Building Strong for Tomorrow: Recommendations for the Organizational Design of the NOAA Climate Service

The U.S. Congress asked an expert panel of the National Academy of Public Administration to assist NOAA with a study and analysis of organizational options for a Climate Service within NOAA. Further, NOAA formally asked the Panel to provide an independent assessment of how NOAA should organize its climate capabilities and make recommendations for a Climate Service line office structure that would integrate NOAA's climate science and research with service delivery.Main FindingsThe Panel strongly supports the creation of a Climate Service to be established as a line office within NOAA.The Panel concluded that a NOAA Climate Service, properly configured and implemented, would be uniquely qualified to serve the public and private sectors as a lead federal agency for climate research and services, and to provide an ongoing accessible, authoritative clearinghouse for all federal science and services related to climate.The report also includes the Panel's observations and recommendations regarding the larger federal climate enterprise, key elements of support needed by the NOAA Climate Service and the importance to the new organization of a clear strategic plan and a comprehensive implementation plan. Additionally, the Panel offered observations about institutional change management in the federal sector, identified several management recommendations for implementation and addressed operational priorities and budget challenges

Heteroplasmic mitochondrial DNA mutations in frontotemporal lobar degeneration.

Frontotemporal lobar degeneration (FTLD) is a common cause of young onset dementia and is characterised by focal neuropathology. The reasons for the regional neuronal vulnerability are not known. Mitochondrial mechanisms have been implicated in the pathogenesis of FTLD, raising the possibility that frontotemporal regional mutations of mitochondrial DNA (mtDNA) are contributory causes. Here we applied dual sequencing of the entire mtDNA at high depth to identify high-fidelity single nucleotide variants (mtSNVs) and mtDNA rearrangements in post mortem brain tissue of people affected by FTLD and age-matched controls. Both mtSNVs and mtDNA rearrangements were elevated in the temporal lobe, with the greatest burden seen in FTLD. mtSNVs found in multiple brain regions also reached a higher heteroplasmy levels in the temporal lobe. The temporal lobe of people with FTLD had a higher burden of ribosomal gene variants predicted to affect intra-mitochondrial protein synthesis, and a higher proportion of missense variants in genes coding for respiratory chain subunits. In conclusion, heteroplasmic mtDNA variants predicted to affect oxidative phosphorylation are enriched in FTLD temporal lobe, and thus may contribute to the regional vulnerability in pathogenesis

High-Depth PRNP Sequencing in Brains With Sporadic Creutzfeldt-Jakob Disease.

BACKGROUND AND OBJECTIVES: Sporadic Creutzfeldt-Jakob disease (sCJD) has established genetic risk factors, but, in contrast to genetic and acquired CJD, the initial trigger for misfolded prion aggregation and spread is not known. In this study, we tested the hypotheses that pathologic somatic variants in the prion gene PRNP are increased in sCJD, potentially leading to the seeding of misfolded prion protein. METHODS: High-depth amplicon-based short read sequencing of the PRNP coding region was performed on postmortem brain tissue from patients with a clinical and neuropathologic diagnosis of sCJD (n = 142), Alzheimer disease (AD) (n = 51) and controls with no clinical or neuropathologic diagnosis of a neurodegenerative disease (n = 71). Each DNA sample was sequenced twice, including independent PCR amplification, library preparation, and sequencing. We used RePlow to call somatic variants with high sensitivity and specificity and optimal sequence kernel association test to compare variant burden between groups. RESULTS: Two sCJD cases had somatic (variant allele frequency 0.5-1%) PRNP variants not previously identified, but with high in silico predicated pathogenicity. However, the pathogenicity of these variants is uncertain, as both located in the octapeptide repeat region where no point variations have previously been associated with sCJD. There was no overall difference in burden somatic PRNP in sCJD compared with controls and a lower burden compared with Alzheimer disease. DISCUSSION: Somatic variants in PRNP are unlikely to play a major role in sCJD but may contribute to the disease mechanism in a minority of cases

High-Depth PRNP Sequencing in Brains With Sporadic Creutzfeldt-Jakob Disease.

BACKGROUND AND OBJECTIVES: Sporadic Creutzfeldt-Jakob disease (sCJD) has established genetic risk factors, but, in contrast to genetic and acquired CJD, the initial trigger for misfolded prion aggregation and spread is not known. In this study, we tested the hypotheses that pathologic somatic variants in the prion gene PRNP are increased in sCJD, potentially leading to the seeding of misfolded prion protein. METHODS: High-depth amplicon-based short read sequencing of the PRNP coding region was performed on postmortem brain tissue from patients with a clinical and neuropathologic diagnosis of sCJD (n = 142), Alzheimer disease (AD) (n = 51) and controls with no clinical or neuropathologic diagnosis of a neurodegenerative disease (n = 71). Each DNA sample was sequenced twice, including independent PCR amplification, library preparation, and sequencing. We used RePlow to call somatic variants with high sensitivity and specificity and optimal sequence kernel association test to compare variant burden between groups. RESULTS: Two sCJD cases had somatic (variant allele frequency 0.5-1%) PRNP variants not previously identified, but with high in silico predicated pathogenicity. However, the pathogenicity of these variants is uncertain, as both located in the octapeptide repeat region where no point variations have previously been associated with sCJD. There was no overall difference in burden somatic PRNP in sCJD compared with controls and a lower burden compared with Alzheimer disease. DISCUSSION: Somatic variants in PRNP are unlikely to play a major role in sCJD but may contribute to the disease mechanism in a minority of cases

A System for Resilience Learning: Developing a Community-Driven, Multi-Sector Research Approach for Greater Preparedness and Resilience to Long-Term Climate Stressors and Extreme Events in the Miami Metropolitan Region

There is a growing need for integrated approaches that align community priorities with strategies that build resilience to climate hazards, societal shocks, and economic crises to ensure more equitable and sustainable outcomes. We anticipate that adaptive management and resilience learning are central elements for these approaches. In this paper, we describe an approach to build and test a Resilience Learning System to support research and implementation of a resilience strategy developed for the Greater Miami and the Beaches or the Resilient305 Strategy. Elements foundational to the design of this integrated research strategy and replicable Resilience Learning System are: (1) strong partnerships among community members, government and non-government organization leaders, and researchers from multiple academic institutions; (2) contributions of subject matter expertise and local knowledge to identify information and translational gaps, formulate metrics and evaluate outcomes of Resilient305 Strategy actions from the community perspective; and (3) a comprehensive understanding of civic engagement activities, technological tools, and resilience-building capacities, including policy and financial innovations, from which to advance socio-technological, smart and connected regional-to-hyperlocal community translation through co-design/co-production. Initial results on co-produced metrics are provided. This work produces a new, replicable framework for resilience research that includes a comprehensive set of metrics, translation to communities through structured dialogues, a collaborative process involving all stakeholders and researchers, and evaluation of resilience actions to inform new investments and improve understanding and effectiveness over time

Evaluation of the fullerene compound DF-1 as a radiation protector

<p>Abstract</p> <p>Background</p> <p>Fullerene compounds are known to possess antioxidant properties, a common property of chemical radioprotectors. DF-1 is a dendrofullerene nanoparticle with antioxidant properties previously found to be radioprotective in a zebrafish model. The purpose of this study was to evaluate the radioprotective effects of DF-1 in a murine model of lethal total body irradiation and to assess for selective radioprotection of normal cells versus tumor cells.</p> <p>Methods</p> <p><it>In vitro </it>radioresponse was evaluated with clonogenic assays with human tumor cells and fibroblast lines in the presence of varying concentrations of DF-1 or vehicle. DNA double strand break induction and repair was evaluated with immunocytochemistry for γH2AX. Lethal total body irradiation was delivered with 137Cs after intraperitoneal delivery of DF-1 or vehicle control. Bone marrow hypoxia was evaluated with piminidazole uptake assessed by flow cytometry.</p> <p>Results</p> <p>DF-1 provided modest radioprotection of human cancer cell lines and fibroblast cell lines when delivered prior to irradiation (dose modifying factor or 1.1). There was no evidence of selective protection of fibroblasts versus tumor cells. Cells treated with DF-1 at radioprotective doses were found to have fewer γH2AX foci at 1 and 6 hours after irradiation compared to vehicle treated controls. The LD50/30 for C57Bl6/Ncr mice treated with a single 300 mg/kg dose of DF-1 pre-irradiation was 10.09 Gy (95% CI 9.58-10.26) versus 8.29 Gy (95% CI, 8.21-8.32) for control mice. No protective effects were seen with a single 200 mg/kg dose. No increase in pimonidazole uptake was appreciated in bone marrow of mice treated with DF-1 compared to vehicle controls.</p> <p>Conclusions</p> <p>DF-1 has modest activity as a radiation protector <it>in vivo</it>. There was no evidence of selective protection from irradiation of normal versus tumor cells with DF-1.</p