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We present Global.health, a scalable online platform for collecting high-dimensional epidemiological data and transforming those data into a consistent schema to enable distributed analyses. Global.health was originally developed to handle the demands of high-volume, accurate collection of epidemiological line list data in the early months of the COVID-19 pandemic. It has since proven amenable to rapid adjustment as collection of new variables became relevant, for example tracking variants of concern and vaccination status in COVID-19 cases, as well as clinical data. The Global.health platform is based on a microservices architecture deployed to the cloud. We discuss this architecture and the choices that motivated it, as well as the steps needed for an independent group to run their own copy of Global.health in their local environments. We describe the data governance challenges related to providing appropriate privacy to people in multiple jurisdictions while fulfilling the project’s goal to enable open data sharing and rapid science during health emergencies.

Overstating the impact of interventions through incomplete or inaccurate reporting can lead to inappropriate scale-up of interventions with low impact. Accurate reporting of the impact of interventions is of great importance in global health research to protect scarce resources. In global health, the cluster randomised trial design is commonly used to evaluate complex, multicomponent interventions, and outcomes are often binary. Complete reporting of impact for binary outcomes means reporting both relative and absolute measures. We did a systematic review to assess reporting practices and potential to overstate impact in contemporary cluster randomised trials with binary primary outcome. We included all reports registered in the Cochrane Central Register of Controlled Trials of two-arm parallel cluster randomised trials with at least one binary primary outcome that were published in 2017. Of 73 cluster randomised trials, most (60 [82%]) showed incomplete reporting. Of 64 cluster randomised trials for which it was possible to evaluate, most (40 [63%]) reported results in such a way that impact could be overstated. Care is needed to report complete evidence of impact for the many interventions evaluated using the cluster randomised trial design worldwide.

Reported herein is the use of chiral cationic polyamines for two intriguing applications: fabrication of chiral covalently-linked microcapsules, and enantiospecific delivery of siRNA to Huh 7 cells. The microcapsules are easily fabricated from homochiral polymers, and the resulting architectures can be used for supramolecular chiral catalysis and many other potential applications. Enantiospecific delivery of siRNA to Huh 7 cells is seen by one ‘enantiomer’ of the polymers delivering siRNA with significantly improved transfection efficiency and reduced toxicity compared to the ‘enantiomeric’ polymer and commercially available transfection reagents. Taken together, the use of these easily accessible polyamine structures for diverse applications is highlighted in this Letter herein and can lead to numerous future research efforts.

SummaryAlthough transcriptional regulation of stem cell pluripotency and differentiation has been extensively studied, only a small number of studies have addressed the roles for posttranslational modifications in these processes. A key mechanism of posttranslational modification is ubiquitination by the ubiquitin-proteasome system (UPS). Here, using shotgun proteomics, we map the ubiquitinated protein landscape during embryonic stem cell (ESC) differentiation and induced pluripotency. Moreover, using UPS-targeted RNAi screens, we identify additional regulators of pluripotency and differentiation. We focus on two of these proteins, the deubiquitinating enzyme Psmd14 and the E3 ligase Fbxw7, and characterize their importance in ESC pluripotency and cellular reprogramming. This global characterization of the UPS as a key regulator of stem cell pluripotency opens the way for future studies that focus on specific UPS enzymes or ubiquitinated substrates.

Hematopoietic stem cells (HSCs) residing in the bone marrow generate mature blood cells throughout the life of the organism. This is accomplished by careful regulation of HSC activity to balance quiescence, self-renewal and differentiation. Studies of the molecular mechanisms governing HSC maintenance have mostly focused on the role of signaling and transcriptional processes. However, it has recently been demonstrated that protein regulation via the ubiquitin proteasome system (UPS) is crucial for normal HSC function; the loss of which can lead to transformation and leukemogenesis. The effective use of a general and reversible inhibitor of the UPS, bortezomib, in treating mantle cell lymphoma and multiple myeloma has demonstrated that targeting the UPS has therapeutic potential. Thus, understanding the emerging field of how the UPS regulates HSC activity may lead to novel targets for therapy of leukemia.

SummarySomatic loss-of-function mutations in the ten-eleven translocation 2 (TET2) gene occur in a significant proportion of patients with myeloid malignancies. Although there are extensive genetic data implicating TET2 mutations in myeloid transformation, the consequences of Tet2 loss in hematopoietic development have not been delineated. We report here an animal model of conditional Tet2 loss in the hematopoietic compartment that leads to increased stem cell self-renewal in vivo as assessed by competitive transplant assays. Tet2 loss leads to a progressive enlargement of the hematopoietic stem cell compartment and eventual myeloproliferation in vivo, including splenomegaly, monocytosis, and extramedullary hematopoiesis. In addition, Tet2+/− mice also displayed increased stem cell self-renewal and extramedullary hematopoiesis, suggesting that Tet2 haploinsufficiency contributes to hematopoietic transformation in vivo.

Hematopoietic stem cells (HSCs) are dormant in the bone marrow and can be activated in response to diverse stresses to replenish all blood cell types. We identified the ubiquitin ligase Huwe1 as a crucial regulator of HSC function via its post-translational control of the oncoprotein N-myc (encoded by Mycn). We found Huwe1 to be essential for HSC self-renewal, quiescence and lymphoid-fate specification in mice. Through the use of a fluorescent fusion allele (MycnM), we observed that N-myc expression was restricted to the most immature, multipotent stem and progenitor populations. N-myc expression was upregulated in response to stress or following loss of Huwe1, which led to increased proliferation and stem-cell exhaustion. Mycn depletion reversed most of these phenotypes in vivo, which suggested that the attenuation of N-myc by Huwe1 is essential for reestablishing homeostasis following stress.

Purpose: The silencing of gene expression through DNA methylation contributes to defects in antigen presentation and apoptosis in melanoma and renal cell cancer. To determine how a hypomethylating agent would modulate the toxicity and antitumor activity of immunotherapy, we initiated a phase I trial of 5-aza-2′-deoxycytidine (decitabine) plus high-dose interleukin 2 (IL-2).Experimental Design: Patients received s.c. decitabine daily × 5 days on weeks 1 and 2 of a 12-week cycle. High-dose IL-2, consisting of two cycles of IL-2 600,000 IU/kg i.v. q8 hours × 14 doses separated by a 2-week break, was administered starting on week 3. Decitabine was escalated from 0.1 to 0.25 mg/kg. The hypomethylating activity of decitabine was assessed during cycle 1 by measuring hemoglobin F levels and changes in DNA methylation in peripheral blood mononuclear cells.Results: Twenty-one patients with melanoma or renal cell cancer were enrolled. Decitabine did not alter the tolerability of IL-2 but caused grade 4 neutropenia in most patients. Grade 4 neutropenia lasting more than 7 days was the only dose-limiting toxicity, with a trend toward a higher incidence with increasing decitabine doses. Infection occurred in only one patient despite the high incidence of neutropenia, and granulocyte colony-stimulating factor use in several patients expedited neutrophil recovery. Decitabine augmented hemoglobin F levels and altered DNA methylation and gene expression in peripheral blood mononuclear cells in a dose-independent manner that overlapped with the administration of IL-2. Objective responses occurred in 31% of melanoma patients.Conclusions: Decitabine can be safely administered with high-dose IL-2 and may enhance the activity of IL-2 in melanoma.

We have utilized a computational structure-based approach to identify nonpeptidic small organic compounds that bind to a human leukocyte antigen (HLA) DR1301 molecule (HLA-DR1301 or DR1301) and block the presentation of myelin basic protein peptide 152-165 (MBP 152-165) to T cells. A three-dimensional (3D) structure of DR1301 was derived by homology modeling followed by extensive molecular dynamics simulation for structural refinement. Computational structure-based database searching was performed to identify nonpeptidic small-molecule candidates from the National Cancer Institute (NCI) database containing over 150 000 compounds that can effectively interact with the peptide-binding groove of the HLA molecule. By in vitro testing of 106 candidate small molecules, two lead compounds were confirmed to specifically block IL-2 secretion by DR1301-restricted T cells in a dose-dependent and reversible manner. The specificity of blocking DR1301-restricted MBP presentation was further validated in a binding assay using an analogue of the most potent lead compound. Computational docking was performed to predict the three-dimensional binding model of these confirmed small molecule blockers to the DR1301 molecule and to gain structural insight into their interactions. Our results suggest that computational structure-based searching is an effective approach to discover nonpeptidic small organic compounds to block the interaction between DR1301 and T cells. The nonpeptidic small organic compounds identified in this study are useful pharmacological tools to study the interactions between HLA molecules and T cells and a starting point for the development of a novel therapeutic strategy for the treatment of multiple sclerosis (MS) or other immune-related disorders.

Developing effective data-driven algorithms and visualizations for disease surveillance hinges on the ability to provide application developers with realistic data. However, the sensitivity of the data creates a barrier to its distribution. We have created a tool that assists data providers with de-identifying their data in preparation for sharing. The functions in the tool help data providers comply with the HIPAA "Safe Harbor" de-identification standard [1] by removing or obscuring information such as names, geographic locations, and identifying numbers.

Humans are fragile beings easily influenced by the verbal behaviors of others. Spoken words can have a multitude of effects on an individual, and the phrases and statements teachers use in their classrooms on a daily basis have the potential to be either detrimental or inspirational. As increasing numbers of students arrive at schools from broken families, possessing poor nutritional habits and debilitating health concerns, and experiencing greater exposure to violence in the media and within their communities, educators need to be keenly aware of the impact their verbal behaviors have on children. Teachers need to be mindful of the words they choose to speak when attempting to elevate each child’s self-worth. In addition to the external factors affecting children that erect hurdles for teachers to overcome, continuously changing educational policy creates additional obstacles for teachers attempting to increase student achievement. New state and federal mandates force teachers to make changes to instructional practice and assessment with the start of each new school year. Recent legislation in Ohio requiring students to be retained who fall below a specific score on the Grade Three Reading Ohio Achievement Assessment has caused students to become increasingly more sensitive to verbal teacher feedback and in some cases resulted in a loss of overall self-esteem due to fears of failure. Words are impactful; therefore, educators hoping to increase academic achievement in literacy skills development as a means to prevent possible student retention need to study the verbal behaviors of effective reading teachers. This paper will argue that teachers’ intentional preplanning of verbal word choice can increase students’ reading achievement. Additionally the paper will synthesize the relevance, content, and impact of current literature on the topic of verbal practices of effective reading teachers and provide recommendations for practical implications for successful reading instruction in the regular elementary classroom setting.

Access to the internet advances many facets of life including education, economic development, and health care quality. Africa is the least connected region in the world. As of 2008, only 5 percent of its population has access to the internet. IMAGINE Africa (IMplementing A Global Internet NEtwork) is a system design study for providing access to these unconnected areas. This system consists of geostationary assets along with easily deployed ground stations to quickly and efficiently provide internet access to the rural population of Africa. In addition to being cost effective, it is also implementable today. This paper provides a description of a roll-out plan for internet access, the system architecture, and the design of an easily deployable ground station.

A risk-based decision-making process conceived of and developed at JPL and NASA, has been used to help plan and guide novel technology applications for use on spacecraft. These applications exemplify key challenges inherent in multidisciplinary design of novel technologies deployed in mission-critical settings: 1) Cross-disciplinary concerns are numerous (e.g., spacecraft involve navigation, propulsion, telecommunications). These concerns are cross-coupled and interact in multiple ways (e.g., electromagnetic interference, heat transfer). 2) Time and budget pressures constrain development, operational resources constrain the resulting system (e.g., mass, volume, power). 3) Spacecraft are critical systems that must operate correctly the first time in only partially understood environments, with no chance for repair. 4) Past experience provides only a partial guide: New mission concepts are enhanced and enabled by new technologies, for which past experience is lacking. The decision-making process rests on quantitative assessments of the relationships between three classes of information-objectives (the things the system is to accomplish and constraints on its operation and development), risks (whose occurrence detracts from objectives), and mitigations (options for reducing the likelihood and/or severity of risks). The process successfully guides experts to pool their knowledge, using custom-built software to support information gathering and decision-making.