Metabolic rate and rates of protein turnover in food-deprived cuttlefish, Sepia officinalis (Linnaeus 1758)

To determine the metabolic response to food deprivation, cuttlefish (Sepia officinalis) juveniles were either fed, fasted (3 to 5 days food deprivation), or starved (12 days food deprivation). Fasting resulted in a decrease in triglyceride levels in the digestive gland, and after 12 days, these lipid reserves were essentially depleted. Oxygen consumption was decreased to 53% and NH4 excretion to 36% of the fed group following 3-5 days of food deprivation. Oxygen consumption remained low in the starved group, but NH4 excretion returned to the level recorded for fed animals during starvation. The fractional rate of protein synthesis of fasting animals decreased to 25% in both mantle and gill compared with fed animals and remained low in the mantle with the onset of starvation. In gill, however, protein synthesis rate increased to a level that was 45% of the fed group during starvation. In mantle, starvation led to an increase in cathepsin A-, B-, H-, and L-like enzyme activity and a 2.3-fold increase in polyubiquitin mRNA that suggested an increase in ubiquitin-proteasome activity. In gill, there was a transient increase in the polyubiquitin transcript levels in the transition from fed through fasted to the starved state and cathepsin A-, B-, H-, and L-like activity was lower in starved compared with fed animals. The response in gill appears more complex, as they better maintain rates of protein synthesis and show no evidence of enhanced protein breakdown through recognized catabolic processes

Enzymatic capacities of metabolic fuel use in cuttlefish (Sepia officinalis) and responses to food deprivation: insight into the metabolic organization and starvation survival strategy of cephalopods

Food limitation is a common challenge for animals. Cephalopods are sensitive to starvation because of high metabolic rates and growth rates related to their "live fast, die young" life history. We investigated how enzymatic capacities of key metabolic pathways are modulated during starvation in the common cuttlefish (Sepia officinalis) to gain insight into the metabolic organization of cephalopods and their strategies for coping with food limitation. In particular, lipids have traditionally been considered unimportant fuels in cephalopods, yet, puzzlingly, many species (including cuttlefish) mobilize the lipid stores in their digestive gland during starvation. Using a comprehensive multi-tissue assay of enzymatic capacities for energy metabolism, we show that, during long-term starvation (12 days), glycolytic capacity for glucose use is decreased in cuttlefish tissues, while capacities for use of lipid-based fuels (fatty acids and ketone bodies) and amino acid fuels are retained or increased. Specifically, the capacity to use the ketone body acetoacetate as fuel is widespread across tissues and gill has a previously unrecognized capacity for fatty acid catabolism, albeit at low rates. The capacity for de novo glucose synthesis (gluconeogenesis), important for glucose homeostasis, likely is restricted to the digestive gland, contrary to previous reports of widespread gluconeogenesis among cephalopod tissues. Short-term starvation (3-5 days) had few effects on enzymatic capacities. Similar to vertebrates, lipid-based fuels, putatively mobilized from fat stores in the digestive gland, appear to be important energy sources for cephalopods, especially during starvation when glycolytic capacity is decreased perhaps to conserve available glucose

Seasonality in Human Zoonotic Enteric Diseases: A Systematic Review

BACKGROUND: Although seasonality is a defining characteristic of many infectious diseases, few studies have described and compared seasonal patterns across diseases globally, impeding our understanding of putative mechanisms. Here, we review seasonal patterns across five enteric zoonotic diseases: campylobacteriosis, salmonellosis, vero-cytotoxigenic Escherichia coli (VTEC), cryptosporidiosis and giardiasis in the context of two primary drivers of seasonality: (i) environmental effects on pathogen occurrence and pathogen-host associations and (ii) population characteristics/behaviour. METHODOLOGY/PRINCIPAL FINDINGS: We systematically reviewed published literature from 1960-2010, resulting in the review of 86 studies across the five diseases. The Gini coefficient compared temporal variations in incidence across diseases and the monthly seasonality index characterised timing of seasonal peaks. Consistent seasonal patterns across transnational boundaries, albeit with regional variations was observed. The bacterial diseases all had a distinct summer peak, with identical Gini values for campylobacteriosis and salmonellosis (0.22) and a higher index for VTEC (Gini  0.36). Cryptosporidiosis displayed a bi-modal peak with spring and summer highs and the most marked temporal variation (Gini = 0.39). Giardiasis showed a relatively small summer increase and was the least variable (Gini = 0.18). CONCLUSIONS/SIGNIFICANCE: Seasonal variation in enteric zoonotic diseases is ubiquitous, with regional variations highlighting complex environment-pathogen-host interactions. Results suggest that proximal environmental influences and host population dynamics, together with distal, longer-term climatic variability could have important direct and indirect consequences for future enteric disease risk. Additional understanding of the concerted influence of these factors on disease patterns may improve assessment and prediction of enteric disease burden in temperate, developed countries

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Graduate Student Pedagogical Impact Through Development and Delivery of a Collaborative Inquiry-focused High School STEM Program

© 2020 American Society for Engineering EducationConsidering a changing academic landscape that desires skill development beyond that of traditional research, post-secondary STEM students now require broad opportunities to improve their translatable skill set. Notably, we routinely observe an increasing number of doctoral students focused on developing their teaching skills, given opportunities to pursue teaching-centred careers post-graduation; therefore, practice in innovative pedagogy is highly advantageous during graduate training. Discovery is a secondary school STEM education program wherein graduate students work collaboratively with secondary school educators to develop unique, inquiry focused programming that bridges the gap between secondary and post-secondary curriculum delivery and learning. Beyond meaningful impact to participating secondary students, the unique leadership, mentorship, and autonomy graduate students possess in the execution of this teaching model provides invaluable opportunity in pedagogical practice. Depending upon the degree of involvement, graduate trainees may be involved in collaborative curriculum design, act as student group mentors, be points of contact to educators, and/or administrators to Discovery program operation. To date, 93 instructors have developed and delivered this unique educational program to more than 500 senior science secondary students. Quantified self-assessment reveals that the Discovery platform provides opportunities to improve instructor pedagogical skills while positively impacting the secondary school student STEM experience. Collaboration with experienced secondary school educators allows for instructors to combine their cutting-edge technological expertise with learned comprehension of effective teaching pedagogy appropriate for senior secondary school learning. This learning model provides opportunity for educators to share fundamental strategies in teaching with instructors that have a vested interest in developing this skill set. We observe a high level of overall personal satisfaction among trainee instructors, who further indicate a variety of goals for participation including improvement of teaching skills, knowledge translation, and development of community. Repeated instructor participation from term-to-term indicates positive self-perception of the program, in addition to direct impact on the secondary school STEM experience. The strong support and leadership of trainee instructors therefore allows Discovery to be a platform that blurs the divide between secondary and post-secondary learning, fostering the development of critical thinking skills crucial for the success of future STEM generations.This program is financially supported by the IBBME and the NSERC PromoScience program(PROSC 515876-2017)

IBBME Discovery: Biomedical Engineering-based Iterative Learning in a High School STEM Curriculum (Evaluation)

© 2018 American Society for Engineering Education.Senior high school students often struggle with recognizing the link between human health care and engineering, resulting in limited recruitment for post-secondary biomedical engineering (BME) study. To enhance student comprehension and recruitment in the field, BME graduate student instructors have developed and launched Discovery, a collaborative high school outreach program that promotes and engages students in the application of science, technology, engineering, and math (STEM) concepts. The program offers a unique, immersive semester-long practicum that complements classroom curriculum but is delivered within university facilities. Further to this, BME graduate students have the opportunity to develop and deliver STEM curriculum directly aligned with their thesis research. The overall goal of the program is to immerse high school science students in inquiry-based experiential learning in a post-secondary BME environment, enhancing BME literacy and stimulating pursuit of post-secondary STEM study. This program is a collaboration between graduate student instructors and science educators from one local public high school. Each semester, approximately 65 secondary STEM students, 4 educators, 15 graduate student instructors, and 2 faculty members are involved in Discovery. Small student groups work in a capstone format, incorporating iterative design principles and the scientific method to address thematically-related but subject-specific research projects that satisfy curriculum requirements. Educators assign 10-15% of semester course grades to deliverables and quantitatively assess student comprehension. The semester culminates in a final symposium where students present their findings in scientific poster format. Discovery is unique in its delivery of iterative design to a class cohort accompanied by their educator and carries the benefit of removing socio-economic barriers to student learning and success. High school educators further benefit through co-instruction with graduate instructors within university facilities, increasing student comfort within laboratory environments. High-school educators have identified difficulties with student involvement in the regular classroom. Comparatively, to date, all students have successfully engaged in the various Discovery activities. During the pilot year, > 85% of participants exhibited perfect Discovery attendance; these students demonstrated absence for ~ 10% of classes in their school environment. Students view this experience as an integral part of their classroom curriculum and are both excited and engaged in their scientific outcomes. In post-hoc surveys, over 75% of student participants stated that this program impacted their pursuit of future studies in STEM, indicating a greater understanding of BME theory and practice, while anecdotally graduate instructors indicated that their pedagogical training greatly improved.This program was financially supported by the IBBME and the NSERC PromoScience program