HTCA: a database with an in-depth characterization of the single-cell human transcriptome.

Single-cell RNA-sequencing (scRNA-seq) is one of the most used single-cell omics in recent decades. The exponential growth of single-cell data has immense potential for large-scale integration and in-depth explorations that are more representative of the study population. Efforts have been made to consolidate published data, yet extensive characterization is still lacking. Many focused on raw-data database constructions while others concentrate mainly on gene expression queries. Hereby, we present HTCA (www.htcatlas.org), an interactive database constructed based on ∼2.3 million high-quality cells from ∼3000 scRNA-seq samples and comprised in-depth phenotype profiles of 19 healthy adult and matching fetal tissues. HTCA provides a one-stop interactive query to gene signatures, transcription factor (TF) activities, TF motifs, receptor-ligand interactions, enriched gene ontology (GO) terms, etc. across cell types in adult and fetal tissues. At the same time, HTCA encompasses single-cell splicing variant profiles of 16 adult and fetal tissues, spatial transcriptomics profiles of 11 adult and fetal tissues, and single-cell ATAC-sequencing (scATAC-seq) profiles of 27 adult and fetal tissues. Besides, HTCA provides online analysis tools to perform major steps in a typical scRNA-seq analysis. Altogether, HTCA allows real-time explorations of multi-omics adult and fetal phenotypic profiles and provides tools for a flexible scRNA-seq analysis.

Dynamic immunoediting by macrophages in homologous recombination deficiency-stratified pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease, notably resistant to existing therapies. Current research indicates that PDAC patients deficient in homologous recombination (HR) benefit from platinum-based treatments and poly-ADP-ribose polymerase inhibitors (PARPi). However, the effectiveness of PARPi in HR-deficient (HRD) PDAC is suboptimal, and significant challenges remain in fully understanding the distinct characteristics and implications of HRD-associated PDAC. We analyzed 16 PDAC patient-derived tissues, categorized by their homologous recombination deficiency (HRD) scores, and performed high-plex immunofluorescence analysis to define 20 cell phenotypes, thereby generating an in-situ PDAC tumor-immune landscape. Spatial phenotypic-transcriptomic profiling guided by regions-of-interest (ROIs) identified a crucial regulatory mechanism through localized tumor-adjacent macrophages, potentially in an HRD-dependent manner. Cellular neighborhood (CN) analysis further demonstrated the existence of macrophage-associated high-ordered cellular functional units in spatial contexts. Using our multi-omics spatial profiling strategy, we uncovered a dynamic macrophage-mediated regulatory axis linking HRD status with SIGLEC10 and CD52. These findings demonstrate the potential of targeting CD52 in combination with PARPi as a therapeutic intervention for PDAC.

Ursa: A Comprehensive Multiomics Toolbox for High-Throughput Single-Cell Analysis.

The burgeoning amount of single-cell data has been accompanied by revolutionary changes to computational methods to map, quantify, and analyze the outputs of these cutting-edge technologies. Many are still unable to reap the benefits of these advancements due to the lack of bioinformatics expertise. To address this issue, we present Ursa, an automated single-cell multiomics R package containing 6 automated single-cell omics and spatial transcriptomics workflows. Ursa allows scientists to carry out post-quantification single or multiomics analyses in genomics, transcriptomics, epigenetics, proteomics, and immunomics at the single-cell level. It serves as a 1-stop analytic solution by providing users with outcomes to quality control assessments, multidimensional analyses such as dimension reduction and clustering, and extended analyses such as pseudotime trajectory and gene-set enrichment analyses. Ursa aims bridge the gap between those with bioinformatics expertise and those without by providing an easy-to-use bioinformatics package for scientists in hoping to accelerate their research potential. Ursa is freely available at https://github.com/singlecellomics/ursa.

Differential expression of ADRB1 causes different responses to norepinephrine in adipocytes of Duroc-Landrace-Yorkshire pigs and min pigs.

Research has shown that pigs from different regions exhibit varying responses to cold stimuli. Typically, cold stimuli induce browning of white adipose tissue mediated by adrenaline, promoting non-shivering thermogenesis. However, the molecular mechanisms underlying differential response of pig breeds to norepinephrine are unclear. The aim of this study was to investigate the differences and molecular mechanisms of the effects of norepinephrine (NE) treatment on adipocytes of Min pigs (a cold-resistant pig breed) and Duroc-Landrace-Yorkshire (DLY) pigs. Real time-qPCR, western blot, and immunofluorescence were performed following NE treatment on cell cultures of adipocytes originating from Min pigs (n = 3) and DLY pigs (n = 3) to assess the expressions of adipogenesis markers, beige fat markers, and mitochondrial biogenesis markers. The results showed that NE did not affect browning of adipocytes in DLY pigs, whereas promoted browning of adipocytes in Min pigs. Further, the expression of ADRB1 (Adrenoceptor Beta 1, ADRB1) was higher in subcutaneous adipose tissue and adipocytes of Min pigs than those of DLY pigs. Overexpression of ADRB1 in DLY pig adipocytes enhanced sensitivity to NE, exhibiting decreased adipogenesis markers, upregulated beige fat markers, and increased mitochondrial biogenesis. Conversely, adipocytes treated with ADRB1 antagonist in Min pigs resulted in decreased cellular sensitivity to NE. Further studies revealed differential CpG island methylation in ADRB1 promoter region, with lower methylation levels in Min pigs compared to DLY pigs. In conclusion, differential methylation of the ADRB1 promoter region leads to different ADRB1 expression, resulting in varying responsiveness to NE in adipocytes of two pig breeds. Our results provide new insights for further analysis of the differential cold responsiveness in pig breeds from different regions.

A 5-year follow-up assessment of anxiety and depression in postoperative prostate cancer patients: longitudinal progression and prognostic value.

Anxiety and depression are prevalent in cancer patients and correlate with poor prognosis. Nevertheless, their clinical role in prostate cancer patients after tumor resection is limited. Thus, the present study aimed to explore the longitudinal progression of anxiety and depression, and their association with prognosis in these patients. Two hundred and sixty-two prostate cancer patients after tumor resection were enrolled. Hospital Anxiety and Depression Scale (HADS) for anxiety (HADS-A) and for depression (HADS-D), disease-free survival (DFS) and overall survival (OS) were documented during 5-year follow-up. HADS-A score (from 7.73 at baseline to 8.48 at 5 years, P = 0.002) and anxiety severity (P = 0.001) but not anxiety rate (from 37.8% at baseline to 45.4% at 5 years, P = 0.067) were gradually elevated with time. HADS-D score (from 7.43 at baseline to 8.37 at 5 years, P < 0.001), depression rate (from 34.0% at baseline to 46.9% at 5 years, P < 0.001) and depression severity (P < 0.001) were also obviously increased with time. Moreover, baseline, 1-year, 2-year, 3-year, 4-year and 5-year anxiety correlated with worse DFS and OS (all P < 0.05, except for 2-year anxiety with OS: P = 0.126). In addition, baseline, 1-year, 2-year, 3-year, 4-year and 5-year depression associated with worse DFS (all P < 0.05); while only baseline, 1-year, 2-year depression related to worse OS (all P < 0.05). In conclusion, anxiety and depression continuously aggravate, and associate with poor prognosis in prostate cancer patients after tumor resection, indicating the necessity of proper management of anxiety and depression in these patients.

[Decreased Expression of Mitochondrial Calcium Uptake Protein 1 Leads to Skeletal Muscle Dysfunction in Septic Mice].

Objective: To observe the effect of sepsis on skeletal muscle function and to explore the role of skeletal muscle mitochondrial calcium uptake protein 1 (MICU1). Methods: A total of 40 specific-pathogen-free (SPF) healthy male C57BL/6J mice were randomly assigned to 4 groups, a sham operation group (Sham group, n=8), a sepsis modeling 6 h group (cecal ligation and puncture [CLP]-6 h group, n=10), a sepsis modeling 12 h group (CLP-12 h group, n=10), and a sepsis modeling 24 h group (CLP-24 h, n=12). The sepsis model was established by CLP. Mice in the Sham group only underwent laparotomic exploration of the cecum. Another 20 SPF mice were selected. The tibialis anterior muscle on one side was empty-transfected with adeno-associated virus (AAV) as controls (AAV-C), and the tibialis anterior muscle on the other side was transfected with AAV to enhance MICU1 expression (AAV-M). The mice were randomly assigned to two groups, a sham operation group (AAV-C-Sham and AAV-M-Sham, n=8) and a sepsis model 24 h group (AAV-C-CLP and AAV-M-CLP, n=12). The grip strength and compound muscle action potential (CMAP) of the tibialis anterior muscle were measured in each group at the corresponding time points. The levels of inflammatory factors, including tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6), in the skeletal muscle were measured by ELISA. The morphological changes of skeletal muscle cells were observed through H&E staining. The expression levels of MICU1 and muscle atrophy-related proteins, including muscle RING-finger containing protein 1 (MuRF1) and muscle atrophy Fbox protein (MAFbx), were determined by Western blot. The expression levels of MICU1 mRNA in skeletal muscle were determined by RT-qPCR. Results: Compared with mice in the Sham group, mice in the CLP group showed decreased body weight ( P<0.05); their grip strength decreased with the prolongation of CLP modeling time ( P<0.05); the amplitude of CMAP decreased, showing prolonged duration and latency ( P<0.05); the expression levels of inflammatory factors, including TNF-α and IL-6, in skeletal muscle increased gradually ( P<0.05); the fiber diameter and cross-sectional area of skeletal muscle decreased gradually with the prolongation of modeling time ( P<0.05); the protein expression levels of MuRF1and MAFbx proteins increased gradually ( P<0.05); the expression levels of MICU1 protein and mRNA decreased gradually ( P<0.05). There was no significant difference in all indices between AAV-M-Sham and AAV-C-Sham groups ( P>0.05). Compared with mice in the AAV-C-CLP group, mice in the AAV-M-CLP group showed increased grip strength ( P<0.05); the amplitude of CMAP increased, showing shortened duration and latency ( P <0.05); the fiber diameter and cross-sectional area of skeletal muscle increased ( P<0.05); the expression levels of MuRF1and MAFbx decreased ( P<0.05). Conclusion: Sepsis leads to skeletal muscle dysfunction, which is related to the decrease in mitochondrial MICU1 expression.

TMEM184B promotes proliferation, migration and invasion, and inhibits apoptosis in hypopharyngeal squamous cell carcinoma.

Several members of the transmembrane protein family are associated with the biological processes of human malignancies; however, the expression pattern and biological function of one family member, TMEM184B, in hypopharyngeal squamous cell carcinoma (HPSCC) are not fully understood. The expression between HPSCC tumours and adjacent normal tissues was determined by the Immunohistochemistry (IHC). A bioinformatics analysis was performed to verify the expression pattern of TMEM184B in The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Furthermore, in vitro assays on cell proliferation, invasion, migration and in vivo experiments on tumour growth and apoptosis of TMEM184B in HPSCC were performed. We found that the HPSCC tissues had a significantly higher expression of TMEM184B than the adjacent normal tissues. Bioinformatics analysis confirmed the different expression of TMEM184B expression in HPSCC. Furthermore, in vitro and in vivo experiments demonstrated that TMEM184B promotes HPSCC cell growth, cell invasion and migration in FaDu cells, whereas flow cytometry assay showed that TMEM184B inhibited cell apoptosis. Our study revealed for the first time that TMEM184B might serve an oncogenic function in HPSCC and could be a potential diagnostic biomarker and therapeutic target for HPSCC.

MiR-144 regulates adipogenesis by mediating formation of C/EBPα-FOXO1 protein complex.

CeRNA effect was an important regulation mode of miRNA mediated bio-activities, however, most of the researches of ceRNA were on ncRNAs synergetic with mRNAs, the exploration of ceRNA effect regulated mRNA interaction was still lack of. Besides, C/EBPα was one of the most crucial adipogenic regulators, which has been demonstrated to form a protein complex with FOXO1 to mediate AdipoQ expression. So that, we try to explore whether the ceRNA effect mediated the interaction of C/EBPα and FOXO1, and identified the key miRNAs of their ceRNA effect. In this paper, we found the ceRNA effect of C/EBPα and FOXO1 mediated their protein complex formation, furthermore regulated its transcriptional role for AdipoQ, thereby influencing pre-adipocytes adipogenesis. More importantly, we demonstrated that the miR-144 was the decisive factor that mediated the ceRNA effect of C/EBPα and FOXO1 to influence AdipoQ, thus regulated pre-adipocytes adipogenesis. This research will provide a new supplementary idea of the miRNA role in mediating coding RNA interaction that regulates pre-adipocyte adipogenesis.

Nonivamide induces brown fat-like characteristics in porcine subcutaneous adipocytes.

Obesity, which is associated with type 2 diabetes, is a threat to human health. There are studies, which suggest that some compounds can induce browning of white adipocytes to combat obesity. In this study, we selected nonivamide, an analog of capsaicin, to detect whether it influenced the browning of porcine white adipocytes. First, we found 25 µM nonivamide promoted apoptosis of porcine subcutaneous pre-adipocytes. After pre-adipocytes differentiation, nonivamide inhibited adipogenesis by reducing the expressions of Pparγ, Cebpα, while it promoted lipolysis by up-regulating Hsl, Atgl. Nonivamide also induced browning of porcine subcutaneous adipocytes by up-regulating the expression of brown and beige adipocyte gene markers, such as Prdm16, Cidea, and Slc27a1. Additionally, thermogenesis gene markers Cpt1a and Cpt1b were significantly up-regulated by nonivamide. Furthermore, nonivamide promoted mitochondrial biogenesis by up-regulating the expression of Tfam, Nrf1, Nrf2, and Tomm20. In conclusion, nonivamide is a potent compound to induce porcine adipocyte browning for treating obesity.

Endogenous stimuli-responsive nanoparticles for cancer therapy: From bench to bedside.

Cancer is complicated to treat because of its high propensity for recurrence and metastasis, and various side effects of conventional cancer treatments. With the development of nanotechnology, biology, material science and pharmacy, nanoparticles emerge as a promising method to load anti-cancer drugs to deal with the downsides of conventional treatments. Among the various class of nanoparticles, endogenous stimuli-responsive nanoparticles exert significant anti-cancer effects by releasing drugs due to the stimulations from pH gradient, redox as well as other enzymes of cancer microenvironment. Extraordinary progress has been achieved as the latest endogenous stimuli-responsive nanoparticles exhibit better therapeutic effects, lower toxicity, and superior biocompatibility, indicating brighter prospects for cancer therapy. However, these stimuli-responsive nanoparticles are still not ready for large-scale clinical application, due to reasons such as the lack of clinical trials and high cost of manufacturing. Here, we consolidate the advancements and limitations of various endogenous stimuli-responsive nanoparticles, as well as critically discuss the prospects of this kind of nanoparticles in tumor treatments.

Flaxseed-derived peptides ameliorate hepatic cholesterol metabolism in Sprague-Dawley rats fed a high-cholesterol and high-fat diet.

BACKGROUND: Plant peptides have been reported to have cholesterol-lowering activities. Previous research has found that ≤1 kDa flaxseed peptide (FP5 ) reduces cholesterol absorption and synthesis in vitro. In this research, we investigated the cholesterol-lowering activity of FP5 in Sprague-Dawley (SD) rats fed a high-cholesterol and high-fat diet. In addition, amino acid sequences of FP5 were determined by high-performance liquid chromatography-electrospray ionization-Orbitrap mass spectrometry. RESULTS: FP5 supplement significantly decreased the serum and hepatic cholesterol levels and modulated the hepatic gene and protein expression of cholesterol metabolism-related enzymes or regulators (3-hydroxy-3-methylglutaryl coenzyme A reductase, Low-Density Lipoprotein Receptor (LDLR), Cholesterol 7 α-hydroxylase, Niemann-Pick C1-like 1, ATP-binding cassette transporters G5 and G8). Eleven peptides were identified from FP5 . These peptides were characterized as hydrophobic amino acids such as leucine (L), proline (P), glycine (G), isoleucine (I) and continuous sequences, including LP, LL, LG and II, with low molecular weights. CONCLUSION: FP5 has a certain cholesterol-lowering activity in SD rats fed a high-cholesterol and high-fat diet. The possible mechanism for ameliorating hepatic cholesterol metabolism of FP5 includes inhibiting hepatic cholesterol de novo synthesis, promoting the synthesis and excretion of bile acids, and inhibiting the reabsorption of bile acids during enterohepatic circulation. © 2022 Society of Chemical Industry.

A Guillain-Barré syndrome-associated SIGLEC10 rare variant impairs its recognition of gangliosides.

Guillain-Barré syndrome (GBS), including its variant Miller Fisher syndrome (MFS), is an acute peripheral neuropathy that involves autoimmune mechanisms leading to the production of autoantibodies to gangliosides; sialic acid-containing glycosphingolipids. Although association with various genetic polymorphisms in the major histocompatibility complex (MHC) is shown in other autoimmune diseases, GBS is an exception, showing no such link. No significant association was found by genome wide association studies, suggesting that GBS is not associated with common variants. To address the involvement of rare variants in GBS, we analyzed Siglec-10, a sialic acid-recognizing inhibitory receptor expressed on B cells. Here we demonstrate that two rare variants encoding R47Q and A108V substitutions in the ligand-binding domain are significantly accumulated in patients with GBS. Because of strong linkage disequilibrium, there was no patient carrying only one of them. Recombinant Siglec-10 protein containing R47Q but not A108V shows impaired binding to gangliosides. Homology modeling revealed that the R47Q substitution causes marked alteration in the ligand-binding site. Thus, GBS is associated with a rare variant of the SIGLEC10 gene that impairs ligand binding of Siglec-10. Because Siglec-10 regulates antibody production to sialylated antigens, our finding suggests that Siglec-10 regulates development of GBS by suppressing antibody production to gangliosides, with defects in its function predisposing to disease.

Mid-term outcomes of symptomatic isolated superior mesenteric artery dissection with endovascular management.

OBJECTIVES: The clinical outcomes, safety, and efficacy of endovascular management are explored for symptomatic isolated superior mesenteric artery dissection (ISMAD). METHODS: In this retrospective study, 51 consecutive patients with symptomatic ISMAD received endovascular management from three institutions between January 2011 and December 2019.These patients were categorized into group A (endovascular treatment was used as the first-line therapy) and group B(endovascular treatment was used as the second-line therapy). The general epidemiological data, clinical manifestations, first-episode symptoms, treatment process, imaging findings, follow-up outcomes were analyzed from the medical records. RESULTS: A total of 51 patients with endovascular management were collected in this study. Significant differences were observed between the two groups with respect to the course (150 h vs. 57 h; p < 0.001), intestinal ischemia (26.32% vs. 6,25%; p = 0.04) and dissection length (45.26 ± 13.78 mm vs. 63.37 ± 12.73 mm; p < 0.001). Technical success rate was 90.2% (46/51). There was significant difference in the MOD (42.27 ± 23.41 min vs. 76.63 ± 28.62 min p < 0.001), MPSRT (4.67 ± 2.65 h vs. 7.32 ± 2.49 h, p = 0.02), LOS (9.52 ± 3.72 days vs. 11.86 ± 4.13 days; p = 0.01) between the two groups. The bleeding complication rate was 7.84% (one patient in group A and three patients in group B). A total of 48 (94.12%, 48/51) patients were followed up for a median of 36.51 months (range, 4-87 months). Positive events of the SMA were achieved in 81.25% (39/48), and negative events of the SMA were achieved in 18.75% (8/48) based on the follow-up contrast-enhanced CT scan. CONCLUSIONS: Endovascular management of symptomatic ISMAD has a high technical success rate and efficient at controlling symptoms. Furthermore, as more positive events occur, endovascular management should be encouraged early when pain persists after conservative management or there are signs of disease progression.

Experimental and Numerical Investigation of Dustfall Effect on Remote Sensing Retrieval Accuracy of Chlorophyll Content.

Chlorophyll is the dominant pigment in the photosynthetic light-harvesting complexes that is related to the physiological function of leaves and is responsible for light absorption and energy transfer. Dust pollution has become an environmental problem in many areas in China, indicating that accurately estimating chlorophyll content of vegetation using remote sensing for assessing the vegetation growth status in dusty areas is vital. However, dust deposited on the leaf may affect the chlorophyll content retrieval accuracy. Thus, quantitatively studying the dustfall effect is essential. Using selected vegetation indices (VIs), the medium resolution imaging spectrometer terrestrial chlorophyll index (MTCI), and the double difference index (DD), we studied the retrieval accuracy of chlorophyll content at the leaf scale under dusty environments based on a laboratory experiment and spectra simulation. First, the retrieval accuracy under different dustfall amounts was studied based on a laboratory experiment. Then, the relationship between dustfall amount and fractional dustfall cover (FDC) was experimentally analyzed for spectra simulation of dusty leaves. Based on spectral data simulated using a PROSPECT-based mixture model, the sensitivity of VIs to dust under different chlorophyll contents was analyzed comprehensively, and the MTCI was modified to reduce its sensitivity to dust. The results showed that (1) according to experimental investigation, the DD model provides low retrieval accuracy, the MTCI model is highly accurate when the dustfall amount is less than 80 g/m2, and the retrieval accuracy decreases significantly when the dustfall amount is more than 80 g/m2; (2) a logarithmic relationship exists between FDC and dustfall amount, and the PROSPECT-based mixture model can simulate the leaf spectra under different dustfall amounts and different chlorophyll contents with a root mean square error of 0.015; and (3) according to numerical investigation, MTCI's sensitivity to dust in the chlorophyll content range of 25 to 60 µg/cm2 is lower than in other chlorophyll content ranges; DD's sensitivity to dust was generally high throughout the whole chlorophyll content range. These findings may contribute to quantitatively understanding the dustfall effect on the retrieval of chlorophyll content and would help to accurately retrieve chlorophyll content in dusty areas using remote sensing.

Remote Sensing Assessment of Safety Risk of Iron Tailings Pond Based on Runoff Coefficient.

Iron tailings ponds are engineered dam and dyke systems used to capture iron tailings. They are high-risk hazards with high potential energy. If the tailings dam broke, it would pose a serious threat to the surrounding ecological environment, residents' lives, and property. Rainfall is one of the most important influencing factors causing the tailings dam break. This paper took Chengde Area, a typical iron-producing area, as the study area, and proposed a remote sensing method to evaluate the safety risk of tailings ponds under rainfall condition by using runoff coefficient and catchment area. Firstly, the vegetation coverage in the study area was estimated using the pixel dichotomy model, and the vegetation type was classified by the support vector machine (SVM) method from Landsat 8 OLI image. Based on DEM, the slope of the study area was extracted, and the catchment area of the tailings pond was plotted. Then, taking slope, vegetation coverage, and vegetation type as three influencing factors, the runoff coefficient was constructed by weight assignment of each factor using analytic hierarchy process (AHP) model in both quantitative and qualitative way. Finally, the safety risk of tailings ponds was assessed according to average runoff coefficient and catchment area in the study area. The results showed that there were 124 low-risk tailings ponds, 16 moderate-risk tailings ponds, and 4 high-risk tailings ponds in the study area. This method could be useful for selecting targeted tailings ponds for focused safety monitoring. Necessary monitoring measurements should be carried out for the high-risk and moderate-risk tailings ponds in rainy season.

Remote Sensing Extraction Method of Tailings Ponds in Ultra-Low-Grade Iron Mining Area Based on Spectral Characteristics and Texture Entropy.

With the rapid development of the steel and iron industry, ultra-low-grade iron ore has been developed extensively since the beginning of this century in China. Due to the high concentration ratio of the iron ore, a large amount of tailings was produced and many tailings ponds were established in the mining area. This poses a great threat to regional safety and the environment because of dam breaks and metal pollution. The spatial distribution is the basic information for monitoring the status of tailings ponds. Taking Changhe Mining Area as an example, tailings ponds were extracted by using Landsat 8 OLI images based on both spectral and texture characteristics. Firstly, ultra-low-grade iron-related objects (i.e., tailings and iron ore) were extracted by the Ultra-low-grade Iron-related Objects Index (ULIOI) with a threshold. Secondly, the tailings pond was distinguished from the stope due to their entropy difference in the panchromatic image at a 7 × 7 window size. This remote sensing method could be beneficial to safety and environmental management in the mining area.

A single-cell pan-cancer analysis to show the variability of tumor-infiltrating myeloid cells in immune checkpoint blockade.

Myeloid cells are vital components of the immune system and have pivotal functions in orchestrating immune responses. Understanding their functions within the tumor microenvironment and their interactions with tumor-infiltrating lymphocytes presents formidable challenges across diverse cancer types, particularly with regards to cancer immunotherapies. Here, we explore tumor-infiltrating myeloid cells (TIMs) by conducting a pan-cancer analysis using single-cell transcriptomics across eight distinct cancer types, encompassing a total of 192 tumor samples from 129 patients. By examining gene expression patterns and transcriptional activities of TIMs in different cancer types, we discern notable alterations in abundance of TIMs and kinetic behaviors prior to and following immunotherapy. We also identify specific cell-cell interaction targets in immunotherapy; unique and shared regulatory profiles critical for treatment response; and TIMs associated with survival outcomes. Overall, our study illuminates the heterogeneity of TIMs and improves our understanding of tissue-specific and cancer-specific myeloid subsets within the context of tumor immunotherapies.

Vitamin K1 ameliorates lipopolysaccharide-triggered skeletal muscle damage revealed by faecal bacteria transplantation.

BACKGROUND: Sepsis-associated muscle weakness is common in patients of intensive care units (ICUs), and it is closely associated with poor outcomes. The mechanism of sepsis-induced muscle weakness is unclear. Recent studies have found that gut microbiota and metabolites are involved in the regulation of skeletal muscle mass and metabolism. This study aimed to investigate the effects of gut microbiota and metabolites on sepsis-associated muscle weakness. METHODS: In a lipopolysaccharide (LPS)-induced inflammation mouse model, mice with different sensitivities to LPS-induced inflammation were considered as donor mice for the faecal microbiota transplantation (FMT) assay, and recipient mice were divided into sensitive (Sen) and resistant (Res) groups. Skeletal muscle mass and function, as well as colonic barrier integrity were tested and gut microbiota and metabolite composition were analysed in both groups of mice. The effect of intestinal differential metabolite vitamin K1 on LPS-triggered muscle damage was investigated, and the underlying mechanism was explored. RESULTS: Recipients exhibited varying LPS-triggered muscle damage and intestinal barrier disruption. Tibialis anterior (TA) muscle of Sen exhibited upregulated expression levels of MuRF-1 (0.825 ± 0.063 vs. 0.304 ± 0.293, P = 0.0141) and MAFbx (1.055 ± 0.079 vs. 0.456 ± 0.3, P = 0.0092). Colonic tight junction proteins ZO-1 (0.550 ± 0.087 vs. 0.842 ± 0.094, P = 0.0492) and occludin (0.284 ± 0.057 vs. 0.664 ± 0.191, P = 0.0487) were significantly downregulated in the Sen group. Metabolomic analysis showed significantly higher vitamin K1 in the faeces (P = 0.0195) and serum of the Res group (P = 0.0079) than those of the Sen group. After vitamin K1 intervention, muscle atrophy-related protein expression downregulated (P < 0.05). Meanwhile SIRT1 protein expression were upregulated (0.320 ± 0.035 vs. 0.685 ± 0.081, P = 0.0281) and pNF-κB protein expression were downregulated (0.815 ± 0.295 vs. 0.258 ± 0.130, P = 0.0308). PI3K (0.365 ± 0.142 vs. 0.763 ± 0.013, P = 0.0475), pAKT (0.493 ± 0.159 vs. 1.183 ± 0.344, P = 0.0254) and pmTOR (0.509 ± 0.088 vs. 1.110 ± 0.190, P = 0.0368) protein expression levels were upregulated in TA muscle. Meanwhile, vitamin K1 attenuated serum inflammatory factor levels. CONCLUSIONS: Vitamin K1 might ameliorate LPS-triggered skeletal muscle damage by antagonizing NF-κB-mediated inflammation through upregulation of SIRT1 and regulating the balance between protein synthesis and catabolism.

Fluoxetine reverses early-life stress-induced depressive-like behaviors and region-specific alterations of monoamine transporters in female mice.

The sex difference that females are more vulnerable to depression than males has been recently replicated in an animal model of early-life stress (ES) called the limited bedding and nesting material (LBN) paradigm. Adopting this animal model, we have previously examined the effects of ES on monoamine transporter (MATs) expression in stress-related regions in adult female mice, and the reversal effects of a novel multimodal antidepressant, vortioxetine. In this study, replacing vortioxetine with a classical antidepressant, fluoxetine, we aimed to replicate the ES effects in adult female mice and to elucidate the commonality and differences between fluoxetine and vortioxetine. We found that systemic 30-day treatment with fluoxetine successfully reversed ES-induced depression-like behaviors (especially sucrose preference) in adult female mice. At the molecular level, we largely replicated the ES effects, such as reduced serotonin transporter (SERT) expression in the amygdala and increased norepinephrine transporter (NET) expression in the medial prefrontal cortex (mPFC) and hippocampus. Similar reversal effects of fluoxetine and vortioxetine were observed, including SERT in the amygdala and NET in the mPFC, whereas different reversal effects were observed for NET in the hippocampus and vesicular monoamine transporters expression in the nucleus accumbens. Overall, these results demonstrate the validity of the LBN paradigm to induce depression-like behaviors in female mice, highlight the involvement of region-specific MATs in ES-induced depression-like behaviors, and provide insights for further investigation of neurobiological mechanisms, treatment, and prevention associated with depression in women.

Single Cell Atlas: a single-cell multi-omics human cell encyclopedia.

Single-cell sequencing datasets are key in biology and medicine for unraveling insights into heterogeneous cell populations with unprecedented resolution. Here, we construct a single-cell multi-omics map of human tissues through in-depth characterizations of datasets from five single-cell omics, spatial transcriptomics, and two bulk omics across 125 healthy adult and fetal tissues. We construct its complement web-based platform, the Single Cell Atlas (SCA, www.singlecellatlas.org ), to enable vast interactive data exploration of deep multi-omics signatures across human fetal and adult tissues. The atlas resources and database queries aspire to serve as a one-stop, comprehensive, and time-effective resource for various omics studies.