in patients with HCC. Given that the potential benefits may outweigh the risks and the continuing emergences of novel severe acute respiratory syndrome coronavirus 2 variants, we suggest HCC patients to be vaccinated against COVID-19. Future validation studies are warranted.

Safety and immunogenicity of SARS-CoV-2 vaccines in Chinese patients with cirrhosis: a prospective multicenter study.

BACKGROUND: Data on safety and immunogenicity of coronavirus disease 2019 (COVID-19) vaccination in patients with compensated (C-cirrhosis) and decompensated cirrhosis (D-cirrhosis) are limited. METHODS: In this prospective multicenter study, adult participants with C-cirrhosis and D-cirrhosis were enrolled and received two doses of inactivated whole-virion COVID-19 vaccines. Adverse events were recorded within 14 days after any dose of vaccination, and serum samples of enrolled patients were collected and tested for SARS-CoV-2 neutralizing antibodies at least 14 days after the second dose. Risk factors for negative neutralizing antibody were analyzed. RESULTS: In total, 553 patients were enrolled from 15 centers in China, including 388 and 165 patients with C-cirrhosis and D-cirrhosis. The vaccines were well tolerated, most adverse reactions were mild and transient, and injection site pain (23/388 [5.9%] vs 9/165 [5.5%]) and fatigue (5/388 [1.3%] vs 3/165 [1.8%]) were the most frequently local and systemic adverse events in both the C-cirrhosis and D-cirrhosis groups. Overall, 4.4% (16/363) and 0.3% (1/363) of patients were reported Grades 2 and 3 alanine aminotransferase (ALT) elevations (defined as ALT > 2 upper limit of normal [ULN] but ≤ 5 ULN, and ALT > 5 ULN, respectively). The positive rates of COVID-19 neutralizing antibodies were 71.6% (278/388) and 66.1% (109/165) in C-cirrhosis and D-cirrhosis groups. Notably, Child-Pugh score of B and C levels was an independent risk factor of negative neutralizing antibody. CONCLUSIONS: Inactivated COVID-19 vaccinations are safe with acceptable immunogenicity in cirrhotic patients, and Child-Pugh score of B and C levels is associated with hyporesponsive to COVID-19 vaccination.

Erratum: Deep learning-based autofocus method enhances image quality in light-sheet fluorescence microscopy: publisher's note.

[This corrects the article on p. 5214 in vol. 12, PMID: 34513252.].

Safety and Immunogenicity of SARS-CoV-2 Vaccines in Patients With Chronic Liver Diseases (CHESS-NMCID 2101): A Multicenter Study.

BACKGROUND & AIMS: We aimed to assess the safety and immunogenicity of inactivated whole-virion severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines in patients with chronic liver diseases (CLD) in this study. METHODS: This was a prospective, multi-center, open-label study. Participants aged over 18 years with confirmed CLD and healthy volunteers were enrolled. All participants received 2 doses of inactivated whole-virion SARS-CoV-2 vaccines. Adverse reactions were recorded within 14 days after any dose of SARS-CoV-2 vaccine, laboratory testing results were collected after the second dose, and serum samples of enrolled subjects were collected and tested for SARS-CoV-2 neutralizing antibodies at least 14 days after the second dose. RESULTS: A total of 581 participants (437 patients with CLD and 144 healthy volunteers) were enrolled from 15 sites in China. Most adverse reactions were mild and transient, and injection site pain (n = 36; 8.2%) was the most frequently reported adverse event. Three participants had grade 3 aminopherase elevation (defined as alanine aminopherase >5 upper limits of normal) after the second dose of inactivated whole-virion SARS-CoV-2 vaccination, and only 1 of them was judged as severe adverse event potentially related to SARS-CoV-2 vaccination. The positive rates of SARS-CoV-2 neutralizing antibodies were 76.8% in the noncirrhotic CLD group, 78.9% in the compensated cirrhotic group, 76.7% in the decompensated cirrhotic group (P = .894 among CLD subgroups), and 90.3% in healthy controls (P = .008 vs CLD group). CONCLUSION: Inactivated whole-virion SARS-CoV-2 vaccines are safe in patients with CLD. Patients with CLD had lower immunologic response to SARS-CoV-2 vaccines than healthy population. The immunogenicity is similarly low in noncirrhotic CLD, compensated cirrhosis, and decompensated cirrhosis.

Detection and classification of neurons and glial cells in the MADM mouse brain using RetinaNet.

The ability to automatically detect and classify populations of cells in tissue sections is paramount in a wide variety of applications ranging from developmental biology to pathology. Although deep learning algorithms are widely applied to microscopy data, they typically focus on segmentation which requires extensive training and labor-intensive annotation. Here, we utilized object detection networks (neural networks) to detect and classify targets in complex microscopy images, while simplifying data annotation. To this end, we used a RetinaNet model to classify genetically labeled neurons and glia in the brains of Mosaic Analysis with Double Markers (MADM) mice. Our initial RetinaNet-based model achieved an average precision of 0.90 across six classes of cells differentiated by MADM reporter expression and their phenotype (neuron or glia). However, we found that a single RetinaNet model often failed when encountering dense and saturated glial clusters, which show high variability in their shape and fluorophore densities compared to neurons. To overcome this, we introduced a second RetinaNet model dedicated to the detection of glia clusters. Merging the predictions of the two computational models significantly improved the automated cell counting of glial clusters. The proposed cell detection workflow will be instrumental in quantitative analysis of the spatial organization of cellular populations, which is applicable not only to preparations in neuroscience studies, but also to any tissue preparation containing labeled populations of cells.