Children’s knowledge of indefinite and definite reference

After reviewing previous theoretical and empirical investigations, the decision is made that an understanding of both "Familiarity' and 'Specificity' must be necessary for a full appreciation of indefiniteness/definiteness. Moreover, it is argued that knowledge of 'Specificity’ requires an ability to co-ordinate and integrate a number of linguistic and non-linguistic factors appropriately and for this reason, it is suggested that young children’s knowledge of indefinite/definite reference is incomplete.16 experiments are reported, most of which were designed to investigate children's knowledge of 'Familiarity' and 'Specificity' for indefinite/definite reference. Other areas of investigation include children’s ability to use both linguistic and non-linguistic factors in their understanding of definite reference and the way in which older children and adults use these factors for anaphoric reference. The results showed that whilst children from 3 ½ years of age are sensitive to the perceptual information given to listeners and will use their general knowledge to define ‘Familiarity’; they do not appreciate the need to consider the relative status of a referent in their choice of expression. It seems that young children will only consider 'Specificity' when the relative status and/or the identifying features of a referent are salient to them. The failure of the young child to appreciate the necessity of 'Specificity' for indefinite/definite reference may be explained as due to a failure to consider more than one possible interpretation of reference. By contrast, from about 8 years of age, children appear to be integrating contextual information about the number of available referents with their knowledge of linguistic constraints on reference. A model of the processing of definite anaphoric reference in children is proposed based on the 'weak' interactionist view of the effects of informational context on choice of definite construction

Chemical Stripes – Visualizing Chemical Trends of the Past Influencing Today

Platform presentation at the SETAC Europe 33rd Annual Meeting, Dublin Session: 3.20 - PMT/vPvM substances: Assessment, Management and Regulation, 04 May 202

Avoiding the Next Silent Spring: Our Chemical Past, Present, and Future

Rachel Carson's Silent Spring,1 published just over 60 years ago, outlined how the indiscriminate use of dichlorodiphenyltrichloroethane (DDT), a potent, environmentally persistent insecticide, was damaging the world's ecosystems, animals and food supply. There were many other chemicals more persistent than DDT accumulating in the environment when Carson was writing, including per- and polyfluoroalkyl substances (PFAS). Whilst man-made, PFAS were not intended to cause harm, contrary to pesticides such as DDT. Today, ambient PFAS levels are contaminating rain, soil and drinking water resources worldwide to such an extent that they have caused substantial, irreversible health and environmental damage.2 Like DDT, PFAS were long in use by the time Rachel Carson was writing Silent Spring (see Figure 1). However, their environmental presence went unnoticed by Carson and other contemporary environmental researchers. PFAS were entering the environment under the radar, except to those who were manufacturing and emitting them.

Proportional contributions to organic chemical mixture effects in groundwater and surface water

Semi-quantitative GC-MS and LC-MS measurements of organic chemicals in groundwater and surface waters were used to assess the overall magnitude and contribution of the most important substances to calculated mixture hazard. Here we use GC-MS and LC-MS measurements taken from two separate national monitoring programs for groundwater and surface water in England, in combination with chronic species sensitivity distribution (SSD) HC50 values published by Posthuma et al. (2019, Environ. Toxicol. Chem, 38, 905–917) to calculate individual substance hazard quotients and mixture effects using a concentration addition approach. The mixture analysis indicated that, as anticipated, there was an increased hazard from the presence of a cocktail of substances at sites compared to the hazard for any single chemical. The magnitude of the difference between the hazard attributed to the most important chemical and the overall mixture effect, however, was not large. Thus, the most toxic chemical contributed ≥ 20% of the calculated mixture effect in >99% of all measured groundwater and surface water samples. On the basis of this analysis, a 5 fold assessment factor placed on the risk identified for any single chemical would offer a high degree of in cases where implementation of a full mixture analysis was not possible. This finding is consistent with previous work that has assessed chemical mixture effects within field monitoring programs and as such provides essential underpinning for future policy and management decisions on how to effectively and proportionately manage mixture risks

High-throughput RNA interference screening using pooled shRNA libraries and next generation sequencing

RNA interference (RNAi) screening is a state-of-the-art technology that enables the dissection of biological processes and disease-related phenotypes. The commercial availability of genome-wide, short hairpin RNA (shRNA) libraries has fueled interest in this area but the generation and analysis of these complex data remain a challenge. Here, we describe complete experimental protocols and novel open source computational methodologies, shALIGN and shRNAseq, that allow RNAi screens to be rapidly deconvoluted using next generation sequencing. Our computational pipeline offers efficient screen analysis and the flexibility and scalability to quickly incorporate future developments in shRNA library technology

SER-109: An Oral Investigational Microbiome Therapeutic for Patients with Recurrent Clostridioides difficile Infection (rCDI)

Clostridioides difficile infection (CDI) is classified as an urgent health threat by the Centers for Disease Control and Prevention (CDC), and affects nearly 500,000 Americans annually. Approximately 20–25% of patients with a primary infection experience a recurrence, and the risk of recurrence increases with subsequent episodes to greater than 40%. The leading risk factor for CDI is broad-spectrum antibiotics, which leads to a loss of microbial diversity and impaired colonization resistance. Current FDA-approved CDI treatment strategies target toxin or toxin-producing bacteria, but do not address microbiome disruption, which is key to the pathogenesis of recurrent CDI. Fecal microbiota transplantation (FMT) reduces the risk of recurrent CDI through the restoration of microbial diversity. However, FDA safety alerts describing hospitalizations and deaths related to pathogen transmission have raised safety concerns with the use of unregulated and unstandardized donor-derived products. SER-109 is an investigational oral microbiome therapeutic composed of purified spore-forming Firmicutes. SER-109 was superior to a placebo in reducing CDI recurrence at Week 8 (12% vs. 40%, respectively; p \u3c 0.001) in adults with a history of recurrent CDI with a favorable observed safety profile. Here, we discuss the role of the microbiome in CDI pathogenesis and the clinical development of SER-109, including its rigorous manufacturing process, which mitigates the risk of pathogen transmission. Additionally, we discuss compositional and functional changes in the gastrointestinal microbiome in patients with recurrent CDI following treatment with SER-109 that are critical to a sustained clinical response

Serial ruptures of the San Andreas fault, Carrizo Plain, California, revealed by three-dimensional excavations

It is poorly known if fault slip repeats regularly through many earthquake cycles. Well‐documented measurements of successive slips rarely span more than three earthquake cycles. In this paper, we present evidence of six sequential offsets across the San Andreas fault at a site in the Carrizo Plain, using stream channels as piercing lines. We opened a latticework of trenches across the offset channels on both sides of the fault to expose their subsurface stratigraphy. We can correlate the channels across the fault on the basis of their elevations, shapes, stratigraphy, and ages. The three‐dimensional excavations allow us to locate accurately the offset channel pairs and to determine the amounts of motion for each pair. We find that the dextral slips associated with the six events in the last millennium are, from oldest to youngest, ≥ 5.4 ± 0.6, 8.0 ± 0.5, 1.4 ± 0.5, 5.2 ± 0.6, 7.6 ± 0.4 and 7.9 ± 0.1 m. In this series, three and possibly four of the six offset values are between 7 and 8 m. The common occurrence of 7–8 m offsets suggests remarkably regular, but not strictly uniform, slip behavior. Age constraints for these events at our site, combined with previous paleoseismic investigations within a few kilometers, allow a construction of offset history and a preliminary evaluation of slip‐ and time‐predictable models. The average slip rate over the span of the past five events (between A.D. 1210 and A.D. 1857.) has been 34 mm/yr, not resolvably different from the previously determined late Holocene slip rate and the modern geodetic strain accumulation rate. We find that the slip‐predictable model is a better fit than the time‐predictable model. In general, earthquake slip is positively correlated with the time interval preceding the event. Smaller offsets coincide with shorter prior intervals and larger offset with longer prior intervals

CompreHensive geriAtRician-led MEdication Review (CHARMER): protocol for a feasibility study of a hospital deprescribing behaviour change intervention

Introduction Over 50% of older adults are prescribed a medicine where the risk of harm outweighs the chances of benefit. During a hospital admission, older adults and carers expect medicines to be reviewed for appropriateness and any inappropriate medicines proactively deprescribed. While the principle of proactive deprescribing is an expectation of good prescribing practice, it is yet to become routine. The CompreHensive geriAtRician-led MEdication Review (CHARMER) study aims to develop and test a five-component behaviour change intervention to equip geriatricians and pharmacists to proactively deprescribe inappropriate medicines with older adults in hospital. This study aims to test the feasibility and acceptability of study processes and CHARMER implementation. Methods and analysis A two-arm purposive allocation feasibility study is being undertaken at four acute hospitals in England, UK (three intervention and one control). The target sample is 400 patients across all hospitals. Primary outcome measures are: (1) participant recruitment rate and (2) participant attrition rate. Secondary outcome measures are: (1) hospital readmission rate; (2) mortality rate and (3) quality of life. Quantitative data will be checked for completeness and quality, and practitioner and patient demographics descriptively analysed. We will undertake a rapid qualitative analysis on observations, interviews and study meeting minutes data. A subsequent thematic analysis will be undertaken with codes mapped to the Theoretical Domains Framework and Normalisation Process Theory. Triangulation of qualitative and quantitative data will be undertaken. Ethics and dissemination Ethics approval was obtained from Wales Research Ethics Committee 1 (IRAS ID 312494) and study approval from the Health Research Authority (22/WA/0087). Informed consent will be sought from all hospital staff involved in data collection activities and for patients involved in enhanced data collection activities. The findings of this study will be disseminated in peer-reviewed journals and conference presentations

Bromodomain inhibition of the transcriptional coactivators CBP/EP300 as a therapeutic strategy to target the IRF4 network in multiple myeloma

Abstract Pharmacological inhibition of chromatin co-regulatory factors represents a clinically validated strategy to modulate oncogenic signaling through selective attenuation of gene expression. Here, we demonstrate that CBP/EP300 bromodomain inhibition preferentially abrogates the viability of multiple myeloma cell lines. Selective targeting of multiple myeloma cell lines through CBP/EP300 bromodomain inhibition is the result of direct transcriptional suppression of the lymphocyte-specific transcription factor IRF4, which is essential for the viability of myeloma cells, and the concomitant repression of the IRF4 target gene c-MYC. Ectopic expression of either IRF4 or MYC antagonizes the phenotypic and transcriptional effects of CBP/EP300 bromodomain inhibition, highlighting the IRF4/MYC axis as a key component of its mechanism of action. These findings suggest that CBP/EP300 bromodomain inhibition represents a viable therapeutic strategy for targeting multiple myeloma and other lymphoid malignancies dependent on the IRF4 network