100 research outputs found
Austin also must be remembered. The Augustinian legacy in Milton's work
No full textWhen I started working on this project, with a limited knowledge of Augustine, but determined to spot his presence in Miltonâs poetry, I was little aware of the intricacy of the relationship between the two authors. At this stage of my research, I do subscribe to Savoyeâs opinion, that this relationship is pervasive. However, one could safely add, it is as pervasive as it is hidden, primarily because of changed cultural paradigms, so that Miltonâs references are no longer familiar to the reader.
As I have pointed out in my presentation of the state of the art, these articulations are hardly made explicit in Miltonâs Oeuvre and also in critical literature they are hardly brought to the surface. My objective has been to make them a little more visible.
I have started my own process of discovery from the works where Milton more openly (but not completely) acknowledges his Augustinian sources, although arguably mediated. As concerns Samson Agonistes, I have presented a reading through Augustinian lenses. I am by no means claiming that mine is the best of all possible readings, but through those lenses I have been able to see a coherence, in Miltonâs dramatic poem, that is not generally recognized.
On the other hand, I thoroughly agree that âone cannot simply take any English poet and turn the post-structuralist critical machine loose on him or her in good faithâ. In particular, I am aware that I have read Miltonâs works against the current critical grain which, with a powerful turn impressed by Empsonâs Miltonâs God, is continually surfacing Miltonâs idiosyncrasies in order to cancel the received picture of a Christian author. Rather, I agree with Cirillo that Miltonâs perspective is that of âa professed Christian poet whose Christian consciousness, no matter how heterodox, colored virtually everything he wrote.â.We may ask, echoing Febvre on Rabelais, âMais de quel christianisme? In accordance with very traditional, even traditionalist Milton Criticism, I think it can safely be stated that Milton is a post-Reformation religious author, and one whose endeavour to âjustify the ways of God to menâ had to come to terms with the difficult task to find signs of providential history in the aftermath of a civil war and in the adverse context of the Restoration. His last published poems deal with this problem in different terms. As readers, we can come to different conclusions as to the texts. Behind them there is the man, âest abyssus humanae conscientiae,â in front of which, after Augustine, I can only say: "nescio"
Compañía de ópera italiana de primíssimo cartello / bajo la dirección de Rodolfo Ferrari
No full textDon Carlo / Giuseppe Verdi ; Aida / Giuseppe Verdi ; Carmen / Georges Bizet ; Garín / Tomás Bretón ; Orfeo / Christoph Willibald Gluck ; Samson et Dalila / Camille Saint-Saëns ; Manon / Jules Massenet ; Lohengrin / Richard Wagner ; Gioconda / Amilcare Ponchielli ; Mefistofele / Arrigo Boito ; Gli Ugonotti / Giacomo Meyerbeer ; Freischütz / Carl Maria von Weber ; Nerone / Arrigo BoitoIntèrprets: Hariclée Darclée i Elena TheodoriniDe cada obra s'ha digitalitzat un programa sencer. De la resta s'han digitalitzat les parts que són diferents
Abstract 1168: Efficacy of the IRAK4 inhibitor CA-4948 in patient-derived xenograft models of diffuse large B cell lymphoma
No full textAbstract
IRAK4 kinase activity is required for toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling in a variety of myeloid and lymphoid cell types. Recruitment of IRAK4 to these receptors and its subsequent activation is facilitated by the MYD88 adaptor protein, which is mutated in ~22% of DLBCL cases. The MYD88 L265P activating mutation is found in ~30% of the activated B-cell (ABC) and ~6% of germinal center B-cell (GCB) subtypes of DLBCL and leads to constitutive activation of NF-κB signaling that is associated with worse prognosis. Thus, the development of small molecule inhibitors targeting IRAK4 is an attractive anticancer strategy for MYD88 mutation-containing cancers such as DLBCL.
We are developing an IRAK4 inhibitor, CA-4948, as a therapeutic agent for hematological cancers with dysregulated TLR/MYD88/IRAK4 signaling. CA-4948 (previously AU-4948) is a selective and potent IRAK4 kinase inhibitor with in vivo activity in a TLR4-induced cytokine release model. CA-4948 exhibits favorable DMPK properties, oral bioavailability, and is well tolerated in mice. Furthermore, CA-4948 was previously shown to exhibit dose-dependent efficacy in ABC-DLBCL MYD88-L265P xenograft tumor models using cell lines OCI-LY3 and OCI-LY10.
Here, we report the efficacy results from testing CA-4948 in a panel of well characterized, patient-derived DLBCL tumor xenograft (PDX) mouse models. CA-4948 exhibited the greatest efficacy in four of the five ABC-DLBCL PDX models tested as compared to GBC-DLBCL and ABC/GCB DLBCL PDX models. Furthermore, CA-4948 was efficacious in ABC-DLBCL PDX tumors containing activating mutations in both TLR/IL-1R and BCR signaling pathways (MYD88 and CD79B double mutants). Interestingly, the one ABC-DLBCL PDX model that failed to respond to CA-4948 treatment contained a MYD88 L265P mutation as well as a BCL6 translocation. While this particular PDX model was resistant to CA-4948, and showed a weak anti-tumor response to single-agent ibrutinib, the combination treatment of ibrutinib and CA-4948 exhibited a synergistic tumor growth inhibition effect. In summary, CA-4948 exhibited anti-tumor activity in ABC-type DLCBL PDX tumor models including those containing combinations of activating mutations in the TLR/IL-1R and BCR signaling pathways. These results underscore the therapeutic potential of IRAK4 kinase inhibition by CA-4948, as a single-agent or in combination with BCR inhibitors, for the treatment of DLBCL.
Citation Format: Robert N. Booher, Maria Elena Samson, Guang-Xin Xu, Hongsheng Cheng, David P. Tuck. Efficacy of the IRAK4 inhibitor CA-4948 in patient-derived xenograft models of diffuse large B cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1168. doi:10.1158/1538-7445.AM2017-1168</jats:p
SAMson: an automated brain extraction tool for rodents using SAM
No full text[Description of methods used for collection/generation of data]
D1: Images acquired on a 7-T scanner (Bruker, BioSpec 70/30, Ettlingen, Germany) using a T2-weighted RARE (Rapid Acquisition with Relaxation Enhancement) sequence.
D2: Images acquired on a 7-T scanner (Bruker, BioSpec 70/30, Ettlingen, Germany) equipped with an actively shielded gradient system using a T2-weighted sequence.
D3: Images acquired on a 11.4-T MRI scanner (Bruker BioSpec USR 117/16, Ettlingen, Germany) using a T2-weighted RARE sequence.[Methods for processing the data] Panadero Soler, Daniel; Kotb Selim, Mohamed; Martínez-Tazo, Patricia; Muñoz-Moreno, Emma; Ramos-Cabrer, Pedro; López-Larrubia, Pilar; De Santis, Silvia; Canals, Santiago; Pertusa, Antonio; 2025; SAMson: an automated brain extraction tool for rodents using SAM [Dataset]; BioRxiv; https://doi.org/10.1101/2024.03.07.583982S.C. acknowledges support from PCI2024-153491 funded by MICIU /AEI /10.130 39/501100011033 and UE, PID2021-128158NB-C21 funded by MICIU/10.13039/ 50110 0011033 and FEDER, UE, CEX2021-001165-S funded by MICIU/AEI /10.13039/50110 0011033 and Excellence Grant CIPROM/2022/15 and INVESTIGO INVEST/2022/396 funded by the Generalitat Valenciana and Next Generation EU. S.D.S. was supported by the the Spanish Ministerio de Ciencia e Innovación, Agencia Estatal de Investigación (PID2021-128909NA-I00 and CNS2023-14488 ), by the Programs for Centres of Excellence in R\&D Severo Ochoa (CEX2021-001165-S), and by the Generalitat Valenciana through a Subvencion para la contratación de investigadoras e investigadores doctores de excelencia 2021 (CIDEGENT/2021/015) and by a Fundación Pasqual Maragall Research Programme (2024 call). P.L-L. was funded by grant PID2021-122528OB-I00 funded by MICIU/AEI/10.13039/501100011033/FEDER, UE. Some of the mice used in this study were generated in the project funded by MCIU/AEI/FEDER, UE grants PID2022-141700OB-I00, MCIN/AEI/10.13039/501100011033 and CB/07/09/0034 Center for Networked Biomedical Research on Mental Health (CIBERSAM, Bortolozzi A). In addition, the funding sources acknowledged in:
1) Mateu-Bosch A, Segur-Bailach E, Muñoz-Moreno E, Barallobre MJ, Arbonés ML, Gea-Sorlí S, et al. Systemic delivery of AAV-GCDH ameliorates HLDinduced phenotype in a glutaric aciduria type I mouse model. Molecular Therapy - Methods & Clinical Development. 2024;32(3):101276. Available from: https://www.sciencedirect.com/science/article/pii/S2329050124000925.
and 2) Haddad-Tóvolli R, Ramírez S, Muñoz-Moreno E, Milà-Guasch M, Miquel-Rio L, Pozo M, et al. Food craving-like episodes during pregnancy are mediated by accumbal dopaminergic circuits. Nature Metabolism. 2022 Apr;4(4):424-34. Available from: https://doi.org/10.1038/s42255-022-00557-1.With funding from the Spanish government through the "Severo Ochoa Centre of Excellence" accreditation (CEX2021-001165-S).Peer reviewe
Abstract 127: Efficacy of novel IRAK4 inhibitor CA4948 in AML and MDS
No full textAbstract
Myelodysplastic syndrome (MDS) & Acute Myeloid Leukemia (AML) are hematologic malignancies that arise from a population of aberrant hematopoietic stem cells (HSCs). Overactivated innate immune signaling pathways such as IRAK1, TRAF6, IL1RAP, S100A9 and IL8 have been demonstrated in MDS/AML and play important roles in propagation of disease. IRAK4 (interleukin-1 receptor-associated kinase 4), is a protein kinase involved in signaling innate immune responses and forms a critical signaling complex with IRAK1. To determine its role in disease pathobiology, we analyzed transcriptomic data from CD34+ stem and progenitor cells from 183 MDS patients and found significantly increased expression of IRAK4 in MDS samples belonging to the high risk RAEB category (Refractory anemia with excess of blasts, N=80, P Value &lt;0.05 when compared to healthy controls). Furthermore, increased IRAK4 expression was predictive of significantly adverse prognosis (P value &lt; 0.05, median survival of 2.6 years compared to 5.2 years for group with lower IRAK4). Clinical correlations revealed that MDS patients with higher IRAK4 expression in stem/progenitor cells had significantly higher transfusion dependence and had higher leukemic blast counts (Mean Blast Count 9.3% vs 3.9%, P&lt;0.05), further demonstrating IRAK4 to be an adverse prognostic marker in MDS. IRAK4 was also overexpressed in highly purified FACS sorted disease initiating stem cell populations (Long Term-HSC, CD34+/CD38-/CD90+/Lin –ve) from AML patients with complex cytogenetics when compared to healthy controls.
To functionally determine the role of IRAK4 in MDS/AML pathogenesis, we utilized CA-4948, a potent, oral, small-molecule inhibitor of IRAK4, to assess the effect of inhibiting IRAK4 catalytic activity. In vitro, CA-4948 blocked downstream NF-κB pathway signaling, including secretion of proinflammatory cytokines, in Toll-like receptor stimulated THP1 leukemic cells. CA-4948 was tested in clonogenic assays from primary MDS and AML samples. MDS and AML are associated with block in differentiation that leads to cytopenias that are the cause of morbidity in these patients. Treatment with CA-4948 led to increased erythroid and myeloid differentiation in a majority of samples. Furthermore, drug treatment led to decreased viability of MDS/AML stem cells (CD34+/CD38-/Lin-ve) In vivo studies using a THP1 leukemia xenograft model in NSG mice demonstrated that CA-4948 was well tolerated and led to significantly decreased disease burden after 6 weeks of treatment.
In conclusion, we demonstrate that IRAK4 is upregulated in stem and progenitor cells in MDS and AML and is an adverse prognostic marker. Importantly, a novel, specific, inhibitor of IRAK4 shows preclinical in vitro and in vivo efficacy in MDS and AML models.
Citation Format: Gaurav S. Choudhary, Tushar D. Bhagat, Maria Elena S. Samson, Shanisha Gordon, Dagny Von Ahrens, Kith Pradhan, Aditi Shastri, Andrea Pellagatti, Jacqueline Boutlwood, Robert N. Booher, Ulrich Steidl, Amit Verma. Efficacy of novel IRAK4 inhibitor CA4948 in AML and MDS [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 127. doi:10.1158/1538-7445.AM2017-127</jats:p
Effect of abiotic stress on the success of the vertical transmission and survival during seed storage of two novel endophytes in perennial ryegrass : A thesis submitted in partial fulfilment of the requirements for the degree of Doctor of Philosophy at Lincoln University
No full textEpichloë fungal endophytes, which live in symbiosis with perennial ryegrass (Lolium perenne L.) are vertically transmitted only, totally depending on the success of the host plant for their dissemination and survival. New Zealand (NZ) leads the world in terms of adoption of endophyte technology. These novel associations are very successful in farming practices, as the endophytes provide bio-control through the production of secondary metabolites. Alkaloids like ergovaline, lolines, peramine and epoxy-janthitrems control at least six major pasture pests that decrease the quality and persistence of NZ grasslands.
Both endophyte and host plant grow in synchronization via a unique intercalary hyphal extension mechanism. However this relationship is far from being perfect as the endophyte can be lost at any stage of the host plant life cycle, either during the pre or post zygotic stage. This research aimed to identify abiotic factors affecting transmission during the development of the perennial ryegrass seed crop and survival of the endophytes in seed during storage, and used two commercial novel endophytes strains, AR1 and AR37 and three perennial ryegrass cultivars, ‘Prospect’, ‘One -50’ and ‘Samson’.
Waterlogging (WL) was imposed during three plant development stages (GS 30, GS59 and GS 70) to investigate any effect on the vertical transmission of the endophyte. WL had no significant effect on ryegrass seed germination percentage, or on endophyte transmission. In both cultivars and with both endophytes, the transmission exceeded 70%. Germination did not differ between the cultivars or between endophyte strains. For the growth parameters measured, WL had no significant effect on dry matter (DM) production, number of reproductive tillers per plant, seed yield per plant or thousand seed weight (TSW). However, TSW differed significantly between cultivars and between the endophyte strains independently of the WL treatments of the experiment.
The effects of combinations of three rates of nitrogen (0, 150, 250 kg ha⁻¹yr⁻¹) with three rates of potassium (0, 200, 400 kg ha⁻¹yr⁻¹) applied during crop development on the transmission of AR1 and AR37 endophyte strains and the effect on plant growth parameters were investigated. The grand mean transmission was 87%. There were no significance differences among treatments for transmission rate, or between the two cultivars or endophyte strains. However there was a significant linear response (p = 0.05) for transmission between endophyte strains to the applied N only. With no N, strain AR37 transmitted 8.7% more than AR1 in cultivar ‘Prospect’. At 150 and 250 kg N ha⁻¹yr⁻¹, there were no differences either between cultivars (cv) or endophyte strains.
N and K application rates had no significant effect on seed germination between endophyte strains. However, there was a significant difference in germination between cultivars, with ‘Prospect’ having a 5.6% higher germination than ‘One-50’. The grand mean of germination was very low (73%), indicating poor quality.
K significantly increased DM production, but there was no significant difference between the biomass produced when 200 kg or 400 kg ha⁻¹yr⁻¹ of K were used. The production of DM between endophyte strains did not differ. Both fertilisers increased the number of reproductive tillers produced for both cultivars, but not between endophyte strains. Cultivar ‘Prospect’ produced 47 more reproductive tillers than ‘One-50’. Both fertilisers significantly increased seed yield.
Furthermore, the effect of temperature and relative humidity during seed storage on the survival of these endophytic associations was determined. Combinations of four temperatures and four relative humidity levels, created and controlled using saturated salts solutions in sealed containers, were used to determine the endophyte survival in perennial ryegrass infected with strain AR37 during 418 days of storage. The accumulated thermal unit approach (ATU) was used to identify the “best before time” to maintain viable endophyte ≥ 70%. At 4°C endophyte viability remained above 70% for 1800 ATUs at 24%, 40% and 50% RH (relative humidity). At 20°C, endophyte viability at all four % RH remained above the industry threshold for 2500 ATU. At 30°C, by 1500 ATU endophyte viability in seeds stored at 40%, 50% and 70% RH had fallen below the 70% threshold and for those seeds stored at 24% RH, this point was reached at 2500 ATU. Maintaining endophyte viability above 70% was possible at three different temperatures (4°C, 15°C and 20°C) and relative humidity levels of both 24% and 40% when the accumulated thermal units were below 2000. At 70% RH, the endophyte maintained its viability for only up to 1000 ATUs. At 30°C and 24% RH, the endophyte maintained its viability for 45 days, being the only safe storage combination at that high temperature (2250 ATUs). Ambient temperature with higher relative humidity levels increased SMC and as a result negatively affecting endophyte viability when SMC >10 %. For all storage conditions, endophyte viability was always lost before seed viability.
In addition, the effect of different concentrations of carbon dioxide (CO₂) during storage on seed and endophyte viability was investigated. Controlled environments were created by capturing seed respiration at 5°C, 20°C and 30°C in sealed containers and by the use of ascorbic acid dust (AnaeroGen™) which caused anoxia and elevated the CO₂ levels in sealed containers at 20°C. Seeds from cultivar Samson containing the novel AR37 endophyte strain and the same cultivar endophyte free (E-) were used in this experiment. The endophyte viability and the seed germination were assessed after short periods of storage (1, 2, 4, 8, 16 d) and up to 32 days; in airtight glass vials.
Seed respiration rate increased with temperature and seeds containing endophyte (E+) had a higher respiration rate than seeds without endophyte (E-). Seeds stored at higher temperatures (30°C), with higher accumulative CO₂ concentrations due to respiration of seeds, lost the endophytes at a faster rate than seed stored at lower temperatures (5°C). The time of storage had a significant negative effect on endophyte survival. The effect of temperature was significant on endophyte survival between seed stored at 30°C compared with the ones at 5°C or 20°C. At equal temperature regimes there was no significant difference found between seed lots E+ or E-. Overall, there was no significant difference between seeds infected with AR37 and endophyte free seeds after 32 days of storage.
Where anoxic conditions with high concentrations of CO₂ were created, both time of storage and high concentrations of CO₂ in an airtight container negatively affected endophyte viability.
Overall high CO₂ concentrations and lack of O₂ did not reduce the germination rate of either E+ or E- seeds stored for 32 day
LSD1 inhibition improves efficacy of adoptive T cell therapy by enhancing CD8+ T cell responsiveness
No full textAbstract The lysine-specific histone demethylase 1 A (LSD1) is involved in antitumor immunity; however, its role in shaping CD8 + T cell (CTL) differentiation and function remains largely unexplored. Here, we show that pharmacological inhibition of LSD1 (LSD1i) in CTL in the context of adoptive T cell therapy (ACT) elicits phenotypic and functional alterations, resulting in a robust antitumor immunity in preclinical models in female mice. In addition, the combination of anti-PDL1 treatment with LSD1i-based ACT eradicates the tumor and leads to long-lasting tumor-free survival in a melanoma model, complementing the limited efficacy of the immune or epigenetic therapy alone. Collectively, these results demonstrate that LSD1 modulation improves antitumoral responses generated by ACT and anti-PDL1 therapy, providing the foundation for their clinical evaluation
Conditional expression of the TVA receptor allows clonal analysis of descendents from Cre-expressing progenitor cells
No full textAbstractAn understanding of the number and types of progeny produced by progenitor cells during development provides a foundation for studies of when and where cell fate determination takes place. Lineal relationships can be revealed by the identification of descendents of cells that express a recombinase, such as Cre or Flp. This method provides data concerning gene expression history, but does not provide clonal resolution among the descendents. An alternative method employs retroviral labeling, which permits the identification of clones, but does not allow for the tracking of gene expression history. Here we report a combination of these methods to circumvent each method's limitations. By employing the specificity of Cre expression, and by selecting only a subset of cells with a Cre history for retroviral infection, clones with a gene expression history can be labeled. The method utilizes a conditional allele of the avian tumor virus receptor A (TVA), which allows infection of mouse cells following Cre activity, with mammalian retroviral vectors pseudotyped with the ASLV-A envelope glycoprotein (EnvA). We quantified the efficiency and specificity of this system in vivo and in vitro. We also generated a series of retroviral vectors encoding a variety of histochemical and fluorescent reporter genes that enable the tracking of mixtures of clones, thus enabling better resolution of clonal boundaries. This method and new vectors can be used to further our understanding of the gene expression patterns of progenitor cells that make particular daughter cells, as well as provide a platform for manipulating identified subsets of developing cells
The marriage of Philip of Habsburg and Mary Tudor and anti-Spanish sentiment in England : political economies and culture, 1553-1557.
No full textPhDThis thesis examines the early part of Mary I's reign, focusing on her marriage to
Philip of Habsburg and the marginalisation of their co-monarchy in Tudor historiography.
By looking at the diplomatic background and political opposition in England, I interrogate
the notion that anti-Spanish sentiment was a central cause of the Wyatt rebellion, arguing that
instead its aetiology lay in female sovereignty and the constitutional uncertainties produced
by it. Dynasticism tended to alienate power from familiar, local and territorial sources of
political authority. Infant mortality and the vicissitudes of the marriage market in this context
threatened discrete 'national' identities with an incipient imperialist internationalism. I analyse
in detail the marriage contract and 'Act declaring that the regal power of this realm is in the
Queen's Majesty', using them as evidence to show that anxieties about property rights were
not related to the repudiation of the Supremacy, repeal of Henrician legislation and return of
papal jurisdiction. The staging of the wedding harped on Philip's inferior status, inverting that
which the marriage ceremony rehearsed. The Castilian writing of England as a romance of
chivalry sublimated a sexual licence which repeated the fears played upon by exiled
polemicists that the kingdom had been transformed into the feminised subject of Spanish
male authority. Anti-Spanish propaganda did not reflect popular xenophobia. It was literate
and sophisticated, related to sectarian struggle and engaged with theories of justifiable
disobedience. Finally, I treat the joint royal London Entry and representations of Philip and
Mary welcoming his assumption of authority in relation to both England and his new quee
- …
