Modulation Of Mesenchymal And Metastatic Cell Growth

The present invention relates to compositions and methods for the modulation of metastatic and mesenchymal cell growth and mobility via the regulation of the formation of Twist/Twist homodimers and Twist/E heterodimers. The present invention also relates to methods for screening agents and compound libraries for molecules that function to modulate the formation of Twist/Twist homodimers, Twist/E protein heterodimers or their upstream or downstream effector molecules

Erratum: Identification of responsive cells in the developing somite supports a role for β‐catenin‐dependent Wnt signaling in maintaining the DML myogenic progenitor pool

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90355/1/23720_ftp.pd

Concept Mapping As A Tool To Promote Cognitive Integration

For 20 years there has been a push to integrate the basic and clinical sciences in medical school curricula. Recently, studies have suggested that cognitive integration by the student is best achieved when the relationships between basic science and clinical domains are explicitly demonstrated. Concept mapping in response to a prompt, which asks students to create relationships among clinical and basic science concepts, should provide explicit connections that lead to a deeper conceptual understanding of the material. We designed a study to test the hypothesis that concept mapping improves the ability of students to diagnostically discriminate between multiple endocrinopathies when compared to students who were provided with similar resources. We also looked to see if knowledge retention was correlated with concept mapping or the type of notes taken during studying.https://dune.une.edu/cetl_minigrant_posters/1001/thumbnail.jp

Conditional expression of Spry1 in neural crest causes craniofacial and cardiac defects

<p>Abstract</p> <p>Background</p> <p>Growth factors and their receptors are mediators of organogenesis and must be tightly regulated in a temporal and spatial manner for proper tissue morphogenesis. Intracellular regulators of growth factor signaling pathways provide an additional level of control. Members of the Sprouty family negatively regulate receptor tyrosine kinase pathways in several developmental contexts. To gain insight into the role of Spry1 in neural crest development, we analyzed the developmental effects of conditional expression of Spry1 in neural crest-derived tissues.</p> <p>Results</p> <p>Here we report that conditional expression of Spry1 in neural crest cells causes defects in craniofacial and cardiac development in mice. <it>Spry1;Wnt1-Cre </it>embryos die perinatally and exhibit facial clefting, cleft palate, cardiac and cranial nerve defects. These defects appear to be the result of decreased proliferation and increased apoptosis of neural crest and neural crest-derived cell populations. In addition, the domains of expression of several key transcription factors important to normal craniofacial and cardiac development including <it>AP2</it>, <it>Msx2</it>, <it>Dlx5</it>, and <it>Dlx6 </it>were reduced in <it>Spry1;Wnt1-Cre </it>transgenic embryos.</p> <p>Conclusion</p> <p>Collectively, these data suggest that Spry1 is an important regulator of craniofacial and cardiac morphogenesis and perturbations in Spry1 levels may contribute to congenital disorders involving tissues of neural crest origin.</p

Student Perceptions Of Integrated Vs. Separate Basic Science And Clinical Resources

For 20 years there has been a push to integrate the basic and clinical sciences in medical school curricula. Recently, studies have suggested that cognitive integration is achieved when the relationships between basic science and clinical domains are explicitly demonstrated. In order to investigate methods that promote cognitive integration we performed a pilot study to develop and test different learning resources. We then surveyed students’ perceptions of these resources and analyzed how the resources affected their note taking. Our study suggests that the type of resources can influence the type of note-taking done by students, and that the process of taking integrated notes can enhance learning and retention. This was a pilot study and is limited by its small sample size. Additional research is planned to confirm and expand on these results.https://dune.une.edu/cetl_minigrant_posters/1000/thumbnail.jp

Medical Biochemistry Without Rote Memorization: Multi-Institution Implementation And Student Perceptions Of A Nationally Standardized Metabolic Map For Learning And Assessment

Despite the growing number of patients worldwide with metabolism-related chronic diseases, medical biochemistry education is commonly perceived as focusing on recall of facts irrelevant for patient care. The authors suggest that this focus on rote memorization of pathways creates excessive cognitive load that may interfere with learners’ development of an integrated understanding of metabolic regulation and dysregulation. This cognitive load can be minimized by providing appropriate references during learning and assessment. Biochemistry educators collaborated to develop a medically relevant Pathways of Human Metabolism map (MetMap) that is now being used at many medical schools as a nationally standardized resource during learning and assessments. To assess impact, students from three medical schools were surveyed about its benefits and disadvantages. Responses were obtained from 481 students (84%) and were examined using thematic analysis. Five main themes emerged as perceived benefits of using the MetMap: 1) aids visual and mental organization, 2) promotes deep learning and applied understanding, 3) decreases emphasis on memorization, 4) reduces anxiety on exams, and 5) aids recall. Perceived disadvantages were: 1) fear of under-preparation for licensing exams, 2) overwhelming nature of the map, and 3) reduced motivation for and time spent studying. Results affirm that students perceive use of the MetMap promotes focus on broader metabolic concepts and deep versus surface learning, supporting a shift in cognitive load toward desired goals. Although the long-term impact on learning needs to be further studied, the use of the MetMap represents a step toward open-reference exams that reflect “real world” practice

Lkb1 Deficiency Alters Goblet and Paneth Cell Differentiation in the Small Intestine

The Lkb1 tumour suppressor is a multitasking kinase participating in a range of physiological processes. We have determined the impact of Lkb1 deficiency on intestinal homeostasis, particularly focussing on secretory cell differentiation and development since we observe strong expression of Lkb1 in normal small intestine Paneth and goblet cells. We crossed mice bearing an Lkb1 allele flanked with LoxP sites with those carrying a Cyp1a1-specific inducible Cre recombinase. Lkb1 was efficiently deleted from the epithelial cells of the mouse intestine after intraperitoneal injection of the inducing agent β-naphthoflavone. Bi-allelic loss of Lkb1 led to the perturbed development of Paneth and goblet cell lineages. These changes were characterised by the lack of Delta ligand expression in Lkb1-deficient secretory cells and a significant increase in the levels of the downstream Notch signalling effector Hes5 but not Hes1. Our data show that Lkb1 is required for the normal differentiation of secretory cell lineages within the intestine, and that Lkb1 deficiency modulates Notch signalling modulation in post-mitotic cells

EMT Inducers Catalyze Malignant Transformation of Mammary Epithelial Cells and Drive Tumorigenesis towards Claudin-Low Tumors in Transgenic Mice

The epithelial-mesenchymal transition (EMT) is an embryonic transdifferentiation process consisting of conversion of polarized epithelial cells to motile mesenchymal ones. EMT–inducing transcription factors are aberrantly expressed in multiple tumor types and are known to favor the metastatic dissemination process. Supporting oncogenic activity within primary lesions, the TWIST and ZEB proteins can prevent cells from undergoing oncogene-induced senescence and apoptosis by abolishing both p53- and RB-dependent pathways. Here we show that they also downregulate PP2A phosphatase activity and efficiently cooperate with an oncogenic version of H-RAS in malignant transformation of human mammary epithelial cells. Thus, by down-regulating crucial tumor suppressor functions, EMT inducers make cells particularly prone to malignant conversion. Importantly, by analyzing transformed cells generated in vitro and by characterizing novel transgenic mouse models, we further demonstrate that cooperation between an EMT inducer and an active form of RAS is sufficient to trigger transformation of mammary epithelial cells into malignant cells exhibiting all the characteristic features of claudin-low tumors, including low expression of tight and adherens junction genes, EMT traits, and stem cell–like characteristics. Claudin-low tumors are believed to be the most primitive breast malignancies, having arisen through transformation of an early epithelial precursor with inherent stemness properties and metaplastic features. Challenging this prevailing view, we propose that these aggressive tumors arise from cells committed to luminal differentiation, through a process driven by EMT inducers and combining malignant transformation and transdifferentiation

Bacterial Communities of Diverse Drosophila Species: Ecological Context of a Host–Microbe Model System

Drosophila melanogaster is emerging as an important model of non-pathogenic host–microbe interactions. The genetic and experimental tractability of Drosophila has led to significant gains in our understanding of animal–microbial symbiosis. However, the full implications of these results cannot be appreciated without the knowledge of the microbial communities associated with natural Drosophila populations. In particular, it is not clear whether laboratory cultures can serve as an accurate model of host–microbe interactions that occur in the wild, or those that have occurred over evolutionary time. To fill this gap, we characterized natural bacterial communities associated with 14 species of Drosophila and related genera collected from distant geographic locations. To represent the ecological diversity of Drosophilids, examined species included fruit-, flower-, mushroom-, and cactus-feeders. In parallel, wild host populations were compared to laboratory strains, and controlled experiments were performed to assess the importance of host species and diet in shaping bacterial microbiome composition. We find that Drosophilid flies have taxonomically restricted bacterial communities, with 85% of the natural bacterial microbiome composed of only four bacterial families. The dominant bacterial taxa are widespread and found in many different host species despite the taxonomic, ecological, and geographic diversity of their hosts. Both natural surveys and laboratory experiments indicate that host diet plays a major role in shaping the Drosophila bacterial microbiome. Despite this, the internal bacterial microbiome represents only a highly reduced subset of the external bacterial communities, suggesting that the host exercises some level of control over the bacteria that inhabit its digestive tract. Finally, we show that laboratory strains provide only a limited model of natural host–microbe interactions. Bacterial taxa used in experimental studies are rare or absent in wild Drosophila populations, while the most abundant associates of natural Drosophila populations are rare in the lab

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder