Binding of Integrin α6β4 to Plectin Prevents Plectin Association with F-Actin but Does Not Interfere with Intermediate Filament Binding

Hemidesmosomes are stable adhesion complexes in basal epithelial cells that provide a link between the intermediate filament network and the extracellular matrix. We have investigated the recruitment of plectin into hemidesmosomes by the α6β4 integrin and have shown that the cytoplasmic domain of the β4 subunit associates with an NH2-terminal fragment of plectin that contains the actin-binding domain (ABD). When expressed in immortalized plectin-deficient keratinocytes from human patients with epidermol- ysis bullosa (EB) simplex with muscular dystrophy (MD-EBS), this fragment is colocalized with α6β4 in basal hemidesmosome-like clusters or associated with F-actin in stress fibers or focal contacts. We used a yeast two-hybrid binding assay in combination with an in vitro dot blot overlay assay to demonstrate that β4 interacts directly with plectin, and identified a major plectin-binding site on the second fibronectin type III repeat of the β4 cytoplasmic domain. Mapping of the β4 and actin-binding sites on plectin showed that the binding sites overlap and are both located in the plectin ABD. Using an in vitro competition assay, we could show that β4 can compete out the plectin ABD fragment from its association with F-actin. The ability of β4 to prevent binding of F-actin to plectin explains why F-actin has never been found in association with hemidesmosomes, and provides a molecular mechanism for a switch in plectin localization from actin filaments to basal intermediate filament–anchoring hemidesmosomes when β4 is expressed. Finally, by mapping of the COOH-terminally located binding site for several different intermediate filament proteins on plectin using yeast two-hybrid assays and cell transfection experiments with MD-EBS keratinocytes, we confirm that plectin interacts with different cytoskeletal networks

Potential for positive biodiversity outcomes under diet-driven land use change in Great Britain

Background: A shift toward human diets that include more fruit and vegetables, and less meat is a potential pathway to improve public health and reduce food system-related greenhouse gas emissions. Associated changes in land use could include conversion of grazing land into horticulture, which makes more efficient use of land per unit of dietary energy and frees-up land for other uses. Methods: Here we use Great Britain as a case study to estimate potential impacts on biodiversity from converting grazing land to a mixture of horticulture and natural land covers by fitting species distribution models for over 800 species, including pollinating insects and species of conservation priority. Results: Across several land use scenarios that consider the current ratio of domestic fruit and vegetable production to imports, our statistical models suggest a potential for gains to biodiversity, including a tendency for more species to gain habitable area than to lose habitable area. Moreover, the models suggest that climate change impacts on biodiversity could be mitigated to a degree by land use changes associated with dietary shifts. Conclusions: Our analysis demonstrates that options exist for changing agricultural land uses in a way that can generate win-win-win outcomes for biodiversity, adaptation to climate change and public healt

The Science of College: Navigating the First Year and Beyond

The transition to adulthood is a complex process, and college is pivotal to this experience. "The Science of College" aids entering college students--and the people who support them--in navigating college successfully, with up-to-date recommendations based upon real student situations, sound social science research, and the collective experiences of faculty, lecturers, advisors, and student support staff. The stories captured in this book highlight how the challenges that college students encounter vary in important ways based on demographics and social backgrounds. Despite these varied backgrounds, all students are more likely to have successful college experiences if they invest in their communities. Universities have many resources available, but as this book will show, students need to learn when to access which resources and how best to engage with people serving students. This includes having a better awareness of the different roles held by university faculty and staff, and navigating who to go to for what, based upon understanding their distinct sets of expertise and approaches to support. There is no single template for student success. Yet, this book highlights common issues that many students face and provides science-based advice for how to navigate college. Each topic covered is geared towards the life stage that most college students are in: emerging adulthood. In addition to the student-focused chapters, the book includes appendixes with activities for students, tips for parents, and methods information for faculty. Supplemental website materials suggest classroom activities for instructors who adopt this book within first-year seminars and general education courses

Stoichiometry of C, N, P, and Si fluxes in a temperate-climate embayment

Dissolved C, N, P, and Si budgets for Tomales Bay, California, have been used to solve simultaneous stoichiometric equations which describe a plausible material balance for net organic matter reactions in the bay. Dissolved Si and P were both exported hydrographically. Dissolved C and fixed N were imported hydrographically. If we assume that C, N, P, and Si were supplied to the bay as organic detritus and remineralized at a rate required to balance dissolved Si and P exports, we can calculate reasonable rates of denitrification and CO2 gas evasion across the air-water interface. The system is thus interpreted to have been net heterotrophic at the time of our investigation. Fluxes attributed to individual components in the system (benthic respiration, water-column material turnover, biochemical transformations between fixed and gaseous N) were of sufficient magnitude to account for the system-wide net fluxes, although too noisy to allow piecewise derivation of net system fluxes. Denitrification and limitation of primary production by dissolved fixed N in aquatic ecosystems may be symptoms of other system-scale constraints on net C metabolism, rather than themselves being system-level controls of net C metabolism

文献目録

textabstractHuman immunodeficiency virus type I enhancer binding protein 2 (HIVEP2) has been previously associated with intellectual disability and developmental delay in three patients. Here, we describe six patients with developmental delay, intellectual disability, and dysmorphic features with de novo likely gene-damaging variants in HIVEP2 identified by whole-exome sequencing (WES). HIVEP2 encodes a large transcription factor that regulates various neurodevelopmental pathways. Our findings provide further evidence that pathogenic variants in HIVEP2 lead to intellectual disabilities and developmental delay

Hundreds of variants clustered in genomic loci and biological pathways affect human height

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Loss-of-function and missense variants in NSD2 cause decreased methylation activity and are associated with a distinct developmental phenotype

PURPOSE: Despite a few recent reports of patients harboring truncating variants in NSD2, a gene considered critical for the Wolf–Hirschhorn syndrome (WHS) phenotype, the clinical spectrum associated with NSD2 pathogenic variants remains poorly understood. METHODS: We collected a comprehensive series of 18 unpublished patients carrying heterozygous missense, elongating, or truncating NSD2 variants; compared their clinical data to the typical WHS phenotype after pooling them with ten previously described patients; and assessed the underlying molecular mechanism by structural modeling and measuring methylation activity in vitro. RESULTS: The core NSD2-associated phenotype includes mostly mild developmental delay, prenatal-onset growth retardation, low body mass index, and characteristic facial features distinct from WHS. Patients carrying missense variants were significantly taller and had more frequent behavioral/psychological issues compared with those harboring truncating variants. Structural in silico modeling suggested interference with NSD2’s folding and function for all missense variants in known structures. In vitro testing showed reduced methylation activity and failure to reconstitute H3K36me2 in NSD2 knockout cells for most missense variants. CONCLUSION: NSD2 loss-of-function variants lead to a distinct, rather mild phenotype partially overlapping with WHS. To avoid confusion for patients, NSD2 deficiency may be named Rauch–Steindl syndrome after the delineators of this phenotype

Publisher Correction: Toxoplasma Modulates Signature Pathways of Human Epilepsy, Neurodegeneration & Cancer.

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