Virology under the microscope—a call for rational discourse

Viruses have brought humanity many challenges: respiratory infection, cancer, neurological impairment and immunosuppression to name a few. Virology research over the last 60+ years has responded to reduce this disease burden with vaccines and antivirals. Despite this long history, the COVID-19 pandemic has brought unprecedented attention to the field of virology. Some of this attention is focused on concern about the safe conduct of research with human pathogens. A small but vocal group of individuals has seized upon these concerns – conflating legitimate questions about safely conducting virus-related research with uncertainties over the origins of SARS-CoV-2. The result has fueled public confusion and, in many instances, ill-informed condemnation of virology. With this article, we seek to promote a return to rational discourse. We explain the use of gain-of-function approaches in science, discuss the possible origins of SARS-CoV-2 and outline current regulatory structures that provide oversight for virological research in the United States. By offering our expertise, we – a broad group of working virologists – seek to aid policy makers in navigating these controversial issues. Balanced, evidence-based discourse is essential to addressing public concern while maintaining and expanding much-needed research in virology

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Final Report for ''Client Server Software for the National Transport Code Collaboration''

OAK-B135 Tech-X Corporation designed and developed all the networking code tying together the NTCC data server with the data client and the physics server with the data server and physics client. We were also solely responsible for the data and physics clients and the vast majority of the work on the data server. We also performed a number of other tasks

Risk Informed Assessment of Regulatory and Design Requirements for Future Nuclear Power Plants (Cooperative Agreement DE-FC03-99SF21902, Am. M004) Final Technical Report

OAK-B135 Research under this project addresses the barriers to long term use of nuclear-generated electricity in the United States. It was agreed that a very basic and significant change to the current method of design and regulation was needed. That is, it was believed that the cost reduction goal could not be met by fixing the current system (i.e., an evolutionary approach) and a new, more advanced approach for this project would be needed. It is believed that a completely new design and regulatory process would have to be developed--a ''clean sheet of paper'' approach. This new approach would start with risk-based methods, would establish probabilistic design criteria, and would implement defense-in-depth only when necessary (1) to meet public policy issues (e.g., use of a containment building no matter how low the probability of a large release is) and (2) to address uncertainties in probabilistic methods and equipment performance. This new approach is significantly different from the Nuclear Regulatory Commission's (NRC) current risk-informed program for operating plants. For our new approach, risk-based methods are the primary means for assuring plant safety, whereas in the NRC's current approach, defense-in-depth remains the primary means of assuring safety. The primary accomplishments in the first year--Phase 1 were (1) the establishment of a new, highly risk-informed design and regulatory framework, (2) the establishment of the preliminary version of the new, highly risk-informed design process, (3) core damage frequency predictions showing that, based on new, lower pipe rupture probabilities, the design of the emergency core cooling system equipment can be simplified without reducing plant safety, and (4) the initial development of methods for including uncertainties in a new integrated structures-systems design model. Under the new regulatory framework, options for the use of ''design basis accidents'' were evaluated. It is expected that design basis accidents would be an inherent part of the Probabilistic Safety Assessment for the plant and their evaluation would be probabilistic. Other first year accomplishments include (1) the conversion of an NRC database for cross-referencing NRC criteria and industry codes and standards to Microsoft 2000 software, (2) an assessment of the NRC's hearing process which concluded that the normal cross-examination during public hearings is not actually required by the U.S. Administrative Procedures Act, (3) the identification and listing of reliability data sources, and (4) interfacing with other industry groups (e.g., NEI and IAEA) and NRC at workshops for risk-informing regulations. The major accomplishments during the second year consisted of (1) issuance of the final report for Subtask 1.1, ''Identify Current Applicable Regulatory Requirements [and Industry Standards],'' (2) issuance of the final report for Subtask 1.2,'' Identify Structures, Systems, and Components and Their Associate d Costs for a Typical Plant,'' (3) extension of the new, highly risk-informed design and regulatory framework to non-light-water-reactor technology, (4) completion of more detailed thermal-hydraulic and probabilistic analyses of advanced conceptual reactor system/component designs, (6) initial evaluation and recommendations for improvement of the NRC design review process, and (7) initial development of the software format, procedures and statistical routines needed to store, analyze and retrieve the available reliability data. Final reports for Subtasks 1.1 (regulatory and design criteria) and 1.2 (costs for structures, systems, and components) were prepared and issued. A final report for Subtask 1.3 (Regulatory Framework) was drafted with the aim to issue it in Phase 3 (Year 3). One technical report was produced for Subtask 1.4 (methods development) and two technical reports were produced for Subtask 1.6 (sample problem analysis). An interim report on the NRC design review process (Subtask 1.7) was prepared and issued. Finally, a report on Subtask 2.2 (database weaknesses) addressed the initial development of a new database to track reliability data. During the third and final year (Phase 3), work was completed on Subtasks 1.3 (regulatory framework), 1.6 (sample problem analysis), Subtask 1.7 (regulatory analysis), Subtask 1.8 (industry and NRC coordination), and Subtask 2.3 (reliability data improvements)

£5.34

A register of £5.34 might read Georgian settle, Ridley Road Market, Dorset Stone and English Oak, bar snack, remedial inflatables and advancements in vision, David Byrne’s oversized wardrobe and small change. The entries could be scratched and an alternative inventory listed; last few moments of a solitary drinking session, transportation crates of Ghanaian yams, repeated gestures of well being, homely nights in public houses, time ordered health, heroes of our youth and the disused mine. Please settle on the settle

Sensitivity to Fas-mediated apoptosis is determined below receptor level in human vascular smooth muscle cells

Abstract —Despite Fas expression, many cells resist Fas-induced apoptosis. Although differences in surface Fas expression can explain Fas resistance, multiple proteins below receptor level also inhibit Fas-induced apoptosis. To examine the mechanism of Fas resistance, we studied Fas-induced apoptosis in human medial vascular smooth muscle cells (VSMCs) from healthy coronary arteries. VSMCs showed marked heterogeneity to Fas-induced apoptosis, exhibiting both Fas-resistant (98.1±2.3% viable, n=4, P =NS) and Fas-sensitive (31.3±2.6% viable, n=3, P &lt;0.01) cells. Fas-resistant VSMCs expressed surface Fas and could recruit RIP, indicating that functional receptor complexes were formed. However, Fas-resistant cells showed reduced expression of FADD, Fas ligand, and caspases 3, 7, and 8 and increased expression of FLIP and c-IAP-1. Fas-induced apoptosis was associated with cleavage of caspase 3 and blocked by inhibitors of caspase 3 or 8 but not caspase 1, 6, or 7. Selective inhibition of caspase 3 or 8 by antisense transfection inhibited Fas-induced apoptosis, but their reexpression could not rescue the Fas-resistant phenotype. In vivo, medial VSMCs showed marked heterogeneity of expression of caspase 3. We conclude that Fas sensitivity is determined not only by expression of surface Fas but by differential expression of Fas-signaling proteins below receptor level. Subpopulations of cells within the same tissue have different sensitivities to apoptosis, determined by expression of specific death-signaling proteins. </jats:p