Identification of cancer stem cell-related genes through single cells and machine learning for predicting prostate cancer prognosis and immunotherapy.

Background: Cancer stem cells (CSCs) are a subset of cells within tumors that possess the unique ability to self-renew and give rise to diverse tumor cells. These cells are crucial in driving tumor metastasis, recurrence, and resistance to treatment. The objective of this study was to pinpoint the essential regulatory genes associated with CSCs in prostate adenocarcinoma (PRAD) and assess their potential significance in the diagnosis, prognosis, and immunotherapy of patients with PRAD. Method: The study utilized single-cell analysis techniques to identify stem cell-related genes and evaluate their significance in relation to patient prognosis and immunotherapy in PRAD through cluster analysis. By utilizing diverse datasets and employing various machine learning methods for clustering, diagnostic models for PRAD were developed and validated. The random forest algorithm pinpointed HSPE1 as the most crucial prognostic gene among the stem cell-related genes. Furthermore, the study delved into the association between HSPE1 and immune infiltration, and employed molecular docking to investigate the relationship between HSPE1 and its associated compounds. Immunofluorescence staining analysis of 60 PRAD tissue samples confirmed the expression of HSPE1 and its correlation with patient prognosis in PRAD. Result: This study identified 15 crucial stem cell-related genes through single-cell analysis, highlighting their importance in diagnosing, prognosticating, and potentially treating PRAD patients. HSPE1 was specifically linked to PRAD prognosis and response to immunotherapy, with experimental data supporting its upregulation in PRAD and association with poorer prognosis. Conclusion: Overall, our findings underscore the significant role of stem cell-related genes in PRAD and unveil HSPE1 as a novel target related to stem cell.

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A comprehensive understanding of the evolution of soybean climate potential productivity and its response to climate change in Heilongjiang Province can offer reference and basis for further tapping soybean production potential and realizing stable and high yield of soybean in the frigid region. Based on meteorological data from 80 meteorological stations in Heilongjiang Province from 1961 to 2020, we estimated photosynthesis, light temperature, and climate potential productivity of soybean by the stepwise correction method, examined the spatiotemporal variations by spatial interpolation and statistical analysis methods, and analyzed the impact of changes in climate factors such as radiation, temperature, and precipitation on climate potential productivity. The results showed that during the study period, the average values of photosynthesis potential productivity (YQ), light-temperature potential productivity (YT), and climate potential productivity (YW) of soybean in Heilongjiang Province were 7533, 6444, and 3515 kg·hm-2, respectively. The temporal changes of those variables showed significant increasing trends, with increases of 125.9, 182.9, and 116.1 kg·hm-2·(10 a)-1, respectively. For the spatial distribution, YQ, YT, YW were characterized by high values in plains and lower in the mountains, and gradually decreased from southwest to northeast. Compared with that during 1961-1990, the high value zone of YW in period 1991-2020 expanded by 7.1%, and the low value zone decreased by 5.1%. YW showed a significant response to climate change. The potential temperature growth period was extended due to climate warming. The continuous increase in thermal resources, combined with relatively sufficient precipitation, effectively alleviated the negative impact of the decline in light resources on soybean production in Heilongjiang Province. The projected "warm and humid" climate would comprehensively boost climate potential productivity of soybean in Heilongjiang Province.

Whole genome sequencing and analysis of the weed pathogen Trichoderma polysporum HZ-31.

In order to resolve the key genes for weed control by Trichoderma polysporum at the genomic level, we extracted the genomic DNA and sequenced the whole genome of T. polysporum strain HZ-31 on the Illumina Hiseq platform. The raw data was cleaned up using Trimmomatic and checked for quality using FastQC. The sequencing data was assembled using SPAdes, and GeneMark was used to perform gene prediction on the assembly results. The results showed that the genome size of T. polysporum HZ-31 was 39,325,746 bp, with 48% GC content, and the number of genes encoded was 11,998. A total of 148 tRNAs and 45 rRNAs were predicted. A total of 782 genes were annotated in the Carbohydrase Database, 757 genes were annotated to the Pathogen-Host Interaction Database, and 67 gene clusters were identified. In addition, 1023 genes were predicted to be signal peptide proteins. The annotation and functional analysis of the whole genome sequence of T. polymorpha HZ-31 provide a basis for the in-depth study of the molecular mechanism of its herbicidal action and more effective utilization for weed control.

Chiral Herbicide Fluorochloridone: Absolute Configuration, Stereoselective Bioactivity, Toxicity, and Degradation in the Potatoes.

Fluorochloridone (FLC) is a chiral herbicide that has four stereoisomers. This study systematically assessed the stereoselectivity of FLC to reveal the selective environmental behavior of its four isomers. Absolute configuration confirmation, evaluation of stereoselective bioactivity toward monocotyledonous and dicotyledonous weeds, toxicity to Danio rerio, and the stereoselective degradation in the potato system under field conditions of FLC were conducted. The four FLC stereoisomers were effectively separated on a superchiral S-AD column. The absolute configurations of the four stereoisomers of FLC were confirmed as (-)-(3S, 4S), (+)-(3S, 4R), (-)-(3R, 4S), and (+)-(3R, 4R)-FLC using single-crystal X-ray diffraction. The activities of the four stereoisomers were in the order of (-)-(3S, 4S)-FLC > (+)-(3R, 4R)-FLC > (+)-(3S, 4R)-FLC > (-)-(3R, 4S)-FLC, and the rate of selective degradation were in the order of (-)-(3R, 4S)-FLC > (+)-(3R, 4R)-FLC > (-)-(3S, 4R)-FLC > (+)-(3S, 4S)-FLC. The toxicity of the isomers were in the order of (-)-(3R, 4S)-FLC > (+)-(3R, 4R)-FLC > (-)-(3S, 4S)-FLC > (+)-(3S, 4R). Based on the results of bioactivity, toxicity, and degradation behavior assessments, the stereoisomer mixture containing (3R,4R)-FLC and (3S,4S)-FLC was concluded to be a better option than racemic FLC for increasing bioactivity and reducing usage.

Multi-omics analysis and experimental validation of the value of monocyte-associated features in prostate cancer prognosis and immunotherapy.

Background: Monocytes play a critical role in tumor initiation and progression, with their impact on prostate adenocarcinoma (PRAD) not yet fully understood. This study aimed to identify key monocyte-related genes and elucidate their mechanisms in PRAD. Method: Utilizing the TCGA-PRAD dataset, immune cell infiltration levels were assessed using CIBERSORT, and their correlation with patient prognosis was analyzed. The WGCNA method pinpointed 14 crucial monocyte-related genes. A diagnostic model focused on monocytes was developed using a combination of machine learning algorithms, while a prognostic model was created using the LASSO algorithm, both of which were validated. Random forest and gradient boosting machine singled out CCNA2 as the most significant gene related to prognosis in monocytes, with its function further investigated through gene enrichment analysis. Mendelian randomization analysis of the association of HLA-DR high-expressing monocytes with PRAD. Molecular docking was employed to assess the binding affinity of CCNA2 with targeted drugs for PRAD, and experimental validation confirmed the expression and prognostic value of CCNA2 in PRAD. Result: Based on the identification of 14 monocyte-related genes by WGCNA, we developed a diagnostic model for PRAD using a combination of multiple machine learning algorithms. Additionally, we constructed a prognostic model using the LASSO algorithm, both of which demonstrated excellent predictive capabilities. Analysis with random forest and gradient boosting machine algorithms further supported the potential prognostic value of CCNA2 in PRAD. Gene enrichment analysis revealed the association of CCNA2 with the regulation of cell cycle and cellular senescence in PRAD. Mendelian randomization analysis confirmed that monocytes expressing high levels of HLA-DR may promote PRAD. Molecular docking results suggested a strong affinity of CCNA2 for drugs targeting PRAD. Furthermore, immunohistochemistry experiments validated the upregulation of CCNA2 expression in PRAD and its correlation with patient prognosis. Conclusion: Our findings offer new insights into monocyte heterogeneity and its role in PRAD. Furthermore, CCNA2 holds potential as a novel targeted drug for PRAD.

Directed-evolution mutations enhance DNA-binding affinity and protein stability of the adenine base editor ABE8e.

Adenine base editors (ABEs), consisting of CRISPR Cas nickase and deaminase, can chemically convert the A:T base pair to G:C. ABE8e, an evolved variant of the base editor ABE7.10, contains eight directed evolution mutations in its deaminase TadA8e that significantly increase its base editing activity. However, the functional implications of these mutations remain unclear. Here, we combined molecular dynamics (MD) simulations and experimental measurements to investigate the role of the directed-evolution mutations in the base editing catalysis. MD simulations showed that the DNA-binding affinity of TadA8e is higher than that of the original deaminase TadA7.10 in ABE7.10 and is mainly driven by electrostatic interactions. The directed-evolution mutations increase the positive charge density in the DNA-binding region, thereby enhancing the electrostatic attraction of TadA8e to DNA. We identified R111, N119 and N167 as the key mutations for the enhanced DNA binding and confirmed them by microscale thermophoresis (MST) and in vivo reversion mutation experiments. Unexpectedly, we also found that the directed mutations improved the thermal stability of TadA8e by ~ 12 °C (Tm, melting temperature) and that of ABE8e by ~ 9 °C, respectively. Our results demonstrate that the directed-evolution mutations improve the substrate-binding ability and protein stability of ABE8e, thus providing a rational basis for further editing optimisation of the system.

Broad -band nonlinear optical response in Bi2Te0.6S2.4 alloys based on alloy engineering.

Alloy engineering plays an important role in regulating the optoelectronic properties of materials. This work demonstrates that Bi2Te0.6S2.4 alloys can extend nonlinear optical response to the near-infrared range. Te alloying at S sites can narrow the band gap, as proved by density functional theory (DFT) calculations, leading to a broadband saturable absorption response ranging from ultraviolet (350 nm) to near-infrared (1100 nm) wavelength with negative nonlinear optical absorption coefficient ranging from -0.12 cm GW-1 to -1.28 cm GW-1. Moreover, the broadband carrier dynamic of Bi2Te0.6S2.4 alloys was investigated via femtosecond transient absorption (TA) at an excitation of 325 nm. A faster carrier dynamic at near-infrared wavelength was observed because of an increase in electron density at the conduction band minimum due to the additional Bi-Te interaction, which was corroborated by DFT calculations. These results suggest that alloy engineering provides an effective way for the development of broadband nonlinear optical devices.

Genomic analysis of Cobetia sp. D5 reveals its role in marine sulfur cycling.

Dimethylsulfoniopropionate (DMSP) is one of the most abundant sulfur-containing organic compounds on the earth, which is an important carbon and sulfur source and plays an important role in the global sulfur cycle. Marine microorganisms are an important group involved in DMSP metabolism. The strain Cobetia sp. D5 was isolated from seawater samples in the Yellow Sea area of Qingdao during an algal bloom. There is still limited knowledge on the capacity of DMSP utilization of Cobetia bacteria. The study reports the whole genome sequence of Cobetia sp. D5 to understand its DMSP metabolism pathway. The genome of Cobetia sp. D5 consists of a circular chromosome with a length of 4,233,985 bp and the GC content is 62.56%. Genomic analysis showed that Cobetia sp. D5 contains a set of genes to transport and metabolize DMSP, which can cleave DMSP to produce dimethyl sulphide (DMS) and 3-Hydroxypropionyl-Coenzyme A (3-HP-CoA). DMS diffuses into the environment to enter the global sulfur cycle, whereas 3-HP-CoA is catabolized to acetyl CoA to enter central carbon metabolism. Thus, this study provides genetic insights into the DMSP metabolic processes of Cobetia sp. D5 during a marine algal bloom, and contributes to the understanding of the important role played by marine bacteria in the global sulfur cycle.

Clinical and genetic analysis of 18 patients with KCNQ2 mutations from South China.

BACKGROUND: We aimed to delineate the genotype and phenotype of patients with KCNQ2 mutations from South China. METHODS: Clinical manifestations and characteristics of KCNQ2 mutations of patients from South China were analyzed. Previous patients with mutations detected in this study were reviewed. RESULTS: Eighteen epilepsy patients with KCNQ2 mutations, including seven self-limited neonatal epilepsy (SeLNE), two self-limited infantile epilepsy (SeLIE) and nine developmental and epileptic encephalopathy (DEE) were enrolled. The age of onset (p=0.006), mutation types (p=0.029), hypertonia (p=0.000), and seizure offset (p=0.029) were different in self-limited epilepsy (SeLE) and DEE. De novo mutations were mainly detected in DEE patients (p=0.026). The mutation position, EEG or the age of onset were not predictive for the seizure or ID/DD outcome in DEE, while the development of patients free of seizures was better than that of patients with seizures (p=0.008). Sodium channel blockers were the most effective anti-seizure medication, while the age of starting sodium channel blockers did not affect the seizure or development offset. We first discovered the seizure recurrence ratio in SeLNE/SeLIE was 23.1% in South China. Four novel mutations (c.790T>C, c.355_363delGAGAAGAG, c.296+2T>G, 20q13.33del) were discovered. Each of eight mutations (c.1918delC, c.1678C>T, c.683A>G, c.833T>C, c.868G>A, c.638G>A, c.997C>T, c.830C>T) only resulted in SeLE or DEE, while heterogeneity was also found. Six patients in this study have enriched the known phenotype caused by the mutations (c.365C>T, c.1A>G, c.683A>G, c.833T>C, c.830C>T, c.1678C>T). CONCLUSION: This research has expanded known phenotype and genotype of KCNQ2-related epilepsy, and the different clinical features of SeLE and DEE from South China.

MLXIPL associated with tumor-infiltrating CD8+ T cells is involved in poor prostate cancer prognosis.

Introduction: Within tumor microenvironment, the presence of preexisting antitumor CD8+ T Q7 cells have been shown to be associated with a favorable prognosis in most solid cancers. However, in the case of prostate cancer (PCa), they have been linked to a negative impact on prognosis. Methods: To gain a deeper understanding of the contribution of infiltrating CD8+ T cells to poor prognosis in PCa, the infiltration levelsof CD8+ T cells were estimated using the TCGA PRAD (The Cancer Genome Atlas Prostate Adenocarcinoma dataset) and MSKCC (Memorial Sloan Kettering Cancer Center) cohorts. Results: Bioinformatic analyses revealed that CD8+ T cells likely influence PCa prognosis through increased expression of immune checkpoint molecules and enhanced recruitment of regulatory T cells. The MLXIPL was identified as the gene expressed in response to CD8+ T cell infiltration and was found to be associated with PCa prognosis. The prognostic role of MLXIPL was examined in two cohorts: TCGA PRAD (p = 2.3E-02) and the MSKCC cohort (p = 1.6E-02). Subsequently, MLXIPL was confirmed to be associated with an unfavorable prognosis in PCa, as evidenced by an independent cohort study (hazard ratio [HR] = 2.57, 95% CI: 1.42- 4.65, p = 1.76E-03). Discussion: In summary, the findings suggested that MLXIPL related to tumor-infiltrating CD8+ T cells facilitated a poor prognosis in PCa.

Acceleration mechanism of riboflavin on Fe0-to-microbe electron transfer in corrosion of EH36 steel by Pseudomonas aeruginosa.

Riboflavin (RF), as a common electron mediator that can accelerate extracellular electron transfer (EET), is usually used as a probe to confirm EET-microbiologically influenced corrosion (MIC). However, the acceleration mechanism of RF on EET-MIC is still unclear, especially the effect on gene expression in bacteria. In this study, a 13-mer antimicrobial peptide E6 and tetrakis hydroxymethyl phosphonium sulfate (THPS) were used as new tools to investigate the acceleration mechanism of RF on Fe0-to-microbe EET in corrosion of EH36 steel caused by Pseudomonas aeruginosa. 60 min after 20 ppm (v/v) THPS and 20 ppm THPS & 100 nM E6 were injected into P. aeruginosa 1 and P. aeruginosa 2 (two glass bottles containing P. aeruginosa with different treatments) at the 3-d incubation, respectively, P. aeruginosa 1 and P. aeruginosa 2 had a similar planktonic cell count, whereas the sessile cell count in P. aeruginosa 1 was 1.3 log higher than that in P. aeruginosa 2. After the 3-d pre-growth and subsequent 7-d incubation, the addition of 20 ppm (w/w) RF increased the weight loss and maximum pit depth of EH36 steel in P. aeruginosa 1 by 0.7 mg cm-2 and 4.1 µm, respectively, while only increasing those in P. aeruginosa 2 by 0.4 mg cm-2 and 1.7 µm, respectively. This suggests that RF can be utilized by P. aeruginosa biofilms since the corrosion rate should be elevated by the same value if it only acts on the planktonic cells. Furthermore, the EET capacity of P. aeruginosa biofilm was enhanced by RF because the protein expression of cytochrome c (Cyt c) gene in sessile cells was significantly increased in the presence of RF, which accelerated EET-MIC by P. aeruginosa against EH36 steel.

Transcriptome Sequencing and Analysis of Trichoderma polysporum Infection in Avena fatua L. Leaves before and after Infection.

Biological control is a scientific management method used in modern agricultural production, and microbially derived biopesticides are one effective method with which to control weeds in agricultural fields. In order to determine the key genes for weed control by Trichoderma polysporum, transcriptome sequencing was carried out by high-throughput sequencing technology, and the strains of T. polysporum HZ-31 infesting Avena fatua L. at 24, 48, and 72 h were used as the experimental group, with 0 h as the control group. A total of 690,713,176 clean reads were obtained, and the sequencing results for each experimental group and the control group (0 h) were analyzed. In total, 3464 differentially expressed genes were found after 24 h of infection with the pathogen, including 1283 down-regulated genes and 2181 up-regulated genes. After 48 h of infection, the number of differentially expressed genes was 3885, of which 2242 were up-regulated and 1643 were down-regulated. The number of differentially expressed genes after 72 h of infection was the highest among all the groups, with 4594 differentially expressed genes, of which 2648 were up-regulated and 1946 were down-regulated. The up-regulated genes were analyzed by GO and KEGG, and the results showed that the up-regulated differentially expressed genes were mainly enriched in the biosynthesis of phenylalanine, tyrosine, and tryptophan; the degradation of aromatic compounds; methane metabolism; and other pathways. Among them, the PHA2, GDH, ADH2, and AROF genes were significantly enriched in the above-mentioned pathways, so they were hypothesized to play an important role in the synthesis of the herbicidally active substances of T. polysporum HZ-31. The results of this study can provide a theoretical basis for further studies on the pathogenicity of T. polysporum to A. fatua L., and accelerate the development and utilization of new and efficient bioherbicides.

Insights on droplet drift and effective utilization of pesticide in "Third Pole"：Qinghai-Tibet Plateau of China.

Crop protection pesticide spraying aims to greatly improve the utilization rate of pesticides. Controlling pesticides deposition requires a thorough understanding of the spatial behaviour of spray droplets.The Qinghai-Tibet Plateau, which is the headwaters of three largest water resources (Yangtze, Yellow and Lancang) in China, has exceptionally unique climatic characteristics. The goal is to reduce the amount of pesticides entering water resources. The wind tunnel experiment was used to validate the discrete phase method for tracking the trajectories. Cooperation between the smaller and larger droplets (greater than 150 µm) in the dense area around the nozzle can undoubtedly enhance the initial dispersion of droplet sizes. Droplet coalescence, which lowers the proportion of readily dispersed droplets, can greatly boost droplet deposition onto the target location.The crucial drift height is presented and clarified when droplets gradually disperse by identifying the descending length at which efficiency of mass transit starts towards decrease off quickly. The pesticide transport efficiency will not be enhanced by reducing the initial relative spread of droplets if the actual spray height surpasses the crucial drift height, and may even worsen drift loss. The temperature and relative humidity of the air have a greater influence on the evaporation losses of droplets smaller than 150 µm. In addition to providing information about pesticide spraying, the results of studies on droplet drift behaviors also suggest a method for controlling drift.

Common immunological and prognostic features of lung and bladder cancer via smoking-related genes: PRR11 gene as potential immunotherapeutic target.

Smoking is a well-known risk factor for non-small-cell lung cancer (NSCLC) and bladder urothelial carcinoma (BLCA). Despite this, there has been no investigation into a prognostic marker based on smoking-related genes that could universally predict prognosis in these cancers and correlate with immune checkpoint therapy. This study aimed to identify smoking-related differential genes in NSCLC and BLCA, analyse their roles in patient prognosis and immune checkpoint therapy through subgroup analyses, and shed light on PRR11 as a crucial prognostic gene in both cancers. By examining PRR11 co-expressed genes, a prognostic model was constructed and its impact on immunotherapy for NSCLC and BLCA was evaluated. Molecular docking and tissue microarray analyses were conducted to explore the correlation between PRR11 and its reciprocal gene SPDL1. Additionally, miRNAs associated with PRR11 were analysed. The study confirmed a strong link between smoking-related genes, prognosis, and immune checkpoint therapy in NSCLC and BLCA. PRR11 was identified as a key smoking-associated gene that influences the efficacy of immune checkpoint therapy by modulating the stemness of these cancers. A prognostic model based on PRR11 co-expressed genes in BLCA was established and its prognostic value was validated in NSCLC. Furthermore, it was found that PRR11 regulates PDL1 via SPDL1, impacting immunotherapeutic efficacy in both cancers. The involvement of hsa-miR-200b-3p in the regulation of SPDL1 expression by PRR11 was also highlighted. Overall, the study elucidates that PRR11 modulates patient immunotherapy by influencing PDL1 expression through its interaction with SPDL1, with potential upstream regulation by hsa-miR-200b-3p.

[Correlation between clinical phenotypes and genotypes among 46 children with SCN1A-related developmental epileptic encephalopathy].

OBJECTIVE: To explore the correlation between clinical phenotypes and genotypes among 46 children with SCN1A-related developmental epileptic encephalopathy (DEE). METHODS: Clinical data of 46 children with DEE and SCN1A variants identified at the Guangzhou Women and Children's Medical Center between January 2018 and June 2022 were collected. The children were grouped based on their age of onset, clinical manifestations, neurodevelopmental status, and results of genetic testing. The correlation between SCN1A genotypes and clinical phenotypes was analyzed. RESULTS: Among the 46 patients, 2 children (4.35%) had developed the symptoms before 3 months of age, 42 (91.30%) were between 3 to 9 months, and 2 cases (4.35%) were after 10 months. Two cases (4.35%) presented with epilepsy of infancy with migrating focal seizures (EIMFS), while 44 (95.7%) had presented with Dravet syndrome (DS), including 28 cases (63.6%) with focal onset (DS-F), 13 cases (29.5%) with myoclonic type (DS-M), 1 case (2.27%) with generalized type (DS-G), and 2 cases (4.55%) with status epilepticus type (DS-SE). Both of the two EIMFS children had severe developmental delay, and among the DS patients, 7 cases had normal development, while the remaining had developmental delay. A total of 44 variants were identified through genetic sequencing, which included 16 missense variants and 28 truncating variants. All EIMFS children had carried the c.677C>T (p.Thr226Met) missense variant. In the DS group, there was a significant difference in the age of onset between the missense variants group and the truncating variants group (P < 0.05). Missense variants were more common in D1 (7/15, 46.7%) and pore regions (8/15, 53.3%), while truncating variants were more common in D1 (12/28, 42.9%). Children with variants outside the pore region were more likely to develop myoclonic seizures. CONCLUSION: The clinical phenotypes of DEE are diverse. There is a difference in the age of onset between individuals with truncating and missense variants in the SCN1A gene. Missense variants outside the pore region are associated with a higher incidence of myoclonic seizures.

EIF3B stabilizes PCNA by counteracting SYVN1-mediated ubiquitination to serve as a promotor in cholangiocarcinoma.

Cholangiocarcinoma, a prevalent hepatic malignancy, exhibits a progressively rising incidence. While Eukaryotic translation initiation factor 3 subunit B (EIF3B) has been implicated in the occurrence and development of various cancers, its specific roles in cholangiocarcinoma remain unexplored. Immunohistochemical (IHC) analysis was employed to detect EIF3B/PCNA expression in cholangiocarcinoma. Cells were manipulated using short hairpin RNA (shRNA)-mediated lentiviruses or overexpression plasmids. Statistical significance was assessed using the Student's t-test and one-way ANOVA, with P < 0.05 considered statistically significant. EIF3B exhibited robust expression in cholangiocarcinoma, demonstrating a significant correlation with the pathological grade of cholangiocarcinoma patients. Furthermore, modulation of EIF3B expression, either depletion or elevation, demonstrated the ability to inhibit or enhance cholangiocarcinoma cell survival and migration in vitro. Mechanistically, we identified Proliferating Cell Nuclear Antigen (PCNA) as a downstream gene of EIF3B, driving cholangiocarcinoma. EIF3B stabilized PCNA by inhibiting PCNA ubiquitination, a process mediated by E3 ligase SYVN1. Similar to EIF3B, PCNA levels were also abundant in cholangiocarcinoma, and knocking down PCNA impeded cholangiocarcinoma development. Intriguingly, silencing PCNA attenuated the promotion induced by EIF3B overexpression. Furthermore, the elevated P21 protein level in shEIF3B RBE cells was partially attenuated after UC2288 (P21 signaling pathway inhibitor) treatment. Our findings underscored the potential of EIF3B as a therapeutic target for cholangiocarcinoma. Unraveling its functions holds promise for the development of more specific and effective targeted therapy strategies.

GLIPR2: a potential biomarker and therapeutic target unveiled - Insights from extensive pan-cancer analyses, with a spotlight on lung adenocarcinoma.

Background: Glioma pathogenesis related-2 (GLIPR2), an emerging Golgi membrane protein implicated in autophagy, has received limited attention in current scholarly discourse. Methods: Leveraging extensive datasets, including The Cancer Genome Atlas (TCGA), Genotype Tissue Expression (GTEx), Human Protein Atlas (HPA), and Clinical Proteomic Tumor Analysis Consortium (CPTAC), we conducted a comprehensive investigation into GLIPR2 expression across diverse human malignancies. Utilizing UALCAN, OncoDB, MEXPRESS and cBioPortal databases, we scrutinized GLIPR2 mutation patterns and methylation landscapes. The integration of bulk and single-cell RNA sequencing facilitated elucidation of relationships among cellular heterogeneity, immune infiltration, and GLIPR2 levels in pan-cancer. Employing ROC and KM analyses, we unveiled the diagnostic and prognostic potential of GLIPR2 across diverse cancers. Immunohistochemistry provided insights into GLIPR2 expression patterns in a multicenter cohort spanning various cancer types. In vitro functional experiments, including transwell assays, wound healing analyses, and drug sensitivity testing, were employed to delineate the tumor suppressive role of GLIPR2. Results: GLIPR2 expression was significantly reduced in neoplastic tissues compared to its prevalence in healthy tissues. Copy number variations (CNV) and alterations in methylation patterns exhibited discernible correlations with GLIPR2 expression within tumor tissues. Moreover, GLIPR2 demonstrated diagnostic and prognostic implications, showing pronounced associations with the expression profiles of numerous immune checkpoint genes and the relative abundance of immune cells in the neoplastic microenvironment. This multifaceted influence was evident across various cancer types, with lung adenocarcinoma (LUAD) being particularly prominent. Notably, patients with LUAD exhibited a significant decrease in GLIPR2 expression within practical clinical settings. Elevated GLIPR2 expression correlated with improved prognostic outcomes specifically in LUAD. Following radiotherapy, LUAD cases displayed an increased presence of GLIPR2+ infiltrating cellular constituents, indicating a notable correlation with heightened sensitivity to radiation-induced therapeutic modalities. A battery of experiments validated the functional role of GLIPR2 in suppressing the malignant phenotype and enhancing treatment sensitivity. Conclusion: In pan-cancer, particularly in LUAD, GLIPR2 emerges as a promising novel biomarker and tumor suppressor. Its involvement in immune cell infiltration suggests potential as an immunotherapeutic target.

Isotopic insights and integrated analysis for heavy metal levels, ecological risks, and source apportionment in river sediments of the Qinghai-Tibet Plateau.

The research was carried out to examine the pollution characteristics, ecological risk, and origins of seven heavy metals (Hg, As, Pb, Cu, Cd, Zn, and Ni) in 51 sediment samples gathered from 8 rivers located on the Qinghai-Tibet Plateau (QTP) in China. The contents of Hg and Cd were 5.0 and 1.1 times higher than their background values, respectively. The mean levels of other measured heavy metals were below those found naturally in the local soil. The enrichment factor showed that the study area exhibited significantly enriched Hg with 70.6% sampling sites. The Cd contents at 19.6% of sampling sites were moderately enriched. The other sampling sites were at a less enriched level. The sediments of all the rivers had a medium level of potential ecological risk. Hg was the major ecological risk factor in all sampling sites, followed by Cd. The findings from the positive matrix factorization (PMF) analysis shown agricultural activities, industrial activities, traffic emissions, and parent material were the major sources. The upper, middle, and low reaches of the Quanji river had different Hg isotope compositions, while sediments near the middle reaches were similar to the δ202Hg of the industrial source. At the upstream sampling sites, the Hg isotope content was very close to the background level. The results of this research can establish a strong scientific sound to improve the safety of the natural circumstances of rivers on the QTP.

Computational design and engineering of self-assembling multivalent microproteins with therapeutic potential against SARS-CoV-2.

Multivalent drugs targeting homo-oligomeric viral surface proteins, such as the SARS-CoV-2 trimeric spike (S) protein, have the potential to elicit more potent and broad-spectrum therapeutic responses than monovalent drugs by synergistically engaging multiple binding sites on viral targets. However, rational design and engineering of nanoscale multivalent protein drugs are still lacking. Here, we developed a computational approach to engineer self-assembling trivalent microproteins that simultaneously bind to the three receptor binding domains (RBDs) of the S protein. This approach involves four steps: structure-guided linker design, molecular simulation evaluation of self-assembly, experimental validation of self-assembly state, and functional testing. Using this approach, we first designed trivalent constructs of the microprotein miniACE2 (MP) with different trimerization scaffolds and linkers, and found that one of the constructs (MP-5ff) showed high trimerization efficiency, good conformational homogeneity, and strong antiviral neutralizing activity. With its trimerization unit (5ff), we then engineered a trivalent nanobody (Tr67) that exhibited potent and broad neutralizing activity against the dominant Omicron variants, including XBB.1 and XBB.1.5. Cryo-EM complex structure confirmed that Tr67 stably binds to all three RBDs of the Omicron S protein in a synergistic form, locking them in the "3-RBD-up" conformation that could block human receptor (ACE2) binding and potentially facilitate immune clearance. Therefore, our approach provides an effective strategy for engineering potent protein drugs against SARS-CoV-2 and other deadly coronaviruses.

Structural and temporal dynamics analysis of neural circuit from 2002 to 2022: A bibliometric analysis.

Background: In the pursuit of causal insights into neural circuit functionality, various interventions, including electrical, genetic, and pharmacological approaches, have been applied over recent decades. This study employs a comprehensive bibliometric perspective to explore the field of neural circuits. Methods: Reviews and articles on neural circuits were obtained from the Web of Science Core Collection (WOSCC) database on Apr. 12, 2023. In this article, co-authorship analysis, co-occurrence analysis, citation analysis, bibliographic analysis, and co-citation analysis were used to clarify the authors, journals, institutions, countries, topics, and internal associations between them. Results: More than 2000 organizations from 52 different countries published 3975 articles in the field of "neural circuit" were used to analysis. Luo liqun emerged as the most prolific author, and Deisseroth Karl garners the highest co-citations (3643). The Journal of Neuroscience leaded in publications, while Nature toped in citations. Chinese Academy of Science recorded the highest article count institutionally, with Stanford University ranking first with 14,350 citations. Since 2020, neurodynamic, anxiety-related mechanisms, and GABAergic neurons have gained prominence, shaping the trajectory of neural circuitry research. Conclusions: Our investigation has discerned a paradigmatic reorientation towards neurodynamic processes, anxiety-related mechanisms, and GABAergic neurons within the domain of neural circuit research. This identification intimates a prospective trajectory for the field. In the future, it is imperative for research endeavors to accord priority to the translational application of these discernments, with the aim of materializing tangible clinical solutions.