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OBJECTIVES/GOALS: Glioblastomas (GBMs) are heterogeneous, treatment-resistant tumors that are driven by populations of cancer stem cells (CSCs). In this study, we perform an epigenetic-focused functional genomics screen in GBM organoids and identify WDR5 as an essential epigenetic regulator in the SOX2-enriched, therapy resistant cancer stem cell niche. METHODS/STUDY POPULATION: Despite their importance for tumor growth, few molecular mechanisms critical for CSC population maintenance have been exploited for therapeutic development. We developed a spatially resolved loss-of-function screen in GBM patient-derived organoids to identify essential epigenetic regulators in the SOX2-enriched, therapy resistant niche. Our niche-specific screens identified WDR5, an H3K4 histone methyltransferase responsible for activating specific gene expression, as indispensable for GBM CSC growth and survival. RESULTS/ANTICIPATED RESULTS: In GBM CSC models, WDR5 inhibitors blocked WRAD complex assembly and reduced H3K4 trimethylation and expression of genes involved in CSC-relevant oncogenic pathways. H3K4me3 peaks lost with WDR5 inhibitor treatment occurred disproportionally on POU transcription factor motifs, required for stem cell maintenance and including the POU5F1(OCT4)::SOX2 motif. We incorporated a SOX2/OCT4 motif driven GFP reporter system into our CSC cell models and found that WDR5 inhibitor treatment resulted in dose-dependent silencing of stem cell reporter activity. Further, WDR5 inhibitor treatment altered the stem cell state, disrupting CSC in vitro growth and self-renewal as well as in vivo tumor growth. DISCUSSION/SIGNIFICANCE: Our results unveiled the role of WDR5 in maintaining the CSC state in GBM and provide a rationale for therapeutic development of WDR5 inhibitors for GBM and other advanced cancers. This conceptual and experimental framework can be applied to many cancers, and can unmask unique microenvironmental biology and rationally designed combination therapies.
We assess emerging relationships between production decisions and market channel selection among a small sample of hemp growers (22) in Colorado and Kentucky using qualitative interviews. We found producers differences by market channel, product and state. For instance, producers who relied on intermediated marketing strategies cultivated more acres on average and used fewer distinct market channels and strategies than those relying on direct markets. Product differences were found regarding processing, storage and perishability. Respondents identified four factors critical to their choice of market channels for their hemp products: research, profitability, trust and knowledge. The findings can help inform public and private decision-making regarding best hemp marketing practices and future needs of the hemp industry.
Neuropsychiatric disorders are common in 22q11.2 Deletion Syndrome (22q11DS) with about 25% of affected individuals developing schizophrenia spectrum disorders by young adulthood. Longitudinal evaluation of psychosis spectrum features and neurocognition can establish developmental trajectories and impact on functional outcome.
157 youth with 22q11DS were assessed longitudinally for psychopathology focusing on psychosis spectrum symptoms, neurocognitive performance and global functioning. We contrasted the pattern of positive and negative psychosis spectrum symptoms and neurocognitive performance differentiating those with more prominent Psychosis Spectrum symptoms (PS+) to those without prominent psychosis symptoms (PS−).
We identified differences in the trajectories of psychosis symptoms and neurocognitive performance between the groups. The PS+ group showed age associated increase in symptom severity, especially negative symptoms and general nonspecific symptoms. Correspondingly, their level of functioning was worse and deteriorated more steeply than the PS− group. Neurocognitive performance was generally comparable in PS+ and PS− groups and demonstrated a similar age-related trajectory. However, worsening executive functioning distinguished the PS+ group from PS− counterparts. Notably, of the three executive function measures examined, only working memory showed a significant difference between the groups in rate of change. Finally, structural equation modeling showed that neurocognitive decline drove the clinical change.
Youth with 22q11DS and more prominent psychosis features show worsening of symptoms and functional decline driven by neurocognitive decline, most related to executive functions and specifically working memory. The results underscore the importance of working memory in the developmental progression of psychosis.
We use small-amplitude inviscid theory to study the swimming performance of a flexible flapping plate with time-varying flexibility. The stiffness of the plate oscillates at twice the frequency of the kinematics in order to maintain a symmetric motion. Plates with constant and time-periodic stiffness are compared over a range of mean plate stiffnesses, oscillating stiffness amplitudes and oscillating stiffness phases for isolated heaving, isolated pitching and combined leading-edge kinematics. We find that there is a profound impact of oscillating stiffness on the thrust, with a lesser impact on propulsive efficiency. Thrust improvements of up to 35 % relative to a constant-stiffness plate are observed. For large enough frequencies and amplitudes of the stiffness oscillation, instabilities emerge. The unstable regions may confer enhanced propulsive performance; this hypothesis must be verified via experiments or nonlinear simulations.
Abnormal tau, a hallmark Alzheimer’s disease (AD) pathology, may appear in the locus coeruleus (LC) decades before AD symptom onset. Reports of subjective cognitive decline are also often present prior to formal diagnosis. Yet, the relationship between LC structural integrity and subjective cognitive decline has remained unexplored. Here, we aimed to explore these potential associations.
We examined 381 community-dwelling men (mean age = 67.58; SD = 2.62) in the Vietnam Era Twin Study of Aging who underwent LC-sensitive magnetic resonance imaging and completed the Everyday Cognition scale to measure subjective cognitive decline along with their selected informants. Mixed models examined the associations between rostral-middle and caudal LC integrity and subjective cognitive decline after adjusting for depressive symptoms, physical morbidities, and family. Models also adjusted for current objective cognitive performance and objective cognitive decline to explore attenuation.
For participant ratings, lower rostral-middle LC contrast to noise ratio (LCCNR) was associated with significantly greater subjective decline in memory, executive function, and visuospatial abilities. For informant ratings, lower rostral-middle LCCNR was associated with significantly greater subjective decline in memory only. Associations remained after adjusting for current objective cognition and objective cognitive decline in respective domains.
Lower rostral-middle LC integrity is associated with greater subjective cognitive decline. Although not explained by objective cognitive performance, such a relationship may explain increased AD risk in people with subjective cognitive decline as the LC is an important neural substrate important for higher order cognitive processing, attention, and arousal and one of the first sites of AD pathology.
Data from neurocognitive assessments may not be accurate in the context of factors impacting validity, such as disengagement, unmotivated responding, or intentional underperformance. Performance validity tests (PVTs) were developed to address these phenomena and assess underperformance on neurocognitive tests. However, PVTs can be burdensome, rely on cutoff scores that reduce information, do not examine potential variations in task engagement across a battery, and are typically not well-suited to acquisition of large cognitive datasets. Here we describe the development of novel performance validity measures that could address some of these limitations by leveraging psychometric concepts using data embedded within the Penn Computerized Neurocognitive Battery (PennCNB).
We first developed these validity measures using simulations of invalid response patterns with parameters drawn from real data. Next, we examined their application in two large, independent samples: 1) children and adolescents from the Philadelphia Neurodevelopmental Cohort (n = 9498); and 2) adult servicemembers from the Marine Resiliency Study-II (n = 1444).
Our performance validity metrics detected patterns of invalid responding in simulated data, even at subtle levels. Furthermore, a combination of these metrics significantly predicted previously established validity rules for these tests in both developmental and adult datasets. Moreover, most clinical diagnostic groups did not show reduced validity estimates.
These results provide proof-of-concept evidence for multivariate, data-driven performance validity metrics. These metrics offer a novel method for determining the performance validity for individual neurocognitive tests that is scalable, applicable across different tests, less burdensome, and dimensional. However, more research is needed into their application.
Motivational impairment associated with deficits in processing the anticipation of future reward is hypothesized to be a cardinal feature of schizophrenia spectrum disorders (SZ). Evidence from short-term follow-up (6-week post-treatment) studies suggests that these deficits may improve or be reversed with treatment, although longer-term outcomes are unknown. Here we examined the one-year trajectory of functional activation in brain circuitry associated with reward anticipation in people with recent onset SZ who participated in coordinated specialty care (CSC) treatment, hypothesizing normalization of brain response mirroring previous short-term findings in first-episode individuals.
Blood oxygen level-dependent (BOLD) response in the dorsal anterior cingulate cortex, anterior insula, and ventral striatum (VS) associated with reward anticipation during the Incentivized Control Engagement Task (ICE-T) was analyzed in a baseline sample of 49 healthy controls (HCs) and 52 demographically matched people with SZ, with follow-up data available for 35 HCs and 17 people with SZ.
In agreement with our hypothesis, significant time × diagnosis interactions were observed across all regions, in which reward anticipation-associated BOLD response increased in SZ to above baseline HC levels at follow-up. Increased VS activation was associated with decreased reality distortion symptoms over the follow-up period. Baseline reward anticipation-associated BOLD response in the right anterior insula was associated with improvement in reality distortion symptoms.
These findings suggest that functional deficits in reward anticipation may be reversed after one year of CSC in recent onset participants with SZ, and that this improvement is associated with reduced positive symptoms in the illness.
This chapter considers the rhythms of George Eliot’s prose; it shows that George Eliot had a fine ear for the cadences of her writing and that she controlled the fluency and blockage in the progress of her sentences to variously suggestive effects. Her rhythmical prose responds to the balance her realism strikes between immediate description and reflective narration, between dreamy ideals and difficult realities. The tension that her characters experience between a willingness to struggle on and a desire to relent is also registered in the fluency and friction of her sentences.
Style is notoriously difficult to define; there are many different literary styles and many different ways of understanding style. This chapter discusses several of these possibilities and suggests that the work of style will be best understood by close attention to the multiple technical resources that constitute any style. This kind of attention will show that style is not separate to meaning, not merely an adornment or accessory to it, for style is inseparable from expression. In particular, it is style that generates meaning and implication, over and above the apparently paraphraseable sense. Although some Victorian novelists stated that the ideal style effaced its own presence, Victorian novels are more aware of their verbal artistry, and indeed their artifice, than some critics allow or than the ideal of transparency permits. Such a self-understanding is helpfully writ large in novels that dramatize a writer’s development of their literary style, including George Meredith’s Diana of the Crossways, Charlotte Bronte’s Villette and Thomas Hardy’s The Hand of Ethelberta.
Some writers of the Victorian period, as well as more recent critics, have argued that the prose style of Victorian fiction aims to efface itself or that an absence of style may in itself represent the nineteenth-century ideal. This collection provides a major assessment of style in Victorian fiction and demonstrates that style - the language, techniques and artistry of prose - is inseparable from meaning and that it is through the many resources of style that the full compass of meaning makes itself known. Leading scholars in the field present an engaging assessment of major Victorian novelists, illustrating how productive and illuminating close attention to literary style can be. Collectively, they build a fresh and nuanced understanding of how style functioned in the literature of the nineteenth century, and propose that the fiction of this era demands we think about what style does, as much as what style is.
The chapter on sentences shows that the relations made possible by syntax between wording and timing, sequence and consequence, and experience and reflection create an unlimited range of possible effects at the level of the sentence. The chapter explores some of these effects, noting particularly the presence of competing impulses in single sentences, so that any sentence is a negotiation between rival forces and, in its fullest implication, a representation of the mixed conditions of human existence.
The introduction outlines the kind of attention to prose techniques that forms the basis for the chapters that follow. It claims that prose is all too infrequently granted this kind of attention. In part, this is because of the claims to ordinariness that prose writing often proposes for itself, where prose comes to seem either prosaic or prosy. Critical and philosophical traditions have reinforced the view that prose is at its best when it effaces itself, when it conceals its own wording. But this principle has tended to distract from the craft of prose. The introduction outlines the parts of prose (punctuation, words, sentences, and so on) and the various genres (realism, comedy, Gothic, science fiction, and creative non-fiction) that subsequent chapters take up for inspection as regards the techniques of prose themselves.