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- A Mechanistic Framework for Explaining Audience Design in Language Production. [Journal Article]
- ARAnnu Rev Psychol 2018 Sep 19
- Audience design refers to the situation in which speakers fashion their utterances so as to cater to the needs of their addressees. In this article, a range of audience design effects are reviewed, o...
Audience design refers to the situation in which speakers fashion their utterances so as to cater to the needs of their addressees. In this article, a range of audience design effects are reviewed, organized by a novel cognitive framework for understanding audience design effects. Within this framework, feedforward (or one-shot) production is responsible for feedforward audience design effects, or effects based on already known properties of the addressee (e.g., child versus adult status) or the message (e.g., that it includes meanings that might be confusable). Then, a forward modeling approach is described, whereby speakers independently generate communicatively relevant features to predict potential communicative effects. This can explain recurrent processing audience design effects, or effects based on features of the produced utterance itself or on idiosyncratic features of the addressee or communicative situation. Predictions from the framework are delineated. Expected final online publication date for the Annual Review of Psychology Volume 70 is January 4, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
- Case 258: Granulomatous Prostatitis. [Journal Article]
- RRadiology 2018; 289(1):267-271
- History A 68-year-old man with a remote history of a previously resected high-grade urothelial carcinoma in the renal pelvis was being observed and was undergoing urologic treatment for recurrent low...
History A 68-year-old man with a remote history of a previously resected high-grade urothelial carcinoma in the renal pelvis was being observed and was undergoing urologic treatment for recurrent low-grade urothelial carcinoma of the bladder. During his most recent evaluation, he reported no specific symptoms and denied experiencing hematuria, dysuria, or abdominal pain. At routine surveillance MRI of the abdomen and pelvis (images not shown), a lesion was noted in the peripheral zone of the prostate gland. The prostate-specific antigen level was elevated (7.51 ng/mL [normal range, 0.00-4.00 ng/mL]). The patient had no family history of prostate cancer and had never undergone prostate biopsy. MRI of the prostate with an endorectal coil was subsequently performed.
- Atypical Perinuclear Anti-Neutrophil Cytoplasmic Antibodies in Ocular Inflammatory Diseases. [Journal Article]
- OIOcul Immunol Inflamm 2018 Sep 19; :1-5
- CONCLUSIONS: In contrast to typical C-ANCA and P-ANCA, atypical P-ANCA seropositivity was not associated with severe vasculitis or poor prognosis in patients with the OID.
- Chemotherapy and biologic use in the routine management of metastatic colorectal cancer in Australia: is clinical practice following the evidence? [Journal Article]
- IMIntern Med J 2018 Sep 19
- CONCLUSIONS: Doublet chemotherapy plus bevacizumab remains the dominant initial strategy, with limited uptake of triplet chemotherapy and of EGFRi. Potential explanations include uncertainty about the significance of post-hoc analyses for EGFRi and concerns regarding adverse events for both strategies. This article is protected by copyright. All rights reserved.
- Optimizing PARP inhibition through combined epigenetic and immunotherapy. [Journal Article]
- CSCancer Sci 2018 Sep 19
- Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with poor survival outcomes. Currently, there are no targeted therapies available for TNBCs despite remarkable progress in ...
Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with poor survival outcomes. Currently, there are no targeted therapies available for TNBCs despite remarkable progress in targeted and immune-directed therapies for other solid organ malignancies. Poly (ADP-ribose) polymerase inhibitors (PARPi) are effective anticancer drugs that produce good initial clinical responses, especially in homologous recombination (HR) DNA repair-deficient cancers. However, resistance is the rule rather than the exception, and recurrent tumors tend to have an aggressive phenotype associated with poor survival. Many efforts have been made to overcome PARPi resistance, mostly by targeting genes and effector proteins participating in HR that are overexpressed during PARPi therapy. Due to many known and unknown compensatory pathways, genes, and effector proteins, overlap and shared resistance are common. Overexpression of programmed death-ligand 1 (PD-L1) and cancer stem cell (CSC) sparing are novel PARPi resistance hypotheses. Although adding programmed cell death-1 (PD-1)/PD-L1 inhibitors to PARPi may improve immunogenic cell death and be crucial for durable responses, they are less likely to target the CSC population that drives recurrent tumor growth. Lysine-specific histone demethylase-1A (LSD1) and histone deacetylase (HDAC) inhibitors have shown promising activity against CSCs. Combining epigenetic drugs such as LSD1 inhibitors or HDAC inhibitors with PARPi/anti-PD-1/PD-L1 is a novel, potentially synergistic strategy for priming tumors and overcoming resistance. Furthermore, such an approach may pave the way for the identification of new upstream epigenetic and genetic signatures. This article is protected by copyright. All rights reserved.
- Anti-PL-12 antibody-positive antisynthetase syndrome with recurrent digital ulcers. [Letter]
- JDJ Dermatol 2018 Sep 19
- Japanese guidelines for the management and treatment of generalized pustular psoriasis: The new pathogenesis and treatment of GPP. [Letter]
- JDJ Dermatol 2018 Sep 19
- Generalized pustular psoriasis (GPP) is a rare disease characterized by recurrent fever and systemic flushing accompanied by extensive sterile pustules. The committee of the guidelines was founded as...
Generalized pustular psoriasis (GPP) is a rare disease characterized by recurrent fever and systemic flushing accompanied by extensive sterile pustules. The committee of the guidelines was founded as a collaborative project between the Japanese Dermatological Association and the Study Group for Rare Intractable Skin Diseases under the Ministry of Health, Labour, and Welfare Research Project on Overcoming Intractable Diseases. The aim of the guidelines was to provide current information to aid in the treatment of patients with GPP in Japan. Its contents include the diagnostic and severity classification criteria for GPP, its pathogenesis, and recommendations for the treatment of GPP. Since there are few clinical trial data with high levels of evidence for this rare disease, recommendations by the committee are described in the present guidelines.
- Substance use patterns and HIV-1 RNA viral load rebound among HIV-positive illicit drug users in a Canadian setting. [Journal Article]
- ATAntivir Ther 2018 Sep 19
- CONCLUSIONS: The present study suggests that in addition to heavy alcohol use, high-intensity illicit drug use, particularly ≥daily heroin injection and ≥daily crack smoking are risk factors for VL rebound. In addition to the impact of high-intensity drug use on healthcare engagement and ART adherence, some evidence exists on the direct impact of psychoactive substances on ART metabolism and the natural progression of HIV disease. At-risk individuals should be provided additional supports to preserve virologic control and maintain the benefits of ART.
- Brain-Resident T Cells Following Viral Infection. [Journal Article]
- VIViral Immunol 2018 Sep 18
- Activated CD8+ lymphocytes infiltrate the brain in response to many viral infections; where some remain stationed long term as memory T cells. Brain-resident memory T cells (bTRM) are positioned to i...
Activated CD8+ lymphocytes infiltrate the brain in response to many viral infections; where some remain stationed long term as memory T cells. Brain-resident memory T cells (bTRM) are positioned to impart immediate defense against recurrent or reactivated infection. The cytokine and chemokine milieu present within a tissue is critical for TRM generation and retention; and reciprocal interactions exist between brain-resident glia and bTRM. High concentrations of TGF-β are found within brain and this cytokine has been shown to induce CD103 (integrin αeβ7) expression. The majority of T cells persisting within brain express CD103, which aids in retention through interaction with E-cadherin. Likewise, cytokines produced by T cells also modulate microglia. The anti-inflammatory cytokine IL-4 has been shown to preferentially polarize microglial cells toward an M2 phenotype, with a corresponding increase in E-cadherin expression. These findings demonstrate that the brain microenvironment, both during and following inflammation, prominently contributes to the role of CD103 in T cell persistence. Further evidence shows that microglia, and astrocytes, upregulate programmed death (PD) ligand 1 during neuroinflammation, likely to limit neuropathology, and the PD-1: PD-L1 pathway also aids in bTRM generation and retention. Upon reactivation of quiescent neurotropic viruses, bTRM may respond to small amounts of de novo-produced viral antigen by rapidly releasing IFN-γ, resulting in interferon-stimulated gene expression in surrounding glia, thereby amplifying activation of a small number of adaptive immune cells into an organ-wide innate antiviral response. While advantageous from an antiviral perspective; over time, recall response-driven, organ-wide innate immune activation likely has cumulative neurotoxic and neurocognitive consequences.
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- Single molecule approaches for studying gene regulation in metabolic tissues. [Review]
- DODiabetes Obes Metab 2018; 20 Suppl 2:145-156
- Gene expression in metabolic tissues can be regulated at multiple levels, ranging from the control of promoter accessibilities, transcription rates, mRNA degradation rates and mRNA localization. Modu...
Gene expression in metabolic tissues can be regulated at multiple levels, ranging from the control of promoter accessibilities, transcription rates, mRNA degradation rates and mRNA localization. Modulating these processes can differentially affect important performance criteria of cells. These include precision, cellular economy, rapid response and maintenance of DNA integrity. In this review we will describe how distinct strategies of gene regulation impact the trade-offs between the cells' performance criteria. We will highlight tools based on single molecule visualization of transcripts that can be used to measure promoter states, transcription rates and mRNA degradation rates in intact tissues. These approaches revealed surprising recurrent patterns in mammalian tissues, that include transcriptional bursting, nuclear retention of mRNA, and coordination of mRNA lifetimes to facilitate rapid adaptation to changing metabolic inputs. The ability to characterize gene expression at the single molecule level can uncover the design principles of gene regulation in metabolic tissues such as the liver and the pancreas.