Genomic signature of Fanconi anaemia DNA repair pathway deficiency in cancer.

Fanconi anaemia (FA), a model syndrome of genome instability, is caused by a deficiency in DNA interstrand crosslink repair resulting in chromosome breakage1-3. The FA repair pathway protects against endogenous and exogenous carcinogenic aldehydes4-7. Individuals with FA are hundreds to thousands fold more likely to develop head and neck (HNSCC), oesophageal and anogenital squamous cell carcinomas8 (SCCs). Molecular studies of SCCs from individuals with FA (FA SCCs) are limited, and it is unclear how FA SCCs relate to sporadic HNSCCs primarily driven by tobacco and alcohol exposure or infection with human papillomavirus9 (HPV). Here, by sequencing genomes and exomes of FA SCCs, we demonstrate that the primary genomic signature of FA repair deficiency is the presence of high numbers of structural variants. Structural variants are enriched for small deletions, unbalanced translocations and fold-back inversions, and are often connected, thereby forming complex rearrangements. They arise in the context of TP53 loss, but not in the context of HPV infection, and lead to somatic copy-number alterations of HNSCC driver genes. We further show that FA pathway deficiency may lead to epithelial-to-mesenchymal transition and enhanced keratinocyte-intrinsic inflammatory signalling, which would contribute to the aggressive nature of FA SCCs. We propose that the genomic instability in sporadic HPV-negative HNSCC may arise as a result of the FA repair pathway being overwhelmed by DNA interstrand crosslink damage caused by alcohol and tobacco-derived aldehydes, making FA SCC a powerful model to study tumorigenesis resulting from DNA-crosslinking damage.

Universal germline genetic testing in patients with hematologic malignancies using DNA isolated from nail clippings.

Not available.

Psychosocial interventions and needs among individuals and families with Li-Fraumeni syndrome: A scoping review.

Li-Fraumeni syndrome (LFS), a rare cancer predisposition syndrome caused by germline mutations in the TP53 gene, is associated with significant lifetime risk of developing cancer and warrants extensive and long-term surveillance. There are psychosocial impacts on individuals and families living with this condition, from the initial diagnosis throughout multiple stages across the lifespan, but these impacts have not been systematically reviewed and organized. The objective of this scoping review was to synthesize and characterize the literature on psychosocial screening and outcomes, educational needs, support services, and available interventions for patients and families with LFS. A systematic search of six databases was most recently conducted in August 2020: (PubMed/MEDLINE (NLM), EMBASE (Elsevier), Cochrane Library (Wiley), CINAHL (EBSCO), PsycINFO (OVID), and Web of Science (Clarivate Analytics). A total of 15 757 titles were screened, and 24 articles included. Several important themes were identified across studies: factors associated with TP53 genetic testing, LFS surveillance, psychological outcomes, and communication. Findings related to these themes were organized into age-specific categories (age agnostic/across the lifespan, childhood, adolescence and young adulthood, and adulthood).

11p15.5 epimutations in children with Wilms tumor and hepatoblastoma detected in peripheral blood.

BACKGROUND: Constitutional or somatic mosaic epimutations are increasingly recognized as a mechanism of gene dysregulation resulting in cancer susceptibility. Beckwith-Wiedemann syndrome is the cancer predisposition syndrome most commonly associated with epimutation and is extremely variable in its phenotypic presentation, which can include isolated tumors. Because to the authors' knowledge large-scale germline DNA sequencing studies have not included methylation analysis, the percentage of pediatric cancer predisposition that is due to epimutations is unknown. METHODS: Germline methylation testing at the 11p15.5 locus was performed in blood for 24 consecutive patients presenting with hepatoblastoma (3 patients) or Wilms tumor (21 patients). RESULTS: Six individuals with Wilms tumor and 1 patient with hepatoblastoma were found to have low-level gain of methylation at imprinting control 1, and a child with hepatoblastoma was found to have loss of methylation at imprinting control 2. The loss of methylation at imprinting control 2 was found to be maternally inherited, despite not being associated with any detectable genomic alteration. CONCLUSIONS: Overall, 33% of patients (8 of 24 patients) with Wilms tumor or hepatoblastoma were found to have an epigenetic susceptibility that was detectable in the blood. It is interesting to note that low-level gain of methylation at imprinting control 1 predominantly was detected in females with bilateral Wilms tumors. Further studies in larger cohorts are needed to determine the efficacy of testing all patients with Wilms tumor or hepatoblastoma for 11p15.5 epimutations in the blood as part of DNA analysis because this hallmark of predisposition will not be detected by sequencing-based approaches and detecting a cancer predisposition may modify treatment.

Determining climate effects on US total agricultural productivity.

The sensitivity of agricultural productivity to climate has not been sufficiently quantified. The total factor productivity (TFP) of the US agricultural economy has grown continuously for over half a century, with most of the growth typically attributed to technical change. Many studies have examined the effects of local climate on partial productivity measures such as crop yields and economic returns, but these measures cannot account for national-level impacts. Quantifying the relationships between TFP and climate is critical to understanding whether current US agricultural productivity growth will continue into the future. We analyze correlations between regional climate variations and national TFP changes, identify key climate indices, and build a multivariate regression model predicting the growth of agricultural TFP based on a physical understanding of its historical relationship with climate. We show that temperature and precipitation in distinct agricultural regions and seasons explain ∼70% of variations in TFP growth during 1981-2010. To date, the aggregate effects of these regional climate trends on TFP have been outweighed by improvements in technology. Should these relationships continue, however, the projected climate changes could cause TFP to drop by an average 2.84 to 4.34% per year under medium to high emissions scenarios. As a result, TFP could fall to pre-1980 levels by 2050 even when accounting for present rates of innovation. Our analysis provides an empirical foundation for integrated assessment by linking regional climate effects to national economic outcomes, offering a more objective resource for policy making.

Assessing Public Attitudes to Electroconvulsive Therapy: Validation of the Modified ECT Attitudes Questionnaire Using a Systematic Analysis.

INTRODUCTION: Electroconvulsive therapy (ECT) is an established treatment for major depressive disorder, yet it remains controversial. Attitudes toward ECT have been studied in members of the public and service users, with diverse findings. There is no systematically validated scale to quantify attitudes. OBJECTIVES: The aim of this study was to validate a scale measuring attitudes toward ECT using a systematic analysis. METHODS: Validation consisted of 3 stages: item generation, theoretical analysis, and psychometric analysis. A total of 196 members of the public were surveyed, and the findings were used to perform principal component analysis, Cronbach alpha (CA), and interitem correlation. RESULTS: The Modified ECT Attitudes Questionnaire (EAQ) is a 22-item participant-rated questionnaire (0-44) consisting of 2 principal components: "moral and ethical perceptions of ECT" and "ECT as a last resort treatment." There was adequate reliability for the total EAQ (CA, 0.873) and each of the components (component 1 CA, 0.907; component 2 interitem correlation, 0.389). Among the 196 members of the public, the mean score was 20.4 (SD, 8.4), which equates to 46% positive responses. Component 1 elicited 39% positive responses; component 2 elicited 52% positive responses. The emotion components of attitudes elicited particularly negative responses. CONCLUSIONS: The EAQ is a validated and reliable scale for the measurement of attitudes toward ECT. Application of this scale to 196 members of the public indicates that negative attitudes are rooted in individuals' moral and ethical objections to ECT, particularly the emotion components of such attitudes. This scale can be applied to other groups, including service users, to further characterize attitudes that underlie the stigma toward ECT.

Patients' Perceptions of Proton Pump Inhibitor Risks and Attempts at Discontinuation: A National Survey.

OBJECTIVES: Little is known about how reports on the adverse effects of proton pump inhibitors (PPIs) impact patients' perceptions of these drugs and medication use. We sought to determine patients' level of concern about PPI adverse effects and its association with attempts to discontinue these drugs. METHODS: This study is an online survey of US adults who use PPIs for gastroesophageal reflux disease. Topics included awareness of and concern about PPI adverse effects, prior discussion with providers, and attempts to stop PPI because of concern about adverse effects. For the primary analysis, we used logistic regression to identify associations between having attempted to stop PPI and concern about PPI-related adverse effects, a provider's recommendation to stop, risk of upper gastrointestinal bleeding (UGIB), age, and gender. RESULTS: Among 755 patient participants, mean age was 49 years (s.d. 16), 71% were women, and 24% were at high risk of UGIB. Twenty percent of patients were able to write in ≥1 reported adverse effect, and 46% endorsed awareness of ≥1 adverse effect when presented with a list, most commonly chronic kidney disease (17%). Thirty-three percent of patients were slightly concerned, 32% somewhat concerned, and 14% extremely concerned about adverse effects. Twenty-four percent of patients had discussed PPI risks and benefits with a provider, and 9% had been recommended to stop. Thirty-nine percent had attempted to stop their PPI, most (83%) without a provider recommendation. Factors associated with an attempt at stopping PPI included: (i) provider recommendation to stop (odds ratio [OR] 3.26 [1.82-5.83]); (ii) concern about adverse effects (OR 5.13 [2.77-9.51] for slightly, 12.0 [6.51-22.2] for somewhat, and 19.4 [9.75-38.7] for extremely concerned); and (iii) female gender (OR 1.64 [1.12-2.39]). Patients at high risk of UGIB were as likely to have attempted to stop as others (OR 0.98 [0.66-1.44]). CONCLUSIONS: Concern about PPIs is common and strongly associated with attempts at discontinuation, even without a provider's recommendation. Notably, individuals at high risk of UGIB, who benefit from PPIs, were equally likely to have tried stopping PPIs as others. Providers should proactively discuss the risks and benefits of PPIs with their patients, who may otherwise make unwise decisions about PPI management on their own.

An amphipathic α-helix directs palmitoylation of the large intracellular loop of the sodium/calcium exchanger.

The electrogenic sodium/calcium exchanger (NCX) mediates bidirectional calcium transport controlled by the transmembrane sodium gradient. NCX inactivation occurs in the absence of phosphatidylinositol 4,5-bisphosphate and is facilitated by palmitoylation of a single cysteine at position 739 within the large intracellular loop of NCX. The aim of this investigation was to identify the structural determinants of NCX1 palmitoylation. Full-length NCX1 (FL-NCX1) and a YFP fusion protein of the NCX1 large intracellular loop (YFP-NCX1) were expressed in HEK cells. Single amino acid changes around Cys-739 in FL-NCX1 and deletions on the N-terminal side of Cys-739 in YFP-NCX1 did not affect NCX1 palmitoylation, with the exception of the rare human polymorphism S738F, which enhanced FL-NCX1 palmitoylation, and D741A, which modestly reduced it. In contrast, deletion of a 21-amino acid segment enriched in aromatic amino acids on the C-terminal side of Cys-739 abolished YFP-NCX1 palmitoylation. We hypothesized that this segment forms an amphipathic α-helix whose properties facilitate Cys-739 palmitoylation. Introduction of negatively charged amino acids to the hydrophobic face or of helix-breaking prolines impaired palmitoylation of both YFP-NCX1 and FL-NCX1. Alanine mutations on the hydrophilic face of the helix significantly reduced FL-NCX1 palmitoylation. Of note, when the helix-containing segment was introduced adjacent to cysteines that are not normally palmitoylated, they became palmitoylation sites. In conclusion, we have identified an amphipathic α-helix in the NCX1 large intracellular loop that controls NCX1 palmitoylation. NCX1 palmitoylation is governed by a distal secondary structure element rather than by local primary sequence.

Cultural neurobiology and the family: Evidence from the daily lives of Latino adolescents.

Culturally linked family influences during adolescence are important predictors of health and well-being for Latino youth, yet few studies have examined whether these familial influences are associated with indicators of typical physiological stress processes. Following a cultural neurobiology framework, we examined the role of family in the everyday lives of Latino adolescents (N = 209; Mage = 18.10; 85.1% Mexican descent; 64.4% female) by investigating familism values and perceptions of parent support as well as daily family assistance behaviors in relation to hypothalamic-pituitary-adrenal axis diurnal patterns, indexed by salivary cortisol five times a day for 3 weekdays. Three-level growth curve analyses revealed that perceptions of parental support were associated with greater cortisol awakening responses, whereas familism values were not associated with diurnal cortisol patterns. In day-to-day analyses, assisting family during the day (compared to not assisting family) was associated with lower waking cortisol levels and flatter diurnal slopes the next day. Our findings highlight the dynamic associations and multiple time courses between cultural values and behaviors, daily experiences, and physiological stress processes for Latino adolescents. Further, we identified important cultural risk and promotive factors associated with physiological regulation in daily life and potential pathways toward health outcomes in adulthood.

Intracardiac Low-grade Sarcoma Following Treatment for Ewing Sarcoma.

A 16-year-old male was diagnosed with Ewing sarcoma of the ribcage with pulmonary metastases. Six months after completion of scheduled therapy, he was found to have a new intracardiac mass, presumed recurrent Ewing sarcoma. EWSR1 fusion was not detected by droplet digital polymerase chain reaction from blood plasma. After no improvement with salvage chemotherapy, he underwent surgical resection that identified a low-grade spindle cell sarcoma. Despite the near-synchronous presentation of 2 unrelated sarcomas, extensive genomic analyses did not reveal any unifying somatic or germline mutations nor any apparent cancer predisposition. This case also highlights the potential role of utilizing plasma cell-free DNA for diagnosing tumors in locations where biopsy confers high morbidity.

Development of a Culinary Medicine Curriculum to Support Nutrition Knowledge for Gastroenterology Fellows and Faculty.

Gastroenterologists encounter many nutrition-related disorders in their practice, yet the nutritional needs of patients with chronic gastrointestinal (GI) and liver disease are largely unaddressed by treating physicians, due to suboptimal nutrition education. To address this gap, we developed and piloted a culinary medicine course for a GI fellowship training program. The objective of this study is to describe the development, implementation, and acceptability of the course. A registered dietitian, a chef instructor, and a gastroenterology clinical professor trained in culinary medicine developed the four-class tailored curriculum and delivered the classes remotely. Each class had a theme related to commonly encountered GI disorders and included hands-on meal preparation, a nutrition lecture, and a patient case study discussion. Post-course feedback surveys were disseminated. Twenty-three GI physicians enrolled in the course and the attendance rates in classes 1-4 were 83%, 65%, 61%, and 48%, respectively. Among 15 completed feedback surveys, 80% reported that the class contents were either moderately or extremely useful and all endorsed the curriculum for other gastroenterologists. Future studies of culinary medicine programs tailored to medical specialties should identify strategies to maintain engagement and assess the impact on nutrition knowledge, competencies, and translation of these new skills to clinical practice.

Glutathione-dependent depalmitoylation of phospholemman by peroxiredoxin 6.

Phospholemman (PLM) regulates the cardiac sodium pump: PLM phosphorylation activates the pump whereas PLM palmitoylation inhibits its activity. Here, we show that the anti-oxidant protein peroxiredoxin 6 (Prdx6) interacts with and depalmitoylates PLM in a glutathione-dependent manner. Glutathione loading cells acutely reduce PLM palmitoylation; glutathione depletion significantly increases PLM palmitoylation. Prdx6 silencing abolishes these effects, suggesting that PLM can be depalmitoylated by reduced Prdx6. In vitro, only recombinant Prdx6, among several peroxiredoxin isoforms tested, removes palmitic acid from recombinant palmitoylated PLM. The broad-spectrum depalmitoylase inhibitor palmostatin B prevents Prdx6-dependent PLM depalmitoylation in cells and in vitro. Our data suggest that Prdx6 is a thioesterase that can depalmitoylate proteins by nucleophilic attack via its reactive thiol, linking PLM palmitoylation and hence sodium pump activity to cellular glutathione status. We show that protein depalmitoylation can occur via a catalytic cysteine in which substrate specificity is determined by a protein-protein interaction.

Plasticity of Ly-6C(hi) myeloid cells in T cell regulation.

CD11b(+)Ly-6C(hi) cells, including inflammatory monocytes (IMCs) and inflammatory dendritic cells (IDCs), are important in infectious, autoimmune, and tumor models. However, their role in T cell regulation is controversial. In this article, we show that T cell regulation by IMCs and IDCs is determined by their activation state and is plastic during an immune response. Nonactivated IMCs and IDCs function as APCs, but activated IMCs and IDCs suppress T cells through NO production. Suppressive IMCs are induced by IFN-γ, GM-CSF, TNF-α, and CD154 derived from activated T cells during their interaction. In experimental autoimmune encephalomyelitis, CD11b(+)Ly-6C(hi) cells in the CNS are increasingly activated from disease onset to peak and switch their function from Ag presentation to T cell suppression. Furthermore, transfer of activated IMCs or IDCs enhances T cell apoptosis in the CNS and suppresses experimental autoimmune encephalomyelitis. These data highlight the interplay between innate and adaptive immunity: immunization leads to the expansion of Ly-6C(hi) myeloid cells initially promoting T cell function. As T cells become highly activated in the target tissue, they induce activation and NO production in Ly-6C(hi) myeloid cells, which in turn suppress T cells and lead to the contraction of local immune response.

TGF-beta1-Induced MAPK activation promotes collagen synthesis, nodule formation, redox stress and cellular senescence in porcine aortic valve interstitial cells.

BACKGROUND AND AIM OF THE STUDY: Aortic valve stenosis is a major cause of valve replacement, particularly in the elderly. TGF-beta1 is upregulated in stenotic valves and induces calcification and collagen synthesis in cultured valve interstitial cells. It has been shown previously that TGF-beta1 increases reactive oxygen species (ROS) in these cells in association with calcifying nodule formation, but the cellular signaling pathways responsible for these TGF-beta1-induced effects are not well defined. METHODS: Cultured porcine aortic valve interstitial cells were used to investigate the effects of inhibitors of TGF-beta1 signaling pathways on 3H-proline incorporation into the extracellular matrix, the peak number of calcifying nodules formed, redox stress as dichlorofluorescein diacetate (DCF-DA) fluorescence, and senescence-associated beta-galactosidase staining. RESULTS: Nodule formation and proline incorporation were inhibited by SB431542, implicating the Smad pathway, by SB203580, implicating the P38 MAPK pathway, and by U0126, implicating the Mekl/2/Erk1/2 pathway in both processes. Fasudil, an inhibitor of the Rho kinase pathway, was selective in inhibiting nodule formation but not proline incorporation. It was verified that Smad2 phosphorylation, Erk1/2 phosphorylation and p38 MAPK phosphorylation were all induced by TGF-beta1, with Smad 2 phosphorylation peaking at 1-2 h and MAPK phosphorylation at 24-48 h. The effect of TGF-beta1 on phosphorylation of Smad 2 was inhibited by SB431542, on the phosphorylation of p38 MAPK was inhibited by SB203580, and on the phosphorylation of Erk1/2 was inhibited by U0126. ROS generation in response to TGF-beta1, measured as 2,7-dichlorofluorescein-diacetate fluorescence, was inhibited significantly by SB203580 and U0126, implicating both the p38 MAPK and Mekl/2/Erk1/2 signaling pathways. Both pathways also mediated TGF-beta1-induced cellular senescence which was localized to cellular aggregates and mature nodules. CONCLUSION: These data imply that the inhibition of either Smad or MAPK signaling pathways may have a therapeutic benefit in ameliorating the adverse pathological changes associated with aortic valve stenosis.

Talking numbers: how women and providers use risk scores during and after risk counseling - a qualitative investigation from the NRG Oncology/NSABP DMP-1 study.

OBJECTIVES: Little research exists on how risk scores are used in counselling. We examined (a) how Breast Cancer Risk Assessment Tool (BCRAT) scores are presented during counselling; (b) how women react and (c) discuss them afterwards. DESIGN: Consultations were video-recorded and participants were interviewed after the consultation as part of the NRG Oncology/National Surgical Adjuvant Breast and Bowel Project Decision-Making Project 1 (NSABP DMP-1). SETTING: Two NSABP DMP-1 breast cancer care centres in the USA: one large comprehensive cancer centre serving a high-risk population and an academic safety-net medical centre in an urban setting. PARTICIPANTS: Thirty women evaluated for breast cancer risk and their counselling providers were included. METHODS: Participants who were identified as at increased risk of breast cancer were recruited to participate in qualitative study with a video-recorded consultation and subsequent semi-structured interview that included giving feedback and input after viewing their own consultation. Consultation videos were summarised jointly and inductively as a team.tThe interview material was searched deductively for text segments that contained the inductively derived themes related to risk assessment. Subgroup analysis according to demographic variables such as age and Gail score were conducted, investigating reactions to risk scores and contrasting and comparing them with the pertinent video analysis data. From this, four descriptive categories of reactions to risk scores emerged. The descriptive categories were clearly defined after 19 interviews; all 30 interviews fit principally into one of the four descriptive categories. RESULTS: Risk scores were individualised and given meaning by providers through: (a) presenting thresholds, (b) making comparisons and (c) emphasising or minimising the calculated risk. The risk score information elicited little reaction from participants during consultations, though some added to, agreed with or qualified the provider's information. During interviews, participants reacted to the numbers in four primary ways: (a) engaging easily with numbers; (b) expressing greater anxiety after discussing the risk score; (c) accepting the risk score and (d) not talking about the risk score. CONCLUSIONS: Our study highlights the necessity that patients' experiences must be understood and put into relation to risk assessment information to become a meaningful treatment decision-making tool, for instance by categorising patients' information engagement into types. TRIAL REGISTRATION NUMBER: NCT01399359.

Immune modulation by Lacto-N-fucopentaose III in experimental autoimmune encephalomyelitis.

Parasitic infections frequently lead to immune deviation or suppression. However, the application of specific parasitic molecules in regulating autoimmune responses remains to be explored. Here we report on the immune modulatory function of Lacto-N-fucopentaose III (LNFPIII), a schistosome glycan, in an animal model for multiple sclerosis. We found that LNFPIII treatment significantly reduced the severity of experimental autoimmune encephalomyelitis (EAE) and CNS inflammation, and skewed peripheral immune response to a Th2 dominant profile. Inflammatory monocytes (IMCs) purified from LNFPIII-treated mice had increased expression of nitric oxide synthase 2, and mediated T cell suppression. LNFPIII treatment also significantly increased mRNA expression of arginase-1, aldehyde dehydrogenase 1 subfamily A2, indoleamine 2,3-dioxygenase and heme oxygenase 1 in splenic IMCs. Furthermore, LNFPIII treatment significantly reduced trafficking of dendritic cells across brain endothelium in vitro. In summary, our study demonstrates that LNFPIII glycan treatment suppresses EAE by modulating both innate and T cell immune response.

Endothelial function, oxidative stress and inflammatory studies in chronic coronary slow flow phenomenon patients.

The coronary slow flow phenomenon (CSFP) is associated with coronary microvascular dysfunction although the responsible mechanisms are unknown. This study compared endothelial function assessed by changes in augmentation index (AIx) following endothelium-independent (glyceryl trinitrate, GTN) and endothelium-dependent vasodilators (salbutamol), in 40 stable CSFP patients and 23 age-matched healthy controls. Plasma concentrations of inflammatory proteins (myeloperoxidase and high-sensitivity C-reactive protein), oxidative stress biomarkers (malondialdehyde and homocysteine), and asymmetric dimethylarginine levels were also determined. There were no differences between CSFP and controls in response to salbutamol (AIx: -2.28 ± 0.88% vs. -3.22 ± 0.70%, p = 0.4) or GTN (AIx: -11.30 ± 0.75% vs. -13.30 ± 1.00%, p = 0.12). Similarly, there were no differences in the measured biomarkers. Thus, alternate mechanisms to the assessed endothelial function, inflammatory and oxidative stress processes should be explored to explain the microvascular dysfunction in CSFP patients.

Acute modulation of vasoconstrictor responses by pravastatin in small vessels.

BACKGROUND: Statins have been shown to inhibit conduit vessel constrictor responses via the endothelial nitric oxide (NO) pathway. Clinical studies have implicated an effect in microvascular resistance vessels; however, direct effects of therapeutically relevant statin concentrations have not been examined. We examined the effect of acute pravastatin pretreatment on vasoconstrictor responsiveness of isolated rat mesenteric small vessels. METHODS AND RESULTS: Pravastatin (112 nmol/L) pretreatment for 60 min reduced both the potency and maximal constrictor responses to phenylephrine, thromboxane (U46619) and serotonin in small vessels. This effect was abolished by endothelial denudation, NO synthase (NOS) inhibition with N-ω-nitro-L-arginine methyl ester (L-NAME 300 µmol/L) and Akt inhibition (Akt1/2 kinase inhibitor 500 nmol/L), confirming an endothelium-dependent mechanism and implicating a NO-mediated effect via the Akt pathway. Maximal superoxide scavenging with polyethylene glycol-superoxide dismutase (PEG-SOD), 150 U/ml did not influence phenylephrine constrictor responses but potentiated pravastatin's effect, suggesting that the statin did not increase NO bioavailability merely via an antioxidant mechanism. In contrast, pravastatin did not affect endothelin-1 (ET-1) constrictor responses. However, after pre-incubation with a selective endothelin-B (ET(B)) receptor antagonist (BQ788 3 µmol/L) pravastatin inhibited ET-1 constriction, suggesting that its effect is via the same mechanistic pathway as the ET(B) receptor. CONCLUSIONS: In small vessels, pravastatin inhibits constrictor responses by increasing endothelial NO bioavailability via the Akt pathway. Furthermore, ET(B) receptor blockade unmasks this effect in ET-1 constrictor responses.

The Effect of Specifications Grading on Students' Learning and Attitudes in an Undergraduate-Level Cell Biology Course.

Specifications (specs) grading is a grading system in which mastery of specific educational outcomes is the basis for the final grade a student earns in the course. Implementation of the types of assessments used for specs grading has shown to be beneficial for student learning and motivation compared to traditional grading systems. We designed a specs grading strategy in an undergraduate Cell Biology course, creating 20 individual learning outcomes (LOs). The grade earned in lecture depended on the number of LOs the student mastered. If students were unable to master the content on their initial attempt, they could earn retakes for each LO assessment by completing an assignment associated with the information covered in that LO. A student's final class grade was dependent on the number of LOs mastered combined with the grade earned on their final exam. Here, we present how specifications grading was implemented in Cell Biology, differences in overall grade distribution between grading systems, improved performance on content-related assessment questions in sections using specifications grading, and more-positive attitudes for sections using specifications grading than for traditionally graded sections.