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FIGURE 4 from FPFT-2216, a Novel Anti-lymphoma Compound, Induces Simultaneous Degradation of IKZF1/3 and CK1α to Activate p53 and Inhibit NFκB Signaling
No full textSuppression of CBM complex activity/NFκB pathway via CK1α degradation by FPFT-2216. Western blot analysis of DLBCL cell lines (A) and RI-1 cells expressing CK1α G40N mutant (B) cultured for 24 hours in the presence of compounds at different concentrations. Open triangle: Uncleaved BCL10, closed triangle: Cleaved BCL10. C, MG-132 was added after OCI-Ly3 cells were cultured for 23 hours in the presence of compounds at the concentrations shown in the figure. After 1 hour, proteins were extracted from the cells, and Western blot analysis was performed. D, Jurkat cells were cultured for approximately 24 hours in the presence of compounds at the concentrations shown in the figure, and the cells were cultured for 15 minutes after adding PMA/ionomycin. Proteins were extracted from the cells, and Western blot analysis was performed. Representative results from two (B–D) or three (A) independent experiments are shown. GAPDH or α-tubulin was used as a loading control. 2216, FPFT-2216; Lena, lenalidomide; Iber, iberdomide; MALT1i, Z-VRPR-FMK; BAY, BAY 11-7082; Poma, pomalidomide.</p
FIGURE 5 from FPFT-2216, a Novel Anti-lymphoma Compound, Induces Simultaneous Degradation of IKZF1/3 and CK1α to Activate p53 and Inhibit NFκB Signaling
No full textAntitumor activity of FPFT-2216 in CDX and PDX models. FPFT-2216 (10 mg/kg) and siremadlin (100 mg/kg) were administered alone or in combination to mice subcutaneously transplanted with Z-138 cells for three weeks. Tumor volume (A) during the subsequent 3-week washout period and body weight (B) during the treatment period are shown (mean ± SEM, n = 7). **, P P C, Tumor volume when FPFT-2216 (1 mg/kg) and rituximab (30 µg/mouse) were administered alone or in combination to mice subcutaneously transplanted with Z-138 cells (mean ± SEM, n = 10). **, P D, Tumor volume when FPFT-2216 (0.1 mg/kg) and rituximab (30 µg/mouse) were administered alone or in combination to mice subcutaneously transplanted with DOHH-2 cells (mean ± SEM, n = 5–6). ***, P #P E, Cell viability (%) in non-GCB DLBCL patient-derived tumor cells treated with various concentrations of FPFT-2216 for 3 days. Results are presented as mean values (duplicate). F, Tumor volume after administering FPFT-2216 (0.1, 1 mg/kg) or cyclophosphamide (75 mg/kg) to mice subcutaneously transplanted with LYXFDLBC 2835 tumor cells derived from a patient with non-GCB DLBCL (mean ± SEM, n = 6). **, P < 0.01 versus vehicle-treated group (Dunnett test). Each figure (A, C, D, F) shows the time-dependent change in tumor volume of each group until the first individual animal was euthanized. 2216, FPFT-2216; Sire, siremadlin; RTX, rituximab; CPA, cyclophosphamide.</p
Figure S4 from FPFT-2216, a Novel Anti-lymphoma Compound, Induces Simultaneous Degradation of IKZF1/3 and CK1α to Activate p53 and Inhibit NFκB Signaling
No full textFigure S4 shows the genetic characterization of PDX models used in this study.</p
Table S1 from FPFT-2216, a Novel Anti-lymphoma Compound, Induces Simultaneous Degradation of IKZF1/3 and CK1α to Activate p53 and Inhibit NFκB Signaling
No full textTable S1 is the list of cell lines used in this study.</p
Image_2_Comparison of the single-cell and single-nucleus hepatic myeloid landscape within decompensated cirrhosis patients.jpg
No full textBackground and aimsA complete understanding of disease pathophysiology in advanced liver disease is hampered by the challenges posed by clinical specimen collection. Notably, in these patients, a transjugular liver biopsy (TJB) is the only safe way to obtain liver tissue. However, it remains unclear whether successful sequencing of this extremely small and fragile tissue can be achieved for downstream characterization of the hepatic landscape.MethodsHere we leveraged in-house available single-cell RNA-sequencing (scRNA-seq) and single-nucleus (snRNA-seq) technologies and accompanying tissue processing protocols and performed an in-patient comparison on TJB’s from decompensated cirrhosis patients (n = 3).ResultsWe confirmed a high concordance between nuclear and whole cell transcriptomes and captured 31,410 single nuclei and 6,152 single cells, respectively. The two platforms revealed similar diversity since all 8 major cell types could be identified, albeit with different cellular proportions thereof. Most importantly, hepatocytes were most abundant in snRNA-seq, while lymphocyte frequencies were elevated in scRNA-seq. We next focused our attention on hepatic myeloid cells due to their key role in injury and repair during chronic liver disease. Comparison of their transcriptional signatures indicated that these were largely overlapping between the two platforms. However, the scRNA-seq platform failed to recover sufficient Kupffer cell numbers, and other monocytes/macrophages featured elevated expression of stress-related parameters.ConclusionOur results indicate that single-nucleus transcriptome sequencing provides an effective means to overcome complications associated with clinical specimen collection and could sufficiently profile all major hepatic cell types including all myeloid cell subsets.</p
Water quality assessment: a case study in the Tuticorin district of Tamil Nadu in South India
No full textA hydro-geochemical study for water-quality assessment was conducted in the Tuticorin region of Tamil Nadu in southern India during the pre- and post-monsoon seasons of 2022 and the water samples are examined to comply with BIS and WHO guidelines. In the present study, the values of TDS (75%), Mg (37.5%), and TH (25%) have exceeded the permissible limits namely 500, 100, and 600 mg/L, respectively. The WQI proposed by CCME is used to analyze water suitability. The Pearson correlation and principal component analysis are used to study the relationship between various physicochemical parameters and principal components of water quality, respectively. Piper & Gibbs diagrams are plotted to identify the water types and the main water type predicted by the piper plot is Ca-Mg-Cl-SO4 which makes up 74.3% of the the samples studied. WQI suggests that 22.5% and 50.0% specimens have excellent water quality during pre and post-monsoon seasons, respectively.</p
Exploring patterns of polysubstance use among young adults: a latent profile analysis
No full textBackground: Polysubstance use is common among individuals who use psychoactive substances and is associated with higher substance use-related risks than non-polysubstance use. Epidemiological studies show the highest prevalence rates of substance use disorders (SUDs) among young adults. However, determining who will develop SUDs is complicated by an interplay between interactions of biological, psychological, and social factors, and not just the substance use itself. This study sought to explore potential patterns of polysubstance use as an interplay between substance use, substance use setting, and a number of potentially distal outcomes.Method: Latent Profile Analysis of a large, cross-sectional survey of Polish young adults using various substances in the last 12 months (N = 7325; 18–30 years old; M = 22.3, SD = 3.63; 69.1% male), was conducted.Results: Five distinct profiles were identified, that ranged from low, through moderate to high polysubstance use patterns with different prominent substances of use. Cannabis use was high across all profiles and did not differentiate between them well. Use of dissociatives and frequent polysubstance use across settings (except for using alone) were most strongly associated with negative substance-related outcomes (e.g. SUDs).Conclusions: Polysubstance use across different settings may not necessarily carry greater substance-related risks than being alone while using specific substances.</p
Supplementary Data required by article entiled "A c-di-GMP signing module controls responses to iron in Pseudomonas aeruginosa"
No full textSupplementary Data required by article entiled "A c-di-GMP signing module controls responses to iron in Pseudomonas aeruginosa"1) "AF-Q9I243-F1-model_v4.pdb" and "AF-Q9I2P4-F1-model_v4.pdb" are the starting point for IsmP-ImcA complex mdoelling;2) IsmP-ImcA_Hetero-Tetramer_candidate_model.pdb: IsmP-ImcA complex candidate model;3) IsmP_predicted_FE_binding_pocket: predicted Fe binding pocket for IsmP.4）test_86405_relaxed_rank_001_alphafold2_multimer_v3_model_1_seed_000.pdb: predicted apo dimeric model by ColabFOLD </p
Hu and Zhang, China's National Fitness Plan, data
No full textHu and Zhang, China's National Fitness Plan, data</p
Identification of potential regulatory mechanisms and therapeutic targets for lung cancer
No full textLung cancer poses a significant health threat globally, especially in regions like India, with 5-year survival rates remain alarmingly low. Our study aimed to uncover key markers for effective treatment and early detection. We identified specific genes related to lung cancer using the BioXpress database and delved into their roles through DAVID enrichment analysis. By employing network theory, we explored the intricate interactions within lung cancer networks, identifying ASPM and MKI67 as crucial regulator genes. Predictions of microRNA and transcription factor interactions provided additional insights. Examining gene expression patterns using GEPIA and KM Plotter revealed the clinical relevance of these key genes. In our pursuit of targeted therapies, Drug Bank pointed to methotrexate as a potential drug for the identified key regulator genes. Confirming this, molecular docking studies through Swiss Dock showed promising binding interactions. To ensure stability, we conducted molecular dynamics simulations using the AMBER 16 suite. In summary, our study pinpoints ASPM and MKI67 as vital regulators in lung cancer networks. The identification of hub genes and functional pathways enhances our understanding of molecular processes, offering potential therapeutic targets. Importantly, methotrexate emerged as a promising drug candidate, supported by robust docking and simulation studies. These findings lay a solid foundation for further experimental validations and hold promise for advancing personalized therapeutic strategies in lung cancer. Communicated by Ramaswamy H. Sarma</p