Department of Homeland Security Science and Technology Directorate: Developing Technology to Protect America

In response to a congressional mandate and in consultation with Department of Homeland Security's (DHS) Science and Technology Directorate (S&T), the National Academy conducted a review of S&T's effectiveness and efficiency in addressing homeland security needs. This review included a particular focus that identified any unnecessary duplication of effort, and opportunity costs arising from an emphasis on homeland security-related research. Under the direction of the National Academy Panel, the study team reviewed a wide variety of documents related to S&T and homeland security-related research in general. The team also conducted interviews with more than 200 individuals, including S&T officials and staff, officials from other DHS component agencies, other federal agencies engaged in homeland security-related research, and experts from outside government in science policy, homeland security-related research and other scientific fields.Key FindingsThe results of this effort indicated that S&T faces a significant challenge in marshaling the resources of multiple federal agencies to work together to develop a homeland security-related strategic plan for all agencies. Yet the importance of this role should not be underestimated. The very process of working across agencies to develop and align the federal homeland security research enterprise around a forward-focused plan is critical to ensuring that future efforts support a common vision and goals, and that the metrics by which to measure national progress, and make changes as needed, are in place

What Do We Mean by “Transformation”?

What is “defense transformation” (by whatever name), and how might it affect strategy? What might it cost, and how could its cost affect military forces? What systemic impediments to implementation does it face, and what are its competitors in the budgetary realm? A distinguished panel of the Secretary of the Navy’s Current Strategy Forum held at the Naval War College on 12–13 June 2001 addressed these issues from various perspectives

Conference Workshop Proceedings: Developing a Scholarship of Teaching and Learning Portfolio in Applied Horticulture

Preparing faculty to conduct quality teaching is critical to maximize student learning and the educational experience. As increased attention to faculty effectiveness and effect of their teaching program is observed, the more important it becomes for faculty to engage in the scholarship of teaching and learning (SoTL). The workshop “Developing a scholarship of teaching and learning portfolio in applied horticulture” was conducted at the 2022 American Society for Horticultural Science conference in Chicago, IL, USA, and featured a panel of teaching scholars who provided insight and guidance for developing, enhancing, evaluating, and promoting SoTL for both traditional classroom teachers and extension educators

Critical perspectives on ‘consumer involvement’ in health research: epistemological dissonance and the know-do gap

Researchers in the area of health and social care (both in Australia and internationally) are encouraged to involve consumers throughout the research process, often on ethical, political and methodological grounds, or simply as ‘good practice’. This paper presents findings from a qualitative study in the UK of researchers’ experiences and views of consumer involvement in health research. Two main themes are presented in the paper. Firstly, we explore the ‘know-do gap’ which relates to the tensions between researchers’ perceptions of the potential benefits of, and their actual practices in relation to, consumer involvement. Secondly, we focus on one of the reasons for this ‘know-do gap’, namely epistemological dissonance. Findings are linked to issues around consumerism in research, lay/professional knowledges, the (re)production of professional and consumer identities and the maintenance of boundaries between consumers and researchers

Atomic force microscopy study of the growth and annealing of Ge islands on Si(100)

This is the publisher's version, also available electronically from http://scitation.aip.org/content/avs/journal/jvstb/20/2/10.1116/1.1459724.Atomic force microscopy is used to study the growth and annealing of Ge islands on Si(100) by molecular beam epitaxy. The Ge island shape, size distribution, number density, and spatial distribution under various growth conditions, such as different substrate temperatures, Ge beam fluxes, and annealing times, are investigated. By limiting the growth to a low coverage of 6 ML of Ge, we find that either a low growth temperature (⩽875 K) or a high beam flux can produce films dominated by pyramids of {105} facets. Domes of higher aspect ratios only appear at high growth temperatures or after a long time of annealing at low temperatures. This indicates that in the competition between the different kinetic processes responsible for the pyramid and dome formation, the domes require a higher activation energy and grow slower. We also demonstrate that appropriate annealing at low temperature can form locally ordered arrays of pyramids with a narrow size distribution

A framework for evaluating the influence of climate, dispersal limitation, and biotic interactions using fossil pollen associations across the late Quaternary

Environmental conditions, dispersal lags, and interactions among species are major factors structuring communities through time and across space. Ecologists have emphasized the importance of biotic interactions in determining local patterns of species association. In contrast, abiotic limits, dispersal limitation, and historical factors have commonly been invoked to explain community structure patterns at larger spatiotemporal scales, such as the appearance of late Pleistocene no-analog communities or latitudinal gradients of species richness in both modern and fossil assemblages. Quantifying the relative influence of these processes on species co-occurrence patterns is not straightforward. We provide a framework for assessing causes of species associations by combining a null-model analysis of co-occurrence with additional analyses of climatic differences and spatial pattern for pairs of pollen taxa that are significantly associated across geographic space. We tested this framework with data on associations among 106 fossil pollen taxa and paleoclimate simulations from eastern North America across the late Quaternary. The number and proportion of significantly associated taxon pairs increased over time, but only 449 of 56 194 taxon pairs were significantly different from random. Within this significant subset of pollen taxa, biotic interactions were rarely the exclusive cause of associations. Instead, climatic or spatial differences among sites were most frequently associated with significant patterns of taxon association. Most taxon pairs that exhibited co-occurrence patterns indicative of biotic interactions at one time did not exhibit significant associations at other times. Evidence for environmental filtering and dispersal limitation was weakest for aggregated pairs between 16 and 11 kyr BP, suggesting enhanced importance of positive species interactions during this interval. The framework can thus be used to identify species associations that may reflect biotic interactions because these associations are not tied to environmental or spatial differences. Furthermore, temporally repeated analyses of spatial associations can reveal whether such associations persist through time

Informing efficient randomised controlled trials: Exploration of challenges in developing progression criteria for internal pilot studies

Objectives: Designing studies with an internal pilot phase may optimise the use of pilot work to inform more efficient randomised controlled trials (RCTs). Careful selection of preagreed decision or 'progression' criteria at the juncture between the internal pilot and main trial phases provides a valuable opportunity to evaluate the likely success of the main trial and optimise its design or, if necessary, to make the decision not to proceed with the main trial. Guidance on the appropriate selection and application of progression criteria is, however, lacking. This paper outlines the key issues to consider in the optimal development and review of operational progression criteria for RCTs with an internal pilot phase. Design: A structured literature review and exploration of stakeholders' opinions at a Medical Research Council (MRC) Hubs for Trials Methodology Research workshop. Key stakeholders included triallists, methodologists, statisticians and funders. Results: There is considerable variation in the use of progression criteria for RCTs with an internal pilot phase, although 3 common issues predominate: trial recruitment, protocol adherence and outcome data. Detailed and systematic reporting around the decisionmaking process for stopping, amending or proceeding to a main trial is uncommon, which may hamper understanding in the research community about the appropriate and optimal use of RCTs with an internal pilot phase. 10 top tips for the development, use and reporting of progression criteria for internal pilot studies are presented. Conclusions: Systematic and transparent reporting of the design, results and evaluation of internal pilot trials in the literature should be encouraged in order to facilitate understanding in the research community and to inform future trials

Using quantitative single molecule localization microscopy to optimize multivalent HER2-targeting ligands

IntroductionThe progression-free survival of patients with HER2-positive metastatic breast cancer is significantly extended by a combination of two monoclonal antibodies, trastuzumab and pertuzumab, which target independent epitopes of the extracellular domain of HER2. The improved efficacy of the combination over individual antibody therapies targeting HER2 is still being investigated, and several molecular mechanisms may be in play: the combination downregulates HER2, improves antibody-dependent cell mediated cytotoxicity, and/or affects the organization of surface-expressed antigens, which may attenuate downstream signaling.MethodsBy combining protein engineering and quantitative single molecule localization microscopy (qSMLM), here we both assessed and optimized clustering of HER2 in cultured breast cancer cells.ResultsWe detected marked changes to the cellular membrane organization of HER2 when cells were treated with therapeutic antibodies. When we compared untreated samples to four treatment scenarios, we observed the following HER2 membrane features: (1) the monovalent Fab domain of trastuzumab did not significantly affect HER2 clustering; (2) individual therapy with either trastuzumab or (3) pertuzumab produced significantly higher levels of HER2 clustering; (4) a combination of trastuzumab plus pertuzumab produced the highest level of HER2 clustering. To further enhance this last effect, we created multivalent ligands using meditope technology. Treatment with a tetravalent meditope ligand combined with meditope-enabled trastuzumab resulted in pronounced HER2 clustering. Moreover, compared to pertuzumab plus trastuzumab, at early time points this meditope-based combination was more effective at inhibiting epidermal growth factor (EGF) dependent activation of several downstream protein kinases.DiscussionCollectively, mAbs and multivalent ligands can efficiently alter the organization and activation of the HER2 receptors. We expect this approach could be used in the future to develop new therapeutics

ZC4H2, an XLID gene, is required for the generation of a specific subset of CNS interneurons

Miles-Carpenter syndrome (MCS) was described in 1991 as an XLID syndrome with fingertip arches and contractures and mapped to proximal Xq. Patients had microcephaly, short stature, mild spasticity, thoracic scoliosis, hyperextendable MCP joints, rocker-bottom feet, hyperextended elbows and knees. A mutation, p.L66H, in ZC4H2, was identified in a XLID resequencing project. Additional screening of linked families and next generation sequencing of XLID families identified three ZC4H2 mutations: p.R18K, p.R213W and p.V75in15aa. The families shared some relevant clinical features. In silico modeling of the mutant proteins indicated all alterations would destabilize the protein. Knockout mutations in zc4h2 were created in zebrafish and homozygous mutant larvae exhibited abnormal swimming, increased twitching, defective eye movement and pectoral fin contractures. Because several of the behavioral defects were consistent with hyperactivity, we examined the underlying neuronal defects and found that sensory neurons and motoneurons appeared normal. However, we observed a striking reduction in GABAergic interneurons. Analysis of cell-type-specificmarkers showed a specific loss of V2 interneurons in the brain and spinal cord, likely arising from mis-specification of neural progenitors. Injected human wt ZC4H2 rescued the mutant phenotype. Mutant zebrafish injectedwith human p.L66H or p.R213W mRNA failed to be rescued, while the p.R18K mRNA was able to rescue the interneuron defect. Our findings clearly support ZC4H2 as a novel XLID gene with a required function in interneuron development. Loss of function of ZC4H2 thus likely results in altered connectivity ofmany brain and spinal circuits

Genome-wide association and functional studies identify a role for matrix Gla protein in osteoarthritis of the hand

Objective Osteoarthritis (OA) is the most common form of arthritis and the leading cause of disability in the elderly. Of all the joints, genetic predisposition is strongest for OA of the hand; however, only few genetic risk loci for hand OA have been identified. Our aim was to identify novel genes associated with hand OA and examine the underlying mechanism. Methods We performed a genome-wide association study of a quantitative measure of hand OA in 12 784 individuals (discovery: 8743, replication: 4011). Genome-wide significant signals were followed up by analysing gene and allele-specific expression in a RNA sequencing dataset (n=96) of human articular cartilage. Results We found two significantly associated loci in the discovery set: at chr12 (p=3.5 × 10⁻¹⁰) near the matrix Gla protein (MGP) gene and at chr12 (p=6.1×10⁻⁹) near the CCDC91 gene. The DNA variant near the MGP gene was validated in three additional studies, which resulted in a highly significant association between the MGP variant and hand OA (rs4764133, Betameta=0.83, Pmeta=1.8*10⁻¹⁵). This variant is high linkage disequilibrium with a coding variant in MGP, a vitamin K-dependent inhibitor of cartilage calcification. Using RNA sequencing data from human primary cartilage tissue (n=96), we observed that the MGP RNA expression of the hand OA risk allele was significantly lowercompared with the MGP RNA expression of the reference allele (40.7%, p<5*10⁻¹⁶). Conclusions Our results indicate that the association between the MGP variant and increased risk for hand OA is caused by a lower expression of MGP, which may increase the burden of hand OA by decreased inhibition of cartilage calcification