GA4GH: International policies and standards for data sharing across genomic research and healthcare.

The Global Alliance for Genomics and Health (GA4GH) aims to accelerate biomedical advances by enabling the responsible sharing of clinical and genomic data through both harmonized data aggregation and federated approaches. The decreasing cost of genomic sequencing (along with other genome-wide molecular assays) and increasing evidence of its clinical utility will soon drive the generation of sequence data from tens of millions of humans, with increasing levels of diversity. In this perspective, we present the GA4GH strategies for addressing the major challenges of this data revolution. We describe the GA4GH organization, which is fueled by the development efforts of eight Work Streams and informed by the needs of 24 Driver Projects and other key stakeholders. We present the GA4GH suite of secure, interoperable technical standards and policy frameworks and review the current status of standards, their relevance to key domains of research and clinical care, and future plans of GA4GH. Broad international participation in building, adopting, and deploying GA4GH standards and frameworks will catalyze an unprecedented effort in data sharing that will be critical to advancing genomic medicine and ensuring that all populations can access its benefits

Influence of Motion Smear on Visual Acuity in Simulated Infantile Nystagmus

PURPOSE: In persons with infantile nystagmus (IN), visual acuity correlates with the duration of the foveation period of the nystagmus waveform, i.e., when the retinal image is on or near the fovea and moves with low velocity. In this study, we asked how acuity is affected by the non-foveating phases of the nystagmus waveform, when the velocity of retinal image motion is substantially higher. METHODS: Visual acuity was measured in three normal observers for high-contrast, 4-orientation Ts, presented during image motion that simulated either the whole jerk-IN waveform (whole-waveform) or only the foveation periods of the IN waveform (foveation-only). Simulated foveation durations ranged from 20 to 120 ms. For both motion waveforms, we displayed the acuity target for different number of cycles to examine if acuity benefits from multiple presentations of the stimulus. RESULTS: As expected, visual acuity improves with longer simulated foveation durations in both the whole-waveform and foveation-only conditions. Acuity is consistently better (by approximately 0.1 logMAR) in the foveation-only than the whole-waveform condition, indicating that the high-velocity image motion during the simulated IN waveform has a detrimental effect. This difference in acuity between the two waveform conditions increases with the number of cycles, apparently because summation occurs across cycles in the foveation-only condition but not in the whole-waveform condition. CONCLUSIONS: In normal observers, visual acuity in the presence of a simulated nystagmus waveform is limited not only by the duration of the foveation periods, but also by the non-foveating phases of the waveform. However, because persons with IN report little or no motion smear in association with their nystagmus, it remains unclear whether the rapid retinal image motion during the non-foveating phases of the nystagmus waveform generates a similar degradation of visual acuity in IN

Uncovering protein–protein interactions through a team-based undergraduate biochemistry course

How can we provide fertile ground for students to simultaneously explore a breadth of foundational knowledge, develop cross-disciplinary problem-solving skills, gain resiliency, and learn to work as a member of a team? One way is to integrate original research in the context of an undergraduate biochemistry course. In this Community Page, we discuss the development and execution of an interdisciplinary and cross-departmental undergraduate biochemistry laboratory course. We present a template for how a similar course can be replicated at other institutions and provide pedagogical and research results from a sample module in which we challenged our students to study the binding interface between 2 important biosynthetic proteins. Finally, we address the community and invite others to join us in making a larger impact on undergraduate education and the field of biochemistry by coordinating efforts to integrate research and teaching across campuses

General workflow for students investigating the noncovalent interactions involved in P450_sky-catalyzed β-hydroxylation of L-(OMe)-Tyr.

<p>This involves computational analysis (Step 1), molecular biology or synthetic chemistry (Step 2), protein purification (Step 3), chemoenzymatic assays (Step 4), and biochemical and biophysical experiments (Step 5). This workflow is a template for realizing an integrated science curriculum, as described and assessed by the Interdisciplinary Learning Consortium [<a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.2003145#pbio.2003145.ref009" target="_blank">9</a>]. PCP, peptidyl carrier protein.</p

In a semester of Biochemistry Superlab, students investigated the protein–protein interactions involved in the β-hydroxylation of the natural product skyllamycin.

<p>The skyllamycin peptide is constructed by <i>Streptomyces</i> bacteria via a NRPS involving 11 biosynthetic modules (“M”), composed of catalytic domains such as the A, PCP, and C domains. The <i>in trans</i> cytochrome P450 (P450_sky, orange) interacts with PCP-bound amino acids on modules 5, 7, and 11 to install β-hydroxyl groups (highlighted in orange on the structure of skyllamycin, right). As a class, we tackled the central question: What is the biochemical basis for the selectivity of the interaction of PCP from module 7 with P450_sky to install the hydroxyl group on the L-(OMe)-Tyr (incorporated at the boxed position of skyllamycin)? A, adenylation; C, condensation; NRPS, non-ribosomal peptide synthetase; PCP, peptidyl carrier protein.</p

SV-AUC data collected and analyzed by students to obtain dissociation constants for P450_sky and mutants of P450_sky interacting with inhibitor-bound PCP7_sky (L-imidazoyl-PCP7_sky).

<p>Comparisons of the <i>c(s)</i> distributions are shown for 10 μM P450_sky wild type alone and in complex with 60 μM L-imidazoyl-PCP7_sky L62A, L-imidazoyl-PCP7_sky F66A, and L-imidazoyl-PCP7_sky wild type. A) 280 nm (protein), B) 418 nm (heme). In general, shifts to the right suggest that the reaction boundary favors tighter binding. SV-AUC, sedimentation velocity experiments with an analytical ultracentrifuge.</p