The prognostic significance of CDKN2A homozygous deletion in IDH-mutant lower-grade glioma and glioblastoma: a systematic review of the contemporary literature

Journal of Neuro-Oncology - The most recent cIMPACT-NOW update highlighted the homozygous deletion of the Cyclin Dependent Kinase Inhibitor 2A (CDKN2A) gene as a clinically important molecular...     

A Subset of Type I Conventional Dendritic Cells Controls Cutaneous Bacterial Infections through VEGFα-Mediated Recruitment of Neutrophils

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Medicinal plants from the Yanesha (Peru): Evaluation of the leishmanicidal and antimalarial activity of selected extracts

Aim of the study

Ninety-four ethanolic extracts of plants used medicinally by the Yanesha, an Amazonian Peruvian ethnic group, for affections related to leishmaniasis and malaria were screened in vitro against Leishmania amazonensis amastigotes and against a Plasmodium falciparum chloroquine resistant strain.

Materials and methods

The viability of Leishmania amazonensis amastigote stages was assessed by the reduction of tetrazolium salt (MTT) while the impact on Plasmodium falciparum was determined by measuring the incorporation of radio-labelled hypoxanthine.

Results and conclusions

Six plant species displayed good activity against Plasmodium falciparum chloroquine resistant strain (IC₅₀ < 10 μg/ml): a Monimiaceae, Siparuna aspera (Ruiz & Pavon), A. DC., two Zingiberaceae, Renealmia thyrsoidea (Ruiz & Pavon) Poepp. & Endl. and Renealmia alpinia (Rottb.), two Piperaceae (Piper aduncum L. and Piper sp.) and the leaves of Jacaranda copaia (Aubl.) D. Don (Bignoniaceae).Eight species displayed interesting leishmanicidal activities (IC₅₀ < 10 μg/ml): Carica papaya L. (Caricaceae), Piper dennisii Trel (Piperaceae), Hedychium coronarium J. König (Zingiberaceae), Cestrum racemosum Ruiz & Pav. (Solanaceae), Renealmia alpinia (Rottb.) Zingiberaceae, Lantana sp. (Verbenaceae), Hyptis lacustris A. St.-Hil. ex Benth. (Lamiaceae) and Calea montana Klat. (Asteraceae). Most of them are used against skin affections by Yanesha people.Results are discussed herein, according to the traditional use of the plants and compared with data obtained from the literature.     

Genomic context sensitivity of insulator function

The specificity of interactions between genomic regulatory elements and potential target genes is influenced by the binding of insulator proteins such as CTCF, which can act as potent enhancer blockers when interposed between an enhancer and a promoter in a reporter assay. But not all CTCF sites genome-wide function as insulator elements, depending on cellular and genomic context. To dissect the influence of genomic context on enhancer blocker activity, we integrated reporter constructs with promoter-only, promoter and enhancer, and enhancer blocker configurations at hundreds of thousands of genomic sites using the Sleeping Beauty transposase. Deconvolution of reporter activity by genomic position reveals distinct expression patterns subject to genomic context, including a compartment of enhancer blocker reporter integrations with robust expression. The high density of integration sites permits quantitative delineation of characteristic genomic context sensitivity profiles and their decomposition into sensitivity to both local and distant DNase I hypersensitive sites. Furthermore, using a single-cell expression approach to test the effect of integrated reporters for differential expression of nearby endogenous genes reveals that CTCF insulator elements do not completely abrogate reporter effects on endogenous gene expression. Collectively, our results lend new insight into genomic regulatory compartmentalization and its influence on the determinants of promoter–enhancer specificity.

A boundary model offers an attractive paradigm for understanding regulatory specificity in mammalian genomes through the delineation of independent regulatory domains. Insulators are a class of genomic regulatory elements that block interaction of enhancers with their cognate promoters (Phillips and Corces 2009). Enhancer blocker activity is canonically defined by a reporter assay that interposes a candidate insulator element between a weak promoter and an enhancer (Chung et al. 1993), while barrier insulators protect transgenes from silencing owing to spreading of heterochromatin (West et al. 2002). Insulators have also been used to counter genotoxicity from transgene enhancer activation of endogenous oncogenes (Li et al. 2009; Liu et al. 2015). Known insulators such as the chicken beta-globin hypersensitive site 4 element or the Igf2/H19 imprinting control region (Bell and Felsenfeld 2000) are composite elements with enhancer blocker, barrier, and other activities (Dickson et al. 2010), and often have secondary functions, such as silencers (Qi et al. 2015).The architectural protein CTCF is the only known vertebrate insulator protein, and its binding can confer a potent enhancer blocking effect (Phillips and Corces 2009). Additionally, binding sites for CTCF colocalize with genomic features such as topologically associated domain boundaries (Dixon et al. 2012), but direct functional analysis of these sites is impeded by the difficulty of genome engineering at the relevant scales. Although binding affinity, DNA methylation, and recognition sequence orientation appear to confer some specificity for CTCF sites involved in domain organization (de Wit et al. 2015; Guo et al. 2015; Sanborn et al. 2015), these factors alone remain inadequate to distinguish true insulator elements impacting expression of nearby genes from the ∼100,000 CTCF sites genome-wide (Maurano et al. 2015; Tycko et al. 2019). Stably integrated reporter assays have shed light on the mechanics of insulator function, but such methods do not assess interaction with the surrounding endogenous genomic elements (Walters et al. 1999). In contrast, integrated barcoded reporter assays (Akhtar et al. 2013; Maricque et al. 2019; Moudgil et al. 2020) offer the potential to directly assess the interaction between novel CTCF sites and the endogenous genomic landscape.Here, we aim to functionally characterize endogenous genomic regulatory elements through their effect on integrated reporters. We describe a high-throughput randomly integrated barcoded reporter platform based on a previously described enhancer blocker construct interposing a potent CTCF insulator element (Liu et al. 2015) between a weak promoter and a potent enhancer. We integrate these reporters, both with and without insulator elements, randomly throughout the genome of K562 erythroleukemia cells using the Sleeping Beauty transposase system. We use the unique reporter barcodes to map individual insertion locations and enable position-specific readout of genomic context effects. Finally, we apply single-cell RNA-seq (scRNA-seq) to detect specific reporter integrations that perturb endogenous gene expression.     

Investigating Canadian medical school attrition metrics to inform socially accountable admissions planning

Objective: Attrition from Canadian medical degree programs was never described despite differences in admissions requirements at the 17 faculties of medicine. Knowledge on attrition metrics could help the faculties evaluate new avenues for addressing the Association of Faculties of Medicine’s (AFMC) Future of Medical Education in Canada (FMEC MD) recommendation to enhance admissions practices with the goal to improve social accountability and student diversity.

Method: AFMC databases were used to track medical degree completion of all Canadian M.D. students who enrolled between 2003 and 2007. Students were followed and assigned an M.D. completion status as of by July 1, 2013. Bivariate statistics were used to evaluate if demographic, admission and degree progression variables were associated with medical school attrition.

Results: Of 11,454 students enrolled in Canadian M.D. programs from 2003 to 2007, only 197 (1.7%) did not complete. Québec had significantly higher attrition than other jurisdictions with age, educational attainment at time of enrolment, MCAT completion and struggling academically associated with attrition.

Conclusion: Attrition from Canadian MD programs is rare and associated with differences in admission requirements and possibly suggests an optimum life stage for medical studies. Improved knowledge of attrition-related factors may offer an additional level of evidence for improving the alignment between admissions policies and the social accountability objectives of medical schools.     

Neuroprotective effect of transient ischemic attack

Transient ischemic attack (TIA) is a well-recognized risk factor of ischemic stroke. Hence, 7 to 25% of ischemic stroke patients have a history of TIA, and the risk of ischemic stroke after TIA is about 15% at 3 months. However, epidemiological studies have demonstrated that among patients with ischemic stroke, those with a history of TIA have better functional and vital prognoses. This protective effect is particularly found in case of recent and short TIA, and in case of non-lacunar ischemic stroke. Hence, TIA can induce endogenous neuroprotection by the ischemic tolerance phenomenon that decreases the neurodegeneration usually caused by a severe cerebral ischemia in a non-preconditioned brain. The mechanisms of ischemic tolerance appear complex, multiple, and not fully understood. They involve changes in cellular gene expression, metabolic and signaling pathways, and enzymatic expression. The evidence of the neuroprotective effect of TIA offers interesting perspectives for the development of therapeutic strategies targeting the ischemic tolerance phenomenon.     

Serum brain‐derived neurotrophic factor and platelet activation evaluated by soluble P‐selectin and soluble CD‐40‐ligand in patients with acute myocardial infarction

Little is known about the role of neurotrophins (NT) under adult vascular homeostasis in normal and pathological conditions. The NT family, including nerve growth factor and brain‐derived neurotrophic factor (BDNF) are expressed in atherosclerotic vessels. Previous studies demonstrated that plasma BDNF levels were increased in the coronary circulation in patients with unstable angina. However, the role of BDNF during the onset and evolution of unstable angina remains to be elucidated. The objective of this study was to evaluate the relationship between BDNF, functional parameters and biological markers associated with inflammatory processes and platelet activation. BDNF serum levels were assessed in patients with acute myocardial infarction (MI) (n = 20) or stable angina pectoris (SAP) (n = 20) who underwent coronary angiography. Serum levels of IL‐6, MCP1, sVCAM, soluble CD‐40‐ligand (sCD40L) and soluble P‐selectin (sP‐selectin) were measured simultaneously by flux cytometry. Median BDNF levels were higher in the MI than in the SAP group (1730 vs. 877 pg/mL, respectively; P = 0.025). In MI patients, we observed a significant correlation between BDNF and sP‐selectin (r = 0.58, P = 0.023), although we found a non‐significant trend between BDNF and sCD40L (r = +0.35, P = 0.144). By contrast, no such correlation was observed in SAP patients (r = ?0.22, P = 0.425). No difference was observed between the two groups regarding baseline demographics, risk factors, biological data and angiographic findings. The study suggests that BDNF serum levels in MI patients could be related to platelet activation and the inflammatory response. Further studies are needed to investigate the role of NT in the setting of acute MI.     

Aphasia in bilinguals and ASL signers: Implications for a theoretical model of neurolinguistic processing based on a review and synthesis of the literature

Abstract

A comprehensive understanding of language organization in the brain, it is argued, necessitates additional research on both language-particular characteristics and the issue of bilingualism. An analysis of current research on aphasia in bilinguals and American Sign Language (ASL) signers is presented. Central to the presentation is the need for future research to be conducted within the framework advocated.