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"Williams, Grace"
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The big wedding : it's never too late to start acting like a family
To the amusement of their adult children and friends, long divorced couple Don and Ellie Griffin are once again forced to play the happy couple for the sake of their adopted son's wedding after his ultra conservative biological mother unexpectedly decides to fly halfway across the world to attend. With all of the wedding guests looking on, the Griffins are hilariously forced to confront their past, present and future, and hopefully avoid killing each other in the process.
DVD
Lateral bias in the domestic pig (Sus scrofa)
Lateralised motor behaviour can contribute to the study of animal welfare, with links to emotional processing, stress responses and personality. Lateral bias in the domestic pig, a species prone to poor welfare, has been subject to little scientific attention. This study therefore aimed to assess laterality in the form of side preferences in a population of farmed pigs, exploring for differences between the sexes and consistency in side preferences, both between measures and over time. Observations of side preference were recorded in fifty pigs across five measures: a snout use task, step-up task, detour task, tail curling and lying side. Snout use, step-up and detour side preferences were observed twice (3 and 6 weeks-of-age) to evaluate test-retest reliability. Pigs were significantly more likely to be ambilateral than side-preferent for both lying side and snout use at 6 weeks of age. By contrast, animals showed significant side-preferences at the level of the individual on the detour task at 6 weeks of age. Directional laterality index (LI) scores for snout use were positively correlated with those of the step-up task at 6 weeks of age, while strength of laterality index (ABSLI) scores for snout use at 4 weeks of age were positively correlated with the step-up task scores at 6 weeks of age. No other LI or ABSLI scores were significantly correlated. Findings pointed to good test-retest reliability, with animals demonstrating a significant positive correlation in the direction, although not strength, of their lateral biases for the snout use, step-up and detour tasks. A cluster analysis, employed to explore for individual lateralisation patterns across motor functions, revealed a leaning towards left-side preferences on animals’ combined step-up and detour laterality scores. Male and female animals showed no significant difference in either the strength or direction of their side preferences for any of the tasks. Overall, the results from this study point to individual-level lateralised behaviour in the domestic pig for one measure. Findings reveal a lack of sex differences and consistency between tasks, but show stability in pigs’ side preferences over time, at least in the short-term.
Journal Article
Not Your Ordinary Rash
Results are presented in Table 1. Because of the patient's symptoms upon presentation to the emergency department and previously increased urine PBG concentration, she was treated with daily hemin infusions for 4 days and her symptoms resolved. Acute crises are most commonly precipitated by hormonal changes such as increases in progesterone during the luteal phase ofthe natural menstrual cycle, stress, severe illness, surgery, smoking, alcohol, or exposure to drugs that induce synthesis of heme or cytochrome P450 enzymes (CYP) or through other mechanisms. The majority of patients who inherit a pathogenic mutation remain asymptomatic and affected patients may experience cutaneous symptoms, neurovisceral symptoms, or both. Because of the variable presentation and relatively low disease prevalence, VP is often misidentified as another more common condition, in many cases leading to delayed diagnosis. How should molecular testing be integrated into the further workup of this patient? POINTS TO REMEMBER * The acute porphyrias AIP, VP, and HCP are inherited in an autosomal dominant manner but symptom severity is variable owing to incomplete penetrance. * Most patients with a pathogenic PPOX variant never experience symptoms, whereas others may experience severe cutaneous symptoms and acute neurovisceral crises. * Measurement of urine PBG concentration should be performed during initial screening because it is almost always increased during acute crises. * Acute crises are most often precipitated by hormonal changes, such as those observed in the luteal phase of the menstrual cycle, or exposure to CYP- or AÍASÍ-inducing drugs. * Intravenous hemin/heme arginate suppresses the heme synthetic pathway and is front-line therapy for treatment of acute crises in both pregnant and nonpregnant patients.
Journal Article
Acute testicular hyperthermia leads to rapid loss of global piRNA and a concurrent increase in LINE1 activity within heat sensitive male germ cells
Background
Spermatogenesis is a highly temperature sensitive process, which occurs 2–6 °C below core body temperature. Testicular hyperthermia rapidly affects male precursor cells, including spermatocytes and round spermatids, leading to elevated DNA damage. To understand the immediate transcriptional response of these cell types, we subjected mice to testicular hyperthermia and performed whole transcriptome sequencing on round spermatids following testicular hyperthermia.
Results
Analysis of sequencing data revealed that 93% of differentially expressed transcripts were upregulated following heat stress, with a notable trend to upregulation of transposable elements. Further investigation revealed a > 50% global reduction in piRNA levels, which coincided with increased LINE1 transcript abundance, elevated expression of ORF1p and increased DNA damage in heat stressed spermatocytes. The loss of piRNA appears to be driven by the rapid deformation of liquid–liquid phase separated ribonucleoprotein biocondensates, as demonstrated by the chromatoid body, which serves as an epicentre for piRNA processing. This loss of piRNA can cause widespread RNA dysregulation, transposon activation, DNA damage and impair spermatogenesis.
Conclusion
These findings suggest that testicular hyperthermia disrupts piRNA biogenesis by destabilisation of liquid–liquid phase separated ribonucleoprotein biocondensates, including the chromatoid body. As a result, many transcripts, including transposable elements, become dysregulated which leads to DNA damage and impaired sperm quality.
Journal Article
FT-6876, a Potent and Selective Inhibitor of CBP/p300, is Active in Preclinical Models of Androgen Receptor-Positive Breast Cancer
BackgroundPatients with triple-negative breast cancer (TNBC) expressing the androgen receptor (AR) respond poorly to neoadjuvant chemotherapy, although AR antagonists have shown promising clinical activity, suggesting these tumors are AR-dependent. cAMP responsive element binding protein (CREB)-binding protein (CBP) and p300 are transcriptional co-activators for the AR, a key driver of AR+ breast and prostate cancer, and may provide a novel therapeutic target in AR+ TNBC.ObjectivesThe aim of this study was to determine the therapeutic potential of FT-6876, a new CBP/p300 bromodomain inhibitor, in breast cancer models with a range of AR levels in vitro and in vivo.MethodsEffects of FT-6876 on the CBP/p300 pathway were determined by combining chromatin immunoprecipitation (ChIP) with precision run-on sequencing (PRO-seq) complemented with H3K27 acetylation (Ac) and transcriptional profiling. The antiproliferative effect of FT-6876 was also measured in vitro and in vivo.ResultsWe describe the discovery of FT-6876, a potent and selective CBP/p300 bromodomain inhibitor. The combination of ChIP and PRO-seq confirmed the reduction in H3K27Ac at specific promoter sites concurrent with a decrease in CBP/p300 on the chromatin and a reduction in nascent RNA and enhancer RNA. This was associated with a time- and concentration-dependent reduction in H3K37Ac associated with a decrease in AR and estrogen receptor (ER) target gene expression. This led to a time-dependent growth inhibition in AR+ models, correlated with AR expression. Tumor growth inhibition was also observed in AR+ tumor models of TNBC and ER+ breast cancer subtypes with consistent pharmacokinetics and pharmacodynamics.ConclusionOur findings demonstrate FT-6876 as a promising new CBP/p300 bromodomain inhibitor, with efficacy in preclinical models of AR+ breast cancer.
Journal Article
Evaluating Updated Fentanyl Immunoassays for Loperamide Interference
Abstract
Background
Loperamide is a µ-opioid receptor agonist that reduces intestinal peristalsis and is used to treat diarrhea. We previously described significant cross-reactivity of loperamide with 2 fentanyl immunoassays. Since then, new fentanyl immunoassays, including a CLIA-waived point-of-care device, have been approved for clinical use.
Methods
We evaluated new fentanyl immunoassays for cross-reactivity to loperamide and its major metabolites, N-desmethyl loperamide (dLop) and N-didesmethyl loperamide (ddLop). Previously characterized assays were tested for cross-reactivity to ddLop, which recently became commercially available. Loperamide, dLop, and ddLop were spiked in drug-free urine for analysis by 5 enzyme immunoassays run on automated chemistry analyzers and one lateral flow assay for the detection of fentanyl.
Results
Loperamide and its metabolites produced positive results in 3 fentanyl immunoassays. The Immunalysis HEIA was previously determined to be reactive to both loperamide and dLop, but it was not reactive to ddLop. The Immunalysis SEFRIA was reactive to loperamide, dLop, and ddLop at minimum concentrations of 14.7 mg/L, 13.1 mg/L, and 17.0 mg/L. The Thermo Fisher DRI was previously determined to be reactive to loperamide and dLop, and it was reactive to ddLop at a minimum concentration of 33.1 mg/L. The Abbott iCassette, ARK Fentanyl II, and Lin-Zhi LZI II fentanyl assays showed no cross-reactivity to loperamide or its metabolites.
Conclusions
The cross-reactivity of loperamide, dLop, and ddLop in several fentanyl immunoassays has the potential to cause false-positive results during urine drug screening.
Journal Article
How to Inspire Black Youth in America Using Counterspace Pedagogy
Grace-Williams addresses her research participant's concern by calling for a counterspace pedagogy in the teaching of social studies as framed by critical race perspectives and shaped by the nuanced experiences of students of African descent living in America. Since racism is enmeshed in the society, minority students' education must address this problem by naming their realities and challenging their racialization. Social justice advocacy for this heterogeneous group must also focus on the experiences of Black immigrant students, some of whom are facing challenges associated with the heightened sense of anti-immigrant rhetoric and the cancellation of the Deferred Action for Childhood Arrival (DACA).
Journal Article
Evaluation of Strontium Interference in Calcium Measurement Procedures and Content in Supplements as Measured by ICP-MS
Abstract
Background
Bone health supplements containing strontium are available without prescription, however, the effects of strontium interference on clinical laboratory calcium measurement procedures are unknown.
Methods
To evaluate strontium interference on total calcium measurements, plasma pools with exogenously added strontium were measured by 3 total calcium measurement procedures. For ionized calcium measurements, whole blood pools prepared with exogenously added strontium were measured by 2 ionized calcium measurement procedures. An inductively coupled plasma mass spectrometry assay (ICP-MS) was validated for research measurements of strontium content in commercially available supplements.
Results
Exogenous strontium addition to plasma caused positive bias for total calcium measurements. Strontium concentrations of 1.0 mg/dL (0.114 mmol/L), 2.5 mg/dL (0.284 mmol/L), and 5.0 mg/Dl (0.568 mmol/L) resulted in mean biases of 1.9% to 3.5%, 4.9% to 9.0%, and 10.8% to 19.2%, respectively, for total calcium measurement procedures. Biases for ionized calcium measurements were less than 4.5% for a strontium concentration of 5.0 mg/dL (0.568 mmol/L). An in-house–developed ICP-MS assay for strontium in commercially available supplements exhibited within-laboratory and within-run coefficients of variation of less than 3%, and a linear response was obtained over the assay analytical measurement range of 10 to 100 000 ng/mL (0.0001 to 1.141 mmol/L). Strontium recovery for the ICP-MS assay was 97.1% to 105.3%. The largest amount of strontium measured in dietary supplements was 395 mg in a 1054 mg tablet.
Conclusions
Some dietary supplements contain larger amounts of strontium than indicated on the product label. High concentrations of strontium may cause significant interference for total calcium measurement procedures, but ionized calcium measurement procedures are not significantly affected.
Journal Article
Potential Impact of Pharmacogenomic Single Nucleotide Variants in a Rural Caucasian Population
Abstract
Background
In the US adverse drug reactions (ADRs) are estimated to cause 100 000 fatalities and cost over $136 billion annually. A patient’s genes play a significant role in their response to a drug. Pharmacogenomics aims to optimize drug choice and dose for individual patients by characterizing patients’ pharmacologically relevant genes to identify variants of known impact.
Methods
DNA was extracted from randomly selected remnant whole blood samples from Caucasian patients with previously performed complete blood counts. Samples were genotyped by mass spectrometry using a customized pharmacogenomics panel. A third-party result interpretation service used genotypic results to predict likely individual responses to frequently prescribed drugs.
Results
Complete genotypic and phenotypic calls for all tested Cytochrome P450 isoenzymes and other genes were obtained from 152 DNA samples. Of these 152 unique genomic DNA samples, 140 had genetic variants suggesting dose adjustment for at least one drug. Cardiovascular and psychiatry drugs had the highest number of recommendations, which included United States Food and Drug Administration warnings for highly prescribed drugs metabolized by CYP2C19, CYP2C9, CYP2D6, HLA-A, and VKORC1.
Conclusions
Risk for each drug:gene pairing primarily depends upon the degree of predicted enzyme impairment or activation, width of the therapeutic window, and whether parent compound or metabolite is pharmacologically active. The resulting metabolic variations range from risk of toxicity to therapeutic failure. Pharmacogenomic profiling likely reduces ADR potential by allowing up front drug/dose selection to fit a patient’s unique drug-response profile.
Journal Article