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Allogeneic haematopoietic cell transplants as dynamical systems
No full textObjectives Immune recovery following haematopoietic cell transplantation (HCT) functions as a dynamical system. Reducing the duration of intense immune suppression and augmenting antigen presentation has the potential to optimise T‐cell reconstitution, potentially influencing long‐term outcomes. Methods Based on donor‐derived T‐cell recovery, 26 patients were adaptively randomised between mycophenolate mofetil (MMF) administered for 30‐day post‐transplant with filgrastim for cytokine support (MMF30 arm, N = 11), or MMF given for 15 days with sargramostim (MMF15 arm, N = 15). All patients underwent in vivo T‐cell depletion with 5.1 mg kg −1 antithymocyte globulin (administered over 3 days, Day −9 through to Day −7) and received reduced intensity 450 cGy total body irradiation (3 fractions on Day −1 and Day 0). Patients underwent HLA‐matched related and unrelated donor haematopoietic cell transplantation (HCT). Results Clinical outcomes were equivalent between the two groups. The MMF15 arm demonstrated superior T‐cell, as well as T‐cell subset recovery and a trend towards superior T‐cell receptor (TCR) diversity in the first month with this difference persisting through the first year. T‐cell repertoire recovery was more rapid and sustained, as well as more diverse in the MMF15 arm. Conclusion The long‐term superior immune recovery in the MMF15 arm, administered GMCSF, is consistent with a disproportionate impact of early interventions in HCT. Modifying the \u27immune‐milieu\u27 following allogeneic HCT is feasible and may influence long‐term T‐cell recovery
Catching up with AI: Pushing toward a cohesive governance framework
No full textArtificial Intelligence (AI) contributes to public administration by augmenting public services, including managing big data and information technology. AI is currently utilized in e‐government services that contribute value to American citizens, including providing a personalized customer experience, such as linking individualized data and processing individual assistance requests. Furthermore, AI can take over redundant routine tasks such as digital information provisioning and delivering services. However, in the United States, there is no overarching policy that governs AI. Inconsistent public policy contributes to public distrust of AI, concerns about privacy intrusion, and fears of inequitable service delivery. This review article discusses the rapid emergence of government applications of AI and provides a systematic review of proposed AI governance models. It then outlines their common components for the purpose of building a coherent, yet adaptable, AI Governance Framework and proposes a research agenda for policy and administration researchers. Related Articles Glen, Carol M. 2014. "Internet Governance: Territorializing Cyberspace?" Politics & Policy 42(5): 635–57. https://doi.org/10.1111/polp.12093 . Glen, Carol M. 2021. "Norm Entrepreneurship in Global Cybersecurity." Politics & Policy 49(5): 1121–45. https://doi.org/10.1111/polp.12430 . Zeng, Jinghan, Tim Stevens, and Yaru Chen. 2017. "China\u27s Solution to Global Cyber Governance: Unpacking the Domestic Discourse of \u27Internet Sovereignty.\u27" Politics & Policy 45(3): 432–64. https://doi.org/10.1111/polp.12202 . , Poniéndose al día con la IA: empujando hacia un marco de gobernanza cohesivo La inteligencia artificial (IA) contribuye a la administración pública al aumentar los servicios públicos, incluida la gestión de big data y la tecnología de la información. La IA se utiliza actualmente en servicios de gobierno electrónico que aportan valor a los ciudadanos estadounidenses, lo que incluye brindar una experiencia personalizada al cliente, como vincular datos individualizados y procesar solicitudes de asistencia individuales. Además, la IA puede hacerse cargo de tareas rutinarias redundantes, como el suministro de información digital y la prestación de servicios. Sin embargo, en los Estados Unidos, no existe una política general que rija la IA. La política pública inconsistente contribuye a la desconfianza pública en la IA, las preocupaciones sobre la intrusión en la privacidad y los temores de una prestación de servicios no equitativa. Este artículo de revisión analiza la rápida aparición de aplicaciones gubernamentales de IA y proporciona una revisión sistemática de los modelos de gobernanza de IA propuestos. Luego describe sus componentes comunes con el propósito de construir un Marco de Gobernanza de IA coherente, pero adaptable, y propone una agenda de investigación para investigadores de políticas y administración. , 赶上人工智能:推动具有凝聚力的治理框架 人工智能(AI)通过增强公共服务(包括管理大数据和信息技术)，为公共行政作贡献。人工智能目前用于电子政务服务，后者为美国公民带来价值，包括提供个性化的客户体验，例如链接个性化数据和处理个人援助请求。此外，人工智能可接管冗余的日常任务，例如数字信息供应与交付服务。不过，在治理人工智能方面，美国还没有一个总体政策。不一致的公共政策是导致公众不信任人工智能、担忧隐私侵犯和不公平的服务交付的原因之一。本篇述评探讨了政府应用人工智能一事的迅速兴起，并对人工智能治理模型进行了系统性综述。本文随后概述了这些模型的共同组成部分，以建立一个一致的、具有适应性的人工智能治理框架，并为政策和行政研究人员提出了一项研究议程
Random field calibration with data on irregular grid for regional analyses
No full textMany applications in science and engineering involve data defined at specific geospatial locations, which are often modeled as random fields. The modeling of a proper correlation function is essential for the probabilistic calibration of the random fields, but traditional methods were developed with the assumption to have observations with evenly spaced data. Available methods dealing with irregularly spaced data generally require either interpolation or computationally expensive solutions. Instead, we propose a simple approach based on least square regression to estimate the autocorrelation function. We first tested our methodology on an artificially produced dataset to assess the performance of our method. The accuracy of the method and its robustness to the level of noise in the data indicate that it is suitable for use in realistic problems. In addition, the methodology was used on a major application, the modeling of animal species connected with zoonotic diseases. Understanding the population dynamics of reservoirs of zoonotic diseases, such as bats, is a crucial first step to predict and prevent potential spillover of deadly viruses like Ebola. Due to the limited data on bats across Africa, their density and migrations can only be studied with probabilistic numerical models based on samples of the ecological bare carrying capacity (). For this purpose, the bare carrying capacity was modeled as a random field and its statistics calibrated with the available data. The bare carrying capacity of bats was found to be denser in central Africa. This is because climatic and environmental conditions are more suitable for the survival of bats. The proposed methodology for random field calibration was shown to be a promising approach, which can cope with large gaps in data and with complex applications involving large geographical areas and high resolution
Understanding the molecular mechanisms of odorant binding and activation of the human OR52 family
No full textAbstractStructural and mechanistic studies on human odorant receptors (ORs), key in olfactory signaling, are challenging because of their low surface expression in heterologous cells. The recent structure of OR51E2 bound to propionate provided molecular insight into odorant recognition, but the lack of an inactive OR structure limited understanding of the activation mechanism of ORs upon odorant binding. Here, we determined the cryo-electron microscopy structures of consensus OR52 (OR52cs), a representative of the OR52 family, in the ligand-free (apo) and octanoate-bound states. The apo structure of OR52cs reveals a large opening between transmembrane helices (TMs) 5 and 6. A comparison between the apo and active structures of OR52cs demonstrates the inward and outward movements of the extracellular and intracellular segments of TM6, respectively. These results, combined with molecular dynamics simulations and signaling assays, shed light on the molecular mechanisms of odorant binding and activation of the OR52 family.</jats:p
The Urban Poor and Vulnerable Are Hit Hardest by the Heat: A Heat Equity Lens to Understand Community Perceptions of Climate Change, Urban Heat Islands, and Green Infrastructure
No full textAs the global temperature and rapid urbanization continue to rise, urban heat islands (UHIs) also continue to increase across the world. Following the heat equity concept, UHIs disproportionately impact disadvantaged or overburdened communities. Green infrastructure (GI) has been at the forefront of UHI mitigation efforts, including nature-based solutions like parks, pervious open spaces, wooded areas, green roofs, rain gardens, and shade trees. In this paper, we use a heat equity lens to analyze community perceptions of the intersection of climate change, UHI, and GI in Camden, New Jersey—a post-industrial city with a history of environmental injustices. Based on a mixed-methods analysis of survey responses (n = 107), 11 years of relevant X (formerly Twitter) posts (n = 367), and geospatial data, we present community perceptions of and connections between climate change, UHI, and GI and discuss major themes that emerged from the data: perceived heat inequity in Camden triggers negative emotions; a public knowledge gap exists regarding climate change-UHI-GI connections; and perceived inequitable distribution of GI and certain GI planning and maintenance practices may negatively impact UHI mitigation strategies. We argue these themes are useful to urban planners and relevant professionals while planning for heat equity and mitigating UHI effects in disadvantaged urban communities like Camden.</jats:p
Inverse-Folding Design of Yeast Telomerase RNA Increases Activity In Vitro
No full textSaccharomyces cerevisiae telomerase RNA, TLC1, is an 1157 nt non-coding RNA that functions as both a template for DNA synthesis and a flexible scaffold for telomerase RNP holoenzyme protein subunits. The tractable budding yeast system has provided landmark discoveries about telomere biology in vivo, but yeast telomerase research has been hampered by the fact that the large TLC1 RNA subunit does not support robust telomerase activity in vitro. In contrast, 155–500 nt miniaturized TLC1 alleles comprising the catalytic core domain and lacking the RNA’s long arms do reconstitute robust activity. We hypothesized that full-length TLC1 is prone to misfolding in vitro. To create a full-length yeast telomerase RNA, predicted to fold into its biologically relevant structure, we took an inverse RNA-folding approach, changing 59 nucleotides predicted to increase the energetic favorability of folding into the modeled native structure based on the p-num feature of Mfold software. The sequence changes lowered the predicted ∆G of this “determined-arm” allele, DA-TLC1, by 61 kcal/mol (−19%) compared to wild-type. We tested DA-TLC1 for reconstituted activity and found it to be ~5-fold more robust than wild-type TLC1, suggesting that the inverse-folding design indeed improved folding in vitro into a catalytically active conformation. We also tested if DA-TLC1 functions in vivo, discovering that it complements a tlc1∆ strain, allowing cells to avoid senescence and maintain telomeres of nearly wild-type length. However, all inverse-designed RNAs that we tested had reduced abundance in vivo. In particular, inverse-designing nearly all of the Ku arm caused a profound reduction in telomerase RNA abundance in the cell and very short telomeres. Overall, these results show that the inverse design of S. cerevisiae telomerase RNA increases activity in vitro, while reducing abundance in vivo. This study provides a biochemically and biologically tested approach to inverse-design RNAs using Mfold that could be useful for controlling RNA structure in basic research and biomedicine.</jats:p
Unveiling the Significance of Correlations in K-Space and Configuration Space for Drift Wave Turbulence in Tokamaks
No full textTurbulence and transport phenomena play a crucial role in the confinement and stability of tokamak plasmas. Turbulent fluctuations in certain physical quantities, such as density or temperature fluctuations, can have a wide range of spatial scales, and understanding their correlation length is important for predicting and controlling the behavior of the plasma. The correlation length in the radial direction is identified as the critical length in real space. The dynamics in real space are of significant interest because transport in configuration space is primarily focused on them. When investigating transport caused by the E√óB drift, the correlation length in real space represents the size of E√óB whirls. It was numerically discovered that in drift wave turbulence, this length is inversely proportional to the normalized mode number of the fastest growing mode relative to the drift frequency. Considerable time was required before a proper analytical derivation of this condition was accomplished. Therefore, a connection has been established between phenomena occurring in real space and those occurring in k-space. Although accompanied by a turbulent spectrum in k-space with a substantial width, transport in real space is uniquely determined by the correlation length, allowing for accurate transport calculations through the dynamics of a single mode. Naturally, the dynamics are subject to nonlinear effects, with resonance broadening in frequency being the most significant nonlinear effect. Thus, mode number space is once again involved. Resonance broadening leads to the detuning of waves from particles, permitting a fluid treatment. It should be emphasized that the consideration here involves the total electric field, including the induction part, which becomes particularly important at higher beta plasmas.</jats:p