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this points towards a specific mode of action for the emergence of irAEs A modified treatment regimen with intermittent dosing of PI3Kδi in mouse models led to a significant decrease in tumour growth without inducing pathogenic T cells in colonic tissue indicating that alternative dosing regimens might limit toxicity no trials have been performed to explicitly explore this concept in humans Here we provide an in-depth investigation of the effect of PI3Kδ inhibition on immune cells in patients with solid tumours and also explore the mechanism that leads to irAEs intervals and occurrence and grade of irAEs in PI3Kδi-treated (top) and placebo-treated (bottom) patients; patients with partial response or complete pathological response are highlighted in magenta Vertical dashed lines show average duration of treatment Volcano plots of whole-tumour RNA-seq analysis (b) or bulk RNA-seq analysis of purified tumour-infiltrating CD8+ T cells (d) comparing patients treated with AMG-319 to those treated with placebo DEGs between pre- and post-treatment samples are highlighted in red and were called by DEseq2; adjusted P values were calculated with the Benjamini–Hochberg method Depicted are transcripts that changed in expression by more than 0.75-fold and had an adjusted P value of ≤0.1 (b) or <0.05 (d) Median cell count of FOXP3+ cells in pre- and post-treatment samples of placebo- or AMG319-treated patients AMG-319-treated patients have been further stratified into patients for whom the interval between stopping of treatment and immunohistochemistry assessment was more than four days (long interval (LI)) or less than one day (short interval (SI)) Data are mean ± s.e.m.; two-tailed Wilcoxon matched-pairs signed rank test (c) Source data implying that Treg cell levels normalize quickly once treatment has been stopped these data indicate that PI3Kδ inhibition causes profound changes in the tumour microenvironment (TME) characterized by enhanced CD4+ and CD8+ T cell activation oligoclonal T cell expansion and increased cytolytic activity consistent with a decrease in intratumoural Treg cells enabling T cell activation and leading to a rapid onset of dose-limiting toxicity despite showing high expression of PD-1 and TOX are not functionally exhausted in this tumour model Uniform manifold approximation and projection (UMAP) plots single-cell transcriptomes and T cell receptor (TCR) sequence data of FOXP3+CD4+ T cells in placebo-treated control mice (a; n = 3 mice) and PI-3065-treated mice (b; n = 3 mice) Circle size indicates degree of clonal expansion Violin plots showing Seurat-normalized expression levels (colour scale depicts percentage of expressing cells) of highlighted genes in the indicated clusters from a edges delineate the 25th and 75th percentiles and whiskers extend to minimum and maximum values Scatter plots showing Seurat-normalized expression levels of highlighted genes in colonic Treg cells in placebo-treated and PI-3065-treated mice The dashed line indicates the expression cut-off; numbers indicate the frequency in each quadrant depicting likely developmental trajectories of Treg cells from a Source data Mice were fed either a control diet or a diet containing PI-3065 for the duration of the experiment and were additionally treated with 2.5% dextran sulfate sodium (DSS) from day 14 to day 20 Change in body weight is shown relative to body weight before treatment on day 0 Representative sections from haematoxylin and eosin (H&E) histology scans and colitis scoring from zinc-formalin-fixed colonic tissue sections from mice treated with placebo or PI3Kδi in a n = 10 mice (placebo) and n = 9 (PI3Kδi) (one mouse died before the experimental endpoint); P < 0.0001 for inflammation crypt damage and overall colitis scoring; representative samples from the H&E staining are highlighted in magenta Mice were inoculated subcutaneously with B16F10-OVA cells and fed either a control diet or a diet containing PI-3065 PI3Kδi for 2 days followed by 5 days off drug; intermittent dosing PI3Kδi for 4 days followed by 3 days off drug; continuous dosing Tumour volume (c) and flow-cytometric analyses of cell frequencies (d) of mice treated as indicated n = 8 mice (continuous dosing) and n = 8 mice (infrequent dosing) P = 0.0023; placebo versus continuous dosing (c) P = 0.0059; placebo versus continuous dosing P = 0.003; continuous dosing versus intermittent dosing and infrequent dosing (left) P = 0.0003; placebo versus continuous dosing P = 0.0005; for continuous dosing versus intermittent dosing P = 0.0001; placebo versus infrequent dosing (d; third from left) P < 0.0001; placebo versus continuous dosing P = 0.0086; placebo versus intermittent dosing P = 0.045; continuous dosing versus intermittent dosing and infrequent dosing Data are mean ± s.e.m.; two-tailed Mann–Whitney test (a–c) or one-way ANOVA comparing the mean of each group with the mean of each other group followed by Dunnett’s test (d) Data are representative of at least two independent experiments Source data Mice were inoculated subcutaneously with B16F10-OVA cells and fed either a control diet or a diet containing PI-3065 inhibitor, with treatment conditions as in (Fig. 3c, d) Seurat clustering visualized by UMAP of CD8+ T cells in colonic tissue at day 18 after tumour inoculation of mice treated as indicated Pie charts depict the percentage of each cluster under the different treatment conditions.b Heat map comparing gene expression of cells in all clusters Depicted are transcripts that change in expression by more than 0.5-fold with adjusted P values of ≤0.05 DEGs were called by MAST analysis; adjusted P values were calculated with the Benjamini–Hochberg method Sell is also known as Cd62l; Itgae is also known as Cd103 Seurat-normalized expression of indicated genes in the different clusters Clone size of cells in indicated clusters in UMAP space Euler diagrams show the clonal overlap between CD8+ T cells in the different clusters RNA velocity analysis visualized by UMAP depicting likely developmental trajectories of CD8+ T cells Source data Given that IL-10+ ST2 Treg cells have been implicated in controlling IL-17 responses that would otherwise cause colitis30 our data provide an explanation for the ripple effects ensuing after PI3Kδ inhibition that eventually cause irAEs our data imply that Il10-expressing ST2 Treg cells are highly susceptible to PI3Kδ inhibition leading to a decrease in their abundance and thus to a disruption of gut homeostasis by causing a rapid expansion of pathogenic TH17 and TC17 cells that together with a decrease in innate-like CD8+ T cells intermittent PI3Kδi dosing provides the means to uncouple the anti-tumour effects from irAEs providing ample rationale to test this concept in a follow-up clinical trial Here we find that in human and mouse tumour tissue PI3Kδ inhibition leads to substantial changes in the cell composition of the TME by reducing the number of Treg cells and activating intratumoural CD4+ and CD8+ T cells which clonally expand and display heightened cytotoxic and cytolytic features we find substantial changes in the transcriptional features and composition of colonic Treg cell subsets which indicate that PI3Kδ inhibition affects Treg functionality thus altering Treg cell frequencies or Treg subtype compositions in both tumour and non-malignant tissues specifically the depletion of Il10-expressing ST2 Treg cells is associated with colitis and expansion of pathogenic TC17 and TH17 T cell subsets in colonic tissue these findings might be more broadly applicable as tissue-resident ST2 Treg cells have been described in many non-malignant organs frequently affected by irAEs (for example in skin) or might be affected by other Treg cell-targeting immunotherapies (for example We show in mouse models that intermittent dosing with PI3Kδi is a rational treatment strategy that combines sustained anti-tumour immunity with reduced toxicity Our data show that the immunomodulatory effects of PI3Kδi need to be evaluated judiciously in treatment-naive patients unaffected by multiple lines of treatment and the immunosuppressive effect of haematological malignancies such as chronic lymphocytic leukaemia (CLL) It is clear that in the neoadjuvant setting in patients with HNSCC at the evaluated doses and with daily scheduling PI3Kδ inhibition has an unfavourable safety profile limiting its feasibility and clinical benefit by causing frequent and severe grade 3/4 irAEs probably driven by modulation of Treg cell behaviour in non-malignant tissues decreased dosages or an altered PI3Kδi treatment regimen will be required in solid tumours—especially in immune-competent patients—in order to be able to exploit the clear anti-tumour immune response induced by PI3Kδi while limiting the adverse effects associated with reduced Treg function in healthy tissues our data suggest that the unique cellular composition of effector versus regulatory cells in the TME of each patient might be an important determinant of the efficacy of PI3Kδ inhibition PI3Kδi might be especially useful in patients with high levels of intratumoural Treg cells and an unfavourable ratio of Treg versus CD8+ tumour-infiltrating lymphocytes (TILs) in pre-treatment samples Our study sets the stage for further exploration of PI3Kδ inhibitors as immunomodulatory agents in solid tumours Blood samples were collected during the course of the study from which plasma and peripheral blood mononuclear cells (PBMCs) were collected PBMCs were isolated by centrifugation over lymphoprep (Axis-Shield PoC AS) Double immunostaining for CD8 and FOXP3 was performed on a Leica Bond RX platform with antigen retrieval performed for 20 min at 97 °C Bond ER2 antigen retrieval solution Primary antibodies were incubated for 30 min at room temperature (FoxP3 - Abcam: Clone 236A/E7 1:100 dilution; CD8 - DAKO: Clone C8/144B 1:50 dilution) and detected using the Leica Refine Polymer brown and red detection systems Analysis was performed by two independent and blinded head and neck pathologists counting intratumoural CD8+ and FOXP3+ TIL in multiple random high-power fields at 200× magnification Fifty microlitres of thawed plasma samples were mixed with 300 μl of extraction solution (100 ng ml−1 [2H3 centrifuged at 10,000g for 5 min to precipitate the plasma proteins The supernatant was transferred to a UPLC vial and placed on the autosampler (maintained at 8 °C) for analysis A freshly prepared calibration curve in the range 1–1,000 ng ml−1 and frozen QC samples at 10 500 and 1,000 ng ml−1 (K2 EDTA human plasma spiked with AMG319) were analysed alongside each batch of patient samples Five microlitres of supernatant was injected into the UPLC-MS/MS system configured with a Waters Acquity UPLC and Waters Quattro Premier XE mass spectrometer Analytes were separated on an Acquity UPLC BEH C18 1.7 μm (2.1 mm × 100 mm) column with a mobile phase flow rate of 0.3 ml min−1 Analytes were detected using the multiple reaction monitoring (MRM) mode of the MS/MS system operating in positive ion electrospray mode 251.3→251.3 and 251.3→236.3 for AMG319 and at m/z 390.5→254.4 for [2H3 Waters Ltd.) was used to control the instrumentation and for analysis of the peaks of interest and processing of spectral data Whole blood samples (10 ml) were collected in sodium heparin tubes pre-dose and 4 h post dose on days 1 and 15 for the first 11 patients (day 8 and 15 for the remaining 19 patients) Blood was stimulated with double-diluted anti-IgD (25–0.008 µg ml−1) in deep well plates for 5 min Blood was then lysed and fixed with BD PhosFlow Lyse/Fix buffer Cell pellets were washed and then stored at −80 °C until all samples from the same patient were ready for further analysis cells pellets were incubated with anti-human CD3-FITC and CD14-FITC permeabilized with 80% MeOH and washed again before intracellular staining with CD20-PE Cy7 and pAKT (S473) Stained cell pellets were washed again before staining with a secondary antibody (anti-rabbit Alexa 647) Events were subsequently acquired on a Canto II flow cytometer (BD Bioscience) MFI of pAKT in B cells was plotted against the anti-IgD concentration The area under the curve was calculated and a drop of 50% in area under the curve between pre- and post-dose was validated to be the result of drug inhibition 002665) mice were obtained from Jackson labs Age (6–12 weeks) and sex-matched mice were used for all experiments humidity was monitored but not controlled and ranges from 30–70% The 12 h daily light cycle was from 06:00 to 18:00 All animal work was approved by the relevant La Jolla institute for Immunology Institutional Animal Care and Use Committee Reads from sorted CD8 RNA were mapped to hg19 reference genome using STAR with the same in-house pipeline as above placebo (2 pre-treatment and 3 post-treatment) and treatment (6 pre-treatment and 6 post-treatment) out of which 3 were paired (1 placebo and 2 treatment) The DEGs between post treatment and remaining samples resulted in 455 significant genes (fold change of >log2 0.75 and an adjusted P value <0.05) Cells dispersed from cryopreserved tumour tissue or PBMCs were prepared in staining buffer (PBS with 2% FBS and 2 mM EDTA) BD Biosciences) and stained with antibodies as indicated below for 30 min at 4 °C Cell viability was determined using fixable viability dye (ThermoFisher) Mouse lymphocytes were isolated from the spleen by mechanical dispersion through a 70-μm cell strainer (Miltenyi) to generate single-cell suspensions RBC lysis (Biolegend) was performed to remove red blood cells Tumour samples were harvested and lymphocytes were isolated by dispersing the tumour tissue in 2 ml of PBS followed by incubation of samples at 37 °C for 15 min with DNase I (Sigma) and Liberase DL (Roche) The suspension was then diluted with MACS buffer and passed through a 70-μm cell strainer to generate a single-cell suspension Colons were collected and rinsed in 1 mM dithiothreitol to remove faeces Each colon was cut into 2–3 mm pieces and incubated 3 times in pre-digestion solution (HBSS containing 5% FBS and 2 mM EDTA) at 37 °C for 20 min under high rotation to remove epithelial cells Then tissues were minced with scissors and incubated with digestion solution (HBSS containing 5% FBS 100 μg ml−1 DNase I (Sigma) and 1 mg ml−1 collagenase (Sigma)) at 37 °C for 20 min under high rotation to get single-cell solutions of lamina propria cells Cells were prepared in staining buffer (PBS with 2% FBS and 2 mM EDTA) BD Biosciences) and stained with antibodies as indicated below for 30 min at 4 °C; secondary stains were done for selected markers Samples were then sorted or fixed and intracellularly stained using a FoxP3 transcription factor kit according to manufacturer’s instructions (eBioscience) The following antibodies from BD Biosciences Miltenyi or eBbioscience were used: anti-human PD-1 (EH12.1 All samples were acquired on a BD FACS Fortessa or sorted on a BD FACS Fusion (both BD Biosciences) and analysed using FlowJo 10.4.1 for subsequent scRNA-seq Four randomly selected areas were analysed and a histological score was determined scRNA-seq was performed by Smart-seq2 as described37 Reads were mapped with our in-house pipeline as above Good quality cells were defined as those with at least 200 genes at least 50,000 total counts (reported by STAR excluding tRNA and rRNA) Filtered cells were analysed using the package Seurat (v3.1.5) In order to separate CD4 and CD8 more effectively we performed differential gene expression analysis between single-positive cells using CD4 and CD8B genes Cells were clustered using 178 significant genes (adjusted P value < 0.05) P-values were corrected for multiple comparisons using the Benjamini–Hochberg method Gene Set Enrichment Analysis (GSEA) scores were estimated with fgsea (v1.10.1) in R using signal-to-noise ratio as the metric (minSize = 3 and maxSize = 500) Enrichment scores were shown as GSEA plots Signature scores were computed using Seurat’s AddModuleScore function with default parameters the score is defined for each cell by subtracting the mean expression of an aggregate of control gene lists from the mean of the signature gene list Control gene lists were randomly selected (same size as the signature list) from bins delimited based on the level of expression of the signature list scRNA-seq was performed by using the 10x platform and QC was carried out as described above with the following thresholds: genes per cells range of [300; 4,500] Clusters of contaminant cells expressing epithelial and fibroblast markers were eliminated after the first round of clustering The final number of cells comprised n = 6,415 CD4+ T cells and n = 2,715 CD8+ T cells TCRs were reconstructed from scRNA-seq reads using MiXCR with default parameters shared TCRs were defined by having the same CDR3 sequence in both the alpha and beta chains and coming from the same donor Enriched TCR were defined as those with a frequency higher or equal to two TCR network plots were generated using the Python package graphviz the statistical analyses were performed with Graph Pad Prism 9 and statistical tests used are indicated in the figure legends Further information on research design is available in the Nature Research Reporting Summary linked to this paper Sequencing data has been uploaded onto the Gene Expression Omnibus (accession code GSE166150). Source data are provided with this paper Scripts used for this paper and explanations thereof are available at our GitHub repository (https://github.com/vijaybioinfo/PI3Kd_2022) Idelalisib and rituximab in relapsed chronic lymphocytic leukemia PI3Kδ inhibition by idelalisib in patients with relapsed indolent lymphoma Inactivation of PI(3)K p110δ breaks regulatory T-cell-mediated immune tolerance to cancer Phosphoinositide 3-kinase δ inhibition promotes antitumor responses but antagonizes checkpoint inhibitors Idelalisib given front-line for treatment of chronic lymphocytic leukemia causes frequent immune-mediated hepatotoxicity Phosphoinositide 3-kinase δ is a regulatory T-cell target in cancer immunotherapy The PI3K p110δ isoform inhibitor idelalisib preferentially inhibits human regulatory T cell function TOX is a critical regulator of tumour-specific T cell differentiation TOX transcriptionally and epigenetically programs CD8+ T cell exhaustion TOX reinforces the phenotype and longevity of exhausted T cells in chronic viral infection PI3Kδ-selective and PI3Kα/δ-combinatorial inhibitors in clinical development for B-cell non-Hodgkin lymphoma Molecular diversification of regulatory T cells in nonlymphoid tissues Single-cell transcriptomics of regulatory T cells reveals trajectories of tissue adaptation Regulatory T cells control antigen-specific expansion of Tfh cell number and humoral immune responses via the coreceptor CTLA-4 CTLA-4-mediated transendocytosis of costimulatory molecules primarily targets migratory dendritic cells Regulatory T cells sequentially migrate from inflamed tissues to draining lymph nodes to suppress the alloimmune response Precursors for nonlymphoid-tissue Treg cells reside in secondary lymphoid organs and are programmed by the transcription factor BATF Regulatory T cell adaptation in the intestine and skin A distinct function of regulatory T cells in tissue protection A road map for those who don’t know JAK–STAT Cross-regulation of signaling pathways by interferon-γ: implications for immune responses and autoimmune diseases Generalizing RNA velocity to transient cell states through dynamical modeling Differential regulation of interleukin 17 and interferon gamma production in inflammatory bowel disease Th17 cells give rise to Th1 cells that are required for the pathogenesis of colitis Th17 cells induce colitis and promote Th1 cell responses through IL-17 induction of innate IL-12 and IL-23 production Mouse TCRαβ+CD8αα intraepithelial lymphocytes express genes that down-regulate their antigen reactivity and suppress immune responses A unique subset of self-specific intraintestinal T cells maintains gut integrity CD4+ regulatory T cells control TH17 responses in a STAT3-dependent manner Staging and treatment of oropharyngeal cancer in the human papillomavirus era Gene expression analysis of TIL rich HPV-driven head and neck tumors reveals a distinct B-cell signature when compared to HPV independent tumors Upregulated glucose metabolism correlates inversely with CD8+ T-cell infiltration and survival in squamous cell carcinoma in adult patients with relapsed or refractory lymphoid malignancies Invariant natural killer T cells in asthma and chronic obstructive pulmonary disease PD-L1 on tumor cells is sufficient for immune evasion in immunogenic tumors and inhibits CD8 T cell cytotoxicity Precursors of human CD4+ cytotoxic T lymphocytes identified by single-cell transcriptome analysis MAST: A flexible statistical framework for assessing transcriptional changes and characterizing heterogeneity in single-cell RNA sequencing data Download references Scott for support and help during the initial phases of setting up the CRUK/Amgen collaboration; F Martin for project support over the years; M Lopez and the research pathology core at University Hospital Southampton for performing the immunohistochemistry on the paraffin embedded material; I Henderson for help with the tetanus ELISAs; the La Jolla Institute (LJI) Flow Cytometry Core for assisting with cell sorting; the LJI sequencing core for the bulk and single-cell sequencing; the LJI histology core for processing the mouse histology samples; G Means for method and training for the phospho-AKT assays; P Friedmann for constructive critique of the paper; and D Singh for advice on and help with experimental work This clinical trial work was funded by a CDD trial Grant CRUKD/15/004 (C.H.O.) a Cancer Research UK Centres Network Accelerator Award Grant (A21998) (O.W. the CRUK and NIHR Experimental Cancer Medicine Center (ECMC) Southampton (A15581) Cancer Research UK Programme Grant (C23338/A25722 (E.L.-G and B.V.)); the UK NIHR UCLH Biomedical Research Centre (B.V.) the Deutsche Forschungsgemeinschaft DFG research fellowship no WI 5255/1-1:1 (A.v.W.) and Erwin Schrödinger Fellowship (M.D.) The clinical delivery of this work was supported by the Wessex Clinical Research Network and National Institute of Health Research UK We further acknowledge Cancer Research UK (Centre for Drug Development) as the clinical trial Sponsor and for funding and management of the Phase II clinical trial as well as Amgen for supply of the PI3Kδi AMG319 These authors jointly supervised this work: Pandurangan Vijayanand CRUK and NIHR Experimental Cancer Medicine Center Liverpool Head and Neck Center and Institute of Systems Elena Lopez-Guadamillas & Bart Vanhaesebroeck Clatterbridge Cancer Centre NHS Foundation Trust and Liverpool Cancer Research UK Experimental Cancer Medicine Center Liverpool Liverpool University Hospitals NHS Foundation Trust Southampton University Hospitals NHS Foundation Trust Cancer Research UK and UCL Cancer Trials Centre and A.W.: experimental work and paper review G.H.: generation and provision of placebo and IMP and R.P.S.: patient recruitment and paper review P.L.: data generation and interpretation and paper review W.W.: study design and statistical review for sponsor data generation and interpretation and paper review F.A.: bioinformatic analyses and supervision G.S.: RNA sequencing and quality control supervision K.O.: study design and paper writing and review US) and Olema Pharmaceuticals (San Francisco US) and has received speaker fees from Gilead (Foster City has received consultancy fees from iOnctura Gilead Sciences and Karus Therapeutics and has received research funding from GSK is on the scientific advisory board of Prometheus led the clinical trial of AMG319 with funding by Cancer Research UK Amgen provided clinical grade compound free of charge for this trial All other authors declare no conflicts of interest Nature thanks the anonymous reviewers for their contribution to the peer review of this work. Peer review reports are available Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations Trial schematic of the placebo-controlled randomized phase II study of which 33 were recruited and randomly allocated to the placebo control arm or AMG319 drug-treatment arm; 30 patients ultimately received at least one dose of either AMG319 or placebo Of the 21 patients that were treated with AMG319 6 patients received daily doses of 300 mg and 15 patients (2 patients withdrew consent prior to receiving the first dose) received daily doses of 400 mg An initial biopsy was taken before trial initiation and surgical resection of tumors was performed 4–6 weeks after the first dose of treatment Pre- on- and post-treatment blood samples were collected for further analysis Assessment of the level of AKT phosphorylation in B cells at indicated time points pre-dose and 4h after treatment with AMG319 data from one representative patient are shown Plasma concentrations of AMG319 in placebo-controlled and drug-treated patients at indicated time points n = 9 patients for the Placebo group and n = 18 patients for the AMG319 group Highlighted in red are patients who were either on-treatment or had only recently (2 days prior to analysis) or briefly discontinued treatment Waterfall plot depicting the change in tumor volume from screening to pre-surgery measured by MRI scan in patients treated with AMG319 (blue bars) or placebo (green bars) shown are all patients for which MRI scans have been performed Analysis of smart-seq2 single-cell RNA-seq data of sorted tumor-infiltrating CD3+ T cells from patients 20 Violin plots depicting the Seurat normalized expression of differentially expressed highlighted genes in CD4+ T cells (left) or CD8+ T cells (right) of the 6 patients pertaining to a edges delineate the 25th and 75th percentiles and whiskers depict minimum and maximum values Percentages of non-expanded and expanded CD8+ and CD4+ T cell clones in pre- versus post-treatment samples flow-cytometric analyses of the frequency of and expression of activation markers in circulating TREG cells in placebo-treated (d) and AMG319-treated patients (e) P = 0.0098 for the frequency of circulating TREG cells (baseline vs d8 and baseline vs d22) at indicated time points; the blue lines depict patients with grade 3/4 irAEs and the red dots indicate the patients with CR/PR Significance for comparisons were computed using two-tailed Wilcoxon matched-pairs signed rank test between baseline and d8 or d22 respectively Source data with B16F10-OVA cells and fed either a control diet or a diet containing the PI-3065 PI3Kδ inhibitor for the indicated treatment period Tumor volume (a) and flow-cytometric analyses of cell frequencies (b–g) of mice treated as indicated; P = 0.003 (a) n = 9 mice for the Placebo group and n = 10 mice for the PI3Kδ group for a-f g shown are representative contour plots of intratumoral CD8+ T cells depicting the indicated markers Tumor volume of Rag1−/− or CD8−/− mice treated as indicated n = 6 mice/group for Rag1−/− and n = 5 mice/group for CD8−/− mice flow-cytometric analyses of TREG cell frequencies (b) in indicated organs of mice treated as indicated n = 6 mice for the Placebo group and n = 5 mice for the PI3Kδ group Shown are representative contour plots of FoxP3-expressing (RFP+) CD4+ T cells in indicated organs; P = 0.0043 (spleen) P = 0.1234; *P = 0.0332; ***P = 0.0002; and ****P < 0.0001 Data are mean +/− S.E.M and statistical significance for comparisons was computed using two-tailed Mann-Whitney test; data are representative of at least two independent experiments DEGs in (b–e) were called using MAST and adjusted p-values were calculated with the Benjamini-Hochberg method Source data Flow-cytometric analyses of CD8+ T cell frequencies in colon (d) P = 0.0025 spleen (e) P = 0.0013 and of the expression of PD-1 (f) P = 0.0025 and ICOS (g) P = 0.0025 on colonic CD8+ T cells n = 7 mice for the Placebo group and n = 5 mice for the PI3Kδ group d–g) are mean +/− S.E.M and statistical significance for comparisons was computed using two-tailed Mann-Whitney test; data are representative of at least 2 independent experiments Source data Mice were inoculated s.c. with B16F10-OVA cells and fed either a control diet or a diet containing the PI-3065 PI3Kδ inhibitor, treatment conditions as in (Fig. 3c, d) of CD4+ T cells in colonic tissue at day 18 after tumor inoculation of mice treated as indicated pie charts depict the percentage of each cluster in the different treatment conditions Heatmap comparing gene expression of cells in all clusters Depicted are transcripts that change in expression more than 0.5-fold and adjusted P value of ≤ 0.05 adjusted p-values were calculated with the Benjamini-Hochberg method Seurat-normalized expression of Ifng (top left) Foxp3 (bottom left) and Il4 (bottom right) in the different clusters Euler diagrams show the clonal overlap between the CD4+ T cells in the different clusters RNA velocity analysis visualized by UMAP depicting likely developmental trajectories of CD4+ T cells Download citation DOI: https://doi.org/10.1038/s41586-022-04685-2 Anyone you share the following link with will be able to read this content: a shareable link is not currently available for this article Naunyn-Schmiedeberg's Archives of Pharmacology (2024) Clinical and Translational Oncology (2024) Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research Eschweiler left an enduring mark on Milwaukee thanks to high-profile projects like the Wisconsin Gas Light building facing Water Tower Park on Milwaukee's East Side Bobby received his BA-Mass Communications from UWM in 1989 and has lived in Walker's Point He has published three non-fiction books in Italy – including one about an event in Milwaukee history Bobby released four LPs and had a songs featured in episodes of TV's "Party of Five" and "Dawson's Creek," and films in Japan The Yell Leaders were named the best unsigned band in their region by VH-1 as part of its Rock Across America 1998 Tour the band contributed tracks to a UK vinyl/CD tribute to the Redskins and collaborated on a track with Italian novelist Enrico Remmert He's produced three installments of the "OMCD" series of local music compilations for OnMilwaukee.com and in 2007 produced a CD of Italian music and poetry he was awarded the City of Asti's (Italy) Journalism Prize for his work focusing on that area He has also won awards from the Milwaukee Press Club He has be heard on 88Nine Radio Milwaukee talking about his "Urban Spelunking" series of stories in that station's most popular podcast. most of us hope someone comes along with a plan — and the money — to save it Jim Haertel looked at a doomed century-old school building on what we used to call the County Grounds and thought the best way to preserve it was to turn it into his house A giant and unlikely single-family house for him and his wife 'The movies 'The Money Pit' or 'It's a Wonderful Life' come to mind,' Haertel joked but he's confident the red brick building is structurally sound and full of possibilities but expect to spend between $300,000 and $400,000 to make it livable in honor of its esteemed Milwaukee architect the Downer buildings at UWM and many stately homes Debate went on for years over what would become of the four Eschweiler buildings visible from I-41 and Highway 45 on the National Register of Historic Places originally served as the Milwaukee County School of Agriculture and Domestic Economy then leased to private firms before becoming empty targets for vandals Mandel Group purchased the land and buildings in 2014 and has erected 188 rental units in six three-story buildings nestled in the UWM Innovation Campus development Mandel restored the three-story administration building the most prominent of the Eschweiler structures The old dormitory and dairy buildings have been partly razed and are becoming walled gardens and a dog park that preserve the footprints and arched entrances of the two structures A swimming pool is under construction next to them That left the agriculture school's engineering building the smallest of the four but still 7,400 square feet on two levels Mandel Group sought proposals for the building he goes to the city of Wauwatosa for permits and approvals It's not overstatement to say the engineering building would have come down had the Haertels not come along Some sketches of the area assumed that fact and show a grassy spot where it stands 'They're going to have a single-family home in the middle of these apartments?' I look at it more like they're going to have the coolest apartment among all the apartments,' Aiello said And they will be the only owner-occupants in the complex Karen Haertel was not sold on the idea at first 'People are not going to think you're saving a building They're going to think you finally found a building big enough for your ego.' Sweethearts at Pius XI High School a few decades ago they have lived for 28 years in a modest Wauwatosa bungalow not even one-sixth the size of the place they have in mind The Haertels are not newcomers to historic preservation They own Best Place at the Historic Pabst Brewery downtown which is also on the national historic register They started with a gift shop and have added three halls for weddings and other events they invited me to see their future home in its 'before' condition 'It's a little rough at first,' Haertel said as we entered the building and were immediately greeted by broken glass underfoot holes in the walls and the musty odor of age and neglect and open into a spacious dining room and living room over there and down the hall will be four or five bedrooms and that many bathrooms The ground level of the two-story structure will house a garage with space for at least four vehicles plus a huge rec room roof tiles and copper downspouts salvaged from the other buildings will be available for their use with new apartment buildings on either side of them and an occupancy rate already nearing 80% Their backyard will be the fields and butterfly habitat providing a buffer from the expressway The plan is to fix the outside of the building this year and gut the inside next year said engineering students used to occupy the rooms where we stood and he heard they had chicken coops outside That's what he'll be doing when he retires.' Call Jim Stingl at (414) 224-2017 or email at jstingl@jrn.com. Connect with my public page at Facebook.com/Journalist.Jim.Stingl I stop to envision the mid-December day in 1927 when Martin Grueschow walked into his completed Eschweiler & Eschweiler-designed warehouse for the first time someone else has high hopes for the building While folks have been wondering if Milwaukee County will restore or tear down the Domes few expected the news that County Executive plans to tear down a 1927 Mediterranean Revival mansion designed by Alexander Eschweiler 14-story Drury Plaza Hotel Downtown Milwaukee opened its doors inside a completely renovated 1929 tower designed by Eschweiler and Eschweiler I admit that I've had a love affair with the former Emanuel L since I first stepped inside it six years ago I was charmed before I even crossed the threshold in part by the representations of fauna that adorn the entrance Houston’s Baylor College of Medicine is beefing up its team of cancer researchers The college just received $6 million from the state agency Cancer Prevention and Research Institute of Texas (CPRIT) to recruit three cancer researchers: Graham Erwin the University of Texas MD Anderson Cancer Center snagged a $2 million CPRIT grant to recruit Simon Eschweiler CPRIT recently announced $49 million in cancer research and prevention grants including nearly $24 million for recruitment of cancer researchers Here’s a rundown of the recruitment grants awarded in Houston: three institutions in the Houston area received nearly $6 million in funding for cancer treatment and prevention programs Attorney Corey Eschweiler was selected for exclusive membership to join the 2022 Top 50 Lawyers list by America's Top 50 Lawyers LAS VEGAS, March 14, 2022 /PRNewswire-PRWeb/ -- Attorney Corey Eschweiler was selected for exclusive membership to join the 2022 Top 50 Lawyers list by America's Top 50 Lawyers Of the 1.3 million attorneys practicing in the United States less than 0.05% of attorneys receive this distinction America's Top Lawyers is dedicated to promoting the highest standard of legal excellence members are either first nominated by peers and/or America's Top Lawyers' own research team Final selection is then based on a proprietary research process that includes assessment of a lawyer's overall achievements "I am humbled to be selected to join such an exclusive group of attorneys who are being recognized for providing superior legal work to their clients while also maintaining the highest ethical standards This is truly an honor and would not be possible without all the dedicated support and teamwork provided by the ER Injury Attorneys family," said Corey Eschweiler Visit ERInjuryAttorneys.com to learn more about attorney Corey Eschweiler's many professional achievements Helping southern Nevada injury victims put their lives back on track after an accident is a top priority of the legal team at ER Injury Attorneys their award-winning lawyers have built a reputation for providing the highest level of service by taking the time to listen and evaluate the needs of those who contact their law firm This attention to detail not only promotes a positive and open collaboration but also a higher success rate in terms of negotiating the best possible results For more information about ER Injury Attorneys and their dedication to serve and assist local community members please visit ERInjuryAttorneys.com or call 702-968-7500 Corey Eschweiler, ESQ., ER Injury Attorneys, 702-968-7500, [email protected] Do not sell or share my personal information: talented interior designers and hardworking volunteers have transformed a Milwaukee-area home into the Wisconsin Breast Cancer Showhouse which will be open to the public June 3 to 18 And like the 19 homes that have been showcased before it this year’s home and its new décor are striking has nearly 7,000 square feet and was designed in 1903 by Alexander C Its amenities include multiple gable roofs there’s a limestone and leaded glass bay window complex from a 14th-century Belgian monastery and a unique plaster ceiling design showing hops vines a board member for the showhouse who assists in finding the homes said other unique aspects of this house include a chimney made of Chicago red brick using standard and non-standard size bricks to form an overlapping design and floors done in a very wide plank that give the rooms a “comfortable Queen Anne cottage feel.” In addition to seeing the amenities in the home and the way it’s been decorated by local designers tour-goers also will be interested in its neighborhood “People will want to attend the tour to see this home because it’s located in the middle of the area where the most prestigious mansions were built in that era,” Brogelman said “This home has been classified as a Queen Anne style and also as English Arts and Crafts It has definite characteristics of both and is surrounded by homes that are different styles Just looking at the immediate four or five homes surrounding it and the large English Tudor Eschweiler right next door,” she said Brogelman said the house was built for the family of Clarence and Margaret Sawyer Falk and that an addition also was designed by Eschweiler for the family in 1909 “The Falks were very family-oriented and wanted a comfortable home to raise their family but they also wanted a high-quality built home in a prestigious neighborhood,” she said Brogelman added that Clarence and his brother Herman founded the Falk Manufacturing Co Clarence and Margaret Sawyer Falk were world travelers and generous philanthropists hosted Charles Lindbergh at the house as part of Mr Lindberg’s victory tour of the country in 1927. The home is owned by entrepreneur Andy Nunemaker He said he bought the home he lives in now in 2011 and that it was the 2012 Breast Cancer Showhouse Prior to that he lived in the current showhouse for 10 years to the public because he has enjoyed working with the designers and because money earned goes to a great cause “They pick amazing designers,” he said “They all have their own unique styles There is a common thread throughout that really works,” he said Ellen Irion said the home has five bedrooms on the second floor and three bedrooms on the third floor but that the designers for the showhouse changed how some of the rooms are used “Now the home is designed with three bedrooms on the second floor and two on the third floor,” she said “One of the bedrooms on the second floor became a walk-in master closet “There are four full baths on the second floor a full bath on the third floor and two powder rooms on the first floor.” Two of her favorite rooms include the master bathroom and a third-floor children’s area “The master bath is fabulous,” she said “The original footprint of the bath was retained but it was originally three rooms — a master bathroom proper and two large walk-in closets One of the closets is now a shower and one is now a water closet “The entire third floor was decorated as a children’s floor “There are three rooms and a bathroom and all are dedicated to children There’s a toy room with a teepee and girls and boys rooms are decorated in cowgirl and cowboy motifs he looked at other areas of the house to determine how to keep its original style when adding modern features “we are taking a part of history and paying homage to that era but are also putting in convenience and luxuries people use today,” he said “I looked at the other bathrooms to get a sense of the style The master bathroom I did had been gutted in the ’80s and a horrible renovation had been done.” and white hexagon-shaped tiles on the shower floor “with black grout for a very high contrast he used a handmade cement tile that is black and white with geometric patterns “That piece really pushes the envelope of the design … I didn’t add any other color in the room It’s a look that is very dynamic in itself,” he said as well as tones of antique gold and very dark brown “I went with a wall cover that was black and white There’s a handcrafted mirror from India and a raffia rug with a Greek key design in a very dark brown.” Konzal said furnishings in the room are a classic modern but that antiques were added too as they add “depth and personality” to a room turned one of the second-floor bedrooms into a ladies office “The room has an ethereal and restful quality using blush and creams,” she said “The walls were originally a dark terra cotta The cream color is in the woodwork and other accents “I also brought in some texture by using a juju hat I also used some pieces from local artists for my artwork and two are large fine art photography.” There’s also a traditional ladies desk and a curio cabinet that are filled with pieces someone might have collected when traveling which is right around the corner from the bedroom That room has blue walls and some original fixtures “I replaced old lighting around the sink — it was a ’70s look — but I kept the original overhead ceiling fixture That fixture had some nice details and a beautiful and unusual glass globe "I also kept the original built-in medicine cabinet The color scheme is a warm gray and white and I also used a rug and some of the owner’s artwork that is very colorful.” who handles public relations for the event and is the volunteer coordinator said this year close to 20 interior designers have donated their time and talent to transform the home and that there also will be close to 1,000 other volunteers who will lend a hand with other aspects of the tour “In takes a village,” she said “If it weren’t for the designers and each year it’s a challenge for them to create unique new rooms.” In addition to the designers there are volunteers who help with events connected to the tour and even volunteers who house-sit while renovations are being done some volunteers donate their time over about a three-month period Designer Konzal said he has been involved for the past seven years “It’s a great way for designers to give back to the community and the showhouse is a great event for the community,” he said People should come out and support this event Short said the showhouse started in 1998 as an all-volunteer charitable organization with a mission to raise money to support early-stage breast cancer and prostate cancer research at The Medical College of Wisconsin WBCS has donated more than $6.15 million to the college for research and to endow the showhouse’s professor of breast cancer research Past research has led to more than $45.4 million in additional competitive extramural research grants to the college What: 20th Annual Showhouse for a Cure — 2017 Wisconsin Breast Cancer Showhouse Tickets: $20 in advance, $25 at the door. Ticket information is available at breastcancershowhouse.org Tickets also can be purchased at a number of Milwaukee-area stores and at the showhouse An evening of live music and small plate dining Designer Day: Meet the designers and tour the showhouse Pinktacular Fashion Show and Luncheon: From 10:30 a.m Luncheon at noon followed by a fashion show featuring breast cancer and prostate cancer survivors For more information: See the showhouse website or call (414) 297-9152 the four remaining Agricultural College buildings designed by Alexander Eschweiler and erected in 1911-12 They're perched above Swan Boulevard in a position that suggests respect But they're also obscured from the road because they're peeking out from trees and overgrown tangles of weeds lurking like escaped prisoners hiding from their fate Home » News and Features By Rory Linnane When Alexander Eschweiler designed the buildings for the Milwaukee County School of Agriculture and Domestic Economy around 1910 the project might have been overly ambitious A 1916 report by the Taxpayers' League of Milwaukee found enrollment was already faltering with only about 30 percent of the campus space being used This foreshadowed its eventual closure in 1928 "The school could very well have gotten along if two fewer buildings had been built," the 1916 report stated the buildings' worth is still being debated Having fallen into severe disrepair on Innovation Campus near Swan Boulevard and Discovery Parkway it's unclear whether a developer will see enough potential in them to merit the estimated $8 million to $11 million price tag to renovate them wants to turn the main administration building into a leasing office and other amenities for its residents The other buildings, which had originally been sought by a charter school, were left hanging when the University Laboratory School failed to reach a required agreement with the Wauwatosa School District Mandel Group senior development manager Phillip Aiello said he is hoping another proposal will come to the table He said Mandel has been meeting with individuals and public organizations to brainstorm other ideas for the buildings Aiello said Mandel plans to put out an official request for proposals for the buildings The Wisconsin Historical Society will be involved in vetting the ideas we've tried to find a use for all the Eschweiler buildings and here we are four years later and we're still trying to find a use for them," Aiello said "There's just something special about the setting they create at the site." The Eschweiler buildings have been vacant for several years left in disarray under the ownership of Milwaukee County until an affiliate of the UWM Real Estate Foundation acquired the property in February 2011 Inside are remnants of various decades: a beam from a pulley system that might have been used to haul up farm equipment for repair a "while you were out" note likely from when a building was converted to office space in the 1980s an agent for the UWM Real Estate Foundation pulls out power tools and gets to work unscrewing boards from the doors so it's dark inside as he steps in and flicks on his flashlight "It wasn't taken good care of before the foundation took over," Peters says stepping through shattered glass and uprooted nails It's clear right away that although people stopped caring for the buildings Peters said he has seen people flee when he comes to check on the grounds ranges from obscene to creepy ("See you in the mourning") "The main culprit has been kids looking for something to do," Peters said "It seems like a right of passage to come here." the buildings have larger structural problems the buildings would need all new utilities and interior reconstruction for things like elevators to accommodate disabilities Windows and walls are crumbling under water damage and wear "To try to restore it is difficult because we have nothing to start with," Peters said it's hard for people to see past the current state and imagine what they could be." Peters hopes Mandel can find a use that honors their history even if they are demolished for walled gardens as has been proposed if renovations aren't feasible Peter Lescrenier remembers exploring the tunnels between the buildings back in the 80s as his dad operated his company Gammex on the campus until about 2006 Lescrenier helped install the carpeting and paneled walls that still decorate parts of the buildings He said he would understand if the buildings had to come down but he hoped the administration building could at least be saved "I absolutely see that building as some kind of an entertainment center," he said I was in my concert years so I thought it would be a great place for music." Aiello said Mandel plans to fill the first floor with leasing offices The second floor could have office space for non-profits He hopes it won't be the last Eschweiler standing and there's something very pleasant about being in that quadrangle and looking around being surrounded by those three historic buildings," Aiello said Mandel planned to have a ceremonial groundbreaking on its apartments Oct All Galleries Of the of many breweries that have opened in Milwaukee recently, City Lights is perhaps the most exciting for me. But not necessarily for the beer - though I'm eager to try that, too, of course - as much as for its Alexander Eschweiler-designed home. Born in Brooklyn, N.Y., where he lived until he was 17, Bobby received his BA-Mass Communications from UWM in 1989 and has lived in Walker's Point, Bay View, Enderis Park, South Milwaukee and on the East Side. He has published three non-fiction books in Italy – including one about an event in Milwaukee history, which was published in the U.S. in autumn 2010. Four more books, all about Milwaukee, have been published by The History Press. With his most recent band, The Yell Leaders, Bobby released four LPs and had a songs featured in episodes of TV's "Party of Five" and "Dawson's Creek," and films in Japan, South America and the U.S. The Yell Leaders were named the best unsigned band in their region by VH-1 as part of its Rock Across America 1998 Tour. Most recently, the band contributed tracks to a UK vinyl/CD tribute to the Redskins and collaborated on a track with Italian novelist Enrico Remmert. He's produced three installments of the "OMCD" series of local music compilations for OnMilwaukee.com and in 2007 produced a CD of Italian music and poetry. In 2005, he was awarded the City of Asti's (Italy) Journalism Prize for his work focusing on that area. He has also won awards from the Milwaukee Press Club. He has be heard on 88Nine Radio Milwaukee talking about his "Urban Spelunking" series of stories, in that station's most popular podcast. Chenequa - A judge this week is scheduled to resolve a bitter family dispute over the future of a historic estate overlooking North Lake. Descendants of Alexander Eschweiler are divided over whether the famed 20th-century architect's former summer home and surrounding 11 acres should be split in half, possibly opening the door to demolition of the home. Now vacant, the three-bedroom home features an enclosed porch, natural stone walls, multiple fireplaces and many other comforts. The 1870s-era home was not designed by Alexander Eschweiler, but it was the centerpiece of more than 100 acres that he purchased for his family in the early 1900s. The Boston-born son of German immigrants won acclaim as the designer of European-style mansions for Milwaukee's elite. Although he and his wife maintained another home in Milwaukee, the Waukesha County property was a sentimental favorite. According to family members, it is where Alexander Eschweiler died in 1940 at age 75. Perched high atop a ridge on the far southern shore of North Lake, the family's property is known as much for its location and environmental quality as for its monetary value. In addition to North Lake, the heavily wooded acreage overlooks the much smaller Cornell Lake to the south and Pine Lake just beyond that. As his three sons and one daughter grew and started families of their own, some built additional homes on the North Lake grounds. The main homestead went to Eschweiler's daughter, Francesca, and later to her son, Thomas Holbrook. When Holbrook moved to divide the property and market it for redevelopment, family members objected. Carl Eschweiler Jr. and Thomas Eschweiler, cousins whose fathers were both sons of Alexander Eschweiler, joined forces and persuaded Chenequa village officials to block Holbrook's plan. Then the two cousins purchased the property from Holbrook for $3.1 million. Both have their own cottages nearby, and both feared the impact of Holbrook's plan on their property. Their partnership, however, soon fell apart, resulting in the squabble that is expected to play out in court this week. Carl Eschweiler and his wife, Mary Alice, filed suit in November 2007 against Elisabeth Lavery and Andrea Rendleman, sisters who had been assigned by their parents, Thomas and Gabriele Eschweiler, as trustees of their family's 50% interest in the property. Thomas and Gabriele Eschweiler, who are both in their 80s, were later added as co-defendants. The suit seeks a judge's ruling dividing the 11-acre site in half, on the belief that the property would be more valuable and would give the two partners a better chance of recouping their investment. The potential sale price for the two parcels combined is estimated in the suit at $3.8 million. In a countersuit, Lavery and Rendleman contend that breaking up the property could jeopardize their interests, including what they contend was their parents' earlier offer to buy the entire site. Another court filing from the sisters reflects family suspicions that Carl and Mary Alice Eschweiler, both in their 60s, are "taking advantage of Tom and Gabi, who are much older." Last week, Waukesha County Circuit Judge Michael Bohren denied a request from Eschweiler family members to rule out the possibility of ordering demolition of the late architect's former home. Those family members also questioned whether the judge could order property easements for road improvements that might be needed if the site is divided. In the civil case scheduled for trial this week, Bohren ruled that he would not pre-judge potential outcomes in the dispute. "The court wants to have all of its options open," he said. Another possible outcome available to Bohren in the suit is ordering that the property be auctioned at a sheriff's sale. Through their attorney, Carl and Mary Alice Eschweiler issued a statement that they are seeking only to carry out plans for the property to which all the parties previously agreed. The statement also notes that Carl and Mary Alice Eschweiler have made a permanent home in their cottage, while Thomas and Gabriele Eschweiler generally spend only summers there. "What this case is about," they said, "is absentee landowners wanting property next to theirs preserved for free." Gabriele Eschweiler and her daughter, Elisabeth, said their side of the family is trying to preserve Alexander Eschweiler's legacy: a place where his family can enjoy the natural beauty of the Wisconsin countryside. "This is a little corner of the universe in which time has stopped," Lavery said. "And once it's gone, there's no retrieving it." Popular Franklin breakfast and brunch eatery Mimosa recently opened a second location, in the former Louise's Trattoria space at 275 Regency Ct., and while that's good news for Brookfield pancake lovers, it's also surprisingly good news for preservationists. Volume 7 - 2019 | https://doi.org/10.3389/fevo.2019.00213 This article is part of the Research TopicEcosystem Services and Disservices Provided by Plant-Feeding Predatory ArthropodsView all 12 articles a special group of plant-feeding omnivorous predators have become important biological control agents for pest control in greenhouse cropping systems Their efficacy and behavior may potentially be affected by microorganisms that induce plant defenses or change plant quality Here we studied the interaction between a root restricted endophytic non-pathogenic strain of Fusarium oxysporum (Fo162) in tomato plants the greenhouse whitefly Trialeurodes vaporariorum (Westwood) and the plant-feeding mirid predator Macrolophus pygmaeus (Rambur) inoculation of tomato plants with the Fo162 endophyte significantly reduced the reproduction of M pygmaeus compared to plants without the endophyte pygmaeus was not affected by the Fo162 endophyte in the presence of whiteflies the combination of the predator and endophyte resulted in lower whitefly densities than the predator alone Whitefly population development was not different between endophyte-inoculated and untreated plants endophyte inoculation of tomato plants seems to shift the feeding preference of this omnivorous predator from plant consumption toward relatively more prey consumption resulting in enhanced suppression of the herbivore pygmaeus reproduction could easily be eliminated by providing decapsulated cysts of Artemia franciscana Kellogg as a supplemental food source this suggests an overall net positive effect of the Fo162 endophyte on a preventive biological control strategy in tomato using M endophyte-inoculation of tomato plants both with or without the predator also resulted in a higher yield and a reduced number of fruits with blossom-end rot a disorder caused by limitations in uptake and transport of calcium to the fruits This suggests that the Fo162 endophyte is also involved in the acquisition of essential nutrients for the benefit for the plant Since both the Fo162 endophyte and the predator M further studies need to elucidate the exact mechanisms that occur when both organisms are present Our findings confirm the importance of studying endophytes and induced plant responses in a multi-trophic context with herbivores and their natural enemies Induced plant responses or plant quality can also influence the feeding behavior of omnivores themselves. Induced plant responses caused a shift in the feeding preferences of the omnivorous thrips F. occidentalis from plant feeding to prey feeding (spider mite eggs) (Agrawal et al., 1999). Studies with host plants from different quality confirmed that low host plant quality increases prey consumption of this omnivore (Magalhães et al., 2005) Besides the herbivores themselves also their natural enemies can be affected by endophytes, and this has been reported for both parasitoids and predators (Omacini et al., 2001; Bultman et al., 2009; Hartley and Gange, 2009; Saari et al., 2014; Garantonakis et al., 2018; Pappas et al., 2018) Plant-mediated effects of endophytes on natural enemies may increase in complexity when the natural enemies are plant-feeding it is not known if and how endophytes can affect such multitrophic food-web interactions between plants herbivores and plant-feeding natural enemies Here we studied how the presence of a root-restricted non-pathogenic endophytic strain of Fusarium oxysporum in tomato plants affects the performance of the greenhouse whitefly Trialeurodes vaporariorum (Westwood) and its control by the plant-feeding mirid predator M When inducing plant defense responses or altering plant quality the endophyte may directly affect the survival and/or reproduction of whiteflies and mirid predators the endophyte may indirectly affect whitefly densities by changing the feeding behavior of the plant-feeding predator The results of our study may be interesting for both understanding endophyte-mediated multitrophic interactions and for further developing biological pest control strategies Endophyte inoculum was produced on solid potato dextrose agar (PDA) in petri dishes The number of tomatoes affected by blossom-end rot were counted separately from “healthy” tomatoes Temperature and relative humidity were registered every 5 min throughout the experiment with a climate recorder (Hoogendoorn Growth Management) inside one of the cages The experiment was conducted in March-June and during that period the average daily temperature and relative humidity in the cages was 20.0°C (range 18.2–21.7°C) and 62% (range 47–77%) Plants were grown under natural light conditions All four combinations of endophyte and alternative food were tested in a two-factorial randomized complete block design containing 5 replicates Capricia) were placed individually in insect cages (60*60*90 cm mesh size 0.5 mm) in a greenhouse compartment similar to the one used in the previous experiment Nutrients were supplied through drip irrigation without recirculation in order to prevent contamination with endophyte spores among treatments Fertilization was similar to the previous experiment Also endophyte inoculation was performed in the same way as in the population dynamic experiment One week after the second endophyte inoculation pygmaeus males and females were introduced in each cage The supplemental food was added weekly by dusting 0.5 g of A franciscana cysts with a brush over the entire plant all juvenile and adult predators present on each plant were collected with an aspirator the number of nymphs were counted separately per stage in the laboratory under a binocular microscope (40x) after putting the individuals on a white filter paper Temperature and relative humidity in the greenhouse compartment were recorded every 5 min throughout the experiment with the same climate recorder as the one used in the population dynamic experiment The experiment was conducted in September-October and the average daily temperature and relative humidity in the greenhouse during the presence of the predators was 19.4°C (range 18.5–21.2°C) and 74% (range 69–79%) Natural light was supplemented with 9000 lux artificial light for 2 hours per day during the last 4 weeks of the trial Artificial lights were also switched on during the day when the natural light intensity was below 300 Watt All whitefly and predator density data in the population dynamic trial were log (+1) transformed to adjust the data for homogeneity of variance and normality with predator and endophyte presence as factors Differences among treatments were analyzed by Fisher's Least Significant Difference (LSD) post hoc tests (p < 0.05) Differences among treatments in the total number of produced tomato fruits per plant and the percentage of tomato fruit with blossom-end rot was analyzed with a two-way ANOVA with predator and endophyte as factors Fruit numbers were log (+1) transformed and fractions of fruit with blossom-end rot arcsine transformed prior to this analyses to meet the requirements for a normal distribution of the data followed by Fisher's LSD post hoc tests (p < 0.05) A two-way ANOVA was also used to analyse the data of the predator survival and reproduction trial with endophyte and supplemental food application as the two factors Because a faster juvenile development would result in a larger proportion of the older nymphal stages we also looked at differences in the proportion of third nymphal stages among treatments (the oldest nymphal stage found after 25 days) The proportion of surviving adults and third nymphal stages were arcsin transformed and the total number of offspring were log transformed to get a normal distribution of the data prior the ANOVA analyses All statistical analyses were performed using the statistical package GenStat Population dynamics of (A) the greenhouse whitefly Trialeurodes vaporariorum and (B) the predator Macrolophus pygmaeus on tomato plants treated with the endophyte Fo162 Predators were added 1 week and the endophyte inoculations were done 2 and 3 weeks prior to the whitefly release Data shown are the mean (± SE) (Log) densities of juvenile whiteflies per 6 leaflets and predator densities per plant Different letters next to the curves indicate overall significant differences among treatments (Fisher's LSD-tests Total number (±SE) of fruits (A) and the percentage (±SE) of these fruits with blossom-end rot (B) from tomato plants without or with inoculation of the endophyte Fo162 Different letters above bars indicate significant differences between treatments (ANOVA The application of supplemental food also enhanced juvenile developmental time since a significantly larger proportion of third nymphal stages were present in these treatments than in the treatments without food [F(1 reflected by the proportion of third nymphal stages was not affected by the factor endophyte [F(1 nor was the interaction between the factors endophyte and food significant [F(1 Survival (A) and reproduction (B) of the predator Macrolophus pygmaeus on tomato plants treated with the endophyte Fo162 the supplemental food source Artemia franciscana or a combination of both compared to untreated plants Shown is the mean (±SE) percentage of survival of 24 released adult predators 2 weeks after their introduction (A) and the mean (±SE) total number of first Different letters above bars indicate significant differences among treatments (Fisher's LSD-tests but that such a shift from plant to prey feeding can be mediated by an endophyte was unknown Fo162 not only positively affected the whitefly control by a plant-feeding predator but also reduced blossom-end rot and increased yield a synergistic effect of the predator induced and endophyte-induced plant defenses on whiteflies is not likely how those two defense inducers interact is not known and deserves further studies pygmaeus to tomato plants that were colonized by this same endophyte (FsK) This attraction to pest-free plants that are colonized by endophytes might result in an additional negative effect on M any negative effects of endophytes on population growth of omnivorous predators can probably be eliminated rather easily by providing supplemental food sources even in simplified ecosystems as described by us Changing plant quality by endophytes may also be a useful tool for enhancing biological pest control with omnivorous predators and reducing plant damage caused by omnivorous plant feeding The datasets generated for this study are available on request to the corresponding author The authors declare that the 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This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) distribution or reproduction in other forums is permitted provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited in accordance with accepted academic practice distribution or reproduction is permitted which does not comply with these terms *Correspondence: Gerben J. Messelink, Z2VyYmVuLm1lc3NlbGlua0B3dXIubmw= †Present Address: Alexander Schouten Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher 94% of researchers rate our articles as excellent or goodLearn more about the work of our research integrity team to safeguard the quality of each article we publish By Tom Tolan of the Journal Sentinel Bill and Janice Doyle of Bay View decided on their equivalent of retirement: After 45 years of buying remodeling and renting out properties in the neighborhood where Bill grew up then 93-year-old Dorothea Halser fell in her S home and set in motion a series of events that pulled the Doyles out of retirement and presented them with what a friend describes as the crowning project of Bill's career The project: restoring to its former glory one of just two south side homes designed by pre-eminent Milwaukee architect Alexander Eschweiler a house that doubled as a doctor's office for three generations of physicians caring for the little forest of ginkgo trees Halser raised in the yard "The house has been here 106 years," Doyle said last week "To watch it demolished would break your heart." According to an October story in the Bay View Compass Eschweiler - founder of the firm responsible for what's now the Charles Allis Art Museum building and many more Milwaukee landmarks - designed the Arts and Crafts-style house in 1903 for a doctor named William Batchelor The plans included a residence for the family and a couple of rooms in which Batchelor saw patients There was also a carriage house in those days before Henry Ford put a car in every garage who got a copy of Eschweiler's original drawings from the Milwaukee Public Library delights in that the box for the horse manure was drawn right in and his widow sold the house to another doctor and they raised three boys there between seeing patients "Younger people don't know how different the life of a doctor was at that time," says Joseph Halser III people couldn't pay for it and he'd come out with a pie or a couple of jars of canned tomatoes." his dad was the company physician at Ladish Co. an assignment that kept him busy with workplace injuries in those booming employment years "The whole practice was right in the house," he said "They'd be bringing people any time of the night with a smashed finger you couldn't guarantee he'd be with the family." Joe Halser's mom was developing a love of the ginkgo tree a native of China with fan-like leaves that turn a brilliant yellow in the fall A 1970 story in The Milwaukee Journal quotes Dorothea Halser as saying the first trees were a gift to the Batchelors around 1900 from a U.S She donated their offspring to many people including to the Boerner Botanical Gardens in Whitnall Park investigators representing the University of Wisconsin Extension and the state Department of Natural Resources have stopped by and established that the two biggest trees on the property are the 13th and 14th largest in the state A neighbor who collects Bonsai has collected some of the smallest specimens "It's a happy place for ginkgo trees," remarked Dennis Lukaszewski a UW Extension official who came to view the mini-forest and he and his brothers decided to move their mom to assisted living The house had deteriorated significantly in recent years Halser - who owns the Terminal restaurant on S in a remodeled truck terminal - decided he couldn't afford the time and effort to fix up the place with whom he'd had business relations for years and Halser should sell it to somebody else Then came the call from the Las Vegas vacation: "Don't sell it redid the cedar shingle siding and removed some bushes that obscured the house they've replaced the leaky old lead-pipe plumbing and the ancient wiring and - with the help of floor-refinisher Joseph Slane - stripped and refinished the first-floor woodwork They knocked down a partition added in the 1920s to wall off a waiting room and restored a landing that had been sliced up by the partition - finding the old newel post in the carriage house Halser hauled away a vintage X-ray machine The second floor remains a work in progress "I probably bit off more than I could chew." And it didn't help that he had a heart attack on Thanksgiving and heart surgery the next week seem relaxed and happy to have the project Sitting in a spacious front room with a brick fireplace built-in bookcases and timbered ceiling last week the Doyles were expansive about their long history in Bay View many of which they bought in dilapidated condition and fixed up They own several buildings on the commercial strip surrounding S and they have been partners in several others a Realtor who has done business with Doyle for 25 years says he's done a great deal to bring back what was a blighted neighborhood - at least the north end of it - when Doyle first got into the business in the 1960s Patty Thompson, president of the Bay View Neighborhood Association Bill Doyle's first priority has not always been historical preservation Years ago he bought old houses and essentially gutted them to prepare them to rent Doyle said - adding that to do more would have been impractical He's absolutely in love with it," she said There's a great deal of interest in it in the neighborhood enough that she's scheduling the next meeting of her association at the house Doyle says he doesn't have specific plans for it yet but he wants it to be an asset to the neighborhood where he's spent his life and where he's always been a booster "I'm aggressively looking for people with ideas," he said He says he's responsible for the old bumper sticker that said "Bay View: The Other East Side" - but with "Other" crossed out and replaced with "Better." "Bay View's just taken off," he says They were looking for four bedrooms in the Washington Highlands That was the main thing for Andrew and Laura Brusky who were living in the Washington Highlands in Wauwatosa when they began their home search in 2009 They liked their home well enough: a 1,700-square-foot Tudor built in 1920 and an annual holiday party the weekend after Thanksgiving you just felt they were on top of you," says Andrew an attorney specializing in elder and special needs law a special-needs child adopted several years ago They were anticipating adopting another child The expansive red brick Tudor caught their eye with its rich woodwork and big backyard she longed for a kitchen with more space to entertain and live Two other offers were contingent on a home sale Here they would have four bedrooms (one of them a study) They'd been hoping for 4,000 square feet in their next home This place had 5,800 square feet and an equally expansive history that's a classic Milwaukee tale The 1910 Jacobean Revival home they had bought was designed by widely known architect Alexander Eschweiler described in historic documents as the secretary-treasurer of Hurley "gentleman's haberdashers on Wisconsin Ave." Reilly's father The home has all the hallmarks of Eschweiler: arched doorways carved woodwork featuring dimensional oak panels and beamed ceilings pocket doors and a plaster ceiling in the formal dining room by Orlandini A stone English fireplace anchors the living room which has doors opening to the spacious backyard A lower-level rathskeller has a beamed ceiling and a fireplace The original blueprints for the home are framed and hang on a wall in the rathskeller lived in the home with their two daughters and housed in spacious quarters on the third floor (now home to the Bruskys' au pair Other owners have maintained the home well Its two porches have been rebuilt in the last 20 years or so and the home's brickwork had been tuck-pointed a porch area was made into a family room overlooking the backyard Equipped with a built-in entertainment center the spacious and casual room is where the Bruskys spend most of their time in the evening More than a century after the home was built the Bruskys find that it suits them perfectly It will enable them to host philanthropic events Their interest in the area has led to work with the Historic Water Tower Neighborhood including hosting house and garden parties held by the organization Andrew is vice president of membership for the group And if their home is a bit more grand a home than they envisioned for themselves when they came to the house for the first time 'You're lookin' at him,'" Andrew says So he kind of built his homes grand and with a focus on entertaining: A grand entry way leading to a great room .. who pointed out a subtle but important Eschweiler detail: The pitch of the stairway is low with deep steps designed to minimize the sound of footsteps "The whole idea was not only flow and generous sizes but to keep the noise level down when people ascended and descended on the staircase and that is definitely a feature in many of his homes," he says With their work schedules and Andrew taking on the law firm after his father's death three years ago the couple decided not to adopt a second child Andrew considers this grand home his part-time job He handles the maintenance and landscaping "These homes really are a labor of love," he says we really kind of feel like stewards of history but you feel like you have an obligation to maintain it We wake up in the morning sometimes and we're like But this grandfather clock is unique because it was purchased from my great aunt's farm after she died It's not old — 1999 — but it's something from family with a new closet system and better lighting But a new fence outside is the first priority but I just hate to have a small kitchen where you can't really move I truly love my back patio and yard the most Because I do all the landscaping and yard work I'm in constant contact with neighbors who walk and nights outside with a good glass of wine are like vacation to me funky or exquisite living space that you'd like to see featured in At Home Contact Fresh home and garden editor Tina Maples at (414) 223-5500 or email tmaples@journalsentinel.com © 2016 Do you, or does someone you know, have a cool, funky or exquisite living space that you’d like to see featured in At Home With? Contact Fresh home and garden editor Nancy Stohs at (414) 224-2382 or email nstohs@journalsentinel.com E-edition PLUS unlimited articles & videos Personalized news alerts with our mobile app *Refers to the latest 2 years of stltoday.com stories Please subscribe to continue reading… The Eschweiler Scholar Athlete winners. From left, Kacy, Karan and Dani Eschweiler were each recipiants of the award. Gordon Radford, Special to STLhighschoolsports.com CHARLES • Every so often Mike Eschweiler likes to just sit back and listen Louis Post-Dispatch Scholar Athletes and husband of another admits there are advantages to living in the same house with a trio of female brainiacs and then repeat it and it makes me look pretty good," he joked there is an overflow of intelligence at the Eschweiler house in St Charles West senior basketball and volleyball standout Kacy Eschweiler is the third member of the high-IQ family to win the Post-Dispatch Scholar Athlete award who is headed to the University of Southern Indiana on a basketball scholarship is the valedictorian in her graduating class of 165 students Kacy follows in the footsteps of big sister An all-state volleyball and basketball player Karan Rengers grabbed Scholar Athlete honors at St and Karan are believed to be the first three females from the same family to claim the honor in its 49 years Mike and Karan are extremely proud of their daughters and share credit for an impressive gene pool that led to Dani and Kacy being ranked No 1 in their respective classes in a three-year period Although he likes to joke about lagging scholastically behind the females in the family He is a 1982 graduate of Parkway North High "I still say the girls got their intelligence from both me and (Karan)," he said The Eschweiler girls will be leaving a legacy that may never be surpassed received one B in her entire academic career — that came in a third-grade handwriting class now a sophomore at Truman State University in Kirksville has been a straight-A student since she first entered a classroom I'm amazed at what they've accomplished," Karan said Of all the awards they can win in high school Karan says over the years she has grown to appreciate the Scholar Athlete award more than her other achievements I didn't really understand what it was or what it meant," she said you realize what it really means is that you are a well-rounded person and not just an athlete or just a straight-A student." Kacy says the award means more because she is following in the footsteps of her mom and sister I was told that there was nothing I couldn't do if I set my mind to it and worked hard," Kacy said my mom told me it would be cool if I could get it but I told her I would try as hard as I could I know getting it has made her really happy." Kacy may end up being the most successful member of the trio in college Karan had an impressive volleyball career at Missouri State University and Saint Louis University But Kacy has a huge upside to her basketball game She has added a tough defensive presence to her already top-notch scoring abilities "There's still a lot I have to work on," Kacy said turned down a volleyball scholarship to the University of South Carolina Upstate to concentrate on her studies The 20-year-old enjoys watching her little sister on the court and returns home as much as possible for Kacy's games "Watching her play is such an amazing experience," Dani said Kacy is coming off an eye-popping campaign She averaged 19.2 points and 9.5 rebounds for the Warriors losing to eventual state champion Incarnate Word in the quarterfinal round A four-year starter in basketball and volleyball Kacy eclipsed numerous school basketball records during her career including several set by her mom 30 years ago Kacy's 23.2 points-per-game average as a junior wiped out the mark of 21.6 set by mom in 1985 Kacy pulled down 1,116 rebounds in her time at West blowing away the previous record of 857 set by Karan Kacy finished as the school's all-time leading scorer with 1,950 points When Kacy scored 46 points against Winfield last season she broke her mother's single-game mark of 44 points against Duchesne in 1984 "Records are made to be broken and it's great when your daughter breaks your records," Karan said "I still kid her that everyone's going to forget about me now because you're wiping me off the (record) books All three Eschweiler girls remain intensely competitive A friendly game of horse in the driveway can easily turn into a hard-fought battle for bragging rights "I've still got a pretty good shot," Karan said Karan recalls enjoying the perks of her Scholar Athlete award all of the winners were treated to a gala dinner at the Chase Park Plaza Hotel I still take a lot of pride in it," Karan said but eventually (my daughters) will come to realize what a great accomplishment this is not only for them as individuals Get up-to-the-minute news sent straight to your device - designed by Alexander Eschweiler as a replacement for the congregation's previous Edward Townsend Mix-designed house of worship Downtown - and you will likely find it difficult to ignore the nine Tiffany Studios windows that adorn the sanctuary Listen to the Urban Spelunking Audio Stories on 88Nine Radio Milwaukee. 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By continuing to use & browse this site, we assume you agree to our Privacy Policy 2012 at 8:42 pm CTSaying that the historic Eschweiler Buildings on the County Grounds have proved too costly to rehabilitate as apartments developer Barry Mandel proposed Tuesday night a plan to tear down four of the five structures Under his proposal to the Wauwatosa Historic Preservation Commission would be preserved as a centerpiece to the development he also said that rather than tear the others down he would happily give them away – free to anyone who could demonstrate an ability to restore and maintain them for a compatible use Mandel, CEO of the Mandel Group cited offices for non-profit organizations as a preferred use but indicated he was willing to entertain any reasonable proposal you should know why Mandel doesn't want them After analyzing the costs of restoring and reconfiguring all five buildings to historic preservation standards for use in his larger residential apartment complex the estimate came to a whopping $11 million – far more than he had anticipated The five buildings together would have yielded only 41 small dwelling units of about 800 square feet each and those would have cost $365,000 each to produce "It's much more expensive to retrofit than to build new," said Phil Aiello of Mandel's firm "It would have required a subsidy of $5 million to $7 million to make it viable." Aiello said that the firm had sought such subsidies, including a 9 percent tax credit through the Wisconsin Housing and Economic Development Authority But that would have required a waiver of WHEDA's $200,000 per unit limit we thought it was unthinkable to take down one or more than one of the Eschweiler Buildings," Mandel said we are now proposing taking down four of the buildings saving the best – the Adminstration Building." Mandel presented a design plan that would not increase the amount of new building he had already proposed for the tract There would be no replacement of the "lost buildings" with new-built units but rather gardens or plazas outlining their footprints one of the most significant architects Milwaukee has produced and the Milwaukee County School of Agriculture for which the buildings were originally created The Administration Building would not hold any residential units but perhaps a leasing office for the larger complex public areas and offices for non-profits such as the Friends of the Monarch Trail The meeting had been moved to the larger of the committee rooms but most chairs were full – the largest crowd for a Historic Preservation Commission meeting in memory but most comments in the "opposed" category were really more polite questions or suggestions Former Community Development Director Nanch Welch "What I'm seeing here is a betrayal of the public trust," she said Preservation of all the buildings "has been approved over and over again It goes contrary to what the public has been told." Resident Dave Maddox echoed that he felt betrayed "having sat in many meetings in which the main component of discussion was the preservation of the buildings." if "It may be that their historic designation is causing them to be demolished," referring to the costs of meeting historic preservation standards questioned whether Mandel Group had tried to negotiate every avenue with state and federal thistoric preservation boards and I have had historic preservationists say to me A historic preservation that happens is better than one that gets torn down.'" The people of Wauwatosa have been at this since 1995 This community has always found a way – it is who we are." Eiff also questioned the assertion that the buildings were in any way as bad a shape as they are being portrayed "I have been in them many times," she said "and I'm sorry that the pictures in the paper were the worst they could find "People would be amazed at the integrity of these buildings Get more local news delivered straight to your inbox. Sign up for free Patch newsletters and alerts.