Pyrimidine metabolism regulator-mediated molecular subtypes display tumor microenvironmental hallmarks and assist precision treatment in bladder cancer

BackgroundBladder cancer (BLCA) is a common urinary system malignancy with a significant morbidity and death rate worldwide. Non-muscle invasive BLCA accounts for over 75% of all BLCA cases. The imbalance of tumor metabolic pathways is associated with tumor formation and proliferation. Pyrimidine metabolism (PyM) is a complex enzyme network that incorporates nucleoside salvage, de novo nucleotide synthesis, and catalytic pyrimidine degradation. Metabolic reprogramming is linked to clinical prognosis in several types of cancer. However, the role of pyrimidine metabolism Genes (PyMGs) in the BLCA-fighting process remains poorly understood.MethodsPredictive PyMGs were quantified in BLCA samples from the TCGA and GEO datasets. TCGA and GEO provided information on stemness indices (mRNAsi), gene mutations, CNV, TMB, and corresponding clinical features. The prediction model was built using Lasso regression. Co-expression analysis was conducted to investigate the relationship between gene expression and PyM.ResultsPyMGs were overexpressed in the high-risk sample in the absence of other clinical symptoms, demonstrating their predictive potential for BLCA outcome. Immunological and tumor-related pathways were identified in the high-risk group by GSWA. Immune function and m6a gene expression varied significantly between the risk groups. In BLCA patients, DSG1, C6orf15, SOST, SPRR2A, SERPINB7, MYBPH, and KRT1 may participate in the oncology process. Immunological function and m6a gene expression differed significantly between the two groups. The prognostic model, CNVs, single nucleotide polymorphism (SNP), and drug sensitivity all showed significant gene connections.ConclusionsBLCA-associated PyMGs are available to provide guidance in the prognostic and immunological setting and give evidence for the formulation of PyM-related molecularly targeted treatments. PyMGs and their interactions with immune cells in BLCA may serve as therapeutic targets

Topological analysis of functional connectivity in Parkinson’s disease

Parkinson’s disease (PD) is a clinically heterogeneous disorder, which mainly affects patients’ motor and non-motor function. Functional connectivity was preliminary explored and studied through resting state functional magnetic resonance imaging (rsfMRI). Through the topological analysis of 54 PD scans and 31 age-matched normal controls (NC) in the Neurocon dataset, leveraging on rsfMRI data, the brain functional connection and the Vietoris-Rips (VR) complex were constructed. The barcodes of the complex were calculated to reflect the changes of functional connectivity neural circuits (FCNC) in brain network. The 0-dimensional Betti number β0 means the number of connected branches in VR complex. The average number of connected branches in PD group was greater than that in NC group when the threshold δ ≤ 0.7. Two-sample Mann–Whitney U test and false discovery rate (FDR) correction were used for statistical analysis to investigate the FCNC changes between PD and NC groups. In PD group, under threshold of 0.7, the number of FCNC involved was significantly differences and these brain regions include the Cuneus_R, Lingual_R, Fusiform_R and Heschl_R. There are also significant differences in brain regions in the Frontal_Inf_Orb_R and Pallidum_R, when the threshold increased to 0.8 and 0.9 (p < 0.05). In addition, when the length of FCNC was medium, there was a significant statistical difference between the PD group and the NC group in the Neurocon dataset and the Parkinson’s Progression Markers Initiative (PPMI) dataset. Topological analysis based on rsfMRI data may provide comprehensive information about the changes of FCNC and may provide an alternative for clinical differential diagnosis

Correlation of pain with substance P and neurokinin-1 receptor in the L5–S2 spinal cord in rats with chronic nonbacterial prostatitis

The incidence of prostate pain is 90%–95% in prostatitis. The symptoms are persistent, which is prone to relapse and difficult to be cured. It seriously affects the survival and quality of life of patients. This study analyzed the correlation between pain and substance P (SP) and neurokinin-1 receptors (NK-1R) in the L5–S2 spinal cord of chronic nonbacterial prostatitis (CNP) rats, which may give a new way to explore the pathogenesis and treatment of pain in prostatitis. We randomly divided the rats into control group, 45 d group, 60 d group, and 90 d group. After making a rat model with autoimmune method, the paw withdrawal threshold (PWT) was measured, the histomorphological changes in the prostate was observed by transmission electron microscopy and light microscopy. The expression of SP and NK-1R was measured by immunohistochemistry, and the concentrations of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-2 (IL-2), and interleukin-10 (IL-10) were measured by enzyme linked immunosorbent assay (ELISA). Compared with the control group, the PWT was decreased by 34.21%, 41.90% and 64.79%, TNF-α was increased by 74.19%, 89.45% and 132.15%, IL-1β was increased by 148.88%, 181.95% and 250.74%, IL-2 was increased by 75.97%, 82.15% and 128.57% and IL-10 was increased by 31.04%, 63.28% and 212.99% in the 45 d group, 60 d group and 90 d group respectively. Microscope observation showed the structure of prostate tissue in control group was normal. However, the prostate tissue had obvious inflammatory response with the model extension. The expressions of SP and NK-1R in each model group were significantly higher than the control group. There was a significant correlation between pain and SP in L5–S2 spinal cord in CNP rats. These findings are indicative of a correlation between pain and the expression levels of SP and NK-1R in the L5–S2 spinal cord of CNP rats

CD8(+) T Cells Involved in Metabolic Inflammation in Visceral Adipose Tissue and Liver of Transgenic Pigs

Anti-inflammatory therapies have the potential to become an effective treatment for obesity-related diseases. However, the huge gap of immune system between human and rodent leads to limitations of drug discovery. This work aims at constructing a transgenic pig model with higher risk of metabolic diseases and outlining the immune responses at the early stage of metaflammation by transcriptomic strategy. We used CRISPR/Cas9 techniques to targeted knock-in three humanized disease risk genes, GIPR(dn) , hIAPP and PNPLA3(I148M) . Transgenic effect increased the risk of metabolic disorders. Triple-transgenic pigs with short-term diet intervention showed early symptoms of type 2 diabetes, including glucose intolerance, pancreatic lipid infiltration, islet hypertrophy, hepatic lobular inflammation and adipose tissue inflammation. Molecular pathways related to CD8(+) T cell function were significantly activated in the liver and visceral adipose samples from triple-transgenic pigs, including antigen processing and presentation, T-cell receptor signaling, co-stimulation, cytotoxicity, and cytokine and chemokine secretion. The similar pro-inflammatory signaling in liver and visceral adipose tissue indicated that there might be a potential immune crosstalk between the two tissues. Moreover, genes that functionally related to liver antioxidant activity, mitochondrial function and extracellular matrix showed distinct expression between the two groups, indicating metabolic stress in transgenic pigs' liver samples. We confirmed that triple-transgenic pigs had high coincidence with human metabolic diseases, especially in the scope of inflammatory signaling at early stage metaflammation. Taken together, this study provides a valuable large animal model for the clinical study of metaflammation and metabolic diseases.Peer reviewe

Study of the Nature of Formic Acid Adsorbates on Rough Pt and its Interaction with CO

应用现场红外反射光谱（ＦＴＩＲ）和微分电化学质谱（ｄｉｆｆｅｒｅｎｔｉａｌｅｌｅｃｔｒｏｃｈｅｍｉｃａｌｍａｓｓｓｐｅｃｔｒｏｍｅｔｅｒ，ＤＥＭＳ）研究了甲酸在多孔Ｐｔ上吸附质的性质．伏安结果显示了甲酸在多孔Ｐｔ上吸附质的氧化与吸附电位和吸附时间有关．在线质谱结果表明从甲酸吸附质氧化成二氧化碳所需要的电子数（ｎｅ）与吸附电位无关．显然地ｎｅ＝２．２说明了甲酸吸附质是由ＣＯ和ＣＯＨ组成，而不是只有单一的ＣＯ或者ＣＯＨ．另一方面，在１２６２ｃｍ－１和２０４８ｃｍ－１出现的现场红外光谱带证实了甲酸在多孔Ｐｔ上的吸附质中存在ＣＯ和ＣＯＨ表面物质．此外，用ＤＥＭＳ技术和碳－１３同位素标的甲酸作探针研究了甲酸吸附质和ＣＯ的相互作用．结果表明溶液中的甲酸不能取代先吸附的ＣＯ，而溶液中的ＣＯ可以与７５％先吸附的甲酸吸附质发生交换．The nature of formic acid adsorbates formed on porous platinum electrode has been studied by in situ infrared reflectance spectroscopic (FTIR) and differential electrochemical mass spectroscopic (DEMS) techniques. By carefully avoiding the contamination of the environment( i.e ., air) voltammetric experiments show that the oxidation of formic acid adsorbates depends on both adsorption potential and adsorption time. The online DEMS results show furthermore that the number of electrons necessary for the formation of one molecule of CO 2 from adsorbed formic acid is independent of the adsorption potential. Its value of 2.2 demonstrates that the composition of formic acid adsorbates is a mixture of CO and COH, but not CO or COH alone. The existence of these two species has been clearly proved by in situ FTIR experiments on electrodeposited platinum with a roughness factor of 11. The bands at 1 262 cm -1 , 1 840 cm -1 , and in the frequency range of 2 048 to 2 060 cm -1 are due to the surface adsorbed COH, bridge and linearly bound CO ad , respectively. In addition, the interaction between formic acid adsorbates and CO has been investigated by using DEMS via isotopic labelled 13 C formic acid as a probe as well. These experiments show that the surface species previously fromed from CO and formic acid cannot be exchanged by formic acid in solution. whereas about 75 percent of the firstly formed formic acid adsorbates can be replaced by bulk CO.作者联系地址：波恩大学物理化学所Author's Address: Institute of Physical Chemistry, Bonn University, Wegelerstrabe 12, D 53115 Bonn 1, German

A heterozygous moth genome provides insights into herbivory and detoxification

How an insect evolves to become a successful herbivore is of profound biological and practical importance. Herbivores are often adapted to feed on a specific group of evolutionarily and biochemically related host plants1, but the genetic and molecular bases for adaptation to plant defense compounds remain poorly understood2. We report the first whole-genome sequence of a basal lepidopteran species, Plutella xylostella, which contains 18,071 protein-coding and 1,412 unique genes with an expansion of gene families associated with perception and the detoxification of plant defense compounds. A recent expansion of retrotransposons near detoxification-related genes and a wider system used in the metabolism of plant defense compounds are shown to also be involved in the development of insecticide resistance. This work shows the genetic and molecular bases for the evolutionary success of this worldwide herbivore and offers wider insights into insect adaptation to plant feeding, as well as opening avenues for more sustainable pest management.Minsheng You … Simon W Baxter … et al