Data Harmonization for a Molecularly Driven Health System.

Data commons have emerged as the best current method for enabling data aggregation across multiple projects and multiple data sources. Good data harmonization techniques are critical to maintain quality of data within a data commons, as well as to allow future meta-analysis across different data commons. We present some of the current best practices for data harmonization.

Getting Data Sharing Right to Help Fulfill the Promise of Cancer Genomics.

Limited access to the profusion of sequence information derived from cancer patients worldwide stymies basic research and clinical decisions. Efforts are underway to streamline and safeguard data use.

Human SRMAtlas: A Resource of Targeted Assays to Quantify the Complete Human Proteome.

The ability to reliably and reproducibly measure any protein of the human proteome in any tissue or cell type would be transformative for understanding systems-level properties as well as specific pathways in physiology and disease. Here, we describe the generation and verification of a compendium of highly specific assays that enable quantification of 99.7% of the 20,277 annotated human proteins by the widely accessible, sensitive, and robust targeted mass spectrometric method selected reaction monitoring, SRM. This human SRMAtlas provides definitive coordinates that conclusively identify the respective peptide in biological samples. We report data on 166,174 proteotypic peptides providing multiple, independent assays to quantify any human protein and numerous spliced variants, non-synonymous mutations, and post-translational modifications. The data are freely accessible as a resource at http://www.srmatlas.org/, and we demonstrate its utility by examining the network response to inhibition of cholesterol synthesis in liver cells and to docetaxel in prostate cancer lines.

Meet the authors: Katalin Karikó and Drew Weissman.

We talk to first and last authors Katalin Karikó and Drew Weissman about their seminal 2005 paper ''Suppression of RNA recognition by Toll-like receptors: the impact of nucleoside modification and the evolutionary origin of RNA", about how they see the work in retrospect, the current progress in the field, and their inspiration-then and now.

A genomic mutational constraint map using variation in 76,156 human genomes.

The depletion of disruptive variation caused by purifying natural selection (constraint) has been widely used to investigate protein-coding genes underlying human disorders1-4, but attempts to assess constraint for non-protein-coding regions have proved more difficult. Here we aggregate, process and release a dataset of 76,156 human genomes from the Genome Aggregation Database (gnomAD)-the largest public open-access human genome allele frequency reference dataset-and use it to build a genomic constraint map for the whole genome (genomic non-coding constraint of haploinsufficient variation (Gnocchi)). We present a refined mutational model that incorporates local sequence context and regional genomic features to detect depletions of variation. As expected, the average constraint for protein-coding sequences is stronger than that for non-coding regions. Within the non-coding genome, constrained regions are enriched for known regulatory elements and variants that are implicated in complex human diseases and traits, facilitating the triangulation of biological annotation, disease association and natural selection to non-coding DNA analysis. More constrained regulatory elements tend to regulate more constrained protein-coding genes, which in turn suggests that non-coding constraint can aid the identification of constrained genes that are as yet unrecognized by current gene constraint metrics. We demonstrate that this genome-wide constraint map improves the identification and interpretation of functional human genetic variation.

Genomic data in the All of Us Research Program.

Comprehensively mapping the genetic basis of human disease across diverse individuals is a long-standing goal for the field of human genetics1-4. The All of Us Research Program is a longitudinal cohort study aiming to enrol a diverse group of at least one million individuals across the USA to accelerate biomedical research and improve human health5,6. Here we describe the programme's genomics data release of 245,388 clinical-grade genome sequences. This resource is unique in its diversity as 77% of participants are from communities that are historically under-represented in biomedical research and 46% are individuals from under-represented racial and ethnic minorities. All of Us identified more than 1 billion genetic variants, including more than 275 million previously unreported genetic variants, more than 3.9 million of which had coding consequences. Leveraging linkage between genomic data and the longitudinal electronic health record, we evaluated 3,724 genetic variants associated with 117 diseases and found high replication rates across both participants of European ancestry and participants of African ancestry. Summary-level data are publicly available, and individual-level data can be accessed by researchers through the All of Us Researcher Workbench using a unique data passport model with a median time from initial researcher registration to data access of 29 hours. We anticipate that this diverse dataset will advance the promise of genomic medicine for all.

Rights, interests and expectations: Indigenous perspectives on unrestricted access to genomic data.

Addressing Indigenous rights and interests in genetic resources has become increasingly challenging in an open science environment that promotes unrestricted access to genomic data. Although Indigenous experiences with genetic research have been shaped by a series of negative interactions, there is increasing recognition that equitable benefits can only be realized through greater participation of Indigenous communities. Issues of trust, accountability and equity underpin Indigenous critiques of genetic research and the sharing of genomic data. This Perspectives article highlights identified issues for Indigenous communities around the sharing of genomic data and suggests principles and actions that genomic researchers can adopt to recognize community rights and interests in data.

An open-source drug discovery platform enables ultra-large virtual screens.

On average, an approved drug currently costs US$2-3 billion and takes more than 10 years to develop1. In part, this is due to expensive and time-consuming wet-laboratory experiments, poor initial hit compounds and the high attrition rates in the (pre-)clinical phases. Structure-based virtual screening has the potential to mitigate these problems. With structure-based virtual screening, the quality of the hits improves with the number of compounds screened2. However, despite the fact that large databases of compounds exist, the ability to carry out large-scale structure-based virtual screening on computer clusters in an accessible, efficient and flexible manner has remained difficult. Here we describe VirtualFlow, a highly automated and versatile open-source platform with perfect scaling behaviour that is able to prepare and efficiently screen ultra-large libraries of compounds. VirtualFlow is able to use a variety of the most powerful docking programs. Using VirtualFlow, we prepared one of the largest and freely available ready-to-dock ligand libraries, with more than 1.4 billion commercially available molecules. To demonstrate the power of VirtualFlow, we screened more than 1 billion compounds and identified a set of structurally diverse molecules that bind to KEAP1 with submicromolar affinity. One of the lead inhibitors (iKeap1) engages KEAP1 with nanomolar affinity (dissociation constant (Kd) = 114 nM) and disrupts the interaction between KEAP1 and the transcription factor NRF2. This illustrates the potential of VirtualFlow to access vast regions of the chemical space and identify molecules that bind with high affinity to target proteins.

Publishing in the Open Access and Open Science era.

Our research activities would be better served if they were communicated in a manner that is openly accessible to the public and all researchers. The research we share is often limited to representative data included in research papers-science would be much more efficient if all reproducible research data were shared alongside detailed methods and protocols, in the paradigm called Open Science. On the other hand, one primary function of research journals is to select manuscripts of good quality, verify the authenticity of the data and its impact, and deliver to the appropriate audience for critical evaluation and verification. In the current paradigm, where publication in a subset of journals is intimately linked to research evaluation, a hypercompetitive "market" has emerged where authors compete to access a limited number of top-tier journals, leading to high rejection rates. Competition among publishers and scientific journals for market dominance resulted in an increase in both the number of journals and the cost of publishing and accessing scientific papers. Here we summarize the current problems and potential solutions from the development of AI technology discussed in the seminar at the 46th Annual Meeting of the Molecular Biology Society of Japan.

Open Access for Open Science.

The EMBO Journal and EMBO Reports join EMBO Molecular Medicine, Molecular Systems Biology and Life Science Alliance as Open Access journals from 2024. Full Open Access at EMBO Press completes another step towards the goal of an integrated Open Science approach for the dissemination of highly selected and curated science.

COVID-19 increased censorship circumvention and access to sensitive topics in China.

Crisis motivates people to track news closely, and this increased engagement can expose individuals to politically sensitive information unrelated to the initial crisis. We use the case of the COVID-19 outbreak in China to examine how crisis affects information seeking in countries that normally exert significant control over access to media. The crisis spurred censorship circumvention and access to international news and political content on websites blocked in China. Once individuals circumvented censorship, they not only received more information about the crisis itself but also accessed unrelated information that the regime has long censored. Using comparisons to democratic and other authoritarian countries also affected by early outbreaks, the findings suggest that people blocked from accessing information most of the time might disproportionately and collectively access that long-hidden information during a crisis. Evaluations resulting from this access, negative or positive for a government, might draw on both current events and censored history.

A Laboratory-Developed Assay for Clade II Human Mpox Virus on the Panther Fusion Open Access System.

This paper describes the methods for developing and optimizing a laboratory-developed assay (LDA) for detecting clade II human mpox virus using the automated Panther Fusion platform and Open Access software. Various concentrations of reagents in a primer-probe mix were tested to optimize the LDA. The LDA was validated using 10 previously characterized positive and 10 negative human mpox samples, resulting in 95% accuracy and 100% precision. The LDA resulted in 100% specificity among previously tested HSV1-, HSV2-, and VZV-positive human samples. Several spiked media extensions were also validated and achieved 98% accuracy and 100% precision across all collection media types. The assay's limit of detection was calculated to be 1.475 copies/reaction, and the polymerase chain reaction efficiency resulted in 89.87% (slope, -3.5911; R2 = 0.9947). The methods described here can be applied to the rapid optimization and development of LDAs for many possible pathogens of public health importance.

Switching between External and Internal Attention in Hippocampal Networks.

Everyday experience requires processing external signals from the world around us and internal information retrieved from memory. To do both, the brain must fluctuate between states that are optimized for external versus internal attention. Here, we focus on the hippocampus as a region that may serve at the interface between these forms of attention and ask how it switches between prioritizing sensory signals from the external world versus internal signals related to memories and thoughts. Pharmacological, computational, and animal studies have identified input from the cholinergic basal forebrain as important for biasing the hippocampus toward processing external information, whereas complementary research suggests the dorsal attention network (DAN) may aid in allocating attentional resources toward accessing internal information. We therefore tested the hypothesis that the basal forebrain and DAN drive the hippocampus toward external and internal attention, respectively. We used data from 29 human participants (17 female) who completed two attention tasks during fMRI. One task (memory-guided) required proportionally more internal attention, and proportionally less external attention, than the other (explicitly instructed). We discovered that background functional connectivity between the basal forebrain and hippocampus was stronger during the explicitly instructed versus memory-guided task. In contrast, DAN-hippocampus background connectivity was stronger during the memory-guided versus explicitly instructed task. Finally, the strength of DAN-hippocampus background connectivity was correlated with performance on the memory-guided but not explicitly instructed task. Together, these results provide evidence that the basal forebrain and DAN may modulate the hippocampus to switch between external and internal attention.SIGNIFICANCE STATEMENT How does the brain balance the need to pay attention to internal thoughts and external sensations? We focused on the human hippocampus, a region that may serve at the interface between internal and external attention, and asked how its functional connectivity varies based on attentional states. The hippocampus was more strongly coupled with the cholinergic basal forebrain when attentional states were guided by the external world rather than retrieved memories. This pattern flipped for functional connectivity between the hippocampus and dorsal attention network, which was higher for attention tasks that were guided by memory rather than external cues. Together, these findings show that distinct networks in the brain may modulate the hippocampus to switch between external and internal attention.

Open Access: A Role for p53 in c9ALS/FTD?

Poly(PR), a toxic dipeptide-repeat protein, translated from the pathogenic G4C2 repeat expansion in C9orf72, contributes to c9 amyotrophic lateral sclerosis/frontotemporal dementia (c9ALS/FTD). However, precisely how poly(PR) elicits neurodegeneration has remained unclear. Maor-Nof et al. now establish that poly(PR) remodels the neuronal epigenome to promote proapoptotic p53 activity involving PUMA, which drives neurodegeneration in several models.

Maximizing Access and Minimizing Barriers to Research in Low- and Middle-Income Countries: Open Access and Health Equity.

Access to published research has always been difficult for researchers and clinicians in low- and middle-income countries, because of the cost of and lack of access to the relevant publications. The dramatic recent increase in electronic research publications has resulted in a marked improvement in reader access to these publications through their mainly Open Access policies, however the costs of processing of submissions and publication have now become the burden of the researchers wishing to publish, rather than the readers. For many researchers working in LMIC, the Article Processing Charges (APC) are prohibitive, hampering the publication of research being conducted in and relevant to these countries. A number of grant funding agencies and international not-for-profit organizations are trying to address these issues by including funding for article publications in their grants, or by supporting publishing entities by subsiding the cost of publication, but more needs to be done by major journal publishers through markedly reducing the APC being charged to researchers in LMIC for open access facilities.

The Association of Metabolic Brain MRI, Amyloid PET, and Clinical Factors: A Study of Alzheimer's Disease and Normal Controls From the Open Access Series of Imaging Studies Dataset.

BACKGROUND: Although brain activities in Alzheimer's disease (AD) might be evaluated MRI and PET, the relationships between brain temperature (BT), the index of diffusivity along the perivascular space (ALPS index), and amyloid deposition in the cerebral cortex are still unclear. PURPOSE: To investigate the relationship between metabolic imaging measurements and clinical information in patients with AD and normal controls (NCs). STUDY TYPE: Retrospective analysis of a prospective dataset. POPULATION: 58 participants (78.3 ± 6.8 years; 30 female): 29 AD patients and 29 age- and sex-matched NCs from the Open Access Series of Imaging Studies dataset. FIELD STRENGTH/SEQUENCE: 3T; T1-weighted magnetization-prepared rapid gradient-echo, diffusion tensor imaging with 64 directions, and dynamic 18 F-florbetapir PET. ASSESSMENT: Imaging metrics were compared between AD and NCs. These included BT calculated by the diffusivity of the lateral ventricles, ALPS index that reflects the glymphatic system, the mean standardized uptake value ratio (SUVR) of amyloid PET in the cerebral cortex and clinical information, such as age, sex, and MMSE. STATISTICAL TESTS: Pearson's or Spearman's correlation and multiple linear regression analyses. P values <0.05 were defined as statistically significant. RESULTS: Significant positive correlations were found between BT and ALPS index (r = 0.44 for NCs), while significant negative correlations were found between age and ALPS index (rs = -0.43 for AD and - 0.47 for NCs). The SUVR of amyloid PET was not significantly associated with BT (P = 0.81 for AD and 0.21 for NCs) or ALPS index (P = 0.10 for AD and 0.52 for NCs). In the multiple regression analysis, age was significantly associated with BT, while age, sex, and presence of AD were significantly associated with the ALPS index. DATA CONCLUSION: Impairment of the glymphatic system measured using MRI was associated with lower BT and aging. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY STAGE: 1.

Racial differences in knowledge, attitudes, and sources of information about germline cancer genetic testing in the U.S.A.: An analysis of the health information National Trends Survey System.

PURPOSE: To understand racial disparities in germline cancer genetic testing and the role of prior knowledge, attitudes, and sources of information. METHODS: A cross-sectional analysis of the Health Information National Trends Survey 5 (HINTS 5) was conducted between February 24th and June 15th, 2020. The study aimed to investigate knowledge and receipt of genetic testing, attitudes toward the importance of genetic testing in preventing, detecting, and treating cancer, and information sources of genetic testing in the United States of America. RESULTS: Non-Hispanic Black (NHB) and Hispanic race/ethnicity were associated with lower odds of being informed about genetic testing, whereas those of NHB race were more likely to endorse the importance of genetic testing in cancer prevention and treatment. Regarding sources of information about genetic testing: Non-Hispanic Asians were less likely to be informed about genetic testing from television (Mean Predicted Probability (MPP) 0.38 95%CI; 0.21-0.55, (Adjusted Risk Difference) ARD vs. Non-Hispanic White (NHW); -0.228, p = 0.01), NHB were less likely to report being informed about genetic testing from social media (MPP 0.27 95%CI; 0.20-0.34, ARD vs. NHW; -0.139, p < 0.01). CONCLUSIONS: NHB and Hispanic groups face unequal access to information about genetic testing. There are significant race-based differences in information sources. These differences could be used to promote equitable access to cancer genetic testing.