23,442 research outputs found

    Identification and characterisation of drug-tolerant persister cells arising in response to targeted CHK1 inhibition

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    Drug-tolerant persisters (DTPs) are a subpopulation of slow-cycling cells that have been identified in several cancer cell lines following lethal exposure to targeted and cytotoxic therapeutics and shown to precede acquisition of diverse and clinically relevant drug resistance mechanisms. To date, much of the data comes from studies using tyrosine kinase inhibitors and it is unclear if this persister phenotype is broadly observed in response to drugs that act by various anti-tumour mechanisms. Herein, a subpopulation of slow-cycling SK-N-AS cells survived treatment with lethal concentrations of SRA737; a clinically relevant CHK1 inhibitor. Surviving cells represent a large proportion of the starting population and have increased global histone H3 lysine 27 trimethylation (H3K27me3). Continued lethal SRA737 exposure leads to the emergence of a drugtolerant expanded persister (DTEP) population, marked by resumed proliferation and cross-resistance to other small molecule CHK1/CHK2 and DNA damage response (DDR) inhibitors. H3K27me3 remains elevated in DTEPs but is diminished after drug release, suggesting a role for epigenetic regulation/reprogramming in both DTP formation and progression. Inhibition of the H3K27 methyltransferase EZH2 using tazemetostat inhibits DTP-to-DTEP transition but fails to abrogate DTP formation or DTEP survival, confirming the requirement of epigenetic plasticity for persister cell progression. Comparison to SRA737 resistant populations generated by dose-escalation revealed differential responses to further CHK1 inhibition and specific enrichment of genes associated with JAK-STAT signalling in persister-derived populations. Interestingly, exogenous IFNγ, but not JAK inhibition, delayed the emergence of a drug resistant population from an SRA737-induced DTP bottleneck, suggesting that overactivation of the IFNγ signalling pathway is detrimental to DTP progression. In conclusion, I have characterised DTPs arising within a novel and clinically relevant therapeutic context, defined differences between pathways to drug resistance through DTPs and dose escalation, and uncovered EZH2 activity and IFNγ signalling as potential intervention points to eradicate this persistent population

    Sensory Diets within Pediatric Occupational Therapy Practice: A Scoping Review

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    Abstract: Occupational therapists use sensory diets to help clients address challenging behaviors, promote development, and optimize daily functions, performance and participation in daily activities. Sensory diets are specific routine-based schedules that are designed and applied by Occupational Therapists in order to meet the needs of the client (Peterson et al., 2018). A plethora of literature addresses how sensory diets are used to support those with sensory disorders (Mills and Chapparo, 2018). The purpose of this scoping review is to appraise and synthesize the literature supporting the use of sensory diets and to identify the gaps in the evidence and inform future research. Methods: The research was collected using the following databases: CINAHL Complete, ERIC, PsychInfo, ScienceDirect, Google Scholar, Iceberg, and PubMed. The websites used are as follows: AOTA, AJOT, Australian OTA, Sensory Integration Global Network, and Gray literature sources such as occupational therapy dissertations and theses. Results: 8 articles met the inclusion criteria. Overall, the evidence demonstrated a positive effect of sensory diets to support children with sensory processing disorders. Sensory diets led to positive behaviors and supported a child\u27s optimal performance throughout their daily life. SD’s were used in multiple settings, creating a wide environmental scope of practice for occupational therapists. Conclusion: Occupational Therapists can utilize sensory diets within their practice to promote engagement and participation in one’s day-to-day occupations.https://scholar.dominican.edu/occupational-therapy-student-research-posters/1009/thumbnail.jp

    Omega-3 Blood Levels and Stroke Risk:A Pooled and Harmonized Analysis of 183 291 Participants from 29 Prospective Studies

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    BACKGROUND: The effect of marine omega-3 PUFAs on risk of stroke remains unclear. METHODS: We investigated the associations between circulating and tissue omega-3 PUFA levels and incident stroke (total, ischemic, and hemorrhagic) in 29 international prospective cohorts. Each site conducted a de novo individual-level analysis using a prespecified analytical protocol with defined exposures, covariates, analytical methods, and outcomes; the harmonized data from the studies were then centrally pooled. Multivariable-adjusted HRs and 95% CIs across omega-3 PUFA quintiles were computed for each stroke outcome. RESULTS: Among 183 291 study participants, there were 10 561 total strokes, 8220 ischemic strokes, and 1142 hemorrhagic strokes recorded over a median of 14.3 years follow-up. For eicosapentaenoic acid, comparing quintile 5 (Q5, highest) with quintile 1 (Q1, lowest), total stroke incidence was 17% lower (HR, 0.83 [CI, 0.76-0.91]; P&lt;0.0001), and ischemic stroke was 18% lower (HR, 0.82 [CI, 0.74-0.91]; P&lt;0.0001). For docosahexaenoic acid, comparing Q5 with Q1, there was a 12% lower incidence of total stroke (HR, 0.88 [CI, 0.81-0.96]; P=0.0001) and a 14% lower incidence of ischemic stroke (HR, 0.86 [CI, 0.78-0.95]; P=0.0001). Neither eicosapentaenoic acid nor docosahexaenoic acid was associated with a risk for hemorrhagic stroke. These associations were not modified by either baseline history of AF or prevalent CVD. CONCLUSIONS: Higher omega-3 PUFA levels are associated with lower risks of total and ischemic stroke but have no association with hemorrhagic stroke.</p

    Rapid specific detection of oral bacteria using Cas13-based SHERLOCK

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    ABSTRACTDecades of ongoing research has established that oral microbial communities play a role in oral diseases such as periodontitis and caries. Yet the detection of oral bacteria and the profiling of oral polymicrobial communities currently rely on methods that are costly, slow, and technically complex, such as qPCR or next-generation sequencing. For the widescale screening of oral microorganisms suitable for point-of-care settings, there exists the need for a low-cost, rapid detection technique. Here, we tailored the novel CRISPR-Cas-based assay SHERLOCK for the species-specific detection of oral bacteria. We developed a computational pipeline capable of generating constructs suitable for SHERLOCK and experimentally validated the detection of seven oral bacteria. We achieved detection within the single-molecule range that remained specific in the presence of off-target DNA found within saliva. Further, we adapted the assay for detecting target sequences directly from unprocessed saliva samples. The results of our detection, when tested on 30 healthy human saliva samples, fully aligned with 16S rRNA sequencing. Looking forward, this method of detecting oral bacteria is highly scalable and can be easily optimized for implementation at point-of-care settings

    GXM decreases the trans-endothelial electrical resistance (TEER) and transmigration of <i>C</i>. <i>neoformans</i> through HBECs in a blood brain barrier (BBB) model.

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    Graphic representation of the HBECs and pericytes BBB model used for the (A) TEER measurements and (C) HBEC barrier permeability assay and HBEC model used for the (E) fungal transmigration assay. For A and C, HBECs and pericytes were grown separately (HBECs, 0.4 μm pore insert; pericytes, bottom of a well) and co-incubated using a microtiter transwell system that permits chemotactic exchange through the supernatant. (B) Relative TEER of HBECs incubated with GXM (10, 50, or 100 μg/mL) for 5 h at 37°C and 5% CO2. HBECs incubated alone (negative), with EDTA (10 μg/mL; positive), or with mock extract from acapsular strain cap59 (negative) were used as controls. Time points are the averages of the results for three different TEER measurements (n = 3 wells per group per experiment), and error bars denote SDs. Symbols (*, #, ϕ, and x) indicate P value significance (P (D) Relative HBEC barrier permeability to streptavidin-horseradish peroxidase (HRP) after incubation with GXM (10, 50, or 100 μg/mL) for 30 min at 37°C and 5% CO2. HBECs incubated alone (negative), with EDTA (10 μg/mL; positive), or with mock extract (negative) were used as controls. (E) HBECs were cultured for 2 h with 10 μg/mL of GXM in a microtiter transwell system (5 μm pore insert). Then, 105 cryptococci were added to the well and fungal transmigration through the HBECs was determined for 4 h using CFU. (F) CFU determinations after fungal transmigration are shown. HBECs incubated alone or with EDTA (10 μg/mL) were used as negative and positive controls, respectively. For B, D, and F, bars and error bars denote the means and SDs, respectively. Each symbol denotes a single well measurement (n = 3 wells per group for B and D) or CFU determinations from a single well (n = 5 wells per group for F). Asterisks indicate P-value significance (* P P P P < 0.0001) calculated using one-way ANOVA and adjusted using the Tukey’s post-hoc analysis. These experiments were performed thrice, similar results were obtained each time, and all the results combined are presented.</p

    Resilience and Systems—A Building Structure Case Example

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    The resilience of building structures—as plain technical/physical/engineering systems or complex sociotechnical systems exposed to perturbations and change—has become increasingly important as natural disasters are on the rise and the world is changing rapidly. Existing resilience frameworks are focused mainly on the responses of building systems to perturbation events and their functional recovery, while change appears to be left out. This study applies the resilience system interpretation framework, which defines resilience in a cross-disciplinary environment as adaptation and adaptive systems, to analyze actual and conceptual building structure systems. The system framework, using modern control systems theory, defines resilience as the ability of the system state and form to return to their initial or other suitable states or forms through passive and active feedback mechanisms. A sample SMRF office building structure system is utilized to simulate the system state and form return abilities that are demonstrated by the system functional recovery time and functional recovery curve shape, respectively. This novel understanding of resilience accommodates a holistic and systematic integration of both perturbation and change in the portfolios of various building structures. The framework also provides a practical roadmap for resilience design and building of structures that effectively respond to perturbation while dynamically adapting to change in order to avoid obsolescence, as well as to increase the building’s useful life

    Synergistic combination of information from ground observations, geostationary satellite, and air quality modeling towards improved PM2.5 predictability

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    Abstract Concentrations of ambient particulate matter (such as PM2.5 and PM10) have come to represent a serious environmental problem worldwide, causing many deaths and economic losses. Because of the detrimental effects of PM2.5 on human health, many countries and international organizations have developed and operated regional and global short-term PM2.5 prediction systems. The short-term predictability of PM2.5 (and PM10) is determined by two main factors: the performance of the air quality model and the precision of the initial states. While specifically focusing on the latter factor, this study attempts to demonstrate how information from classical ground observation networks, a state-of-the-art geostationary (GEO) satellite sensor, and an advanced air quality modeling system can be synergistically combined to improve short-term PM2.5 predictability over South Korea. Such a synergistic combination of information can effectively overcome the major obstacle of scarcity of information, which frequently occurs in PM2.5 prediction systems using low Earth orbit (LEO) satellite-borne observations. This study first presents that the scarcity of information is mainly associated with cloud masking, sun-glint effect, and ill-location of satellite-borne data, and it then demonstrates that an advanced air quality modeling system equipped with synergistically-combined information can achieve substantially improved performances, producing enhancements of approximately 10%, 19%, 29%, and 10% in the predictability of PM2.5 over South Korea in terms of index of agreement (IOA), correlation coefficient (R), mean biases (MB), and hit rate (HR), respectively, compared to PM2.5 prediction systems using only LEO satellite-derived observations