Structure of Native Lens Connexin 46/50 Intercellular Channels by Cryo-EM

Gap junctions establish direct pathways for cell-to-cell communication through the assembly of twelve connexin subunits that form intercellular channels connecting neighbouring cells. Co-assembly of different connexin isoforms produces channels with unique properties and enables communication across cell types. Here we used single-particle cryo-electron microscopy to investigate the structural basis of connexin co-assembly in native lens gap junction channels composed of connexin 46 and connexin 50 (Cx46/50). We provide the first comparative analysis to connexin 26 (Cx26), which—together with computational studies—elucidates key energetic features governing gap junction permselectivity. Cx46/50 adopts an open-state conformation that is distinct from the Cx26 crystal structure, yet it appears to be stabilized by a conserved set of hydrophobic anchoring residues. ‘Hot spots’ of genetic mutations linked to hereditary cataract formation map to the core structural–functional elements identified in Cx46/50, suggesting explanations for many of the disease-causing effects

Cross-cutting principles for planetary health education

Since the 2015 launch of the Rockefeller Foundation Lancet Commission on planetary health,1 an enormous groundswell of interest in planetary health education has emerged across many disciplines, institutions, and geographical regions. Advancing these global efforts in planetary health education will equip the next generation of scholars to address crucial questions in this emerging field and support the development of a community of practice. To provide a foundation for the growing interest and efforts in this field, the Planetary Health Alliance has facilitated the first attempt to create a set of principles for planetary health education that intersect education at all levels, across all scales, and in all regions of the world—ie, a set of cross-cutting principles

A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants.

This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/ng.3448Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. Here we report on a study of >12 million variants, including 163,714 directly genotyped, mostly rare, protein-altering variants. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P < 5 × 10(-8)) distributed across 34 loci. Although wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first genetic association signal specific to wet AMD, near MMP9 (difference P value = 4.1 × 10(-10)). Very rare coding variants (frequency <0.1%) in CFH, CFI and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.We thank all participants of all the studies included for enabling this research by their participation in these studies. Computer resources for this project have been provided by the high-performance computing centers of the University of Michigan and the University of Regensburg. Group-specific acknowledgments can be found in the Supplementary Note. The Center for Inherited Diseases Research (CIDR) Program contract number is HHSN268201200008I. This and the main consortium work were predominantly funded by 1X01HG006934-01 to G.R.A. and R01 EY022310 to J.L.H

International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist

The Pipeline and Beyond

Women have been involved with IT since the 19th century, when Ada the countess of Lovelace was the first programmer for Charles Babbage’s analytical engine. Grace Murray Hopper’s contributions to COBOL and computing several decades ago are considered so significant that an annual conference is held in her honor (see http://www.grace hopper.org). In fact, the earliest computer programmers tended to be women more often than men (Panteli, Stack, & Ramsay, 2001). As the IT field progressed, however, it evolved into what many still view as a male-dominated domain, some say due to its increasing association with power and money (Tapia, Kvasny, & Trauth, 2003). Today, women make up at least half of World Wide Web users (Newburger, 2001), but this has apparently not translated into a proportionate participation in IT careers. IT managers must recruit and retain a skilled and diverse workforce in order to meet the needs of increasingly global enterprises where cross-cultural, heterogeneous work groups are the norm. However, numerous sources (Information Technology Association of America [ITAA], 2003; Zweben, 2005) agree that the proportion of females to males selecting and completing degrees in IT-related fields is declining. Not only are women missing out on career opportunities, but the IT profession is also missing potentially valuable alternative perspectives on system design (Woodfield, 2002). Worldwide, the digital divide is more extreme for women than men (Hafkin & Taggart, 2001), with the result that in many developing countries, women’s access to computers is more limited than men’s access. However, IT is an important driver for economic development and should provide women with new opportunities to better their circumstances, provided that a variety of challenges, such as technical education and social and political norms, can be addressed (Hafkin & Taggart, 2001). Even in more developed countries, females face well-documented (Margolis & Fisher, 2002; von Hellens, Nielsen, & Beekhuyzen, 2004) obstacles all along the pipeline beginning as early as middle school and continuing through college, graduate school, and the career. Developing solutions to recruit and retain women in IT may serve other underrepresented groups as well, making IT classrooms and IT workplaces more inviting and ultimately more productive environments for everyone

Women in the IT Profession

Women have been involved with information technology (IT) since the 19th century, when Ada the Countess of Lovelace served as the first programmer of Charles Babbage’s analytical engine. Grace Murray Hopper’s contributions to COBOL and computing several decades ago are considered so significant that an annual conference is held in her honor (see www.gracehopper.org). In fact, the earliest computer programmers tended to be women more often than men (Panteli, Stack & Ramsay, 2001). As the IT field progressed, however, it evolved into what many still view as a male-dominated domain, some say due to its increasing association with power and money (Tapia, Kvasny & Trauth, 2003). Today, women are estimated to make up nearly half of World Wide Web users (Newburger, 2001), but this has apparently not translated into a proportionate participation in IT careers

The CaMKII Holoenzyme Structure in Activation Competent Conformations

The Ca2+/calmodulin-dependent protein kinase II (CaMKII) assembles into large 12-meric holoenzymes, which is thought to enable regulatory processes required for synaptic plasticity underlying learning, memory and cognition. Here we used single particle electron microscopy (EM) to determine a pseudoatomic model of the CaMKIIα holoenzyme in an extended and activation-competent conformation. The holoenzyme is organized by a rigid central hub complex, while positioning of the kinase domains is highly flexible, revealing dynamic holoenzymes ranging from 15–35 nm in diameter. While most kinase domains are ordered independently, ~20% appear to form dimers an

Diversity and the Information Technology Workforce: Barriers and Opportunities

This paper reviews the academic community\u27s response through research and curriculum initiatives to the practitioner\u27s requirements for a diverse information technology (IT) workforce. The paper then highlights opportunities for future IT research by matching current academic research to organizational diversity issues, exposing the gaps and opportunities therein. This issue is important because the call for a diverse workforce has been heard for some time now with varying degrees of implementation. Diversity in the workforce has multiple dimensions, from diversity in perspectives to diversity in terms of ethnicity, age, gender and disabilities. It will be shown that little if any IT research has addressed IT recruitment and management for diversity although the effects of this diversity on team processes and performance can and will impact organizational outcomes

Visualization of Protein-Lipid Interactions in Connexin-46/50 Intercellular Channels by Cryo-EM and MD-Simulation

Cell-to-cell communication by gap junctions is facilitated by a unique macromolecular architecture, where intercellular channels directly couple the plasma membranes of two neighboring cells. In each membrane, a “hemi-channel” is formed by the oligomerization of six individual subunits (called connexins). To gain insight toward how gap junctions interact with their local membrane environment, we used lipid nanodisc technology to incorporate native connexin-46/50 (Cx46/50) intercellular channels into a dual lipid membrane system – closely mimicking a native cell-to-cell junction. Structural characterization of Cx46/50 lipid-embedded channels by single particle CryoEM revealed a drastic lipid-induced stabilization to the channel architecture, resulting in a 3D reconstruction at 2.1 Å resolution – providing an unprecedented level of detail for the class of protein. The subunit packing within each hemi-channel is buttressed by a bouquet of highly-stabilized lipid acyl-chains. Remarkably, the stabilizing effects to the lipid-bilayer extends well beyond the annular layer of lipids and effectively immobilizes the extra-cellular leaflets of the two connected membranes. In addition, over 150 water molecules are resolved within the channel architecture. Time-averaged densities of the lipids and water obtained by MD simulation display the same pattern of stabilization seen in the CryoEM reconstruction. MD analysis suggest lipid headgroups remain highly dynamic relative to the lipid acyl-chains, rationalizing the absence of headgroup densities in the 2.1 Å CryoEM density map. 3D heterogeneity analysis of the CryoEM data identified 4 distinct classes of lipid headgroup configurations, which were also detected by network analysis of extracellular lipids in MD-simulations. Lipid and water binding sites identified in Cx46/50 are remarkably conserved across the connexin family, suggesting these stabilizing features are key contributors to the structure and function of gap junction intercellular communication