We find that variation in the
gene underlies natural differences in
responses to the toxin arsenic. This gene encodes the E2 subunit of the branched-chain α-keto acid dehydrogenase (BCKDH) complex, a ...core component of branched-chain amino acid (BCAA) metabolism. We causally linked a non-synonymous variant in the conserved lipoyl domain of DBT-1 to differential arsenic responses. Using targeted metabolomics and chemical supplementation, we demonstrate that differences in responses to arsenic are caused by variation in iso-branched chain fatty acids. Additionally, we show that levels of branched chain fatty acids in human cells are perturbed by arsenic treatment. This finding has broad implications for arsenic toxicity and for arsenic-focused chemotherapeutics across human populations. Our study implicates the BCKDH complex and BCAA metabolism in arsenic responses, demonstrating the power of
natural genetic diversity to identify novel mechanisms by which environmental toxins affect organismal physiology.
This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).
Developing vascular networks that integrate with the host circulation and support cells engrafted within engineered tissues remains a key challenge in tissue engineering. Most previous work in this ...field has focused on developing new methods to build human vascular networks within engineered tissues prior to their implant in vivo, with substantively less attention paid to the role of the host in tissue vascularization and engraftment. Here, we assessed the role that different host animal models and anatomic implant locations play in vascularization and cardiomyocyte survival within engineered tissues. We found major differences in the formation of graft-derived blood vessels and survival of cardiomyocytes after implantation of identical tissues in immunodeficient athymic nude mice versus rats. Athymic mice supported robust guided vascularization of human microvessels carrying host blood but relatively sparse cardiac grafts within engineered tissues, regardless of implant site. Conversely, athymic rats produced substantive inflammatory changes that degraded grafts (abdomen) or disrupted vascular patterning (heart). Despite disrupted vascular patterning, athymic rats supported > 3-fold larger human cardiomyocyte grafts compared to athymic mice. This work demonstrates the critical importance of the host for vascularization and engraftment of engineered tissues, which has broad translational implications across regenerative medicine.
The molecular mechanisms underlying major phenotypic changes that have evolved repeatedly in nature are generally unknown. Pelvic loss in different natural populations of threespine stickleback fish ...has occurred through regulatory mutations deleting a tissue-specific enhancer of the Pituitary homeobox transcription factor 1 (Pitx1) gene. The high prevalence of deletion mutations at Pitx1 may be influenced by inherent structural features of the locus. Although Pitx1 null mutations are lethal in laboratory animals, Pitx1 regulatory mutations show molecular signatures of positive selection in pelvic-reduced populations. These studies illustrate how major expression and morphological changes can arise from single mutational leaps in natural populations, producing new adaptive alleles via recurrent regulatory alterations in a key developmental control gene.
In this review, we synthesize evidence to highlight cognitive appraisal as an important developmental antecedent of individual differences in emotion differentiation and adept emotion regulation. ...Emotion differentiation is the degree to which emotions are experienced in a nuanced or “granular” way—as specific and separable phenomena. More extensive differentiation is related to positive wellbeing and has emerged as a correlate of emotion regulation skill among adults. We argue that the cognitive appraisal processes that underlie these facets of emotional development are instantiated early in the first year of life and tuned by environmental input and experience. Powerful socializing input in the form of caregivers’ contingent and selective responding to infants’ emotional signals carves and calibrates the infant’s appraisal thresholds for what in their world ought to be noticed, deemed as important or personally meaningful, and responded to (whether and how). These appraisal thresholds are thus unique to the individual child despite the ubiquity of the appraisal process in emotional responding. This appraisal infrastructure, while plastic and continually informed by experience across the lifespan, likely tunes subsequent emotion differentiation, with implications for children’s emotion regulatory choices and skills. We end with recommendations for future research in this area, including the urgent need for developmental emotion science to investigate the diverse sociocultural contexts in which children’s cognitive appraisals, differentiation of emotions, and regulatory responses are being built across childhood.
•Cognition-emotion interactions in infancy create the foundation for emotional development.•Appraisal is an antecedent of emotion differentiation and emotion regulation.•Contingent responding calibrates infants’ unique appraisal thresholds.•Relational and sociocultural contexts shape infants’ emotional development.
Armor plate changes in sticklebacks are a classic example of repeated adaptive evolution. Previous studies identified ectodysplasin (EDA) gene as the major locus controlling recurrent plate loss in ...freshwater fish, though the causative DNA alterations were not known. Here we show that freshwater EDA alleles have cis-acting regulatory changes that reduce expression in developing plates and spines. An identical T → G base pair change is found in EDA enhancers of divergent low-plated fish. Recreation of the T → G change in a marine enhancer strongly reduces expression in posterior armor plates. Bead implantation and cell culture experiments show that Wnt signaling strongly activates the marine EDA enhancer, and the freshwater T → G change reduces Wnt responsiveness. Thus parallel evolution of low-plated sticklebacks has occurred through a shared DNA regulatory change, which reduces the sensitivity of an EDA enhancer to Wnt signaling, and alters expression in developing armor plates while preserving expression in other tissues.
Active learning strategies engage students in instruction by making them an integral part of the teaching process. Gamification is one type of active learning approach that incentivises student ...participation by incorporating gaming elements into the learning experience. Although gamification might be an effective strategy for the introduction of new material, adding gaming elements to a review activity can motivate students to study, help them organise material, and identify material that they should review further before an exam. Escape rooms are collaborative problem-solving challenges and aspects of escape-room experiences can be applied to active learning. Here, we describe an escape room inspired review game for an advanced genetic analysis class at Northwestern University. We provide a detailed account of each puzzle within the review game and assess the impact of the game on learning outcomes.
The biology of follicular lymphoma (FL) is largely dictated by the immune-effector and stromal cells that comprise its tumor microenvironment. FL-infiltrating T-cell populations that are thought to ...be fundamental to FL biology are follicular helper T-cells (TFH), follicular regulatory T-cells (TFR), a recently described population that regulates TFH activity, and regulatory T-cells (Treg). These T-cell populations have dynamic interactions with mesenchymal stromal cells (MSCs) in the tumor microenvironment. Whereas MSCs have been shown to support FL B-cell and Treg viability, their effects on FL-infiltrating TFH and TFR cells have not been described. Herein we show that MSCs support the viability of FL-infiltrating TFH and TFR, as well as Tregs, in part through an IL-6-dependent mechanism. We further demonstrate that MSCs mediate TFH to TFR conversion by inducing the expression of FoxP3 in TFH cells, demonstrating for the first time that human TFR can be derived from TFH cells. Given that the balance of TFH and TFR populations likely dictate, in part, the biology of this disease, our data support the potential for targeting MSCs as a therapeutic strategy.
Fermentation-based chemical production strategies provide a feasible route for the rapid, safe, and sustainable production of a wide variety of important chemical products, ranging from fuels to ...pharmaceuticals. These strategies have yet to find wide industrial utilization due to their inability to economically compete with traditional extraction and chemical production methods. Here, we engineer for the first time the complex microbial biosynthesis of an anthocyanin plant natural product, starting from sugar. This was accomplished through the development of a synthetic, 4-strain
polyculture collectively expressing 15 exogenous or modified pathway enzymes from diverse plants and other microbes. This synthetic consortium-based approach enables the functional expression and connection of lengthy pathways while effectively managing the accompanying metabolic burden. The
production of specific anthocyanin molecules, such as calistephin, has been an elusive metabolic engineering target for over a decade. The utilization of our polyculture strategy affords milligram-per-liter production titers. This study also lays the groundwork for significant advances in strain and process design toward the development of cost-competitive biochemical production hosts through nontraditional methodologies.
To efficiently express active extensive recombinant pathways with high flux in microbial hosts requires careful balance and allocation of metabolic resources such as ATP, reducing equivalents, and malonyl coenzyme A (malonyl-CoA), as well as various other pathway-dependent cofactors and precursors. To address this issue, we report the design, characterization, and implementation of the first synthetic 4-strain polyculture. Division of the overexpression of 15 enzymes and transcription factors over 4 independent strain modules allowed for the division of metabolic burden and for independent strain optimization for module-specific metabolite needs. This study represents the most complex synthetic consortia constructed to date for metabolic engineering applications and provides a new paradigm in metabolic engineering for the reconstitution of extensive metabolic pathways in nonnative hosts.
Bleomycin is a powerful chemotherapeutic drug used to treat a variety of cancers. However, individual patients vary in their responses to bleomycin. The identification of genetic differences that ...underlie this response variation could improve treatment outcomes by tailoring bleomycin dosages to each patient. We used the model organism
to identify genetic determinants of bleomycin-response differences by performing linkage mapping on recombinants derived from a cross between the laboratory strain (N2) and a wild strain (CB4856). This approach identified a small genomic region on chromosome V that underlies bleomycin-response variation. Using near-isogenic lines, and strains with CRISPR-Cas9 mediated deletions and allele replacements, we discovered that a novel nematode-specific gene (
) is required for bleomycin resistance. Although the mechanism by which this gene causes variation in bleomycin responses is unknown, we suggest that a rare variant present in the CB4856 strain might cause differences in the potential stress-response function of
between the N2 and CB4856 strains, thereby leading to differences in bleomycin resistance.
Describes use of guided imagery in a family of origin group. Outlines three stages in the process of differentiation from family: identification, integration, and activation of the individual's ...thoughts, feelings and behaviors. Use of guided imagery is highlighted as a means for accessing the unconscious and increasing the clients' awareness of family issues and promoting self-differentiation. (Author)
PDF
