SEQUENCING OF ESTROGEN RELATED RECEPTOR BETA (ESRRB) AND ITS ROLE IN DENTAL CARIES EXPERIENCE

Dental caries is a significant public health problem and is estimated to affect 60 to 90 percent of school children as well as a large number of adults. It is a chronic, infectious, multifactorial disease in which the host’s diet, microbiota, and genetic background play a role. Initial linkage studies suggested the estrogen related receptor beta (ESRRB) locus is linked to high caries experience in humans. Our hypothesis is that rare genetic variation in the coding region of ESRRB influences caries. Ninety-three whole saliva samples from a clinically well-characterized cohort were collected and extracted (62 caries samples and 31 caries free controls). We sequenced the exons and exon-intron boundaries of ESRRB and compared our results with the reference sequence transcript ENST00000505752 from the Ensembl genome browser. Eight SNPs were found in our samples with no evidence indicating these are disease-causing variants. Individuals with dental caries have an over-representation of the T allele of rs55835922 (74% versus 54%; p = 0.01). The SNP rs61742642 is a missense mutation (P386S), but its frequency was just slightly elevated in cases with dental caries (13% versus 9.5%). SNP rs35544003 is a synonymous change. Through bioinformatics analysis, we determined the SNP rs61742642 missense mutation is a benign change. Our results indicate that ESRRB may contribute to caries, but coding mutations causing the disease are not commonly found

Flipping the Classroom to Train Citizen Scientists in Invasive Species Detection and Response

Extension educators are increasingly using flipped classrooms, wherein online content delivery precedes in-person learning. We have applied this approach to two Extension programs in which citizen scientists are trained in early detection of invasive species. Our goal in using the tool of flipped classrooms is to accommodate large amounts of content while focusing classroom time on skills development. In 2017, we assessed efficacy of the flipped classroom through knowledge tests and surveys completed by 174 participants and 106 participants, respectively. Results demonstrated large knowledge gains and high participant satisfaction. We encourage Extension professionals to consider whether use of the flipped classroom format could advance achievement of their programs\u27 learning objectives

Clinical readiness for essential maternal and child health services in Kenya: A cross-sectional survey

High rates of maternal and neonatal morbidity and mortality in Kenya may be influenced by provider training and knowledge in emergency obstetric and neonatal care in addition to availability of supplies necessary for this care. While post-abortion care is a key aspect of life-saving maternal health care, no validated questionnaires have been published on provider clinical knowledge in this arena. Our aim was to determine provider knowledge of maternal-child health (MCH) emergencies (post-abortion care, pre-eclampsia, postpartum hemorrhage, neonatal resuscitation) and determine factors associated with clinical knowledge. Our secondary aim was to pilot a case-based questionnaire on post-abortion care. We conducted a cross-sectional survey of providers at health facilities in western Kenya providing maternity services. Providers estimated facility capacity through perceived availability of both general and specialized supplies. Providers reported training on the MCH topics and completed case-based questions to assess clinical knowledge. Knowledge was compared between topics using a linear mixed model. Multivariable models identified variables associated with scores by topic. 132 providers at 37 facilities were interviewed. All facilities had access to general supplies at least sometime while specialized supplies were available less frequently. While only 56.8% of providers reported training on post-abortion care, more than 80% reported training on pre-eclampsia, postpartum hemorrhage, and neonatal resuscitation. Providers’ clinical knowledge across all topics was low (mean score of 63.3%), with significant differences in scores by topic area. Despite less formal training in the subject area, providers answered 71.6% (SD 16.7%) questions correctly on post-abortion care. Gaps in supply availability, training, and clinical knowledge on MCH emergencies exist. Increasing training on MCH topics may decrease pregnancy and postpartum complications. Further, validated tools to assess knowledge in post-abortion care should be created, particularly in sub-Saharan Africa where legal restrictions on abortion services exist and many abortions are performed in unsafe settings

IFNAR1-Signalling Obstructs ICOS-mediated Humoral Immunity during Non-lethal Blood-Stage Plasmodium Infection

Funding: This work was funded by a Career Development Fellowship (1028634) and a project grant (GRNT1028641) awarded to AHa by the Australian National Health & Medical Research Council (NHMRC). IS was supported by The University of Queensland Centennial and IPRS Scholarships. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewedPublisher PD

Requirements for Efficient Proteolytic Cleavage of Prelamin A by ZMPSTE24

The proteolytic maturation of the nuclear protein lamin A by the zinc metalloprotease ZMPSTE24 is critical for human health. The lamin A precursor, prelamin A, undergoes a multi-step maturation process that includes CAAX processing (farnesylation, proteolysis and carboxylmethylation of the C-terminal CAAX motif), followed by ZMPSTE24-mediated cleavage of the last 15 amino acids, including the modified C-terminus. Failure to cleave the prelamin A "tail", due to mutations in either prelamin A or ZMPSTE24, results in a permanently prenylated form of prelamin A that underlies the premature aging disease Hutchinson-Gilford Progeria Syndrome (HGPS) and related progeroid disorders.Here we have investigated the features of the prelamin A substrate that are required for efficient cleavage by ZMPSTE24. We find that the C-terminal 41 amino acids of prelamin A contain sufficient context to allow cleavage of the tail by ZMPSTE24. We have identified several mutations in amino acids immediately surrounding the cleavage site (between Y646 and L647) that interfere with efficient cleavage of the prelamin A tail; these mutations include R644C, L648A and N650A, in addition to the previously reported L647R. Our data suggests that 9 of the 15 residues within the cleaved tail that lie immediately upstream of the CAAX motif are not critical for ZMPSTE24-mediated cleavage, as they can be replaced by the 9 amino acid HA epitope. However, duplication of the same 9 amino acids (to increase the distance between the prenyl group and the cleavage site) impairs the ability of ZMPSTE24 to cleave prelamin A.Our data reveals amino acid preferences flanking the ZMPSTE24 cleavage site of prelamin A and suggests that spacing from the farnesyl-cysteine to the cleavage site is important for optimal ZMPSTE24 cleavage. These studies begin to elucidate the substrate requirements of an enzyme activity critical to human health and longevity

Evidence in the learning organization

<p>Abstract</p> <p>Background</p> <p>Organizational leaders in business and medicine have been experiencing a similar dilemma: how to ensure that their organizational members are adopting work innovations in a timely fashion. Organizational leaders in healthcare have attempted to resolve this dilemma by offering specific solutions, such as evidence-based medicine (EBM), but organizations are still not systematically adopting evidence-based practice innovations as rapidly as expected by policy-makers (the knowing-doing gap problem). Some business leaders have adopted a systems-based perspective, called the learning organization (LO), to address a similar dilemma. Three years ago, the Society of General Internal Medicine's Evidence-based Medicine Task Force began an inquiry to integrate the EBM and LO concepts into one model to address the knowing-doing gap problem.</p> <p>Methods</p> <p>During the model development process, the authors searched several databases for relevant LO frameworks and their related concepts by using a broad search strategy. To identify the key LO frameworks and consolidate them into one model, the authors used consensus-based decision-making and a narrative thematic synthesis guided by several qualitative criteria. The authors subjected the model to external, independent review and improved upon its design with this feedback.</p> <p>Results</p> <p>The authors found seven LO frameworks particularly relevant to evidence-based practice innovations in organizations. The authors describe their interpretations of these frameworks for healthcare organizations, the process they used to integrate the LO frameworks with EBM principles, and the resulting Evidence in the Learning Organization (ELO) model. They also provide a health organization scenario to illustrate ELO concepts in application.</p> <p>Conclusion</p> <p>The authors intend, by sharing the LO frameworks and the ELO model, to help organizations identify their capacities to learn and share knowledge about evidence-based practice innovations. The ELO model will need further validation and improvement through its use in organizational settings and applied health services research.</p

Intended Consequences Statement in Conservation Science and Practice

As the biodiversity crisis accelerates, the stakes are higher for threatened plants and animals. Rebuilding the health of our planet will require addressing underlying threats at many scales, including habitat loss and climate change. Conservation interventions such as habitat protection, management, restoration, predator control, trans location, genetic rescue, and biological control have the potential to help threatened or endangered species avert extinction. These existing, well-tested methods can be complemented and augmented by more frequent and faster adoption of new technologies, such as powerful new genetic tools. In addition, synthetic biology might offer solutions to currently intractable conservation problems. We believe that conservation needs to be bold and clear-eyed in this moment of great urgency

Altered versican cleavage in ADAMTS5 deficient mice : a novel etiology of myxomatous valve disease

AbstractIn fetal valve maturation the mechanisms by which the relatively homogeneous proteoglycan-rich extracellular matrix (ECM) of endocardial cushions is replaced by a specialized and stratified ECM found in mature valves are not understood. Therefore, we reasoned that uncovering proteases critical for ‘remodeling’ the proteoglycan rich (extracellular matrix) ECM may elucidate novel mechanisms of valve development. We have determined that mice deficient in ADAMTS5, (A Disintegrin-like And Metalloprotease domain with ThromboSpondin-type 1 motifs) which we demonstrated is expressed predominantly by valvular endocardium during cardiac valve maturation, exhibited enlarged valves. ADAMTS5 deficient valves displayed a reduction in cleavage of its substrate versican, a critical cardiac proteoglycan. In vivo reduction of versican, in Adamts5−/− mice, achieved through Vcan heterozygosity, substantially rescued the valve anomalies. An increase in BMP2 immunolocalization, Sox9 expression and mesenchymal cell proliferation were observed in Adamts5−/− valve mesenchyme and correlated with expansion of the spongiosa (proteoglycan-rich) region in Adamts5−/− valve cusps. Furthermore, these data suggest that ECM remodeling via ADAMTS5 is required for endocardial to mesenchymal signaling in late fetal valve development. Although adult Adamts5−/− mice are viable they do not recover from developmental valve anomalies and have myxomatous cardiac valves with 100% penetrance. Since the accumulation of proteoglycans is a hallmark of myxomatous valve disease, based on these data we hypothesize that a lack of versican cleavage during fetal valve development may be a potential etiology of adult myxomatous valve disease