Journal: Antimicrobial Agents and Chemotherapy

Article Title: Pharmacodynamics of Tebipenem: New Options for Oral Treatment of Multidrug-Resistant Gram-Negative Infections

doi: 10.1128/AAC.00603-19

Figure Lengend Snippet: Challenge strains used in this study

Article Snippet: The genotypes of the challenge strains are shown in . table ft1 table-wrap mode="anchored" t5 TABLE 1 caption a7 Species Strain identifier Genotype Modal (range) tebipenem MIC (mg/liter) E. coli NCTC 13462 CTX-M2 0.016 (0.016) E. coli ATCC 35218 TEM-1 ESBL 0.016 (0.008–0.016) E. coli ATCC 25922 Wild type 0.016 (0.008–0.016) E. coli SPT 719 (JMI 742654) SHV-12, TEM-1 0.03 (0.03–0.25) E. coli SPT 720 (JMI 850505) mcr-1 , CMY-2, OXA-1, TEM1 0.5 (0.25–0.5) E. coli SPT 731 (JMI 845741) CTX-M-15, OXA-1/30, TEM-1 ST131 a O25b clade 0.03 (0.015–0.03) K. pneumoniae NCTC 13465 ESBL and CTX-M25 0.03 (0.015–0.03) K. pneumoniae ATCC 27736 Wild type 0.03 (0.03–0.06) K. pneumoniae SPT 725 (JMI 776273) SHV-12 0.125 (0.06–0.25) K. pneumoniae SPT 722 (JMI 934954) CTX-M-15, OXA-1, OXA-9, SHV-28, TEM-1, OmpK35 disrupted, OmpK36 altered 0.25 (0.12–0.5) K. pneumoniae SPT 723 (JMI 632346) CTX-M-15, OXA-1, SHV-12 0.125 (0.12) Open in a separate window a ST131, sequence type 131.

Techniques:

Journal: Antimicrobial Agents and Chemotherapy

Article Title: Pharmacodynamics of Tebipenem: New Options for Oral Treatment of Multidrug-Resistant Gram-Negative Infections

doi: 10.1128/AAC.00603-19

Figure Lengend Snippet: Pharmacodynamics of tebipenem against E. coli ATCC 25922 in a neutropenic thigh infection model. The data are the mean ± standard deviation for 3 mice collected over the course of three independently conducted experiments. The solid squares are the bacterial density at the commencement of therapy, which was at 2 h postinoculation. The mean of these points defines the stasis line, depicted by the broken horizontal line. The open circles are the data points from mice sacrificed after receiving 24 h of antibacterial therapy. The solid line is the fit of an inhibitory sigmoid Emax model.

Article Snippet: The genotypes of the challenge strains are shown in . table ft1 table-wrap mode="anchored" t5 TABLE 1 caption a7 Species Strain identifier Genotype Modal (range) tebipenem MIC (mg/liter) E. coli NCTC 13462 CTX-M2 0.016 (0.016) E. coli ATCC 35218 TEM-1 ESBL 0.016 (0.008–0.016) E. coli ATCC 25922 Wild type 0.016 (0.008–0.016) E. coli SPT 719 (JMI 742654) SHV-12, TEM-1 0.03 (0.03–0.25) E. coli SPT 720 (JMI 850505) mcr-1 , CMY-2, OXA-1, TEM1 0.5 (0.25–0.5) E. coli SPT 731 (JMI 845741) CTX-M-15, OXA-1/30, TEM-1 ST131 a O25b clade 0.03 (0.015–0.03) K. pneumoniae NCTC 13465 ESBL and CTX-M25 0.03 (0.015–0.03) K. pneumoniae ATCC 27736 Wild type 0.03 (0.03–0.06) K. pneumoniae SPT 725 (JMI 776273) SHV-12 0.125 (0.06–0.25) K. pneumoniae SPT 722 (JMI 934954) CTX-M-15, OXA-1, OXA-9, SHV-28, TEM-1, OmpK35 disrupted, OmpK36 altered 0.25 (0.12–0.5) K. pneumoniae SPT 723 (JMI 632346) CTX-M-15, OXA-1, SHV-12 0.125 (0.12) Open in a separate window a ST131, sequence type 131.

Techniques: Infection, Standard Deviation

Journal: Antimicrobial Agents and Chemotherapy

Article Title: Pharmacodynamics of Tebipenem: New Options for Oral Treatment of Multidrug-Resistant Gram-Negative Infections

doi: 10.1128/AAC.00603-19

Figure Lengend Snippet: Pharmacokinetics of tebipenem. The data are the mean ± standard deviation for 3 mice. A destructive design was used. Mice sampled in the period from 16 to 24 h had received drug at 0, 8, and 16 h. The mice were infected with E. coli ATCC 25922.

Article Snippet: The genotypes of the challenge strains are shown in . table ft1 table-wrap mode="anchored" t5 TABLE 1 caption a7 Species Strain identifier Genotype Modal (range) tebipenem MIC (mg/liter) E. coli NCTC 13462 CTX-M2 0.016 (0.016) E. coli ATCC 35218 TEM-1 ESBL 0.016 (0.008–0.016) E. coli ATCC 25922 Wild type 0.016 (0.008–0.016) E. coli SPT 719 (JMI 742654) SHV-12, TEM-1 0.03 (0.03–0.25) E. coli SPT 720 (JMI 850505) mcr-1 , CMY-2, OXA-1, TEM1 0.5 (0.25–0.5) E. coli SPT 731 (JMI 845741) CTX-M-15, OXA-1/30, TEM-1 ST131 a O25b clade 0.03 (0.015–0.03) K. pneumoniae NCTC 13465 ESBL and CTX-M25 0.03 (0.015–0.03) K. pneumoniae ATCC 27736 Wild type 0.03 (0.03–0.06) K. pneumoniae SPT 725 (JMI 776273) SHV-12 0.125 (0.06–0.25) K. pneumoniae SPT 722 (JMI 934954) CTX-M-15, OXA-1, OXA-9, SHV-28, TEM-1, OmpK35 disrupted, OmpK36 altered 0.25 (0.12–0.5) K. pneumoniae SPT 723 (JMI 632346) CTX-M-15, OXA-1, SHV-12 0.125 (0.12) Open in a separate window a ST131, sequence type 131.

Techniques: Standard Deviation, Infection

Journal: Antimicrobial Agents and Chemotherapy

Article Title: Pharmacodynamics of Tebipenem: New Options for Oral Treatment of Multidrug-Resistant Gram-Negative Infections

doi: 10.1128/AAC.00603-19

Figure Lengend Snippet: Pharmacodynamics of tebipenem against E. coli and K. pneumoniae. Data are the mean ± standard deviation for 3 mice. (A) Pharmacodynamics of E. coli versus K. pneumoniae; (B) pharmacodynamics of ESBL-producing Enterobacteriaceae versus the wild type. Data from the strains were comodeled using fAUC0-24/MIC · 1/tau.

Article Snippet: The genotypes of the challenge strains are shown in . table ft1 table-wrap mode="anchored" t5 TABLE 1 caption a7 Species Strain identifier Genotype Modal (range) tebipenem MIC (mg/liter) E. coli NCTC 13462 CTX-M2 0.016 (0.016) E. coli ATCC 35218 TEM-1 ESBL 0.016 (0.008–0.016) E. coli ATCC 25922 Wild type 0.016 (0.008–0.016) E. coli SPT 719 (JMI 742654) SHV-12, TEM-1 0.03 (0.03–0.25) E. coli SPT 720 (JMI 850505) mcr-1 , CMY-2, OXA-1, TEM1 0.5 (0.25–0.5) E. coli SPT 731 (JMI 845741) CTX-M-15, OXA-1/30, TEM-1 ST131 a O25b clade 0.03 (0.015–0.03) K. pneumoniae NCTC 13465 ESBL and CTX-M25 0.03 (0.015–0.03) K. pneumoniae ATCC 27736 Wild type 0.03 (0.03–0.06) K. pneumoniae SPT 725 (JMI 776273) SHV-12 0.125 (0.06–0.25) K. pneumoniae SPT 722 (JMI 934954) CTX-M-15, OXA-1, OXA-9, SHV-28, TEM-1, OmpK35 disrupted, OmpK36 altered 0.25 (0.12–0.5) K. pneumoniae SPT 723 (JMI 632346) CTX-M-15, OXA-1, SHV-12 0.125 (0.12) Open in a separate window a ST131, sequence type 131.

Techniques: Standard Deviation

Journal: Antimicrobial Agents and Chemotherapy

Article Title: Pharmacodynamics of Tebipenem: New Options for Oral Treatment of Multidrug-Resistant Gram-Negative Infections

doi: 10.1128/AAC.00603-19

Figure Lengend Snippet: Histogram of the magnitude of the fAUC0-24/MIC · 1/tau value required to achieve stasis for tebipenem against strains of E. coli (n = 6) and K. pneumoniae (n = 5). The median fAUC0-24/MIC · 1/tau value was 23.

Article Snippet: The genotypes of the challenge strains are shown in . table ft1 table-wrap mode="anchored" t5 TABLE 1 caption a7 Species Strain identifier Genotype Modal (range) tebipenem MIC (mg/liter) E. coli NCTC 13462 CTX-M2 0.016 (0.016) E. coli ATCC 35218 TEM-1 ESBL 0.016 (0.008–0.016) E. coli ATCC 25922 Wild type 0.016 (0.008–0.016) E. coli SPT 719 (JMI 742654) SHV-12, TEM-1 0.03 (0.03–0.25) E. coli SPT 720 (JMI 850505) mcr-1 , CMY-2, OXA-1, TEM1 0.5 (0.25–0.5) E. coli SPT 731 (JMI 845741) CTX-M-15, OXA-1/30, TEM-1 ST131 a O25b clade 0.03 (0.015–0.03) K. pneumoniae NCTC 13465 ESBL and CTX-M25 0.03 (0.015–0.03) K. pneumoniae ATCC 27736 Wild type 0.03 (0.03–0.06) K. pneumoniae SPT 725 (JMI 776273) SHV-12 0.125 (0.06–0.25) K. pneumoniae SPT 722 (JMI 934954) CTX-M-15, OXA-1, OXA-9, SHV-28, TEM-1, OmpK35 disrupted, OmpK36 altered 0.25 (0.12–0.5) K. pneumoniae SPT 723 (JMI 632346) CTX-M-15, OXA-1, SHV-12 0.125 (0.12) Open in a separate window a ST131, sequence type 131.

Techniques:

Journal: Antimicrobial Agents and Chemotherapy

Article Title: Pharmacodynamics of Tebipenem: New Options for Oral Treatment of Multidrug-Resistant Gram-Negative Infections

doi: 10.1128/AAC.00603-19

Figure Lengend Snippet: Pharmacodynamics of ertapenem against E. coli. Data are the mean ± standard deviation for 3 mice. (A) Pharmacodynamics determined using fT>MIC, which is the traditional measure of drug exposure for the carbapenems. Stasis was achieved with a fT>MIC of 0.60. (B) The same data from the assay whose results are presented in panel A, but using fAUC0-24/MIC · 1/tau as the pharmacodynamic index. Stasis was achieved with a value of 46.

Article Snippet: The genotypes of the challenge strains are shown in . table ft1 table-wrap mode="anchored" t5 TABLE 1 caption a7 Species Strain identifier Genotype Modal (range) tebipenem MIC (mg/liter) E. coli NCTC 13462 CTX-M2 0.016 (0.016) E. coli ATCC 35218 TEM-1 ESBL 0.016 (0.008–0.016) E. coli ATCC 25922 Wild type 0.016 (0.008–0.016) E. coli SPT 719 (JMI 742654) SHV-12, TEM-1 0.03 (0.03–0.25) E. coli SPT 720 (JMI 850505) mcr-1 , CMY-2, OXA-1, TEM1 0.5 (0.25–0.5) E. coli SPT 731 (JMI 845741) CTX-M-15, OXA-1/30, TEM-1 ST131 a O25b clade 0.03 (0.015–0.03) K. pneumoniae NCTC 13465 ESBL and CTX-M25 0.03 (0.015–0.03) K. pneumoniae ATCC 27736 Wild type 0.03 (0.03–0.06) K. pneumoniae SPT 725 (JMI 776273) SHV-12 0.125 (0.06–0.25) K. pneumoniae SPT 722 (JMI 934954) CTX-M-15, OXA-1, OXA-9, SHV-28, TEM-1, OmpK35 disrupted, OmpK36 altered 0.25 (0.12–0.5) K. pneumoniae SPT 723 (JMI 632346) CTX-M-15, OXA-1, SHV-12 0.125 (0.12) Open in a separate window a ST131, sequence type 131.

Techniques: Standard Deviation

Journal: Antimicrobial Agents and Chemotherapy

Article Title: Pharmacodynamics of Tebipenem: New Options for Oral Treatment of Multidrug-Resistant Gram-Negative Infections

doi: 10.1128/AAC.00603-19

Figure Lengend Snippet: Hollow-fiber infection model. The challenge strain (SPT719) used in this experiment is an ESBL-producing E. coli strain (tebipenem MIC, 0.03 mg/liter). Each panel represents the data from an individual fiber. The data represent the total bacterial population (open red triangles), a resistant subpopulation (open blue circles), and the pharmacokinetic profile of tebipenem (open black squares). The outputs from the mathematical model are shown using the same colors. The Bayesian posterior estimates for each fiber are shown. The fAUC0-24/MIC · 1/tau index values associated with the q24h, q12h, q8h, and q6h schedules are 17.3, 34.58, 51.87, and 69.15, respectively. Logarithmic killing was observed with at fAUC0-24/MIC · 1/tau values of 34.58 to 51.87, and suppression of resistance was observed at a value of 69.15. Panel A shows the control. In panels B to E, the same total amount of SPR859 has been administered in different schedules.

Article Snippet: The genotypes of the challenge strains are shown in . table ft1 table-wrap mode="anchored" t5 TABLE 1 caption a7 Species Strain identifier Genotype Modal (range) tebipenem MIC (mg/liter) E. coli NCTC 13462 CTX-M2 0.016 (0.016) E. coli ATCC 35218 TEM-1 ESBL 0.016 (0.008–0.016) E. coli ATCC 25922 Wild type 0.016 (0.008–0.016) E. coli SPT 719 (JMI 742654) SHV-12, TEM-1 0.03 (0.03–0.25) E. coli SPT 720 (JMI 850505) mcr-1 , CMY-2, OXA-1, TEM1 0.5 (0.25–0.5) E. coli SPT 731 (JMI 845741) CTX-M-15, OXA-1/30, TEM-1 ST131 a O25b clade 0.03 (0.015–0.03) K. pneumoniae NCTC 13465 ESBL and CTX-M25 0.03 (0.015–0.03) K. pneumoniae ATCC 27736 Wild type 0.03 (0.03–0.06) K. pneumoniae SPT 725 (JMI 776273) SHV-12 0.125 (0.06–0.25) K. pneumoniae SPT 722 (JMI 934954) CTX-M-15, OXA-1, OXA-9, SHV-28, TEM-1, OmpK35 disrupted, OmpK36 altered 0.25 (0.12–0.5) K. pneumoniae SPT 723 (JMI 632346) CTX-M-15, OXA-1, SHV-12 0.125 (0.12) Open in a separate window a ST131, sequence type 131.

Techniques: Infection

Journal: Molecular Systems Biology

Article Title: Probing cell identity hierarchies by fate titration and collision during direct reprogramming

doi: 10.15252/msb.202211129

Figure Lengend Snippet: Overview of different reprogramming factor and the characteristics of their target cells.

Article Snippet: Finally, Ascl1 was amplified from pCAG‐Ascl1‐IRES‐DsRed (Heinrich et al , ), MyoD1 was amplified from pCAG‐MyoD1‐IRES‐GFP (in‐house), Oct4 was amplified from pLV‐TetO‐Oct4 (see above), Sox2 was amplified from pCAG‐Sox2‐IRES‐GFP (in‐house), FoxA2 was amplified from pLV‐PGK‐FoxA2 (pLV.PGK.mFoxa2 was a gift from Malin Parmar, Addgene plasmid # 33014; http://n2t.net/addgene:33014 ; RRID:Addgene_33,014) and Hnf1a was amplified from E14.5 mouse liver cDNA.

Techniques:

Journal: Molecular Systems Biology

Article Title: Probing cell identity hierarchies by fate titration and collision during direct reprogramming

doi: 10.15252/msb.202211129

Figure Lengend Snippet: A Bar plot of transgene‐wise coefficient vector magnitude as a measure of induced transcriptomic changes by individual reprogramming transcription factors (see Differential expression analysis section in for further details, A = Ascl1, M = MyoD1, F = FoxA2, S = Sox2, O = Oct4). B Latent pseudotime (lineage progression) superimposed on a Uniform Manifold Approximation and Projection (UMAP) of the dataset computed with scVelo (Bergen et al , ; see RNA velocity and CellRank analysis section in for further details). C Heatmap showing the intersection of upregulated genes in individual factor conditions ( y ‐axis) vs. putative binding sites derived from a publicly available ChIP dataset for MyoD1 (M), Ascl1 (A), FoxA2 (F), and Sox2 (S) ( x ‐axis; Oki et al , ). D Matrixplot showing the relative mean expression of key target genes related to the different lineages for the indicated single factor conditions and control vector expressing fibroblasts (Fib.). E Fibroblast score (see Unsupervised analysis of single‐cell RNA‐seq data in and Appendix Table for further details) for single factor conditions compared with fibroblasts expressing only control vectors (Fib. = Fibroblasts). The number of data points per violin plot is the number of cells per matched condition shown in Fig . For each violin, the center dot represents the median, the centerline defines the range and the solid box marks the interquartile range (IQR). F Venn diagram of downregulated gene overlap between single factor conditions. Downregulated genes were determined by performing differential expression between each condition and the control vector carrying fibroblasts (See Differential expression section in for further details).

Article Snippet: Finally, Ascl1 was amplified from pCAG‐Ascl1‐IRES‐DsRed (Heinrich et al , ), MyoD1 was amplified from pCAG‐MyoD1‐IRES‐GFP (in‐house), Oct4 was amplified from pLV‐TetO‐Oct4 (see above), Sox2 was amplified from pCAG‐Sox2‐IRES‐GFP (in‐house), FoxA2 was amplified from pLV‐PGK‐FoxA2 (pLV.PGK.mFoxa2 was a gift from Malin Parmar, Addgene plasmid # 33014; http://n2t.net/addgene:33014 ; RRID:Addgene_33,014) and Hnf1a was amplified from E14.5 mouse liver cDNA.

Techniques: Plasmid Preparation, Expressing, Binding Assay, Derivative Assay, RNA Sequencing Assay

Journal: Molecular Systems Biology

Article Title: Probing cell identity hierarchies by fate titration and collision during direct reprogramming

doi: 10.15252/msb.202211129

Figure Lengend Snippet: A Fibroblast score (see Unsupervised analysis of single‐cell RNA‐seq data section in for further details) for single and double factor conditions in comparison to control vector carrying fibroblasts. The number of data points per violin plot is the number of cells per matched condition shown in Fig . For each violin, the center dot represents the median, the centerline defines the range and the solid box marks the interquartile range (IQR). B PCA scatter plot of first (PC1, vertical) and second (PC2, horizontal) loading of the different conditions after collapsing into pseudobulk samples. Colored rectangles correspond to clusters defined in Fig . CV: Control vector expressing fibroblasts. C Correlation matrix of linear model effects for single (left panel) and double factor (right panel) collisions. Color defines direction of correlation of gene‐wise coefficient vectors (negative = blue, positive = red) and color tone depicts size of correlation. See Differential expression analysis section in for further details. D Stacked violin plots showing the standardized median expression of several lineage marker genes for single factor conditions (bold) and upon collision with the indicated factors (A = Ascl1, M = MyoD1, F = FoxA2, S = Sox2). E Conceptual summary of fate titration analysis (upper left panel) and data‐derived examples for the indicated combinations of factors. Shown are the Louvain cluster assignments for the indicated collisions (upper panels) and the decision boundaries for indicated intermediate fates according to transcription factor levels (lower panels). Transcription factor levels shown on the x ‐ and y ‐axis are log‐normalized expression values scaled into the dynamic range of the single‐positive condition. Cells are colored according to their Louvain cluster identity. See Fate titration section in for further details. F, G Predictive performance for a linear model of the categorical condition variable (L‐C: Linear condition.), a linear model of the log of the transgene expression (L‐E: Linear expression), and a nonlinear model of the log of the transgene expression (NL‐E: Nonlinear expression) in randomly held‐out test cells ( n = 1,184 cells). For the task of Louvain cluster assignment prediction (F), shown are the area under the receiver–operator characteristic curve (ROC AUC), top 3 accuracy (Top 3 Acc.), Accuracy (Acc.), and class‐balanced accuracy (Bal. Acc.). For the task of prediction of log‐normalized expression values of highly variable genes (G), shown is the cell‐wise R2 (G). See Supervised modeling section in for further details. For each box in G, the centerline defines the median, the height of the box is given by the interquartile range (IQR), the whiskers are given by 1.5 * IQR, and the outliers are given as points beyond the minimum or maximum whisker. H, I Predictive performance on held‐out reprogramming conditions for models and metrics as described in (H), with the exception of the baseline model, which is a linear model of binary transgene presence (L‐B: Linear binary). The hold‐out task in (H) is a particular triple‐positive condition as indicated in the legend ( N = 4). The hold‐out task in (I) is the set of all triple‐positive conditions and models are either trained on single‐positive conditions only or on single‐ and double‐positive conditions ( N = 4). See Supervised modeling section in for further details. For each box, the centerline defines the median, the height of the box is given by the interquartile range (IQR), the whiskers are given by 1.5 * IQR, and the outliers are given as points beyond the minimum or maximum whisker.

Article Snippet: Finally, Ascl1 was amplified from pCAG‐Ascl1‐IRES‐DsRed (Heinrich et al , ), MyoD1 was amplified from pCAG‐MyoD1‐IRES‐GFP (in‐house), Oct4 was amplified from pLV‐TetO‐Oct4 (see above), Sox2 was amplified from pCAG‐Sox2‐IRES‐GFP (in‐house), FoxA2 was amplified from pLV‐PGK‐FoxA2 (pLV.PGK.mFoxa2 was a gift from Malin Parmar, Addgene plasmid # 33014; http://n2t.net/addgene:33014 ; RRID:Addgene_33,014) and Hnf1a was amplified from E14.5 mouse liver cDNA.

Techniques: RNA Sequencing Assay, Plasmid Preparation, Expressing, Marker, Titration, Derivative Assay, Whisker Assay