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"Pratt, Jonathan"
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On the Threshold of Rhetoric
The Helen of Gorgias is designed to provoke the aspiring speaker to consider his relationship with society as a whole. The speech's extreme claims regarding the power of logos reflect simplistic ideas about speaker-audience relations current among Gorgias' target audience, ideas reflected in an interpretive stance towards model speeches that privileges method over truth. The Helen pretends to encourage this conception of logos and interpretive stance in order to expose the intense desire and naïve credulity that drive a coolly technical appraisal of model speeches. The Helen thus manifests, with a playfulness suited to its liminal position, a concern for the ethical and social formation of those who might accept the invitation to study logos.
Journal Article
TRPV4 and KRAS and FGFR1 gain-of-function mutations drive giant cell lesions of the jaw
Giant cell lesions of the jaw (GCLJ) are debilitating tumors of unknown origin with limited available therapies. Here, we analyze 58 sporadic samples using next generation or targeted sequencing and report somatic, heterozygous, gain-of-function mutations in
KRAS, FGFR1
, and p.M713V/I-
TRPV4
in 72% (42/58) of GCLJ.
TRPV4
p.M713V/I mutations are exclusive to central GCLJ and occur at a critical position adjacent to the cation permeable pore of the channel. Expression of TRPV4 mutants in HEK293 cells leads to increased cell death, as well as increased constitutive and stimulated channel activity, both of which can be prevented using TRPV4 antagonists. Furthermore, these mutations induce sustained activation of ERK1/2, indicating that their effects converge with that of
KRAS
and
FGFR1
mutations on the activation of the MAPK pathway in GCLJ. Our data extend the spectrum of TRPV4 channelopathies and provide rationale for the use of TRPV4 and RAS/MAPK antagonists at the bedside in GCLJ.
Giant cell lesions of the jaw (GCLJ) are debilitating benign tumors of unclear origin. The authors identify driver recurrent somatic mutations in TRPV4, KRAS and FGFR1 and show they converge on aberrant activation of the MAPK pathway. Their findings extend the spectrum of TRPV4 channelopathies and provide rationale for targeted therapies at the bedside in GCLJ.
Journal Article
Detrital zircon geochronology of Mesozoic sediments in the Rif and middle Atlas belts of Morocco; provenance constraints and refinement of the West African signature
Despite the presence of a deep history of continental evolution from Archean to Recent and a wealth of outcrop, existing studies of detrital zircon geochronology in Morocco are limited, focused mostly in the Cambrian and Neoproterozoic Pan-African exposures in the Anti-Atlas belt. We broaden the use of this tool by surveying the detrital zircon geochronology of three stratigraphic units from three distinct Mesozoic terranes: the Tisiren unit of the Maghrebian flysch domain, the Ketama unit of the Intrarif, and the Bou Rached sandstones of the Middle Atlas Mountains. Samples were analyzed for zircon U-Pb ages using laser-ablation inductively coupled plasma mass spectrometry, and zircon fission-track (ZFT) ages were analyzed using the emerging technique of scanning electron microscope high-density fission-track analysis. In total, 259 U-Pb ages are presented, along with 60 ZFT ages. U-Pb ages reveal dominant Pan-African (Cryogenian-Ediacaran) and West African cratonic (Paleoproterozoic) signatures that are typical of northwest Africa. All samples also include significant Mesoproterozoic U-Pb populations that are hitherto unknown in Morocco and scarce in North Africa. Proposed scenarios for the provenance of these zircons include delivery to Morocco from the Amazonian craton or the African Volta basin during Ordovician glaciation and/or delivery from Avalonian terranes during the Variscan orogeny. The Bou Rached sandstones contain a significant Ordovician-Devonian U-Pb population not found in the other samples and are of an age without a viable source currently dated in Morocco. An Avalonian source is likewise suggested for these Ordovician-Devonian ages. The Ketama and Tisiren units have comparable U-Pb ages, but their preliminary ZFT cooling age distributions differ, lending support to the idea that different source regions are required for the two domains.
Journal Article
Case Comment: Privy Council Corrects Cayman Companies Act to Confer Appraisal Rights on Minority Shareholders in Short-Form Mergers
In Changyou.com Ltd v FourWorld Global Opportunities Fund Ltd & Others, the Privy Council upheld the decisions of the Cayman Islands Grand Court and Court of Appeal that minority shareholders in a short-form merger have the right to apply to the Court for an appraisal of the 'fair value' of their shares and that this right is not limited to shareholders in a long-form merger. The judgment is important because it corrects an apparent anomaly in the Cayman Companies Act. It is also of interest because it considers the (limited) circumstances in which the Court can correct an oversight in the drafting of a statute.
Journal Article
Tetracycline Derivative Minocycline Inhibits Autophagy and Inflammation in Concanavalin-A-Activated Human Hepatoma Cells
Inhibition of soluble matrix metalloproteinase (MMP) activity is among the non-antibiotic cellular effects exerted by the anti-inflammatory tetracycline derivative minocycline. The impact of minocycline on the signal transduction functions of membrane-bound MMPs is however unknown. We assessed minocycline in a concanavalin-A (ConA)-activated human HepG2 hepatoma cell model, a condition known to increase the expression of membrane type-1 MMP (MT-MMP) and to trigger inflammatory and autophagy processes. We found that minocycline inhibited ConA-induced formation of autophagic acidic vacuoles, green fluorescent microtubule-associated protein 1 light chain 3 (GFP-LC3) puncta formation, gene and protein expression of autophagy biomarker BCL2/adenovirus E1B 19 kDa interacting protein 3 (BNIP3), invasion biomarker MT1-MMP, and inflammation biomarker cyclooxygenase (COX)-2. Gene silencing of MT1-MMP abrogated ConA-induced formation of autophagic acidic vacuoles and ConA-induced expressions of BNIP3 and COX-2. Minocycline was also shown to inhibit ConA-induced signal transducer and activator of transcription 3 (STAT3) phosphorylation as well as gene expression of NANOS1, a biomarker believed to colocalize with MT1-MMP and the specific silencing of which further inhibited ConA-induced STAT3 phosphorylation. Collectively, our data demonstrate that part of minocycline's effects on autophagy could be exerted through the inhibition of MT1-MMP signaling functions, which contribute to the autophagy and inflammatory phenotype of ConA-activated HepG2 cells.
Journal Article
MT1-MMP Expression Levels and Catalytic Functions Dictate LDL Receptor-Related Protein-1 Ligand Internalization Capacity in U87 Glioblastoma Cells
Modulations in cell surface receptor ectodomain proteolytic shedding impact on receptor function and cancer biomarker expression. As such, heavily pursued therapeutic avenues have exploited LDL receptor-related protein-1 (LRP-1)-mediated capacity in internalizing Angiopep-2 (An2), a brain-penetrating peptide that allows An2–drug conjugates to cross the blood–brain tumor barrier (BBTB). Given that LRP-1 is proteolytically shed from the cell surface through matrix metalloproteinase (MMP) activity, the balance between MMP expression/function and LRP-1-mediated An2 internalization is unknown. In this study, we found that membrane type-1 (MT1)-MMP expression increased from grade 1 to 4 brain tumors, while that of LRP-1 decreased inversely. MMP pharmacological inhibitors such as Ilomastat, Doxycycline and Actinonin increased in vitro An2 internalization by up to 2.5 fold within a human grade IV-derived U87 glioblastoma cell model. Transient siRNA-mediated MT1-MMP gene silencing resulted in increased basal An2 cell surface binding and intracellular uptake, while recombinant MT1-MMP overexpression reduced both cell surface LRP-1 expression as well as An2 internalization. The addition of Ilomastat to cells overexpressing recombinant MT1-MMP restored LRP-1 expression at the cell surface and An2 uptake to levels comparable to those observed in control cells. Collectively, our data suggest that MT1-MMP expression status dictates An2-mediated internalization processes in part by regulating cell surface LRP-1 functions. Such evidence prompts preclinical evaluations of combined MMP inhibitors/An2–drug conjugate administration to potentially increase the treatment of high-MT1-MMP-expressing brain tumors.
Journal Article
On the Threshold of Rhetoric,On the Threshold of Rhetoric: Gorgias’ Encomium of Helen
The Helen of Gorgias is designed to provoke the aspiring speaker to consider his relationship with society as a whole. The speech's extreme claims regarding the power of logos reflect simplistic ideas about speaker-audience relations current among Gorgias' target audience, ideas reflected in an interpretive stance towards model speeches that privileges method over truth. The Helen pretends to encourage this conception of logos and interpretive stance in order to expose the intense desire and naïve credulity that drive a coolly technical appraisal of model speeches. The Helen thus manifests, with a playfulness suited to its liminal position, a concern for the ethical and social formation of those who might accept the invitation to study logos.
Journal Article
On the threshold of rhetoric: Gorgias' \Ecomium of Helen\
The \"Helen\" of Gorgias is designed to provoke the aspiring speaker to consider his relationship with society as a whole. The speech's extreme claims regarding the power of \"logos\" reflect simplistic ideas about speaker-audience relations current among Gorgias' target audience, ideas reflected in an interpretive stance towards model speeches that privileges method over truth. The \"Helen\" predents to encourage this conception of \"logos\" and interpretive stance in order to expose the intense desire and naïve credulity that drive a coolly technical appraisal of model speeches. The \"Helen\" thus manifests, with a playfulness suited to its liminal position, a concern for the ethical and social formation of those who might accept the invitation to study \"logos.\" OA
Journal Article
Germline HAVCR2 mutations altering TIM-3 characterize subcutaneous panniculitis-like T cell lymphomas with hemophagocytic lymphohistiocytic syndrome
Subcutaneous panniculitis-like T cell lymphoma (SPTCL), a non-Hodgkin lymphoma, can be associated with hemophagocytic lymphohistiocytosis (HLH), a life-threatening immune activation that adversely affects survival
1
,
2
. T cell immunoglobulin mucin 3 (TIM-3) is a modulator of immune responses expressed on subgroups of T and innate immune cells. We identify in ~60% of SPTCL cases germline, loss-of-function, missense variants altering highly conserved residues of TIM-3, c.245A>G (p.Tyr82Cys) and c.291A>G (p.Ile97Met), each with specific geographic distribution. The variant encoding p.Tyr82Cys TIM-3 occurs on a potential founder chromosome in patients with East Asian and Polynesian ancestry, while p.Ile97Met TIM-3 occurs in patients with European ancestry. Both variants induce protein misfolding and abrogate TIM-3’s plasma membrane expression, leading to persistent immune activation and increased production of inflammatory cytokines, including tumor necrosis factor-α and interleukin-1β, promoting HLH and SPTCL. Our findings highlight HLH–SPTCL as a new genetic entity and identify mutations causing TIM-3 alterations as a causative genetic defect in SPTCL. While HLH–SPTCL patients with mutant TIM-3 benefit from immunomodulation, therapeutic repression of the TIM-3 checkpoint may have adverse consequences.
This study finds germline loss-of-function mutations in
HAVCR2
, which encodes the immune modulator TIM-3, in individuals with subcutaneous panniculitis-like T cell lymphomas and hemophagocytic lymphohistiocytosis, a life-threatening inflammatory condition.
Journal Article