Adaptations to Climate-Mediated Selective Pressures in Humans

Humans inhabit a remarkably diverse range of environments, and adaptation through natural selection has likely played a central role in the capacity to survive and thrive in extreme climates. Unlike numerous studies that used only population genetic data to search for evidence of selection, here we scan the human genome for selection signals by identifying the SNPs with the strongest correlations between allele frequencies and climate across 61 worldwide populations. We find a striking enrichment of genic and nonsynonymous SNPs relative to non-genic SNPs among those that are strongly correlated with these climate variables. Among the most extreme signals, several overlap with those from GWAS, including SNPs associated with pigmentation and autoimmune diseases. Further, we find an enrichment of strong signals in gene sets related to UV radiation, infection and immunity, and cancer. Our results imply that adaptations to climate shaped the spatial distribution of variation in humans

CDKN2B-AS1 Genotype–Glaucoma Feature Correlations in Primary Open-Angle Glaucoma Patients From the United States

To assess the association between single nucleotide polymorphisms (SNPs) of the gene region containing cyclin dependent kinase inhibitor 2B antisense noncoding RNA (CDKN2B-AS1) and glaucoma features among primary open-angle glaucoma (POAG) patients

Two lineage boundaries coordinate vertebrate apical ectodermal ridge formation

Proximal–distal outgrowth of the vertebrate limb bud is regulated by the apical ectodermal ridge (AER), which forms at an invariant position along the dorsal–ventral (D/V) axis of the embryo. We have studied the genetic and cellular events that regulate AER formation in the mouse. In contrast to implications from previous studies in chick, we identified two distinct lineage boundaries in mouse ectoderm prior to limb bud outgrowth using a Cre/loxP-based fate-mapping approach and a novel retroviral cell-labeling technique. One border is transient and at the limit of expression of the ventral gene En1, which corresponds to the D/V midline of the AER, and the second border corresponds to the dorsal AER margin. Labeling of AER precursors using an inducible Cre showed that not all cells that initially express AER genes form the AER, indicating that signaling is required to maintain an AER phenotype. Misexpression of En1 at moderate levels specifically in the dorsal AER of transgenic mice was found to produce dorsally shifted AER fragments, whereas high levels of En1 abolished AER formation. In both cases, the dorsal gene Wnt7a was repressed in cells adjacent to the En1-expressing cells, demonstrating that signaling regulated by EN1 occurs across the D/V border. Finally, fate mapping of AER domains in these mutants showed that En1 plays a part in positioning and maintaining the two lineage borders

Implications of the Dunning-Kruger Effect: Finding Balance between Subjective and Objective Assessment in Debriefing Professional Development

Background The ability to debrief is considered an essential clinical and simulation teaching skill because of the deep learning cultivated. Regulatory bodies identify the need for debriefing training and professional development followed by formative and summative assessment. Method The Debriefing for Meaningful Learning Evaluation Scale (DMLES) is a behaviorally anchored rating scale developed to assess 20 behaviors aligned with Debriefing for Meaningful Learning (DML). Participants from five baccalaureate pre–licensure nursing programs were recruited to receive DML training, then facilitate and record a debriefing for subjective and objective assessment using the DMLES. Results A total of 52 debriefers submitted 81 recorded debriefings. DMLES subjective ratings at two time points were higher than that of expert raters of the same debriefings demonstrating statistically significant differences between subjective and objective mean scores. Conclusions The difference between subjective and objective scores demonstrated the Dunning-Kruger Effect (DKE), a subjective overestimation of skill performance when compared to objective assessment. The potential for DKE is an important consideration for determining assessment methods

Inhibiting influenza virus transmission using a broadly acting neuraminidase that targets host sialic acids in the upper respiratory tract

ABSTRACTThe ongoing transmission of influenza A viruses (IAV) for the past century continues to be a burden to humans. IAV binds terminal sialic acids (SA) of sugar molecules present within the upper respiratory tract (URT) in order to successfully infect hosts. The two most common SA structures that are important for IAV infection are those with α2,3- and α2,6-linkages. While mice were once considered to be an unsuitable system for studying IAV transmission due to their lack of α2,6-SA in the trachea, we have successfully demonstrated that IAV transmission in infant mice is remarkably efficient. This finding led us to re-evaluate the SA composition of the URT of mice using in situ immunofluorescence and examine its in vivo contribution to transmission for the first time. We demonstrate that mice express both α2,3- and α2,6-SA in the URT and that the difference in expression between infants and adults contributes to the variable transmission efficiencies observed. Furthermore, selectively blocking α2,3-SA or α2,6-SA within the URT of infant mice using lectins was necessary but insufficient at inhibiting transmission, and simultaneous blockade of both receptors was crucial in achieving the desired inhibitory effect. By employing a broadly acting neuraminidase to indiscriminately remove both SA moieties in vivo, we effectively suppressed viral shedding and halted the transmission of different strains of influenza viruses. These results emphasize the utility of the infant mouse model for studying IAV transmission and strongly indicate that broadly targeting host SA is an effective approach that inhibits IAV contagion.IMPORTANCEInfluenza virus transmission studies have historically focused on viral mutations that alter hemagglutinin binding to sialic acid (SA) receptors in vitro. However, SA binding preference does not fully account for the complexities of influenza A virus transmission in humans. Our previous findings reveal that viruses that are known to bind α2,6-SA in vitro have different transmission kinetics in vivo, suggesting that diverse SA interactions may occur during their life cycle. In this study, we examine the role of host SA on viral replication, shedding, and transmission in vivo. We highlight the critical role of SA presence during virus shedding, such that attachment to SA during virion egress is equally important as detachment from SA during virion release. These insights support the potential of broadly acting neuraminidases as therapeutic agents capable of restraining viral transmission in vivo. Our study unveils intricate virus-host interactions during shedding, highlighting the necessity to develop innovative strategies to effectively target transmission

Debriefing for Meaningful Learning: Implementing a Train-the-Trainer Program for Debriefers

Debriefing for Meaningful Learning (DML) is a method of debriefing grounded in the theory of reflection used following a simulation or clinical learning experience to engage participants in an interactive dialogue aimed at examining and evaluating their thinking and decision-making processes. With increasing adoption of DML worldwide, a sustainable training program for nurse educators is needed. Attending conferences and workshops that provide training is challenging for many nurse educators because of time and cost constraints. One promising solution is the train-the-trainer (TTT) model. In this article, the development and implementation of a TTT model of DML debriefer training, adaptable to both academic and clinical nursing professional development, is described

An acylatable residue of hedgehog is differentially required in Drosophila and mouse limb development

The Drosophila Hedgehog protein and its vertebrate counterpart Sonic hedgehog are required for a wide variety of patterning events throughout development. Hedgehog proteins are secreted from cells and undergo autocatalytic cleavage and cholesterol modification to produce a mature signaling domain. This domain of Sonic hedgehog has recently been shown to acquire an N-terminal acyl group in cell culture. We have investigated the in vivo role that such acylation might play in appendage patterning in mouse and Drosophila; in both species Hedgehog proteins define a posterior domain of the limb or wing. A mutant form of Sonic hedgehog that cannot undergo acylation retains significant ability to repattern the mouse limb. However, the corresponding mutation in Drosophila Hedgehog renders it inactive in vivo, although it is normally processed. Furthermore, overexpression of the mutant form has dominant negative effects on Hedgehog signaling. These data suggest that the importance of the N-terminal cysteine of mature Hedgehog in patterning appendages differs between species

ADAM12: a potential target for the treatment of chronic wounds

Wound healing is a complex process involving multiple cellular events, including cell proliferation, migration, and tissue remodeling. ADAM12 (a disintegrin and metalloprotease 12) is a membrane-anchored metalloprotease, which has been implicated in activation/inactivation of growth factors that play an important role in wound healing, including heparin-binding EGF-like growth factor (HB-EGF) and insulin growth factor (IGF) binding proteins. Here we report that expression of ADAM12 is fivefold up-regulated in the non-healing edge of chronic ulcers compared to healthy skin, based on microarrays of biopsies taken from five patients and from healthy controls (p=0.013). The increase in ADAM12 expression in chronic ulcers was confirmed by quantitative real time-PCR. Moreover, immunohistochemical analysis demonstrated a pronounced increase in the membranous and intracellular signal for ADAM12 in the epidermis of chronic wounds compared to healthy skin. These findings, coupled with our previous observations that lack of keratinocyte migration contributes to the pathogenesis of chronic ulcers, prompted us to evaluate how the absence of ADAM12 affects the migration of mouse keratinocytes. Skin explants from newborn ADAM12−/− or WT mice were used to quantify keratinocyte migration out of the explants over a period of seven days. We found a statistically significant increase in the migration of ADAM12−/− keratinocytes compared to WT control (P=.0014) samples. Taken together, the upregulation of ADAM12 in chronic wounds, and the increased migration of keratinocytes in the absence of ADAM12 suggest that ADAM12 is an important mediator of wound healing. We hypothesize that increased expression of ADAM12 in chronic wounds impairs wound healing through the inhibition of keratinocyte migration, and that topical ADAM12 inhibitors may therefore prove useful for the treatment of chronic wounds