Current Advances of CO Sensing Based on Low Dimensional Materials.

Carbon monoxide (CO) is a harmful gas with significant impacts on human health and the environment. Its timely detection, especially in the event of thermal runaway in automotive lithium batteries, is crucial to prevent casualties. This paper reviews the progress in the development of efficient, sensitive, and reliable CO sensors, focusing on electrochemical, optical, and resistive sensing materials. Low-dimensional materials have a large specific surface area, providing an abundant number of active sites, which has drawn extensive attention from researchers. According to the different sensor signals, we categorized these sensors into electrical and optical signal sensors. We hope that by systematically introducing the sensing mechanism and sensing performance of these two kinds of sensors, appropriate CO sensors can be developed in different application scenarios so as to realize early warning and monitoring to the maximum extent, reduce industrial losses, and ensure the life and health of personnel.

Artificial Neural Network Analysis of Determinants of Tacrolimus Pharmacokinetics in Liver Transplant Recipients.

BACKGROUND: The efficacy and toxicity of tacrolimus are closely related to its trough blood concentrations. Identifying the influencing factors of pharmacokinetics of tacrolimus in the early postoperative period is conducive to the optimization of the individualized tacrolimus administration protocol and to help liver transplant (LT) recipients achieve the target blood concentrations. OBJECTIVE: This study aimed to develop an artificial neural network (ANN) for predicting the blood concentration of tacrolimus soon after liver transplantation and for identifying determinants of the concentration based on Shapley additive explanation (SHAP). METHODS: In this retrospective study, we enrolled 31 recipients who were first treated with liver transplantation from the Department of Liver Transplantation and Hepatic Surgery, the First Affiliated Hospital of Shandong First Medical University (Shandong Provincial Qianfoshan Hospital) from November 2020 to May 2021. The basic information, biochemical indexes, use of concomitant drugs, and genetic factors of organ donors and recipients were used for the ANN model inputs, and the output was the steady-state trough concentration (C0) of tacrolimus after oral administration in LT recipients. The ANN model was established to predict C0 of tacrolimus, SHAP was applied to the trained model, and the SHAP value of each input was calculated to analyze quantitatively the influencing factors for the output C0. RESULTS: A back-propagation ANN model with 3 hidden layers was established using deep learning. The mean prediction error was 0.27 ± 0.75 ng/mL; mean absolute error, 0.60 ± 0.52 ng/mL; correlation coefficient between predicted and actual C0 values, 0.9677; and absolute prediction error of all blood concentrations obtained by the ANN model, ≤3.0 ng/mL. The results indicated that the following factors had the most significant effect on C0: age, daily drug dose, genotype at CYP3A5 polymorphism rs776746 in both recipient and donor, and concomitant use of caspofungin. The predicted C0 value of tacrolimus in LT recipients increased in a dose-dependent manner when the daily dose exceeded 3 mg, whereas it decreased with age when LT recipients were older than 48 years. The predicted C0 was higher when recipients and donors had the genotype CYP3A5*3*3 than when they had the genotype CYP3A5*1. The predicted C0 value also increased with the use of caspofungin or Wuzhi capsule. CONCLUSION AND RELEVANCE: The established ANN model can be used to predict the C0 value of tacrolimus in LT recipients with high accuracy and good predictive ability, serving as a reference for personalized treatment in the early stage after liver transplantation.

Chronic GPER activation prompted the proliferation of ileal stem cell in ovariectomized mice depending on Paneth cell-derived Wnt3.

Menopausal women often face long-term estrogen treatment. G protein-coupled estrogen receptor (GPER) expressed in intestinal crypt was activated by estrogen therapy, but it was unclear whether chronic GPER activation during menopause had an effect on intestinal stem cells (ISCs). We tested the effect of chronic GPER activation on ISCs of ovariectomized (OVX) mice by injection of the selective GPER agonist G-1 for 28 days, or G-1 stimulation of organoids derived from crypts of OVX mice. G-1 up-regulated crypt depth, the number of Ki67+, bromodeoxyuridine+ cells and Olfm4+ ISCs, and the expression of ISCs marker genes (Lgr5, Olfm4 and Axin2). G-1 administration promoted organoid growth, increased the number of EdU+ cells per organoid and protein expression of Cyclin D1 and cyclin B1 in organoids. After G-1 treatment in vivo or in vitro, Paneth cell-derived Wnt3, Wnt3 effector ß-catenin and Wnt target genes c-Myc and Cyclin D1 increased in ileum or organoids. Once blocking the secretion of Wnt3 from Paneth cells, the effects of G-1 on organoids growth, ISCs marker genes and Wnt/ß-catenin signaling were abolished. G-1 did not affect the number of Paneth cells in ex vivo organoids, while activated Mmp7/cryptdin program in Paneth cells, promoted their maturation, and increased the expression of lysozyme protein. G-1 pretreatment in OVX mice inhibited radiation-induced ISCs proliferation injury and enhanced the resistance of mice to intestinal injury. In conclusion, chronic GPER activation prompted the Wnt3 synthesis in Paneth cells, thus increased the proliferation of ISCs via activation of Wnt3/ß-catenin signaling in OVX mice.

CYP3A5 Genotype-Dependent Drug-Drug Interaction Between Tacrolimus and Voriconazole in Chinese Kidney Transplant Patients.

BACKGROUND: The effect of drug-drug interaction (DDI) between tacrolimus and voriconazole on the pharmacokinetics of tacrolimus in different CYP3A5 genotypes has not been reported in previous studies. OBJECTIVE: The objective of this study was to investigate whether CYP3A5 genotype could influence tacrolimus-voriconazole DDI in Chinese kidney transplant patients. METHODS: All kidney transplant patients were divided into combination and non-combination groups based on whether tacrolimus was combined with or without voriconazole. Each group was subdivided into CYP3A5 expresser (CYP3A5*1/*1 or CYP3A5*1/*3) and CYP3A5 nonexpresser (CYP3A5*3/*3). A retrospective analysis compared tacrolimus dose (D)-corrected trough concentrations (C0) (C0/D) between combination and non-combination groups, respectively. Tacrolimus C0/D was also compared between CYP3A5 expresser and nonexpresser in both groups. RESULTS: The C0/D values of tacrolimus were significantly different between CYP3A5 expresser and nonexpresser in combination group (378.20 [219.38, 633.48] ng/mL/[mg/kg/d] vs 720.00 [595.35, 1681.50] ng/mL/[mg/kg/d], P = 0.0010). Either in CYP3A5 expresser or nonexpresser, we found a statistically significant difference in tacrolimus C0/D between combination and non-combination group (P < 0.0001). The increase in CYP3A5 nonexpresser was 1.38 times higher than that in CYP3A5 expresser (320.93% vs 232.19%). CONCLUSION AND RELEVANCE: The median C0/D values were 90.38% higher in kidney transplant recipients with CYP3A5*3/*3 genotype than in those with CYP3A5*1/*1 or CYP3A5*1/*3 genotype when treated with both tacrolimus and voriconazole. A CYP3A5 genotype-dependent DDI was found between tacrolimus and voriconazole. Therefore, personalized therapy accounting for CYP3A5 genotype detection and therapeutic drug monitoring is necessary for kidney transplant patients when treating with tacrolimus and voriconazole.

Phytic acid is a new substitutable plant-derived antifungal agent for the seedling blight of Pinus sylvestris var. mongolica caused by Fusarium oxysporum.

Phytic acid (PA) is a new substitutable plant-derived antifungal agent; however, few reports have been published regarding its antifungal effects on pathogenic fungi. The present study explored the in vitro antifungal activity of PA against four phytopathogenic fungi and found that PA was the most effective at inhibiting the growth of Fusarium oxysporum. This study aimed to investigate the in vivo and in vitro antifungal activities of PA against the seedling blight of Pinus sylvestris var. mongolica caused by F. oxysporum and to determine its possible mechanism of action. The results showed that PA inhibited spore germination and mycelial growth of F. oxysporum in a concentration-dependent manner and exhibited strong inhibition when its concentration exceeded 1000 mg/L. It mainly destroyed the integrity of the cell membrane, increasing its cell membrane permeability, causing the cell contents to spill out, and impairing fungal growth. In addition, the leakage of intercellular electrolytes and soluble proteins indicated that PA used at its EC20 and EC50 increased the membrane permeability of F. oxysporum. The increase in malondialdehyde and hydrogen peroxide content confirmed that PA treatment at its EC20 and EC50 damaged the cell membrane of the pathogen. Scanning electron microscopy revealed that PA affected the morphology of mycelia, causing them to shrivel, distort, and break. Furthermore, PA significantly reduced the activities of the antioxidant-related enzymes superoxide dismutase and catalase, as well as that of the pathogenicity-related enzymes polygalacturonase, pectin lyase, and endoglucanase (EG) in F. oxysporum (P < 0.05). In particular, EG enzyme activity was maximally inhibited in F. oxysporum treated with PA at its EC50. Moreover, PA significantly inhibited the incidence of disease, and growth indices in Pinus sylvestris var. mongolica seedling blight was determined. In summary, PA has a substantial inhibitory effect on F. oxysporum. Therefore, PA could serve as a new substitutable plant-derived antifungal agent for the seedling blight of P. sylvestris var. mongolica caused by F. oxysporum.

A New Signature of Sarcoma Based on the Tumor Microenvironment Benefits Prognostic Prediction.

Sarcomas are a group of malignant tumors derived from mesenchymal tissues that display complex and variable pathological types. The impact of the immune properties of the tumor microenvironment (TME) on the prognosis, treatment, and management of sarcomas has attracted attention, requiring the exploration of sensitive and accurate signatures. In this study, The Cancer Genome Atlas (TCGA) database was searched to screen for an RNA sequencing dataset, retrieving 263 sarcoma and 2 normal samples with survival data. Genes associated with immune regulation in sarcomas were retrieved from the Tumor Immune Estimation Resource database to estimate tumor purity and immune cell infiltration levels. The samples were then divided into the immune-high and immune-low groups. Then, we screened for differentially expressed genes (DEGs) between the two groups. The intersection between immune-related genes and DEGs was then determined. Univariate Cox and least absolute shrinkage and selection operator analyses were used to select ideal genes for prognostic prediction and subsequent construction of a risk signature. A survival analysis was performed to reveal the dissimilarity in survival between the high- and low-score groups. Finally, a nomogram was generated to verify the accuracy and reliability of the signature. Through Estimation of STromal and Immune cells in MAlignant Tumour tissues using Expression (ESTIMATE) analysis, high ESTIMATE, and low tumor purity were significantly associated with a favorable prognosis. Moreover, a total of 5259 DEGs were retrieved, the majority of which were downregulated. In total, 590 immune-associated genes overlapped with the DEGs, among which nine hub genes were identified. Finally, two candidate genes, ACVR2B and NFYA, were identified, based on which a risk signature was constructed. The risk signature constructed in this study is accurate and reliable for the prognostic prediction and phenotyping of sarcomas.

A bioinformatic analysis study of m7G regulator-mediated methylation modification patterns and tumor microenvironment infiltration in glioblastoma.

BACKGROUND: Glioblastoma is one of the most common brain cancers in adults, and is characterized by recurrence and little curative effect. An effective treatment for glioblastoma patients remains elusive worldwide. 7-methylguanosine (m7G) is a common RNA modification, and its role in tumors has become a research hotspot. METHODS: By searching for differentially expressed genes related to m7G, we generated a prognostic signature via cluster analysis and established classification criteria of high and low risk scores. The effectiveness of classification was validated using the Non-negative matrix factorization (NMF) algorithm, and repeatedly verified using training and test groups. The dimension reduction method was used to clearly show the difference and clinical significance of the data. All analyses were performed via R (version 4.1.2). RESULTS: According to the signature that included four genes (TMOD2, CACNG2, PLOD3, and TMSB10), glioblastoma patients were divided into high and low risk score groups. The survival rates between the two groups were significantly different, and the predictive abilities for 1-, 3-, and 5-year survivals were effective. We further established a Nomogram model to further examine the signature,as well as other clinical factors, with remaining significant results. Our signature can act as an independent prognostic factor related to immune-related processes in glioblastoma. CONCLUSIONS: Our research addresses the gap in knowledge in the m7G and glioblastoma research fields. The establishment of a prognostic signature and the extended analysis of the tumor microenvironment, immune correlation, and tumor mutation burden further suggest the important role of m7G in the development and development of this disease. This work will provide support for future research.

First Report of Black Spot Needle Blight of Pinus sylvestris var. mongolica Litv. Caused by Heterotruncatella spartii in China.

Pinus sylvestris var. mongolica Litv. (Pinales: Pinaceae) is an excellent tree for soil and water conservation in Northeast China. The Honghua'erji area in Inner Mongolia is the "hometown of P. sylvestris var. mongolica", however, in recent years, coniferous diseases of P. sylvestris var. mongolica have frequently occurred here. During the investigation, it was found that some black spot needle blight had been observed in addition to the common blight caused by Sphaeropsis sapinea. From May to September 2020, black spot needle blight was found on hundreds of P. sylvestris var. mongolica trees in four forest farms, and the infection rate among the forests was 24.58 % (n=240). This disease first appeared on the upper part of the needles, and the needles then became withered and gradually showed light black spots, although they remained green. As the disease progressed, the needles eventually died and turned gray with many dark black spots. Fungal isolate named YJ-1 was obtained from infected needles of symptomatic pine trees, and a voucher specimen was deposited in Heilongjiang Province Key Laboratory of Forest Protection. Microscopic observation showed the conidia were 3-septate (4 cells) clavate spindles that measured 23.9 µm (20.8-25.9) × 5.9 µm (4.5-8.2) (n=50). The middle two cells were dark brown, and the septa were darker than the cells. Both apical and basal cells were hyaline. The apical cell had 2-4 appendages (mostly 3), and the basal cell had a truncate base (n=50). The cultural characteristics on potato dextrose agar medium were flat off-white and dense in 3-5 d. At approximately 5-7 d, the reverse side of the colony turned pale to slightly luteous. Superficial black acervuli were distributed in the center of the mature colonies after 10 d. Morphological, cultural and microscopic characteristics observed were similar of Heterotruncatella spartii (basionym: Truncatella spartii) reported by Hlaiem et al (2019). To further identify, total DNA was extracted and the internal transcribed spacer region (ITS-rDNA) was amplified by PCR using the primers ITS1/ITS4 and sequenced for BLASTn analysis and phylogenetic tree construction. The resulting 564 bp sequence (GenBank Accession No. OL662864) had 99.24% (521/525) to H. spartii MFLUCC 15-0537, with bootstrap support of at least 94% using the Neighbor-Joining algorithm by MEGA-X (Felsenstein, 1985). The fungus was identified as H. spartii based on morphology and molecular methods. A pathogenicity test was conducted by preparing a conidial suspension of 2.0 × 107 conidia/mL. The suspension was sprayed onto the needles of 20 pots of annual P. sylvestris ar. mongolica seedlings, and the control was sprayed with sterile water. Then the seedlings were placed in a constant temperature room at 25 °C. After 30 d, typical symptoms appeared on 11 inoculated needles, while the control needles remained symptomless. After 50 d, the re-isolation infection rate reached 66.7 %. The fungus present on the inoculated seedlings was morphologically identical to that originally observed on diseased pines, fulfilling Koch's postulates. The fungus was isolated from Spartium junceum for the first time and designated Truncatella spartii (Senanayake et al, 2015). It was then renamed H. spartii (Liu et al, 2019) and has been reported to infect P. pinea in Tunisia (Hlaiem et al, 2019). To our knowledge, this is the first report of H. spartii causing black spot needle blight on P. sylvestris var. mongolica in China and worldwide.

Inhibitory effects and mechanisms of vanillin on gray mold and black rot of cherry tomatoes.

Vanillin is a natural antimicrobial agent; however, there are few reports on its antifungal effect on postharvest pathogenic fungi. This study aimed to investigate the in vivo and in vitro antifungal activities of vanillin against gray mold (caused by B. cinerea) and black rot (caused by A. alternata) of cherry tomato fruit and to explain its possible mechanism of action. Vanillin strongly inhibits Botrytis cinerea and Alternaria alternata mycelial growth, spore germination, and germ tube elongation in a concentration-dependent manner (P<0.05). In vivo experiments showed that 4000 mg L-1 vanillin treatment inhibited cherry tomato gray mold and black rot occurrence. Besides, intercellular electrolytes, soluble proteins, and soluble sugars leakage indicated that 50 or 100 mg L-1 vanillin treatment increased Botrytis cinerea and Alternaria alternata membrane permeability. The increase of malondialdehyde and hydrogen peroxide contents confirmed that 50 or 100 mg L-1 vanillin treatment damages the pathogen membranes. Importantly, vanillin treatment inhibited the pathogenicity-related enzyme activities of the two pathogens to reduce their infection ability, among them PL enzyme activity in A. alternata was most inhibited, reducing by 94.7 % at 6 h treated with 100 mg L-1 vanillin. The hyphae morphology of the two pathogens changed, the mycelia were severely damaged, and the hyphae surface was deformed, shrunk, or even broken after 100 mg L-1 vanillin treatment. In summary, vanillin had a substantial inhibitory effect on postharvest gray mold and black rot in cherry tomato fruit. Therefore, vanillin can be an effective alternative to prevent and control cherry tomato postharvest diseases.

A Fluorescent Sensor of 3-Aminobenzeneboronic Acid Functionalized Hydrothermal Carbon Spheres for Facility Detection of L-tryptophan.

In the paper, hydrothermal carbon spheres (HTCs) are functionalized by the 3-aminobenzeneboronic acid (3-APBA) as a fluorescence sensor. The modification carbon spheres (3-APBA-HTCs) have shown excellent selectivity and sensitivity for efficient determination of L-tryptophan (L-Trp). The fluorescence sensor can selectively achieve the "On-Off" switchable functionality for L-Trp at an extremely low detection limit of 0.50 × 10- 5 mol/L.

TMT-Based Proteomic Analysis Reveals the Molecular Mechanisms of Sodium Pheophorbide A against Black Spot Needle Blight Caused by Pestalotiopsis neglecta in Pinus sylvestris var. mongolica.

Black spot needle blight is a minor disease in Mongolian Scots pine (Pinus sylvestris var. mongolica) caused by Pestalotiopsis neglecta, but it can cause economic losses in severe cases. Sodium pheophorbide a (SPA), an intermediate product of the chlorophyll metabolism pathway, is a compound with photoactivated antifungal activity, which has been previously shown to inhibit the growth of P. neglecta. In this study, SPA significantly reduced the incidence and disease index and enhanced the chlorophyll content and antioxidant enzyme activities of P. sylvestris var. mongolica. To further study the molecular mechanism of the inhibition, we conducted a comparative proteomic analysis of P. neglecta mycelia with and without SPA treatment. The cellular proteins were obtained from P. neglecta mycelial samples and subjected to a tandem mass tag (TMT)-labelling LC-MS/MS analysis. Based on the results of de novo transcriptome assembly, 613 differentially expressed proteins (DEPs) (p < 0.05) were identified, of which 360 were upregulated and 253 downregulated. The 527 annotated DEPs were classified into 50 functional groups according to Gene Ontology and linked to 256 different pathways using the Kyoto Encyclopedia of Genes and Genomes database as a reference. A joint analysis of the transcriptome and proteomics results showed that the top three pathways were Amino acid metabolism, Carbohydrate metabolism, and Lipid metabolism. These results provide new viewpoints into the molecular mechanism of the inhibition of P. neglecta by SPA at the protein level and a theoretical basis for evaluating SPA as an antifungal agent to protect forests.

Drug-drug interaction between tacrolimus and caspofungin in Chinese kidney transplant patients with different CYP3A5 genotypes.

Background: The effect of drug-drug interaction between tacrolimus and caspofungin on the pharmacokinetics of tacrolimus in different CYP3A5 genotypes has not been reported in previous studies. Objectives: To investigate the effect of caspofungin on the blood concentration and dose of tacrolimus under different CYP3A5 genotypes. Design: We conducted a retrospective cohort study in The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital from January 2015 to December 2022. All kidney transplant patients were divided into the combination or non-combination group based on whether tacrolimus was combined with caspofungin or not. Patients were subdivided into CYP3A5 expressers (CYP3A5*1/*1 or CYP3A5*1/*3) and CYP3A5 non-expressers (CYP3A5*3/*3). Methods: Data from the combination and the non-combination groups were matched with propensity scores to reduce confounding by SPSS 22.0. A total of 200 kidney transplant patients receiving tacrolimus combined with caspofungin or not were enrolled in this study. Statistical analysis was conducted on the dose-corrected trough concentrations (C0/D) and dose requirements (D) of tacrolimus using independent sample two-sided t-test and nonparametric tests to investigate the impact on patients with different. Results: In this study, the C0/D values of tacrolimus were not significantly different between the combination and non-combination groups (p = 0.054). For CYP3A5 expressers, there was no significant difference in tacrolimus C0/D or D values between the combination and non-combination groups (p = 0.359; p = 0.851). In CYP3A5 nonexpressers, the C0/D values of tacrolimus were significantly lower in the combination than in the non-combination groups (p = 0.039), and the required daily dose of tacrolimus was increased by 11.11% in the combination group. Conclusion: Co-administration of caspofungin reduced tacrolimus blood levels and elevated the required daily dose of tacrolimus. In CYP3A5 non-expressers, co-administration of caspofungin had a significant effect on tacrolimus C0/D values. An approximate 10% increase in the weight-adjusted daily dose of tacrolimus in CYP3A5 non-expressers is recommended to ensure the safety of tacrolimus administration.

Differential drug interactions of caspofungin on tacrolimus in Chinese kidney transplant patients with different CYP3A5 genotypes Why was the study done? Currently, there have been studies reporting the effect of caspofungin on tacrolimus blood concentrations, but the conclusions are conflicting, and no study has focused on the effect of CYP3A5 genotypes on the drug-drug interaction. We explored a number of research questions: 1. Does caspofungin have an effect on the pharmacokinetics of the immunosuppressant tacrolimus? 2. How does CYP3A5*3, which affects tacrolimus metabolism significantly, affect tacrolimus blood concentration levels? 3. How should the dose of tacrolimus be adjusted when combined with caspofungin? What did the researchers do? By reviewing literature, we understood the problems related with the kidney transplant patients better, which led to the development of strict inclusion and exclusion criteria. The patients (from January 2015 to December 2022) were categorized into combination and non-combination groups according to whether they were co-administered with caspofungin or not. The results of the study were analyzed using SPSS 22.0. What did the researchers find? The study finally included 200 patients. We found no statistically significant differences in the dose-corrected trough concentrations (C₀/D) and dose requirements (D) of tacrolimus between the combination and non-combination groups. However, in patients with CYPA5*3/*3 genotype, tacrolimus C₀/D values were significantly lower in the combination group than in the non-combination group, and the required daily tacrolimus dose was increased. What do the findings mean? This study has found that co-administration of caspofungin in patients with CYP3A5*3/*3 genotype resulted in a significant decrease in the C₀/D value of tacrolimus, therefore, an appropriate increase in the daily dose of tacrolimus is recommended. The implication is that it is important and necessary to monitor the concentrations of tacrolimus and the CYP3A5 genotypes, and adjust the dose when combined or discontinuing with caspofungin in kidney transplant patients.

Interaction between tacrolimus and calcium channel blockers based on CYP3A5 genotype in Chinese renal transplant recipients.

Objective: To investigate the effect of calcium channel blockers (CCBs) on tacrolimus blood concentrations in renal transplant recipients with different CYP3A5 genotypes. Methods: This retrospective cohort study included renal transplant recipients receiving tacrolimus-based immunosuppressive therapy with or without CCBs in combination. Patients were divided into combination and control groups based on whether or not they were combined with CCBs, and then further analyzed according to the type of CCBs (nifedipine/amlodipine/felodipine). Propensity score matching was conducted for the combination and the control groups using SPSS 22.0 software to reduce the impact of confounding factors. The effect of different CCBs on tacrolimus blood concentrations was evaluated, and subgroup analysis was performed according to the patients' CYP3A5 genotypes to explore the role of CYP3A5 genotypes in drug-drug interactions between tacrolimus and CCBs. Results: A total of 164 patients combined with CCBs were included in the combination groups. After propensity score matching, 83 patients with nifedipine were matched 1:1 with the control group, 63 patients with felodipine were matched 1:2 with 126 controls, and 18 patients with amlodipine were matched 1:3 with 54 controls. Compared with the controls, the three CCBs increased the dose-adjusted trough concentration (C0/D) levels of tacrolimus by 41.61%-45.57% (P < 0.001). For both CYP3A5 expressers (CYP3A5*1*1 or CYP3A5*1*3) and non-expressers (CYP3A5*3*3), there were significant differences in tacrolimus C0/D between patients using felodipine/nifedipine and those without CCBs (P < 0.001). However, among CYP3A5 non-expressers, C0/D values of tacrolimus were significantly higher in patients combined with amlodipine compared to the controls (P = 0.001), while for CYP3A5 expressers, the difference in tacrolimus C0/D values between patients with amlodipine and without was not statistically significant (P = 0.065). Conclusion: CCBs (felodipine/nifedipine/amlodipine) can affect tacrolimus blood concentration levels by inhibiting its metabolism. The CYP3A5 genotype may play a role in the drug interaction between tacrolimus and amlodipine. Therefore, genetic testing for tacrolimus and therapeutic drug monitoring are needed when renal transplant recipients are concurrently using CCBs.

Death receptor 5 is required for intestinal stem cell activity during intestinal epithelial renewal at homoeostasis.

Intestinal epithelial renewal, which depends on the proliferation and differentiation of intestinal stem cells (ISCs), is essential for epithelial homoeostasis. Understanding the mechanism controlling ISC activity is important. We found that death receptor 5 (DR5) gene deletion (DR5-/-) mice had impaired epithelial absorption and barrier function, resulting in delayed weight gain, which might be related to the general reduction of differentiated epithelial cells. In DR5-/- mice, the expression of ISC marker genes, the number of Olfm4+ ISCs, and the number of Ki67+ and BrdU+ cells in crypt were reduced. Furthermore, DR5 deletion inhibited the expression of lineage differentiation genes driving ISC differentiation into enterocytes, goblet cells, enteroendocrine cells, and Paneth cells. Therefore, DR5 gene loss may inhibit the intestinal epithelial renewal by dampening ISC activity. The ability of crypts from DR5-/- mice to form organoids decreased, and selective DR5 activation by Bioymifi promoted organoid growth and the expression of ISC and intestinal epithelial cell marker genes. Silencing of endogenous DR5 ligand TRAIL in organoids down-regulated the expression of ISC and intestinal epithelial cell marker genes. So, DR5 expressed in intestinal crypts was involved in the regulation of ISC activity. DR5 deletion in vivo or activation in organoids inhibited or enhanced the activity of Wnt, Notch, and BMP signalling through regulating the production of Paneth cell-derived ISC niche factors. DR5 gene deletion caused apoptosis and DNA damage in transit amplifying cells by inhibiting ERK1/2 activity in intestinal crypts. Inhibition of ERK1/2 with PD0325901 dampened the ISC activity and epithelial regeneration. In organoids, when Bioymifi's effect in activating ERK1/2 activity was completely blocked by PD0325901, its role in stimulating ISC activity and promoting epithelial regeneration was also eliminated. In summary, DR5 in intestinal crypts is essential for ISC activity during epithelial renewal under homoeostasis.

A single-cell characterised signature integrating heterogeneity and microenvironment of lung adenocarcinoma for prognostic stratification.

BACKGROUND: The high heterogeneity of tumour and the complexity of tumour microenvironment (TME) greatly impacted the tumour development and the prognosis of cancer in the era of immunotherapy. In this study, we aimed to portray the single cell-characterised landscape of lung adenocarcinoma (LUAD), and develop an integrated signature incorporating both tumour heterogeneity and TME for prognosis stratification. METHODS: Single-cell tagged reverse transcription sequencing (STRT-seq) was performed on tumour tissues and matched normal tissues from 14 patients with LUAD for immune landscape depiction and candidate key genes selection for signature construction. Kaplan-Meier survival analyses and in-vitro cell experiments were conducted to confirm the gene functions. The transcriptomic profile of 1949 patients from 11 independent cohorts including nine public datasets and two in-house cohorts were obtained for validation. FINDINGS: We selected 11 key genes closely related to cell-to-cell interaction, tumour development, T cell phenotype transformation, and Ma/Mo cell distribution, including HLA-DPB1, FAM83A, ITGB4, OAS1, FHL2, S100P, FSCN1, SFTPD, SPP1, DBH-AS1, CST3, and established an integrated 11-gene signature, stratifying patients to High-Score or Low-Score group for better or worse prognosis. Moreover, the prognostically-predictive potency of the signature was validated by 11 independent cohorts, and the immunotherapeutic predictive potency was also validated by our in-house cohort treated by immunotherapy. Additionally, the in-vitro cell experiments and drug sensitivity prediction further confirmed the gene function and generalizability of this signature across the entire RNA profile spectrum. INTERPRETATION: This single cell-characterised 11-gene signature might offer insights for prognosis stratification and potential guidance for treatment selection. FUNDING: Support for the study was provided by National key research and development project (2022YFC2505004, 2022YFC2505000 to Z.W. and J.W.), Beijing Natural Science Foundation (7242114 to J.X.), National Natural Science Foundation of China of China (82102886 to J.X., 81871889 and 82072586 to Z.W.), Beijing Nova Program (20220484119 to J.X.), NSFC general program (82272796 to J.W.), NSFC special program (82241229 to J.W.), CAMS Innovation Fund for Medical Sciences (2021-1-I2M-012, 2022-I2M-1-009 to Z.W. and J.W.), Beijing Natural Science Foundation (7212084 to Z.W.), CAMS Key lab of translational research on lung cancer (2018PT31035 to J.W.), Aiyou Foundation (KY201701 to J.W.). Medical Oncology Key Foundation of Cancer Hospital Chinese Academy of Medical Sciences (CICAMS-MOCP2022003 to J.X.).

Identification, Culture Characteristics and Whole-Genome Analysis of Pestalotiopsis neglecta Causing Black Spot Blight of Pinus sylvestris var. mongolica.

Black spot needle blight is a serious conifer disease of Pinus sylvestris var. mongolica occurring in Northeast China, which is usually caused by the plant pathogenic fungus Pestalotiopsis neglecta. From the diseased pine needles collected in Honghuaerji, the P. neglecta strain YJ-3 was isolated and identified as the phytopathogen, and its culture characteristics were studied. Then, we generated a highly contiguous 48.36-Mbp genome assembly (N50 = 6.62 Mbp) of the P. neglecta strain YJ-3 by combining the PacBio RS II Single Molecule Real Time (SMRT) and Illumina HiSeq X Ten sequencing platforms. The results showed that a total of 13,667 protein-coding genes were predicted and annotated using multiple bioinformatics databases. The genome assembly and annotation resource reported here will be useful for the study of fungal infection mechanisms and pathogen-host interaction.

Association between GLP-1R gene polymorphism and dyslipidemia in Chinese patients with type 2 diabetes mellitus: A case-control study.

OBJECTIVE: To evaluate the relationship between GLP-1R gene polymorphisms and type 2 diabetes mellitus with dyslipidemia and without dyslipidemia in China. METHODS: A total of 200 patients with Type 2 Diabetes Mellitus (T2DM) were included in this study, including 115 with dyslipidemia and 85 without dyslipidemia. We used Sanger double deoxygenation terminal assay and PCR-RFLP to detect genotype of the GLP-1R rs10305420 and rs3765467 loci. T-test was used to analyze the association between gene polymorphisms and lipid indicators. SHEsis online analysis software was used to analyze the linkage balance effect of loci, and SPSS 26 was used to calculate the gene interaction by dominant model. RESULTS: The genotype distribution of the two loci in the sample of this study was in accordance with Hardy-weinberg equilibrium. There were significant differences in the genotype distribution and allele frequency of rs3765467 between T2DM patients with and without dyslipidemia (GG 52.9%, GA + AA 47.1% vs. GG 69.6%, GA + AA 30.4%; P = 0.017). Under the dominant model, the effects of rs3765467 A allele and rs10305420 T allele on dyslipidemia had multiplicative interactions (P = 0.016) and additive interactions (RERI = 0.403, 95% CI [-2.708 to 3.514]; AP = 0.376, 95% CI [-2.041, 2.793]). Meanwhile, HbA1c levels in rs3765467 A allele carriers (GA + AA) were found to be significantly lower than those in patients with GG genotype (P = 0.006). CONCLUSION: The rs3765467 (G/A) variant is associated with the incidence of dyslipidemia, and G allele may be a risk factor for dyslipidemia.

Biophysical heterogeneity of myeloid-derived microenvironment to regulate resistance to cancer immunotherapy.

Despite the advances in immunotherapy for cancer treatment, patients still obtain limited benefits, mostly owing to unrestrained tumour self-expansion and immune evasion that exploits immunoregulatory mechanisms. Traditionally, myeloid cells have a dominantly immunosuppressive role. However, the complicated populations of the myeloid cells and their multilateral interactions with tumour/stromal/lymphoid cells and physical abnormalities in the tumour microenvironment (TME) determine their heterogeneous functions in tumour development and immune response. Tumour-associated myeloid cells (TAMCs) include monocytes, tumour-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), dendritic cells (DCs), and granulocytes. Single-cell profiling revealed heterogeneous TAMCs composition, sub-types, and transcriptomic signatures across 15 human cancer types. We systematically reviewed the biophysical heterogeneity of TAMC composition and pro/anti-tumoral and immuno-suppressive/stimulating properties of myeloid-derived microenvironments. We also summarised comprehensive clinical strategies to overcome resistance to immunotherapy from three dimensions: targeting TAMCs, reversing physical abnormalities, utilising nanomedicines, and finally, put forward futuristic perspectives for scientific and clinical research.

The therapeutic effect and targets of cellulose polysaccharide on coronary heart disease (CHD) and the construction of a prognostic signature based on network pharmacology.

Cellulose is the first rich biological polysaccharide in nature and has many excellent properties, so it is being developed as a variety of drug carriers. Moreover, applications in drug delivery, biosensors/bioanalysis, immobilization of enzymes and cells, stem cell therapy, and skin tissue repair are also highlighted by many studies. Coronary heart disease, as one of the diseases with the highest incidence, is urgent to enhance the survival outcome and life quality of patients with coronary heart disease, whereas the mechanism of cellulose's interaction with the human body remains unclear. However, the mechanism of cellulose's interaction with the human body remains unclear. We obtained 92 genes associated with cellulose and coronary heart disease through the intersection of different databases. Ten key genes were identified: HRAS, STAT3, HSP90AA1, FGF2, VEGFA, CXCR4, TERT, IL2, BCL2L1, and CDK1. Molecular docking of the 10 genes revealed their association with their respective receptors. Analysis by KEGG and GO has discovered that these related targets were more enriched in metabolic- and activation-related functions, which further confirmed that cellulose polysaccharides can also interact with cardiovascular diseases as molecules. In the end, we screened out six key genes that were more associated with the prognosis (CDK1, HSP90AA1, CXCR4, IL2, VEGFA, and TERT) and constructed a signature, which has a good predictive effect and has significant statistical significance. Our study is the first study to explore the interaction targets of cellulose and CHD and to construct a prognostic model. Our findings provide insights for future molecular design, drug development, and clinical trials.

Links Between N 6-Methyladenosine and Tumor Microenvironments in Colorectal Cancer.

N 6-methyladenosine (m6A) is a critical epigenetic modification for tumor malignancies, but its role in regulating the tumor microenvironments (TMEs) has not been fully studied. By integrating multiple data sets and multi-omics data, we comprehensively evaluated the m6A "writers," "erasers," and "readers" in colorectal cancer and their association with TME characteristics. The m6A regulator genes showed specific patterns in co-mutation, copy number variation, and expression. Based on the transcriptomic data of the m6A regulators and their correlated genes, two types of subtyping systems, m6AregCluster and m6AsigCluster, were developed. The clusters were distinct in pathways (metabolism/inflammation/extracellular matrix and interaction), immune phenotypes (immune-excluded/immune-inflamed/immune-suppressive), TME cell composition (lack immune and stromal cells/activated immune cells/stromal and immune-suppressive cells), stroma activities, and survival outcomes. We also established an m6Ascore associated with molecular subgroups, microsatellite instability, DNA repair status, mutation burdens, and survival and predicted immunotherapy outcomes. In conclusion, our work revealed a close association between m6A modification and TME formation. Evaluating m6A in cancer has helped us comprehend the TME status, and targeting m6A in tumor cells might help modulate the TME and improve tumor therapy and immunotherapy.