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0.489742 | 44d01dfdecd642598ddacd67e6a4322d | Droplet fluorescence in ddPCR temperature gradient using digested and non-digested DNA. Digestion using HaeIII and different temperatures of annealing/extension step were tested in the temperature gradient analysis. The fluorescence of each droplet is shown as a dot on the graph, with colored droplets being positive (green for reference; blue for target) and grey being negative. Annealing/extension temperatures are shown below each sample (x-axis), separated by a red line. The undigested DNA showed a less focused signal for both reference (A) and target (B) probes. The HaeIII-digested DNA had a better signal-to-noise ratio in both reference (C) and target (D) channels | PMC10155399 | 13007_2023_1019_Fig1_HTML.jpg |
0.40379 | 3c688a9427ee43e1b1e46fc60bf9c4dc | Verification of the number of B chromosomes in the material used for ddPCR optimization. The set of plants of reference line B73 with the respective B chromosome numbers from 1 to 10B (a–j). B chromosomes are marked with B-specific repeat ZmBs (red; indicated by arrowheads). Chromosomes are counterstained with DAPI (blue) | PMC10155399 | 13007_2023_1019_Fig2_HTML.jpg |
0.433902 | ea851eac9aba462ab598db323555a871 | Copy-number results of B chromosome scoring in reference set using ddPCR technique. The value of the estimated number of B chromosomes (copy number; Y-axis) as calculated from ddPCR analysis in each plant (ID in x-axis) over the entire range of values examined. Each estimate is based on a CNV measurement from a single ddPCR well of > 10,000 droplets. Error bars indicate the Poisson 95% confidence intervals for each copy number measurement | PMC10155399 | 13007_2023_1019_Fig3_HTML.jpg |
0.37875 | 8a6b1a39249a4f22a34ace81502256e5 | Determination of B chromosome number based on FISH using B-specific repeat ZmBs in the set of wild landraces. a ARGE_542 (1B), b BOLI_969 (5B), c ECUA_693 (2B), d GUAT_344 (1B), e HOND_52 (1B), f RDOM_261 (1B), g SALV_70 (2B), h YUCA_148 (3B). Chromosomes are counterstained with DAPI (blue). White arrowheads indicate B chromosomes with a B-specific probe (red) | PMC10155399 | 13007_2023_1019_Fig4_HTML.jpg |
0.478025 | ecdbd82462fb47bba36caeae57a936e1 | Scoring the B chromosome copy number using ddPCR technique in wild maize landraces. Each estimate of the number of B chromosomes (Y-axis) is based on a CNV measurement from a single ddPCR well of > 10,000 droplets. Error bars indicate the Poisson 95% confidence intervals for each copy number measurement | PMC10155399 | 13007_2023_1019_Fig5_HTML.jpg |
0.433536 | 5e7bd18e3b3b4a21bf56a5c1cff81072 | Humoral and cellular responses after two and three doses of mRNA vaccine(A) Individual anti-spike antibody concentrations before vaccination (n=211) and after two (n=299) and three doses (n=210; grey lines). Median time since vaccination was shorter for the subset with cell sampling (n=90; red lines); time between sampling and vaccination for each subset varied slightly between second (B) and third (C) vaccinations. CD4 (D) and CD8 (E) T cell responses to SARS-CoV-2 spike peptides before vaccination (n=69) and after two (n=90) and three vaccine doses (n=71), and to cytomegalovirus pp65 peptides (n=69). Unstimulated background was subtracted from all conditions. (F) Correlation of post-vaccination receptor binding domain levels and spike-specific CD4 T cell responses after third dose (n=71) by non-linear regression analysis. Points indicate individual responses for all plots. Box-and-whisker plots (D–E) show the median, IQR, and range; all statistics calculated by paired Wilcoxon tests. | PMC10156136 | gr1_lrg.jpg |
0.476608 | 2169fc2f497c418cb9c5b9d6c338c0af | Vaccine induced CD4 and CD8 T cells also respond to delta and omicron SARS-CoV-2 variantsT cell responses to SARS-CoV-2 spike-specific peptides (n=71) after three vaccine doses. CD4 (A–C) and CD8 (D–F) T cell responses to mutated regions from SARS-CoV-2 variants of concern were upregulated compared with unstimulated cells. CD4 and CD8 T cell responses to the mutated regions correlated with their reference sequences for delta (B and E) and omicron (C and F), respectively. r and p values are shown on each plot. Box-and-whisker plots indicate the median, IQR, and 5th and 95th percentiles. NS=not significant. | PMC10156136 | gr2_lrg.jpg |
0.464089 | e01e25223ae84e44ab372483c9ce4317 | Differences between consecutive RR intervals | PMC10156566 | AIT-55-50477-g001.jpg |
0.441176 | 651e3945003446e399b803fefba4d20f | The influence of the sympathetic and parasympathetic parts of the autonomic nervous system on heart rate | PMC10156566 | AIT-55-50477-g002.jpg |
0.46727 | d89f1b66e7774347ba8fc685f2492181 | Genetic optimizers can ensure maximal cellular performance.Simulation parameters and further details are provided in Supplementary Section 5. a Population-level production of a target gene is maximized when growth rate and cellular synthesis rate are balanced93. The corresponding optimal concentration of a regulator may depend on both cellular and environmental conditions, and can be automatically adjusted by a genetic optimizer. b Gradient-based optimization can successfully track the time-varying optimum, but cannot be immediately translated to a genetic circuit because it may result in infeasible negative quantities. Decreasing ϵx yields faster convergence at the expense of greater control inputs u1 and u2. c Calculating u1 and u2 based on the trend of x and y ensures convergence to the optimum x*. In the four panels at right, ϵy increases by an order of magnitude going from left to right (leading to slower y dynamics), and the delay td increases by an order of magnitude going from top to bottom. | PMC10156725 | 41467_2023_37903_Fig1_HTML.jpg |
0.524068 | 45bb7a19e4554b1e95500b375ee561ec | The delay module ensures tracking of the regulator and the reporter signals.Light, medium, and dark red correspond to ϵd = ϵy/2, ϵd = ϵy, and ϵd = 2ϵy, respectively. The panel in the top left corner corresponds to ϵy = ϵx/100, and ϵy increases towards the lower right panel where ϵy = ϵx/10 (sample points are spaced equidistantly on a logarithmic scale). Simulation parameters and further details are provided in Supplementary Section 5. | PMC10156725 | 41467_2023_37903_Fig2_HTML.jpg |
0.447534 | ec75a4f6d7104710845bc0821779fb16 | The comparator module generates the indicator signals based on the actual and delayed signals for both the regulator and the reporter.Simulation parameters and further details are provided in Supplementary Section 5. a The signal c alternates between two states (c = 0 and c = 1) with period τ, activating two different sets of regulatory interactions94. b During phase 1, (x+, x−) tracks the reference (x, xd), whereas during phase 2, (x+, x−) converges to either of the stable fixed points based on the sign of x − xd. c The signals x+ and x− switch between their ON and OFF states depending on whether x < xd or x > xd (phase 1 is depicted in gray). d Closed loop performance is largely unaffected by the value of αc,2. | PMC10156725 | 41467_2023_37903_Fig3_HTML.jpg |
0.455099 | a45ac1e4df1147d98470fab2413744f7 | The logic module combines the indicator signals to generate the control signals.The dynamic range of the signals in the input, middle (between the AND and OR gates), and output layer of the logic module is denoted by ρ∧, ρ∨, and ρu, respectively. While selecting the dissociation constants K∧ and K∨ in the geometric mean of the respective dynamic ranges may be an intuitive choice (yielding the dark gray lines), the performance of the optimizer displays significant robustness to deviations from this particular baseline choice when tracking the optimum value x* (blue). Colored circles correspond to different choices of αc,2 (affecting the input dynamic range ρ∧), together with substantial perturbations in the dissociation constants compared to the above specified baseline choice. Simulation parameters and further details are provided in Supplementary Section 5. | PMC10156725 | 41467_2023_37903_Fig4_HTML.jpg |
0.463621 | cdb3c8fa7a4e4279a6ec9ca8ece9181b | Closed loop performance and accuracy with the simplified dynamics.Simulation parameters and further details are provided in Supplementary Section 5. a In the absence of additive noise (dark red and dark green), trajectories are confined within the gray region around the time-varying optimum x* (blue) when ϵy = 0 (Supplementary Section 1.5). In the presence of stochastic noise (light red and light green), closed loop trajectories may temporarily leave this region. The value of ϵd is 10-times greater for (light and dark) green than for (light and dark) red. b Performance decreases as the tracking error in the delay module increases. c Shaded regions correspond to initial conditions such that trajectories converge to an incorrect stable fixed point. | PMC10156725 | 41467_2023_37903_Fig5_HTML.jpg |
0.534634 | 676ddc7c82364e6e8452d2754fd4ebef | Genetic layout of the optimizer module.The realization relies on genetic parts and modules that are already available, in particular: (i) protein-based transcriptional control50; (ii) inducible degradation via the M. florum Lon protease and ssrA tag47,48; (iii) a repressilator-based oscillator43,44; (iv) CRISPRi-based toggle switches51; and (v) STAR-based logic gates53,54. The mass action kinetics-based mathematical model underpinning the dynamics of the integrated system is included in Supplementary Section 2.1, together with detailed discussion of the typical range of model parameters in Supplementary Section 2.2, and their selected values in Supplementary Table 1. Here, we assume that the host genome is already equipped with a dCas9 expression cassette95, otherwise the optimizer must also include it. | PMC10156725 | 41467_2023_37903_Fig6_HTML.jpg |
0.458323 | 18439ec271e34553aea2614bf4bf8e04 | The genetic optimizer can be successfully deployed in diverse contexts.Detailed mathematical models and additional data are provided in Supplementary Section 3, together with simulation parameters in Supplementary Section 5. In a, c, mean and error bars denote the average of x and its standard deviation, averaged over 100 independent simulations with randomly selected initial conditions. In b, d, thin red curves correspond to 30 independent closed loop trajectories with random initial points. a The optimizer locates the static optimum. b The optimizer tracks the time-varying optimum (blue) as parameters fluctuate (indicated by the arrowheads). c The expression of \documentclass[12pt]{minimal}
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\begin{document}$$\tilde{y}$$\end{document}y~ can be maximized by minimizing y. d The optimizer tracks the time-varying optimum (blue) even when y is regulated by multiple species. The thick red curves denote the average of 30 independent simulations. e Genetic layout of the multi-dimensional optimizer re-using and modifying the modules originally featured in Fig. 6. | PMC10156725 | 41467_2023_37903_Fig7_HTML.jpg |
0.428162 | 7a89bf236eb54d2ba42fbe9d15724cdd | The genetic optimizer can be deployed to maximize cellular growth rate.Detailed mathematical model and additional data are provided in Supplementary Section 3, together with simulation parameters in Supplementary Section 5. Blue curves indicate performance when SpoTH is exogenously optimized by adjusting the inducer concentration. Green and purple curves denote trajectories with zero and maximal induction of SpoTH. Closed loop performance is evaluated in the presence of stochastic noise impacting the kinetics of all species. Cellular stress is modulated via βp63. a Growth rate is negatively impacted by rising levels of the alarmone (p)ppGpp (p) as it downregulates the production of ribosomes (z). Cellular stress results in elevated RelA (r) expression, which upregulates the synthesis of (p)ppGpp via the increased production rate constant βp. Conversely, (p)ppGpp concentration can be decreased via SpoTH (s) by activating its expression either exogenously63 or by placing its promoter under the control of the regulator x. The dashed red flat headed arrows from SpoTH represent the load that SpoTH expression places on ribosomes as its mRNA is translated. b Expression of SpoTH results in sequestration of shared cellular resources, thus the metabolic burden due to SpoTH overexpression can counteract the positive impact of (p)ppGpp removal on growth rate, resulting in a non-monotonic relationship. c Closed loop performance is evaluated based on 100 independent simulations with random initial conditions during the second half of each simulation by considering the average of y and its standard deviation. Red curve and red shaded region denote the mean of these averages and standard deviations, respectively. d The optimizer successfully tracks the time-varying optimum in response to both abrupt and gradual changes in βp representing cellular stress. Red curves and shaded regions correspond to the mean and standard deviation of trajectories considering 100 independent simulations with random initial conditions. For individual trajectories, see Supplementary Fig. 17. | PMC10156725 | 41467_2023_37903_Fig8_HTML.jpg |
0.435021 | f89d50cbf43842789e1188ad3a50fcfb | Flow chart of the literature search and study selection for relevant studies in the meta-analysis. | PMC10157095 | fmed-10-1137366-g001.jpg |
0.444931 | 8fec5225b5bd47c88d344b89e9686632 | Forest plot of the Parkinson’s disease risk in patients with inflammatory bowel disease, Crohn’s disease, and ulcerative colitis. | PMC10157095 | fmed-10-1137366-g002.jpg |
0.46419 | bc80224a1ec4422db8756df2eb31cbf4 | Sensitivity analysis for the association between inflammatory bowel disease and the risk of Parkinson’s disease. The two ends of the lines represent the 95% CI. | PMC10157095 | fmed-10-1137366-g003.jpg |
0.477183 | 5518b009faf646039c80bbb057440219 | Begg’s funnel plot of all 14 studies the associations between inflammatory bowel disease and the risk of Parkinson’s disease. Each point represents separate study for the indicated association. | PMC10157095 | fmed-10-1137366-g004.jpg |
0.419675 | 62ed12737b50480697c427d6f34bf439 | Induction of an inflammatory response in HT29 cells via the CaSR is ligand dependent. Relative gene expression of IL-8 in (A) HT29CaSR−GFP and (B) HT29GFP cells after 4 h treatment with CaSR ligands (left panel: H2O as vehicle control, 5 mM spermine, 300 µM neomycin, 1 mM L-Phe, 1 mM L-Trp, and 5 mM Ca2+) or CaSR modulators (right panel: 0.1% DMSO as vehicle control, 10 µM GSK3004774, and 1 µM NPS R-568). Mean ± SD, N = 3–5, one-way ANOVA with Dunnett’s post hoc test vs. vehicle control (H2O or 0.1% DMSO), *p < 0.05, ***p < 0.001. | PMC10157649 | fphar-14-1151144-g001.jpg |
0.460215 | 9e4a927ec57641e9a18f43d926f4fc27 | Induction of PGE2 pathway genes by CaSR ligands in HT29CaSR−GFP cells. Relative gene expression of (A) COX-1, (B) COX-2, (C) PGES-1, (D) PGES-2, (E) cPGES, (F) 15-PGDH, (G) EP1, and (H) EP4 in HT29CaSR−GFP cells after 4 h treatment with CaSR ligands (left panel: H2O as vehicle control, 5 mM spermine, 300 µM neomycin, 1 mM L-Phe, 1 mM L-Trp, and 5 mM Ca2+) or CaSR modulators (right panel: 0.1% DMSO as vehicle control, 10 µM GSK3004774, and 1 µM NPS R-568). Mean ± SD, N = 3–5, one-way ANOVA with Dunnett’s post hoc test vs. vehicle control (H2O or 0.1% DMSO), **p < 0.01, ***p < 0.001. | PMC10157649 | fphar-14-1151144-g002.jpg |
0.404417 | b9685dc0c82046faa15bf981c5e2a0c3 | Gene induction by spermine can be suppressed by calcilytics. Relative gene expression of (A) IL-8, (B) CaSR, (C) COX-2, and (D) PGES-1 in HT29CaSR−GFP cells after treatment with 5 mM spermine alone or together with the calcilytic 1 µM NPS 2143 (CL) for 4 h (0.1% DMSO as vehicle control). Mean ± SD, N = 3–5, one-way ANOVA with Tukey’s post hoc test (0.1% DMSO), *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001. | PMC10157649 | fphar-14-1151144-g003.jpg |
0.419917 | c6ab7588b7fe4476a0863c56059dcf1e | Induction and suppression of PGE2 secretion by CaSR activation and inhibition. PGE2 secretion in supernatant of (A) HT29CaSR−GFP and (B) HT29GFP after 4 h treatment with either vehicle control (0.1% DMSO), 1 µM NPS R-568 alone, or together with 1 µM of the calcilytic NPS 2143 (CL). Mean ± SD, N = 6–11, one-way ANOVA with Tukey’s post hoc test (0.1% DMSO), *p < 0.05, **p < 0.01. | PMC10157649 | fphar-14-1151144-g004.jpg |
0.449044 | 18a6b6582ed548feabc0cb5c465e7339 | Induction of IL-8 gene expression via IL-1β is enhanced when the CaSR is present. Dose-response curve of relative gene expression of IL-8 in (A) HT29CaSR−GFP cells and (B) HT29GFP cells after 4 h treatment with IL-1β (0.1 ng/μL–25 ng/μL). Mean ± SD, N = 3–4. Sigmoidal 4-parameter fit, 0-concentration set to 10−20 ng/μL for logarithmic curve fitting. Calculated EC50 equals 2.49 ± 1.27 ng/μL. | PMC10157649 | fphar-14-1151144-g005.jpg |
0.419913 | 04e82c9d88044d088b48f7be5a19a63d | Gene induction and suppression by CaSR ligands in Caco-2CaSR−GFP cells. Relative gene expression of (A) IL-8, (B) CaSR, (C) COX-2, and (D) PGES-1 in Caco-2CaSR−GFP cells after 4 h treatment with either vehicle control (0.1% DMSO), 1 µM NPS R-568, CaSR ligands (5 mM Ca2+, and 5 mM spermine), or 5 mM spermine in combination with 1 µM NPS 2143 (CL). Mean ± SD, N = 3–5, one-way ANOVA with Tukey’s post hoc test (0.1% DMSO), **p < 0.01, ***p < 0.001, ****p < 0.0001. | PMC10157649 | fphar-14-1151144-g006.jpg |
0.395125 | 934a1feaf78346b7aaa28a756682c0a8 | Altered PGE2 pathway genes in CaSR-ligand treated mice with colitis. Relative gene expression of (A) mPGES-2, (B) EP3, and (C) 15-PGDH in the colons of mice with DSS-induced colitis treated with CaSR allosteric modulators (each 10 mg/kg). Mean ± SD, N = 7–10. Proximal and distal colon were analyzed separately by one-way ANOVA with Dunnett’s post hoc test vs. vehicle control (20% cyclodextrin), *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001. | PMC10157649 | fphar-14-1151144-g007.jpg |
0.457094 | f83bb2f2790242b793dcccf250869473 | Cladogram of ZEPs from various organisms. The neighbor-joining method was used to reconstruct the cladograms under the software MEGA6, with the bootstrap value (obtained from 1000 replicates) shown on each node. The GenBank ID is showed right after each protein. At, Arabidopsis thaliana; Ca, Capsicum annuum; Cm, Citrus maxima; Cr, Chlamydomonas reinhardtii; Cz, Chromochloris zofingiensi; Dt, Dunaliella tertiolecta; Fc, Fragilariopsis cylindrus; Hl, Haematococcus lacustris; Li, Lobosphaera incisa; Ma, Metarhizium anisopliae; Me, Madagascaria erythrocladioides; Mn, Monoraphidium neglectum; Mt, Mastigocoleus testarum BC008; Ng, Nannochloropsis gaditana; Nm, Nostoc minutum; Pt, Phaeodactylum tricornutum; Rs, Raphidocelis subcapitat; Sh, Scytonema hofmannii; Ss, Salix suchowensis; St, Solanum tuberosum; Tp, Talaromyces pinophilu; Tps, Thalassiosira pseudonana | PMC10157934 | 13068_2023_2326_Fig1_HTML.jpg |
0.402368 | 6adbfb66cb6b45b5b336235ba00bbb26 | Subcellular localization of NoZEPs in N. oceanica cells. The coding sequence of NoZEP1 or NoZEP2 was fused to upstream of eGFP and introduced into N. oceanica cells for fluorescent microscopy observation. Green indicates the GFP signal, while red indicates the plastid autofluorescence (PAF). Bar, 1 μm | PMC10157934 | 13068_2023_2326_Fig2_HTML.jpg |
0.42685 | ffae04e5832d4cdca36a14e0e57a511d | Pigment profiles and growth parameters as affected by NoZEP1 or NoZEP2 overexpression in N. oceanica. a Relative expression levels of NoZEP1 in WT and NoZEP1-overexpressing lines. The level of NoZEP1 in WT under NL was set as 1. b Relative expression levels of NoZEP2 in WT and NoZEP2-overexpressing lines. The level of NoZEP2 in WT under NL was set as 1. c–e Total carotenoids (TC) content (c), contents of individual carotenoids (d), and chlorophyll a content (e) in WT and NoZEP-overexpressing lines under NL and HL conditions. VE, vaucheriaxanthin ester. f–i Time course of Fv/Fm (f), OD750 (g), cell density (h), and biomass concentration (i) of WT and NoZEP-overexpressing lines. The algal cells were first cultured under NL for 4 days and then transferred to HL for 2 days. The NL and HL samples in (a–e) were from day 4 and day 2, respectively. Data represent mean values ± SD (n = 3). The asterisk indicates the significant difference (Student’s t test, P < 0.05* or P < 0.01**) between WT and overexpression lines | PMC10157934 | 13068_2023_2326_Fig3_HTML.jpg |
0.473012 | f2dd2b15136d430ab44e8c866c9bbfd0 | Pigment profiles and growth parameters as affected by NoZEP1 or NoZEP2 knockdown in N. oceanica under a two-stage culture conditions. a Relative expression levels of NoZEP1 in WT and NoZEP1-knockdown lines. The level of NoZEP1 in WT under NL was set as 1. b Relative expression levels of NoZEP2 in WT and NoZEP2-knockdown lines. The level of NoZEP2 in WT under NL was set as 1. c–e Total carotenoids (TC) content (c), contents of individual carotenoids (d), and chlorophyll a content (e) in WT and NoZEP-knockdown lines under NL and HL conditions. VE, vaucheriaxanthin ester. f–i Time course of Fv/Fm (f), OD750 (g), cell density (h), and biomass concentration (i) of WT and NoZEP-knockdown lines. The algal cells, with a starting OD750 of 0.5, were first cultured under NL for 4 days and then transferred to HL for 2 days. The NL and HL samples in (a–e) were from day 4 and day 2, respectively. Data represent mean values ± SD (n = 3). The asterisk indicates the significant difference (Student’s t test, P < 0.05* or P < 0.01**) between WT and knockdown lines. NS, not significant | PMC10157934 | 13068_2023_2326_Fig4_HTML.jpg |
0.499031 | ab8121f6809c42af8c843752403e872e | Growth parameters and pigment profiles as affected by NoZEP1 or NoZEP2 knockdown in N. oceanica under HL. a–d Time course of Fv/Fm (a), OD750 (b), cell density (c), and biomass concentration (d) of WT and NoZEP-knockdown lines under HL for 4 days. e–g Total carotenoids (TC) content (e), contents of individual carotenoids (f), and chlorophyll a content (g) in WT and NoZEP-knockdown lines after 4 days of HL. VE, vaucheriaxanthin ester. The algal cells, with a starting OD750 of 0.5, were directly cultured under HL for 4 days. Data represent mean values ± SD (n = 3). The asterisk indicates the significant difference (Student’s t test, P < 0.05* or P < 0.01**) between WT and knockdown lines. NS not significant | PMC10157934 | 13068_2023_2326_Fig5_HTML.jpg |
0.410353 | 94b6b13db5634614be0472ee039c7b6e | Profiles of polar lipids and their fatty acid compositions as affected by NoZEP1 or NoZEP2 knockdown in N. oceanica under NL and HL conditions. a Polar membrane lipid (PML) content. b Content of selected chloroplast lipids. c–e Relative fatty acid abundance of MGDG (c), DGDG (d), and SQDG (e). The algal cells were first cultured under NL for 4 days and then transferred to HL for 2 days. The NL and HL samples were from day 4 and day 2, respectively. Data represent mean values ± SD (n = 3). The asterisk indicates the significant difference (Student’s t test, P < 0.05* or P < 0.01**) between WT and knockdown lines | PMC10157934 | 13068_2023_2326_Fig6_HTML.jpg |
0.42118 | 2a625511244147a5b4fffc89a9eb2e93 | Proposed model to show the functional roles of NoZEPs in N. oceanica under NL and HL conditions. Both NoZEP1 and NoZEP2 are functional in N. oceanica and suppressing either one impairs the synthesis of violaxanthin (the major light-harvesting carotenoid), accompanied by the attenuated levels of chlorophyll a and chloroplast membrane lipids. Under NL conditions (below the saturation light intensity), the mutant harvests less light and thus has lower photosynthetic growth than WT. Under HL conditions (above the saturation light intensity), as containing less pigments, the mutant cells are exposed to more light per cell than WT cells and thus likely subjected to more severe light stress (photoinhibition), leading to lowered growth of the mutant | PMC10157934 | 13068_2023_2326_Fig7_HTML.jpg |
0.462014 | 6289003658a14912bbe25ae28e961413 | Head computed tomography image of the patient head CT scan of the patient indicated low-density area beginning to appear in the brainstem and bilateral cerebellum (indicated by white arrows). CT: Computed tomography | PMC10158659 | BC-9-52-g001.jpg |
0.499216 | 7584290146034a25aafb74c371d3260a | PRISMA chart of the study design and included manuscripts. | PMC10159065 | rbccv-38-03-0398-g01.jpg |
0.413807 | ab69d479cc3349b8884b7e7fbbdfe3ce |
MRI T2-weighted STIR images in the axial (
A
) and sagittal (
B
) planes showing longitudinal subfascial accumulation of fluid (blue arrowheads) surrounding the anterior compartment muscles of the arm and forearm, consistent with migrated Aquafilling gel.
| PMC10159694 | 10-1055-s-0042-1756134-i21101485-1.jpg |
0.455555 | e80b818d70f2489d97f39455d8c82ddb |
Gel draining through the incision in the left forearm.
| PMC10159694 | 10-1055-s-0042-1756134-i21101485-2.jpg |
0.42647 | 011d6c8a09e54c45899106ede9b54114 |
The gel creating a canal along the left forearm and arm. We checked it by endoscopy and rinsed off the remaining gel.
| PMC10159694 | 10-1055-s-0042-1756134-i21101485-3.jpg |
0.469417 | a3183302d5da4d86a1e10c877f363184 |
The left breast after removal of the gel as well as necrotic and inflamed tissues. In the upper outer quadrant of the left breast, there is an opening for the canal through the axilla and along the arm almost to the carpal tunnel.
| PMC10159694 | 10-1055-s-0042-1756134-i21101485-4.jpg |
0.447839 | 530a7ffc40f947458592e74b13557bb3 |
Significant amount of the gel draining through the incision in the right inframammary fold.
| PMC10159694 | 10-1055-s-0042-1756134-i21101485-5.jpg |
0.408788 | e021ad026fe04b1f97ade83a6a9f9178 | Pathological changes in placenta of SARS-CoV-2 positive pregnant women in Mizoram. A. Chorionic villi with area of calcification ( × 100); B. Term placenta with chorangiosis ( × 400); C. Villous stromal hemorrhage ( × 100); D. Groups of villi with ischemic necrosis ( × 100); E. Groups of villi surrounding an avascular villi ( × 400); F. Increased syncytial knots ( × 100). | PMC10160527 | gr1_lrg.jpg |
0.405467 | da8de52fc25f4cad901a3f5b3fe27228 | Brain MRI and electroencephalogram of our patient. A. The mid-sagittal view of brain MRI demonstrated cerebellar atrophy. B. Electroencephalography (EEG) showed normal awake EEG background. Interictal EEG demonstrated generalized 2–2.5 Hz polyspike-and-wave complexes with maximum negativity at bifrontal electrodes. | PMC10160684 | gr1.jpg |
0.508884 | 4261d71695a54f6598cde7bb07ebfca9 | Map of the study counties (Inset: The map of Africa with Kenya highlighted in green). Note: Shapefiles sourced from the database of country administrative areas (GADM). | PMC10161611 | gr1.jpg |
0.472027 | 693d9c9c03d642b5860e99fd370de988 | [a -f] Crop yield responses for different agroecological zones. Maize response by fertilizer types (A) and Nitrogen rate levels (kgN ha−1; B) for different AEZs. Bean response by fertilizer types (C) and Nitrogen rate levels (kgN ha−1; D) for different AEZs. Potato response by Nitrogen rate levels (kgN ha−1, F) and fertilizer types (E) for the high-potential AEZ. | PMC10161611 | gr2.jpg |
0.400111 | 31387b325d74408e90b80c620b15e42c | [A – G] BCR distribution for maize [0–30 kg N ha−1 (A), 30–60 kg N ha−1(B) and >60 knN ha−1 (C)], beans [0–30 kg N ha−1 (D), 30–60 kg N ha−1(E) and >60 kgN ha−1 (F)] and Irish potato (G) for different fertilizer types. Fertilizer types are truncated in upper case due to space considerations as follows; CONT-Control, CONV=Conventional, MULT = Multi-nutrient. | PMC10161611 | gr3.jpg |
0.486175 | 952abc79e1b04ad2ab092a84d2c3fe26 | [A – G] BCR distribution for maize [0–30 kg N ha−1 (A), 30–60 kg N ha−1 (B) and >60 kgN ha−1 (C)], beans [0–30 kg N ha−1 (D), 30–60 kg N ha−1(E) and >60 kgN ha−1 (F)] and potato (G) in different agroecological zones. | PMC10161611 | gr4.jpg |
0.386984 | 4950ca5abee34fa088f13599c5e983b5 | [A – F] Regression for fertilizer nitrogen rate and BCR for conventional and multi-nutrient fertilizers [maize, Figure A; beans, Figure B; Potato, Figure C] and AEZ [maize, Figure D; bean, Figure E; Potato, Figure F]. The line is the average regression line for all categories. | PMC10161611 | gr5.jpg |
0.439012 | 2bb375f3b24d40a8bef0dcc9649574a7 | AXL receptor expression. A Representative FACS data of AXL binding on EOC cell lines. B Graphical representation of Antigen Bounding Count (ABC) evaluated on EOC cell lines by flow cytometry. C Representative immunofluorescence microscopy image of AXL (green) expression on the surface of EOC spheroids (red). D MFI (median fluorescence intensity) of AXL on ES-2 untreated cells and ES-2 platinum pre-treated cells compared to isotype control | PMC10161629 | 12967_2023_4101_Fig1_HTML.jpg |
0.518509 | 8633c255e7244a5bb41f8d1613e931fb | pAXLxCD3ε in vitro T cell re-directed cytotoxic activity. A Graphical representation of pAXLxCD3ε structure and mechanism of action. B Relative percentage (%) of mediated killing- represented as % of 7AAD negative and AXL positive cells (SKOV3, ES-2,OVCAR-8 and EFO-21) and AXL negative (RMG-I) ovarian cancer cell lines co-cultured with PBMC from healthy donor at E:T ratio 10:1 in the presence of increasing concentrations (0.1 μg/ml, 1 μg/ml and 2.5 μg/ml) of pAXLxCD3ε or vehicle, 72 h after treatment. C Relative % of T cell mediated killing on ES-2 cells co-cultured with healthy donor-derived PBMC at E:T ratio 10:1 in the presence of increasing concentrations of pAXLxCD3ε (0.1 μg/ml, 1 μg/ml and 2.5 μg/ml) or negative control (pBCMAxCD3ε 2.5 μg/ml) 72 h after treatment. D Viability measured as bioluminescence value of ES-2 LUC cells co-cultured with PBMC from healthy donor at E:T ratio 10:1 in presence of vehicle or increasing concentrations of pAXLxCD3ε (0.1 μg/ml, 1 μg/ml and 2.5 μg/ml) 72 h after treatment. E Representative immunofluorescence microscopy image of EOC spheroids (Red) co-cultured with healthy donor PBMC (green) at E:T ratio 10:1 and treated with vehicle or pAXLxCD3ε 2.5 μg/ml. F Cell viability measured as absorbance at OD (optical density 450 nm) of EOC cells treated with increasing concentrations of pAXLxCD3ε (0.1 μg/ml, 1 μg/ml and 2.5 μg/ml) in the absence of effector cells. Student’s t-test was applied to calculate statistical significance *p < 0.05, **p < 0.01, ***p < 0.001 | PMC10161629 | 12967_2023_4101_Fig2_HTML.jpg |
0.40207 | aeeec85df90741a382fb7ef79901b930 | pAXLxCD3ε BTCE in vitro functional activity. A Early and late T cell activation markers (CD25 and CD69), cytokine release (IFN-y and TNF-α) and cytotoxic enzyme production (perforin). on CD8 T-lymphocytes co-cultured with AXL positive cells (ES-2 and OVCAR-8) at E:T ratio 10:1 in presence of vehicle or increasing concentrations of pAXLxCD3ε. B Representative FACS data of CD107a increase on T-lymphocytes co-cultured with AXL expressing cells (OVCAR-8) treated with pAXLxCD3ε 2.5 μg/ml or vehicle. C CD107a dose-dependent increase on T-lymphocytes co-cultured with AXL expressing cells at E:T ratio 10:1 in presence of vehicle or increasing concentrations of pAXLxCD3ε. D Proliferation of T cells alone or co-cultured with AXL positive cells at E:T ratio 10:1 in presence of increasing concentrations of vehicle or pAXLxCD3ε. Student’s t-test was applied to calculate statistical significance *p < 0.05, **p < 0.01, ***p < 0.001 | PMC10161629 | 12967_2023_4101_Fig3_HTML.jpg |
0.43336 | f0e59d70b07a4708bad2b7ace14390c3 | pAXLxCD3ε and Olaparib combinatorial approach. A Relative % of T cell mediated cytotoxicity of ES-2 cells co-cultured at 10:1 E:T ratio in the presence of vehicle,1 μg/ml of pAXLxCD3ε and Olaparib 1 μM + pAXLxCD3ε 1 μg/ml. B % of IFN-y production in T cells co-cultured with ES-2 cells at 10:1 E:T ratio in the presence of vehicle,1 μg/ml of pAXLxCD3ε and Olaparib 1 μM + pAXLxCD3ε 1 μg/ml. Student’s t-test was applied to calculate statistical significance *p < 0.05, **p < 0.01, ***p < 0.001. p values are calculated by comparing PBMC co-cultured with ES-2 cells treated with vehicle to co-cultures of PBMC + target cells treated with pAXLxCD3ε or Olaparib or pAXLxCD3ε+ Olaparib. Relative toxicity is calculated by normalizing pAXLxCD3ε, Olaparib and pAXLxCD3ε plus Olaparib treated cells co-cultured with PBMC on negative control (co-cultures of ES-2 + PBMC exposed to vehicle) placed equally to zero | PMC10161629 | 12967_2023_4101_Fig4_HTML.jpg |
0.426859 | 471d49be38d54188950d93768fc1f531 | pAXLxCD3ε in vivo activity. A Schematic representation of in vivo EOC xenograft model. B Percentage (%) of malignant cells in the ascites of NSG mice treated with pAXLxCD3ε 0.1 mg/kg compared to mice treated with vehicle alone. C Representative FACS dot plot of T cell engraftment evaluated on the day of sacrifice on (intracardiac) IC blood sample of treated mice. D Tumor volume curve of mice treated with pAXLxCD3ε 0.1 mg/kg as compared to vehicle alone E Survival curves (Kaplan- Meier) of mice treated with pAXLxCD3ε BTCE 0.1 mg/kg as compared to vehicle alone | PMC10161629 | 12967_2023_4101_Fig5_HTML.jpg |
0.426203 | 7304421b147f4ec39447c7f7bb1364ef | A Immunohistochemistry staining of CD3 lymphocytes in explanted tumor from mice treated with vehicle + PBMCs. B Immunohistochemistry staining of CD3 lymphocytes in explanted tumor from mice treated with pAXLxCD3ε 0.1 mg/kg. Arrows indicate the stained CD3 lymphocytes | PMC10161629 | 12967_2023_4101_Fig6_HTML.jpg |
0.391619 | bb433f36da2b48148c079ee9514e0d83 | The continuum of extracorporeal support for acute respiratory failure, characterized by the degree of oxygenation and carbon dioxide removal, the intent of various modes of support, and areas requiring further research. ARDS = acute respiratory distress syndrome; ECCO2R = extracorporeal carbon dioxide removal; ECMO = extracorporeal membrane oxygenation; MV = mechanical ventilation. | PMC10161738 | rccm.202303-0354EDf1.jpg |
0.454335 | 44e3bd7e3f8a42719727c8536e68ff41 | JG98 suppresses prostate cancer cell growth and re-sensitizes enzalutamide treatment A. Chemical structure of JG98. B. C4–2B MDVR, CWR22Rv1, IMR90, and RWPE-1 cells were treated with increasing doses (0.01, 0.1, 0.25, 0.5, 1, 2.5, 5, and 10 μM) of JG98 for 5 days and the viable cells were counted. The results were compared to the control to generate the cell survival rate. C. CWR22Rv1 and C4–2B MDVR cells were treated with control, 20 μM enzalutamide, 0.25 μM JG98 or the combination for 3 and 5 days, and the cell proliferation curves were plotted. D-E. 1000 C4–2B MDVR or CWR22Rv1 cells were treated with control, 0.05, 0.1 μM of JG98 in the absence or presence of enzalutamide (20 μM) and allowed to grow for 2 weeks for clonogenic assays. The colony numbers were counted for comparison. *p < 0.05. Results are the mean of three independent experiments (± S.D.). ns: not significant. | PMC10162009 | nihms-1892140-f0001.jpg |
0.466997 | f07d4b91e0254c919d2d0c7ddefa82a5 | JG98 degrades AR-V7 and suppresses HSP70 induced AR-V7 transcriptional activity A. Whole cell lysates of CWR22Rv1 and C4–2B MDVR cells after 24 h treatment with JG98 (0, 2.5 or 5 μM) were separated by electrophoresis and probed for AR-V7, AR-FL, and HSP70 with their respective antibodies. GAPDH was used as the internal control. B. CWR22Rv1 and C4–2B MDVR cells were treated with DMSO, JG98 (0.25 μM), enzalutamide (20 μM), or the combination for 5 days and the levels of AR-V7 and AR-FL were examined by western blotting. GAPDH was used as the internal control. C. HEK293 cells transfected with the AR-V7 expression construct were treated with or without JG98 (2.5 μM) and immunoprecipitated with anti-AR antibodies and probed for ubiquitin, AR-V7, and HSP70, respectively. IgG antibodies were used as the negative control and whole lysate input were loaded alongside. D. CWR22Rv1 cells with the endogenous AR/AR-V7 were treated with or without JG98 (2.5 μM) for 24 h. Cell lysates were immunoprecipitated with anti-AR antibodies and probed for ubiquitin, AR-V7, AR-FL, and HSP70, respectively. E. CWR22Rv1 cells were treated with 50 μg/ml cycloheximide in the absence or presence of 5 μM of JG98. Total cell lysates were collected 0, 2, 4, 8, and 24 h after treatment. AR-V7 and AR-FL were analyzed by western blotting to calculate the half-life of AR-V7 and AR-FL. F. CWR22Rv1 and C4–2B MDVR cells were treated with or without JG98 (2.5 μM) in the absence or presence of the proteosome inhibitor, MG132 (5 μM), for additional 8 h, and the protein expression of AR-V7 and AR-FL were analyzed by western blotting. G. HEK293 cells were transiently transfected with pcDNA, HSP70, AR-V7, or the combination constructs with PSA-Luc, and treated with control or 1 nM DHT. Cell lysates were harvested 24 h after treatments, and the PSA luciferase activity was assessed. H. HEK293 cells were transiently transfected with vector only, AR-V7, or AR-V7+HSP70 expressing plasmids with PSA-Luc, and subsequently treated with DMSO, JG98 (2.5, 5 μM) or enzalutamide (20 μM). PSA luciferase activity was measured. *p < 0.05. Results are the mean of three independent experiments (± S.D.). ns: not significant. | PMC10162009 | nihms-1892140-f0002.jpg |
0.463872 | e334c188103a424fbf6d7a8c703b3827 | JG98 promotes AR-V7 degradation through STUB1 A. HEK293 cells were co-transfected with AR-V7, HSP70, and Flag-STUB1 for 3 days and then treated with 2.5 μM JG98 for 24 h. The cells were then permeabilized with paraformaldehyde and probed with anti-AR-V7 and anti-Flag antibodies, respectively. Location of AR-V7 was visualized with FITC-conjugated and Flag-STUB1 with Alexa467-conjugated secondary antibodies. Nuclei were stained with DAPI. Merged images displayed interaction between AR-V7 and Flag-STUB1 under JG98 treatment. White arrows indicate the typical staining of cells in each group. Scale bar 20 μm. B. C4–2B MDVR cells treated with STUB1 siRNA or control and treated with various doses of JG98 (0, 1, 2.5 μM) for 24 h. Whole cell lysates were separated by electrophoresis and blotted with AR-V7, AR-FL and STUB1 antibodies. Levels of tubulin were assessed for loading equity. C. C4–2B MDVR cells were transfected with siRNA against STUB1 or control for 5 days. Cell viability was determined by cell counting and represented as cell survival rates. *p < 0.05. Results are the mean of three independent experiments (± S.D.). | PMC10162009 | nihms-1892140-f0003.jpg |
0.360927 | 4ed0377702554524a46ae15fa516041e | JG98 regulates gene programs in enzalutamide resistant prostate cancer A. GSEA of top enriched gene sets in C4–2B MDVR cells treated by JG98. The upregulated and downregulated gene sets from the Hallmark and KEGG platforms were outputted by GSEA. B. Heatmap and hierarchical clustering of the differentially expressed genes (DEGs) between treatments (JG98 2.5 μM and JG98 5 μM) in C4–2B MDVR cells with FPKM> 1 and log2 fold change > 0.25, as compared to vehicle (DMSO). The genes were displayed in rows and the normalized counts per sample were displayed in columns. Red indicates upregulated, and blue designates downregulated expression levels. Right: P53 target, UPR, Cell Cycle, Myc target, and AR/AR-V7 target genes that were altered in expression are displayed. C. GSEA of the gene signatures up or down regulated in C4–2B MDVR cells treated with JG98, as compared to DMSO. The signature was defined by genes that are preferentially downregulated in the androgen response and Myc target pathways. GSEA of the P53 pathway and unfolded protein response signatures were upregulated by JG98. D. qRT-PCR analysis of the indicated genes from the AR and AR-V7 target and UPR pathways in C4–2B MDVR cells treated with DMSO or JG98 (2.5 or 5 μM) for 24 h. *p < 0.05, Results are the mean of three independent experiments (± S.D.). ns: not significant. | PMC10162009 | nihms-1892140-f0004.jpg |
0.426449 | 0e5a64eff2a9421087a2f833ec5dc91b | JG98 improves enzalutamide treatment in CRC and PDX organoid models A. CRCs derived from UCD1172 PDX tumors were treated with various doses of JG98 for 5 days, and the cell growth was determined by the CCK-8 assay. B. CRCs from UCD243009 PDX tumors were treated with JG98 alone or in combination with enzalutamide (20 μM) for 5 days, and the cell proliferation was assayed by CCK-8. C. UCD1172CR cells were seeded in charcoal stripped FBS medium and treated with 10 nM R1881 alone or in combination with antiandrogens (enzalutamide, abiraterone or apalutamide). Cell growth was monitored over 7 days by the CCK-8 assay. Whole cell lysates from UCD1172 and UCD1172CR were separated by electrophoresis. The status of AR-V7 and AR-FL was shown by western blotting. D. UCD1172CR cells were treated with increasing concentrations of JG98 (0, 0.1, 0.25, 0.5, 1, 2.5 μM) in the absence or presence of enzalutamide (20 μM) for 3 days. Cell viability was determined by the CCK-8 assay. E. UCD1172CR cells were treated with JG98 alone or with enzalutamide (20 μM) in the clonogenic assay. The number of colonies in each condition was counted and plotted. F. UCD1172CR cells were treated with DMSO or JG98 (0.25, 0.5, 1 μM) for 5 days and the cell lysates were analyzed for the expression of AR-V7 and AR-FL by western blotting (left). For the combination treatment, these cells were treated with DMSO, JG98 (0.25 μM), enzalutamide (20 μM), and JG98 +enzalutamide for 5 days. Protein expression was examined by western blotting (right). G. Organoids from UCD1178 PDX were treated with JG98 alone or together with enzalutamide (20 μM) for 7 days. Cell viability was assayed by CellTiter-Glo Luminescent assay and the live-and-dead cells were visualized by immunofluorescence. *p < 0.05. Results are the mean of three independent experiments (± S.D.). | PMC10162009 | nihms-1892140-f0005.jpg |
0.441339 | 7d2d4fe9b3234f18a2cec3153a02620d | JG231, the JG98 analog, inhibits AR-V7 and improves ARSI treatment in vitro and in vivo. A. The chemical structure of JG231 B. C4–2B MDVR cells were treated with JG231 (0.1 or 0.25 μM) alone or in combination with enzalutamide (20 μM), and cell viability was measured by cell counting at different time points. C. Clonogenic assay was performed with C4–2B MDVR cells treated with JG231, with or without enzalutamide (20 μM). Colonies were stained by crystal violet and the number was counted. D. C4–2B MDVR cells were treated with increasing concentrations of JG231 (0, 0.25, 0.5, 1, 2.5 μM) for 3 days and the cell lysates were evaluated for AR-V7 and AR-FL expression by western blotting. E. C4–2B MDVR cells were treated with DMSO, enzalutamide (20 μM), JG231 (0.25 μM), or the combination for 5 days, and the expression of AR-V7 and AR were determined by western blotting. F-G. Mice bearing CWR22Rv1 xenografts were treated with vehicle control, enzalutamide (25 mg/Kg p.o), JG231 (4 mg/Kg i.p), or JG231 plus enzalutamide for 18 days (n = 8). Tumor volumes were measured twice weekly. Tumors were photographed and weighed. Data represent means ± S.D. from 8 tumors per group. H. IHC staining of Ki67, AR-V7, and AR in each group was performed. *p < 0.05, Results are the mean of three independent experiments (± S.D.). | PMC10162009 | nihms-1892140-f0006.jpg |
0.426451 | 79ada4e0889241c2850b81ddb21b0d46 | Mechanism of action of PARP inhibitors. (A) Molecular structure of PARP inhibitors and their capacity of trapping PARP; (B) PARP inhibitors lead to tumor cell death through two distinct mechanisms: the inhibition of the PARylation or trapping the PARP. | PMC10162014 | fendo-14-1164067-g001.jpg |
0.505605 | e9e96405532f4033833012bfa2cec799 | Recruitment and randomized allocation group from the CONSORT 2010 flow diagram. | PMC10162529 | pone.0284344.g001.jpg |
0.492034 | a26525b2259347acb5363ffb16f10c51 | The overall flow of research. | PMC10162529 | pone.0284344.g002.jpg |
0.410504 | 036f082d907042c0bab8ae8a6f01b10a | Changes in participants’ SAP expression level before and after AT.(A, B) Western blotting repeated experiments were conducted on four randomly selected participants in the control and experimental groups.
Control group pre- test: A, BControl group post- test: A’, B’Experimental group pre- test: C, DExperimental group post- test: C’, D’.(C) Results of Wilcoxon’s signed-rank test of Western blotting results of the control group (n = 15), and experimental group (n = 20)Control group: JNK (Z = -1.022, p = 0.307), p-JNK (Z = -1.079, p = 0.281), and Elk-1 (Z = -2.613, p = 0.009)Experimental group: JNK (Z = -2.613, p = 0.009), p-JNK (Z = -2.501, p = 0.012), and Elk-1 (Z = -2.651, p = 0.008). ** p <0.01, * p <0.05. | PMC10162529 | pone.0284344.g003.jpg |
0.473785 | ae048b87105147f8974f4872089a7c3f | Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) flowchart. | PMC10163165 | gr1.jpg |
0.485633 | 6d2f94e39b7549448812f8c098c75d58 | Overview of ethnicities in included studies. White patients accounted for 74.7% of all patients enrolled in the 51 studies included in the systematic review and meta-analysis, followed by Asians (17.4%). African Americans and Hispanics were definitely under-tested (1.1% and 2.2%, respectively); the remaining 4.6% gathers uncommon ethnicities (e.g. Hawaiian, Native Americans), Ashkenazi Jewish descendants, mixed ethnicities, and cases of unknown ancestry. | PMC10163165 | gr2.jpg |
0.46898 | 732828d565f34e22bbe6cf3e9e943abe | Geographic distribution of studies on germline BRCA in pancreatic cancer. Overview of the geographic distribution of studies included in the systematic review and meta-analysis. The table shows the number of studies per country, including both those conducted in individual countries and international studies. Countries are classified according to the World Bank as lower-middle-income country (LMIC), upper-middle-income country (UMIC), and high-income country (HIC) (https://datahelpdesk.worldbank.org/knowledgebase/articles/906519). | PMC10163165 | gr3.jpg |
0.470317 | 99ad145502164d5bac818116af824a8d | Conceptual framework on housing and child health outcomes. (adapted from Dunn 2020) | PMC10163804 | 12887_2023_3992_Fig1_HTML.jpg |
0.436055 | d034dc04b2b04242833e2a741b009d70 | Chemical fingerprint chromatograms of YH14642 (a) and YH23537 (b). Notoginsenoside R1 (1), ginsenoside Rg1 (2), Rb1 (3), 20(S)-Rh1 (4), Rd (5), Rh4 (6), Rk3 (7), 20(S)-Rg3 (8), 20(R)-Rg3 (9), Rg5 (10), Rk1 (11). | PMC10163972 | IJD2023-8130287.001.jpg |
0.426336 | 906a1ee8ed1f4c1d8eeb3ea212d0ebfc | IL-6 and IL-8 production in hGF cells stimulated with LPS-PG. Human gingival fibroblast cells (1 × 104) were seeded into 96-well plates. The cells were treated with YH14642 or YH23537 with Porphyromonas gingivalis LPS (LPS-PG, 1 μg/ml) for 24 hr. IL-6 (a) and IL-8 (b) levels in conditioned media were determined using Luminex. Data represent the mean ± SD. ∗∗P < 0.01 and ∗∗∗P < 0.001 compared with the LPS-PG. | PMC10163972 | IJD2023-8130287.002.jpg |
0.472323 | 568dd66ab9d94de6a3007f8928ebe78b | GI in ligature-induced periodontitis dogs. The left upper second premolar (PM2), third premolar (PM3), and fourth premolar (PM4) as well as the left lower PM3, PM4, and first molar (M1) were ligated with silk-wire twisted ligatures and the dogs were fed with soft moistened food. After 8 weeks, the ligatures were removed and the dogs were administered with YH23537 or YH14642 for 4 weeks. CAL was measured every week throughout the experimental period ((a) week 1; (b) week 2; (c) week 3; (d) week 4). Data represent the mean ± SD. ∗P < 0.05 compared with the placebo group. | PMC10163972 | IJD2023-8130287.003.jpg |
0.45819 | 1d451c51fcca441ba94206e1418b31da | PD in ligature-induced periodontitis dogs. The left upper second premolar (PM2), third premolar (PM3), and fourth premolar (PM4) as well as the left lower PM3, PM4, and first molar (M1) were ligated with silk-wire twisted ligatures and the dogs were fed with soft moistened food. After 8 weeks, the ligatures were removed and the dogs were administered with YH23537 or YH14642 for 4 weeks. CAL was measured every week throughout the experimental period ((a) week 1; (b) week 2; (c) week 3; (d) week 4). Data represent the mean ± SD. | PMC10163972 | IJD2023-8130287.004.jpg |
0.484009 | 416d095e2ca54f5083eec929a91bd0ef | Clinical attachment level (CAL) in ligature-induced periodontitis dogs. The left upper second premolar (PM2), third premolar (PM3), and fourth premolar (PM4) as well as the left lower PM3, PM4, and first molar (M1) were ligated with silk-wire twisted ligatures and the dogs were fed with soft moistened food. After 8 weeks, the ligatures were removed and the dogs were administered with YH23537 or YH14642 for 4 weeks. CAL was measured at every week throughout the experimental period ((a) week 1; (b) week 2; (c) week 3; (d) week 4). Data represent the mean ± SD. ∗P < 0.05, ∗∗P < 0.01, and ∗∗∗P < 0.001 compared with the placebo group. | PMC10163972 | IJD2023-8130287.005.jpg |
0.496188 | c56072959b1a4586be9897fcec36c3a0 | GR in ligature-induced periodontitis dogs. The left upper second premolar (PM2), third premolar (PM3), and fourth premolar (PM4) as well as the left lower PM3, PM4, and first molar (M1) were ligated with silk-wire twisted ligatures and the dogs were fed with soft moistened food. After 8 weeks, the ligatures were removed and the dogs were administered with YH23537 or YH14642 for 4 weeks. CAL was measured every week throughout the experimental period ((a) week 1; (b) week 2; (c) week 3; (d) week 4). Data represent the mean ± SD. ∗P < 0.05, ∗∗P < 0.01, and ∗∗∗P < 0.001 compared with the placebo group. | PMC10163972 | IJD2023-8130287.006.jpg |
0.52101 | dfd3af6ea3f045278497c65713792f63 | BeWo differentiation alters metabolite abundance, energy charge, and glucose utilization. (A) Relative abundance of citric acid cycle intermediates 48 h following treatment of BeWo cells with vehicle (0.4% DMSO) or forskolin (FSK, 40 µM). Normalized relative abundance was determined by dividing total signal intensity by mg of total protein and normalizing to DMSO-treated cells. n = 5 biological replicates. (B) AMP/ADP/ATP levels in nmol/µg protein 48 h following treatment of BeWo cells with DMSO or 40 µM forskolin (FSK). n = 5 biological replicates. (C) Graphic depicting path of carbon atoms from glucose after entering the TCA cycle. (D) Percent enrichment of [U-13C6]-glucose in citric acid cycle intermediates 48 h following treatment of BeWo cells with DMSO or forskolin (FSK). n = 6 biological replicates. (E) Ratio of Malate M + 2 to Citrate M + 2 isotopologues, 48 h following treatment of BeWo cells with DMSO or forskolin (FSK). n = 6 biological replicates. All data are representative of mean +/− SEM. *, p < 0.05; **, p < 0.01; ***, p < 0.001; and ****, p < 0.0001. | PMC10164164 | 41598_2023_34435_Fig1_HTML.jpg |
0.457305 | 6eebba68d36d44cdad087b136f334e28 | Trophoblast differentiation decreases expression of the mitochondrial citrate carrier. (A) Schematic of glucose metabolism to acetyl-CoA. Pyruvate is transported via the mitochondrial pyruvate carrier into the inner mitochondrial membrane where it is converted to acetyl-CoA, fueling the tricarboxylic acid cycle (TCA). Citrate is transported by the citrate carrier (CIC) to the cytoplasm where ATP citrate lyase (ACLY) converts it to acetyl-CoA, which can be used for histone acetylation. Acetate may contribute to Acetyl-CoA pools through the activity of Acetyl-CoA Synthetase 2 (ACSS2). Figure generated with Biorender. (B) qPCR analysis showing relative expression of SLC25A1, ACLY and ACSS2 mRNA following 48 h treatment of BeWo cells with DMSO or 40 µM Forskolin (FSK). n = 4 biological replicates. (C) Representative western blot images of HCG, CIC, ACLY, ACSS2 proteins and total protein expression in BeWo cells treated with DMSO or 40 µM forskolin. Please see Supplemental Fig. 2 for images of uncropped blots. (D) Quantification of CIC, ACLY, and ACSS2 protein expression in BeWo cells treated with DMSO or 40 µM Forskolin (FSK). n = 5 biologic replicates. Data are representative of mean +/− SEM. *, p < 0.05; **, p < 0.01; ***, p < 0.001; and ****, p < 0.0001. | PMC10164164 | 41598_2023_34435_Fig2_HTML.jpg |
0.436811 | 0437684907044c6ab05dc8dbdc09aff7 | Loss of CIC impairs biochemical differentiation. (A) Representative western blot image of CIC and total protein expression in empty-vector, non-targeting, and CIC knockout BeWo cells treated cells. Please see Supplemental Fig. 4 for images of uncropped blots. (B) ELISA of HCG production in empty-vector, non-targeting, and CIC knockout BeWo cells treated with DMSO or 40 µM Forskolin (FSK). n = 3 biological replicates. (C) qPCR analysis of CGA, CGB2, ERVW-1, and ERVFRD-1 gene expression in empty vector, non-targeting, and CIC knockout BeWo cells treated with DMSO or 40 µM Forskolin (FSK). n = 3 biological replicates. Data are representative of mean +/− SEM. *, p < 0.05; **, p < 0.01; ***, p < 0.001; and ****, p < 0.0001. | PMC10164164 | 41598_2023_34435_Fig3_HTML.jpg |
0.437789 | c56813c8fd8940a3932b7932892d10aa | Loss of CIC alters gene expression following differentiation. (A) PCA plot comparing control (red) and CIC knockout BeWo cells (blue) treated with DMSO (circle) or 40 µM forskolin (FSK) (triangle). (B) Volcano plot comparing control and CIC knockout BeWo cells treated with DMSO. (C) Volcano plot comparing control and CIC knockout BeWo cells treated with 40 µM forskolin (FSK). (D) Pathway analysis comparing control and CIC knockout BeWo cells treated with 40 µM forskolin (FSK). (E) Heat map of relative gene expression changes of DMSO and 40 µM forskolin treated control and CIC knockout BeWo cells. (F) CGA, CGB2, HSD11B2, ERVW-1, ERVFRD-1, and TEAD4 gene expression by qPCR in control and CIC knockout BeWo cells treated with DMSO or 40 µM Forskolin (FSK). n = 6; Data are representative of mean +/− SEM. *, p < 0.05; **, p < 0.01; ***, p < 0.001; and ****, p < 0.0001. | PMC10164164 | 41598_2023_34435_Fig4_HTML.jpg |
0.452182 | d616627c8ce14188abb347648c917ff9 | Impaired Histone 3 deacetylation following differentiation of CIC knockout BeWo cells with forskolin. (A) Representative western blot of Histone 3 total acetylation, Histone 3 lysine 9 acetylation (H3AcK9), Histone 3 lysine 27 acetylation (H3AcK27), total histone 3 and total protein expression in BeWo cells treated with DMSO or 40 µM forskolin. Please see Supplemental Fig. 6 for images of uncropped blots. (B) Quantification of forskolin to DMSO relative intensity of histone acetylation to total histone 3 acetylation. n = 5, Data are representative of mean +/− SEM. *, p < 0.05; **, p < 0.01; ***, p < 0.001; and ****, p < 0.0001. | PMC10164164 | 41598_2023_34435_Fig5_HTML.jpg |
0.422944 | 6767f4278e7b4aa481c3c459e2d37d88 | Acetate partially rescues markers of differentiation in CIC knockout cytotrophoblasts. CGA, CGB2, HSD11B2, ERVW-1, ERVFRD-1, and TEAD4 gene expression by qPCR in empty-vector, non-targeting, and CIC knockout BeWo cells treated with DMSO or 40 µM Forskolin (FSK), in the presence of 1 mM acetate. n = 4 biologic replicates. Data are representative of mean +/− SEM. *, p < 0.05; **, p < 0.01; ***, p < 0.001; and ****, p < 0.0001. | PMC10164164 | 41598_2023_34435_Fig6_HTML.jpg |
0.400842 | fa6edd8eb163432081f3629ed6b70952 | Loss of mitochondrial citrate efflux impairs metabolic reprogramming. (A) Heat map of normalized relative metabolite abundance of DMSO and 40 µM forskolin treated empty-vector (EV), non-targeting, and CIC knockout BeWo cells. n = 6 biologic replicates. Data are representative of mean +/− SEM. $, p < 0.01 compared to EV-DMSO and #, p < 0.01 compared to EV-FSK using ANOVA. (B–D) Percent enrichment of [U-13C6]-glucose in (B) pyruvate, (C) citrate and (D) malate following treatment of BeWo cells with DMSO or forskolin. (E) Ratio of M + 2 Malate/M + 2 Citrate. n = 6 biological replicates. Data are representative of mean +/− SEM. *, p < 0.05; **, p < 0.01; ***, p < 0.001; and ****, p < 0.0001. | PMC10164164 | 41598_2023_34435_Fig7_HTML.jpg |
0.589641 | 7ccb1c6b8b814deda25e55f65296da0d | Social capital in autocratic and democratic regimes. | PMC10165017 | gr1_lrg.jpg |
0.440901 | c11b9b140d0e4e768b98343d237723da | Patients with RARA overexpression identified with peripheral blood–based clinical trial assay. The blood-based biomarker test (clinical trial assay) was performed at a central laboratory, using frozen peripheral blood mononuclear cells (PBMCs) prepared and shipped from the clinical sites. The assay measures relative RARA mRNA expression levels against a panel of control genes via quantitative reverse transcription polymerase chain reaction (RT-qPCR) in CD34+ and/or CD117+ blasts isolated from PBMCs and applies a predefined cutoff to determine whether any given patient sample is RARA-positive or RARA-negative (patients with RARA overexpression were characterized as RARA-positive and patients without RARA overexpression as RARA-negative). ∗Details of the sample collection, sample analysis, and biomarker outcome reporting process as described in Vigil et al, 2017;6 †Syros Pharmaceuticals, Inc data on file as of 27 May 2022 from studies SY-1425-201 (all cohorts) and SELECT-MDS-1 (#NCT04797780). CPT, cell preparation tube. | PMC10165187 | BLOODA_ADV-2022-008806-gr1.jpg |
0.509796 | c0d77f8c265b4b4cb4066fa1e6ee2817 | Patient disposition, enrollment, and treatment. (A) Patient enrollment and analysis overview. Of the 125 ND unfit patients with AML screened using the blood-based biomarker test, 37 (30%) were RARA-positive and 88 (70%) were RARA-negative. The most frequent reasons for which screened ND unfit patients with AML were not enrolled included RARA-negative status before implementation of a protocol amendment allowing both RARA-positive and RARA-negative patients to enroll, and patients declined. Of the 51 patients with non-APL AML enrolled to receive tamibarotene and azacitidine, all were included in safety and efficacy analyses. The response-evaluable population comprised all patients enrolled who (1) completed 1 cycle of tamibarotene and had a follow-up assessment of disease status or (2) were withdrawn from the study before completion of cycle 1 because of documented disease progression. Figure includes patient status as of data cutoff, 14 February 2022. ∗No postbaseline response evaluation was performed for nonevaluable patients. (B) Patient disposition. ∗One patient died during treatment due to cardiac arrest that was not drug related; †Includes 2 patients who discontinued treatment before the first dose of tamibarotene. Of the 15 patients who discontinued because of AE, 3 patient discontinuations were assessed as related to study treatment; 1 was due to fatigue; 1 was due to fatigue, myalgia, arthralgia, and nausea, and 1 was due to pulmonary embolism. There were no hematologic AEs considered related to study treatment that led to treatment discontinuation. | PMC10165187 | BLOODA_ADV-2022-008806-gr2.jpg |
0.441223 | a8de40a43ede4b4c9366793776f41c40 | Summary of OR. (A) Summary of best OR in ND unfit patients with AML. Table shows a summary of the best efficacy response achieved by all response-evaluable patients. The response-evaluable population comprised all patients enrolled who (1) completed 1 cycle of tamibarotene and had a follow-up assessment of disease status or (2) were withdrawn from the study before completion of cycle 1 because of documented disease progression. Patients listed in the “other” category did not achieve an International Working Group (IWG) response. ∗RARA overexpression was determined in blasts isolated from PBMCs by qRT-PCR assay. The presence of RARA overexpression was characterized as RARA-positive, and the absence of RARA overexpression as RARA-negative; †Disease status was assessed per the revised IWG AML criteria;13,14 ‡All response-evaluable patients. (B) Association of IWG response with DNA mutations and cytogenetic risk in RARA-positive patients. Data are shown for the 18 RARA-positive response evaluable patients. Cytogenetic risk was assessed per National Comprehensive Cancer Network (NCCN) AML guidelines 2018.15 The mutation profiles and cytogenetic risk of patients were site reported. Response was assessed per the revised IWG AML criteria.13,14 | PMC10165187 | BLOODA_ADV-2022-008806-gr3.jpg |
0.488721 | c2258388be1f4c4f9b75315609172740 | OS in RARA-positive patients summarized by response status. The OS graph includes all RARA-positive patients who enrolled in the study. Responders (CR/CRi/CRh), patients who achieved CR, CRi, or CR with partial hematologic recovery (CRh). Nonresponders, patients who did not achieve CR/CRi or CRh. | PMC10165187 | BLOODA_ADV-2022-008806-gr4.jpg |
0.42029 | bd8752465f854db98ee896142b8598b8 | Summary of AEs. All treatment emergent AEs for all enrolled patients (N = 51) were evaluated. The safety population included all patients who received at least 1 dose of study drug (tamibarotene or azacitidine). AEs were evaluated using Common Terminology Criteria for Adverse Events version 4.03. (A) Nonhematologic AEs that were reported in at least 25% of patients. *The term “rash” included the preferred terms of rash maculo-papular, rash, drug eruption, nodular rash, rash erythematous, and rash pruritic. Rash maculopapular and rash were each reported in 5 (10%) of patients, with other terms reported in 1 patient each (2%). (B) Hematologic AEs. | PMC10165187 | BLOODA_ADV-2022-008806-gr5.jpg |
0.449065 | b876411ae56d43048adcdcfd38f39b87 | Association among high RARA expression, monocytic features, MES, and ex vivo venetoclax resistance. Colors denote FAB status, gray indicates unknown. (A) High RARA expression (RARA-high) identifies a population of patients with AML that is enriched for high monocytic gene expression (MES, y-axis) in the TCGA and Beat AML databases. P values by Fisher exact test. Monocytic: MES > 0.5. (B) RARA expression (left, y-axis) and MES (right, y-axis) are associated with venetoclax resistance ex vivo, quantified as area under the dose-response curve (AUC, x-axis). Plots show Spearman correlation (ρ) of normalized RARA expression or MES vs venetoclax response across 90 AML primary cultures (Beat AML).17 M0, undifferentiated acute myeloblastic leukemia; M1, acute myeloblastic leukemia with minimal maturation; M2, acute myeloblastic leukemia with maturation; M4, acute myelomonocytic leukemia; M5, acute monocytic leukemia. | PMC10165187 | BLOODA_ADV-2022-008806-gr6.jpg |
0.390353 | 38b68bd2c29543fc81d4fc3013408dca | Association of RARA overexpression with monocytic features (MES) and venetoclax resistance markers in the SY-1425-201 clinical study ND unfit patients with AML. The MES and venetoclax resistance–associated features were profiled in ND unfit patients with AML. RARA-positive patients (red) were significantly enriched for features associated with venetoclax resistance including a high MES (left, y-axis), and low BCL2 (middle, y-axis) and high MCL1 expression (exp) (right, y-axis) compared with RARA-negative patients (blue). (A) Eighty percent (15/19) of RARA-positive patients and 17% (4/24) of RARA-negative patients are classified as monocytic by MES (MES > 0.5). (B) The majority of RARA-positive ND unfit patients with AML who achieved CR/CRi with tamibarotene plus azacitidine have a monocytic phenotype (high MES) associated with venetoclax resistance, which includes lower BCL2 and higher MCL1 expression. | PMC10165187 | BLOODA_ADV-2022-008806-gr7.jpg |
0.419189 | 97bf2e0cc3cf4098afbb719a1a8d7f06 | Artificially induced hyperventilation in hypoxic rats. A) Flowchart of the studied groups. Studied rats were deeply anaesthetized and mechanically ventilated for 3 hours. No muscle relaxants were used in any of the study groups. During the first hour of the experiment, all the rats were ventilated at an FiO2 of 1 to achieve steady state. Then the rats were randomly allocated to 3 different groups. The control group (n = 5, green) that was mechanically ventilated at an FiO2 of 1, the hypoxic spontaneously hyperventilating group (HSH, n = 10, blue) that was mechanically ventilated at an FiO2 of 0.08, and the hypoxic artificially induced hyperventilation group (HAIH, n = 9, red) that was mechanically ventilated at an FiO2 of 0.08 with a respiratory rate targeting a PaCO2 of 10 mm Hg. B) Mean arterial pressure (MAP) in the studied groups at different time points. MAP for each group is presented at 10-minute intervals throughout the 3-hour experiment period. The data is represented as mean, and the standard error is shown at 120 and 180 minutes. Differences among the HAIH and HSH groups were calculated with the Wilcoxon rank-sum test. Statistical significance was accepted as P < 0.01. During the first hour of the study there were no differences in MAP among the 3 groups. At the end of the steady-state period, the MAP of the HSH and HAIH groups rapidly fell. However, after the acclimatization process driven by the hyperventilation, the HAIH group increased the MAP. At 120 and 180 minutes, the HAIH group had a significantly higher MAP (P < 0.005) than the HSH group | PMC10165328 | AIT-53-44218-g001.jpg |
0.48921 | 8fbf93fb70464728bdf210822ad7e764 | Arterial blood gas results in rat groups at different time points. Arterial blood gases were measured at 60 minutes, 120 minutes, and 180 minutes during the experimental period in all rats. The data is presented in box-and-whisker plots. Whiskers depict the minimum and maximum values. The green boxes represent control rats, which were consistently ventilated throughout the experiment at an FiO2 of 1. The red boxes represent the hypoxic artificially induced hyperventilation (HAIH) group, which were ventilated during the first 60 minutes at an FiO2 of 1 and after that at an FiO2 of 0.08, with a respiratory rate titrated targeting a PaCO2 of 10 mm Hg. The blue boxes represent the hypoxic spontaneously hyperventilating group (HSH) group, which were ventilated during the first 60 minutes at an FiO2 of 1 and after that at an FiO2 of 0.08 without modification in respiratory rate. Differences among the HAIH and HSH groups were calculated with the Wilcoxon rank-sum test. Statistical significance was accepted as P < 0.01. A) The partial pressure of arterial oxygen was significantly higher for the HAIH at 120 minutes and had a tendency towards significance at 180 minutes (P = 0.013). B) The pH was significantly higher in the HAIH rats at 120 and 180 minutes (P = 0.005, P = 0.005). C) The partial pressure of arterial carbon dioxide was lower in the HAIH group (P = 0.005, P = 0.005) | PMC10165328 | AIT-53-44218-g002.jpg |
0.469325 | 998dc5277f9747398dfc64d608b7b9b5 | Selected laboratory results in rat groups at different time points. Laboratory data were measured at 60, 120, and 180 minutes. The data are presented in box-and-whisker plots. Whiskers depict the minimum and maximum values. The green boxes represent the values of the control rats, which were consistently ventilated throughout the experiment at an FiO2 of 1. The red boxes represent the values of the hypoxic artificially induced hyperventilation (HAIH) rats, which were ventilated during the first 60 minutes at an FiO2 of 1 and then at an FiO2 of 0.08, with a respiratory rate titrated targeting a PaCO2 of 10 mm Hg. The blue boxes represent the values of the hypoxic spontaneously hyperventilating (HSH) rats, which were ventilated during the first 60 minutes at an FiO2 of 1 and after that at an FiO2 of 0.08 with no modification in respiratory rate. Differences among the HAIH and HSH groups were calculated with the Wilcoxon rank-sum test. Statistical significance was accepted as P < 0.01. A) Arterial oxygen saturation (SaO2) was significantly higher in the HAIH group at 120 and 180 minutes (P = 0.005, P = 0.005). B) Arterial oxygen concentration (CaO2) was significantly higher in the HAIH group at 120 and 180 minutes (P = 0.005, P = 0.005). C) Serum glucose levels (mg dL-1) was significantly higher in the HAIH group at 180 minutes (P = 0.007). d) Serum lactate was lower in the HAIH group at 120 and 180 minutes, but not statistically significant (P = 0.021, P = 0.039) | PMC10165328 | AIT-53-44218-g003.jpg |
0.452459 | 760c8942abf74918bba0500293a29b29 | Control reactions for EMSA and relaxation assays
AWestern blot of HeLa cells treated with TOP3A siRNA, with or without transient expression of TOP3A Ser810*. The band corresponding to TOP3A Ser810* migrates close to a non‐specific band (indicated with #). β‐actin is used as a loading control.BElectrophoretic mobility shift assay (EMSA) using either 80‐mer or 40‐mer ssDNA substrates. Diagrams indicate singly and doubly shifted substrate.C, DControls for substrate migration in plasmid relaxation assays. Negatively supercoiled pUC19 plasmid DNA was either left untreated (lane 2) or treated with the indicated enzymes. E. coli TopoI‐treated plasmid DNA (lane 3) shows the migration of covalently closed relaxed DNA, BamHI‐treated DNA (lane 4) shows the migration of linearised plasmid and Nt.BspQI‐treated DNA (lane 5) shows the migration of nicked circular plasmid. Reactions were separated either in the absence of ethidium bromide (EtBr) and post‐stained for imaging (C) or run in the presence of EtBr (D). The migration of relaxed open, circular DNA and supercoiled DNA is indicated to the right of figure.EControls for TOP3A nicking activity. Negatively supercoiled pUC19 plasmid DNA was incubated with WT TOP3A protein as in Fig 5A, then separated on an agarose gel containing EtBr. The migration of nicked DNA and supercoiled DNA is indicated to the right of the figure. “M” indicates marker.
Source data are available online for this figure.
| PMC10165364 | EMMM-15-e16775-g001.jpg |
0.508582 | c9f768e183ab44b19fbc2cfdb7fa52cf | Purification of TOP3A variants and DNA‐binding assays
APurification of TOP3A variants. Each variant (3 pmol) was separated on a 4–20% stain‐free Criterion TGX SDS–PAGE gel (Bio‐Rad) and imaged using a stain‐free imager.B–JElectrophoretic mobility shift assay (EMSA) to assess DNA‐binding activity of TOP3A variants to a 5′ radiolabelled 80‐nt‐long ssDNA oligonucleotide.KQuantification of DNA‐binding activity as in (B–J), expressed as the proportion of bound DNA. Data represent mean values with at least three independent experiments per data point. Error bars represent SEM. Symbols represent significance values (one‐way ANOVA) and are colour coded to the data points. *P < 0.05, **P < 0.01, ****P < 0.0001.
Source data are available online for this figure.
| PMC10165364 | EMMM-15-e16775-g002.jpg |
0.421165 | dcdc08d71dae4e4d90f8563fe528de92 | DNA relaxation activity of TOP3A variants
A–IRelaxation of negatively supercoiled pUC19 substrate by recombinant TOP3A variants. “M” indicates marker.JQuantification of DNA relaxation data as in (A–I). Data represent the percentage of substrate released from negatively supercoiled form, expressed as the mean of three independent experiments (except WT, for which n = 4). Error bars represent SEM. Symbols represent significance values (one‐way ANOVA) and are colour coded to the data points. ****P < 0.0001.
Source data are available online for this figure.
| PMC10165364 | EMMM-15-e16775-g003.jpg |
0.390249 | 3100716610f24ba5a3303617ea2de9e7 | Establishing the phase of TOP3A variants using long‐read sequencing
A–ECreation of an assembled haplotype at the TOP3A locus in Pa5‐1. (A) Three reads highlighted in brown, orange and blue span the interval between target variants c.298A>G and c.1723A>G. (B) Read‐level data for the haplotype assembled reads (highlighted brown and orange), which are reference nucleotide supporting at position c.1723. (C) Read‐level data used to create the assembled haplotype through variant‐supporting nucleotides at positions c.1282–21 and c.1468–11. (D) Read‐level data for the haplotype assembled read (highlighted blue), which is variant supporting at position c.298. (E) A schematic illustration of the assembled haplotype, for target variants c.298A>G and c.1723A>G, which are consistent with a trans configuration (arranged on different parental alleles). Nomenclature provided according to transcript NM_004618.5.F–JCreation of an assembled haplotype at the TOP3A locus in Pa6. (F) Two reads highlighted in red and pink span the interval between target variants c.778C>T and c.1723A>G. (G) Read‐level data for the haplotype assembled read (highlighted red), which is variant nucleotide supporting at position c.1723. (H) Read‐level data used to create the assembled haplotype from reference supporting nucleotides at positions chr17:18195268 and chr17:18195287 (red and pink highlighted reads). (I) Read‐level data for the haplotype assembled read (highlighted pink), which is reference supporting at position c.778. (J) A schematic illustration of the assembled haplotype for target variants c.778C>T and c.1723A>G, which are consistent with a trans configuration (arranged on different parental alleles). Nomenclature provided according to transcript NM_004618.5.
| PMC10165364 | EMMM-15-e16775-g004.jpg |
0.425576 | 950ea85209274e47854ff645075162f9 | Assessment of decatenation activity of TOP3A variants
ASchematic of substrate construction for ssDNA decatenation assays. The two ring oligos (R1 and R2) are held in an Lk1 conformation by holder oligos (R1 and R2) and ligated (red arrows) with the aid of splint oligos (S1 and S2), and then purified. Incubation with TOP3A decatenates this substrate into two independent circular ssDNA oligos.B–JssDNA decatenation assays using TOP3A variants, using substrates constructed as in (A).KQuantification of ssDNA decatenation activity as in (B–J). Data represent the percentage of decatenated substrate expressed as mean values, ±SEM, from independent experiments, n = 3 (WT, p.Ala95Val, p.Met100Val and p.Arg558Trp), n = 4 (p.Ala176Val), n = 5 (p.Met575Val) and n = 2 (p.Leu37Val). Symbols represent significance values (one‐way ANOVA) and are colour coded to the data points. *P < 0.05, **P < 0.01.LssDNA decatenation assays using combinations of compound heterozygous TOP3A variants. Reactions contained 50 fmol of protein (for single variants, lanes 2–7) or 25 fmol for each of two variants (lanes 8–10).MQuantifications of ssDNA decatenation assays as in (L). Data represent the mean percentage of decatenated substrate from three independent experiments. Significance values are shown for one‐way ANOVA compared to the WT protein. *P < 0.05, **P < 0.01, ***P < 0.001.
Source data are available online for this figure.
| PMC10165364 | EMMM-15-e16775-g005.jpg |
0.476901 | 7bac19d056454758b7b97201c411e088 | Modelling of TOP3A variants and SNPs
The location of pathological variants within the crystal structure of TOP3A, including RMI1, a nuclear‐binding partner of TOP3A (PDB: 4CGY). The affected residues are shown in red, and domains are coloured according to format shown in Fig 1B.The presence of previously identified SNPs in TOP1MT (rs11544484, p.Val256Ile; and rs2293925, p.Arg525Trp; Zhang et al, 2017) in TOP3A patients reported in this study for which the information is available. Half‐filled rectangles indicate a heterozygous SNP, and filled rectangles indicate a homozygous SNP.
Source data are available online for this figure.
| PMC10165364 | EMMM-15-e16775-g006.jpg |
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