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Nuclear power is a significant source of electricity in the United States, but the average U.S. nuclear power plant is around 40 years old. Safe management of spent nuclear fuel (SNF) is a crucial aspect of the back end of the nuclear fuel cycle. SNF dry storage systems are increasingly popular as they represent an effective solution in this area, given the absence of a final disposal system. In particular, the spent fuel cask system (dry cask method) provides a feasible solution for maintaining SNF (\\(\\sim\\)60 years) prior to the final disposal. The HI-STORM overpack and MPC-32 canister are the primary components of the HI-STORM 100 dry cask storage system. They remove heat from the system via natural circulation with no human intervention required. This characteristic provides passive heat removal while requiring little maintenance in dry cask storage systems. This project aims to validate and compare the capabilities of a thermal model of HI-STORM overpack developed using the Multiphysics Object-Oriented Simulation Environment (MOOSE) based on the author's previous study. MOOSE is an open-source framework developed by Idaho National Laboratory for multiscale, multiphysics simulations. This study will improve the capabilities of the thermal-hydraulic model of the HI-STORM dry cask storage system by producing high-fidelity results for the air circulation in the overpack. Large Eddy Simulations (LES) are performed using the open-source spectral element code NekRS, developed by Argonne National Laboratory (ANL), for simulating transitional and turbulent flows in complex geometries. NekRS will produce high-fidelity results for the HI-STORM overpack to assess the validity of the current thermal-hydraulic model.

Parametric runtime verification is the process of verifying properties of execution traces of (data carrying) events produced by a running system. This paper continues our work exploring the relationship between specification techniques for parametric runtime verification. Here we consider the correspondence between trace-slicing automata-based approaches and rule systems. The main contribution is a translation from quantified automata to rule systems, which has been implemented in Scala . This then allows us to highlight the key differences in how the two formalisms handle data, an important step in our wider effort to understand the correspondence between different specification languages for parametric runtime verification. This paper extends a previous conference version of this paper with further examples, a proof of correctness, and an optimisation based on a notion of redundancy observed during the development of the translation.

Many systems with distributed dynamics are described by partial differential equations (PDEs). Coupled reaction-diffusion equations are a particular type of these systems. The measurement of the state over the entire spatial domain is usually required for their control. However, it is often impossible to obtain full state information with physical sensors only. For this problem, observers are developed to estimate the state based on boundary measurements. The method presented applies the so-called modulating function method, relying on an orthonormal function basis representation. Auxiliary systems are generated from the original system by applying modulating functions and formulating annihilation conditions. It is extended by a decoupling matrix step. The calculated kernels are utilized for modulating the input and output signals over a receding time window to obtain the coefficients for the basis expansion for the desired state estimation. The developed algorithm and its real-time functionality are verified via simulation of an example system related to the dynamics of chemical tubular reactors and compared to the conventional backstepping observer. The method achieves a successful state reconstruction of the system while mitigating white noise induced by the sensor. Ultimately, the modulating function approach represents a solution for the distributed state estimation problem without solving a PDE online.

Connections between magnetic field induced optical activity and chirality have a rich and complicated history. Although the broken inversion symmetry of chiral molecules generates ‘natural’ optical activity, magnetic optical activity is generated by breaking time reversal symmetry. Therefore, molecular chirality is not expected to influence magnetic optical phenomena, such as Faraday rotation. Here we show that the chiral supramolecular assembly of polymers can result in large Faraday effects (Verdet constants = 10 5 °T –1 m –1 ). This strong Faraday rotation, which is amongst the highest value known for organic materials, originates from the so-called Faraday B term. Typically, B term Faraday responses are weak. We demonstrate large amplification through excitonic coupling within the supramolecular assembly, where the chirality of the system controls the assembly formed. These observations provide an alternative means to enhance the Faraday rotation of low symmetry systems and clarify the role of chirality in previous reported materials. The relation between magnetooptical activity and chirality has previously been confused. Chiral polymer films are presented with state-of-the-art Verdet constants, revealing the role of chirality, and a strategy to enhance the magnetooptical B term.

The molecular basis of CD8 + memory is still being delineated. Gattinoni et al . show that the DNA-binding inhibitor Id3 is critical for the formation of long-lived memory. The transcriptional repressor Blimp-1 promotes the differentiation of CD8 + T cells into short-lived effector cells (SLECs) that express the lectin-like receptor KLRG-1, but how it operates remains poorly defined. Here we show that Blimp-1 bound to and repressed the promoter of the gene encoding the DNA-binding inhibitor Id3 in SLECs. Repression of Id3 by Blimp-1 was dispensable for SLEC development but limited the ability of SLECs to persist as memory cells. Enforced expression of Id3 was sufficient to restore SLEC survival and enhanced recall responses. Id3 function was mediated in part through inhibition of the transcriptional activity of E2A and induction of genes regulating genome stability. Our findings identify the Blimp-1–Id3–E2A axis as a key molecular switch that determines whether effector CD8 + T cells are programmed to die or enter the memory pool.

A growing number of natural killer (NK) cell-based immunotherapy trials utilize ex vivo expansion to grow and activate allogenic and autologous NK cells prior to administration to patients with malignancies. Recent data in both murine and macaque models have shown that adoptively infused ex vivo expanded NK cells have extensive trafficking into liver tissue, with relatively low levels of homing to other sites where tumors often reside, such as the bone marrow or lymph nodes. Here, we evaluated gene and surface expression of molecules involved in cellular chemotaxis in freshly isolated human NK cells compared with NK cells expanded ex vivo using two different feeder cells lines: Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines (LCLs) or K562 cells with membrane-bound (mb) 4-1BB ligand and interleukin (IL)-21. Expanded NK cells had altered expression in a number of genes that encode chemotactic ligands and chemotactic receptors that impact chemoattraction and chemotaxis. Most notably, we observed drastic downregulation of C-X-C chemokine receptor type 4 (CXCR4) and upregulation of C-C chemokine receptor type 5 (CCR5) transcription and phenotypic expression. clustered regularly interspaced short palindromic repeats (CRISPR) gene editing of CCR5 in expanded NK cells reduced cell trafficking into liver tissue and increased NK cell presence in the circulation following infusion into immunodeficient mice. The findings reported here show that ex vivo expansion alters multiple factors that govern NK cell homing and define a novel approach using CRISPR gene editing that reduces sequestration of NK cells by the liver.

Insulin resistance (impaired insulin action) has been associated with Alzheimer disease (AD) and memory impairment, independent of AD. Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonists improve insulin sensitivity and regulate in-vitro processing of the amyloid precursor protein (APP). Authors evaluated the effects of the PPAR-gamma agonist rosiglitazone on cognition and plasma levels of the APP derivative beta-amyloid (Abeta) in humans. In a placebo-controlled, double-blind, parallel-group pilot study, 30 subjects with mild AD or amnestic mild cognitive impairment were randomized to a 6-month course of rosiglitazone (4 mg daily; N = 20) or placebo (N = 10). Primary endpoints were cognitive performance and plasma Abeta levels. Relative to the placebo group, subjects receiving rosiglitazone exhibited better delayed recall (at Months 4 and 6) and selective attention (Month 6). At Month 6, plasma Abeta levels were unchanged from baseline for subjects receiving rosiglitazone but declined for subjects receiving placebo, consistent with recent reports that plasma Abeta42 decreases with progression of AD. Findings provide preliminary support that rosiglitazone may offer a novel strategy for the treatment of cognitive decline associated with AD. Future confirmation in a larger study is needed to fully demonstrate rosiglitazone's therapeutic potential.

BackgroundAdoptive transfer of natural killer (NK) cells with augmented antibody-dependent cellular cytotoxicity (ADCC) capabilities and resistance to CD38 targeting has the potential to enhance the clinical anti-myeloma activity of daratumumab (DARA). Therefore, we sought to develop an efficient CRISPR/Cas9-based gene editing platform to disrupt CD38 expression (CD38 knockout (KO)) in ex vivo expanded NK cells and simultaneously arm CD38KO NK cells with a high-affinity CD16 (CD16-158V) receptor.MethodsCD38KO human NK cells were generated using Cas9 ribonucleoprotein complexes. The platform was expanded by incorporating messenger RNA (mRNA) transfection of CD38KO NK cells and targeted gene insertion at the CD38 locus to mediate gene knockin (KI). The capacity of these gene-edited NK cells to persist and mediate ADCC in the presence of DARA was tested in vitro and in a MM.1S xenograft mouse model.ResultsHighly efficient CD38 gene disruption was achieved in ex vivo expanded NK cells without affecting their proliferative or functional capacity. CD38 KO conferred resistance to DARA-induced NK cell fratricide, enabling persistence and augmented ADCC against myeloma cell lines in the presence of DARA in vitro and in a MM.1S xenograft mouse model. CD38KO NK cells could be further modified by transfection with mRNA encoding a CD16-158V receptor, resulting in augmented DARA-mediated ADCC. Finally, we observed that a homology-directed repair template targeted to the CD38 locus facilitated an efficient 2-in-1 CD38 KO coupled with KI of a truncated CD34 reporter and CD16-158V receptor, with CD38KO/CD16KI NK cells demonstrating a further enhancement of DARA-mediated ADCC both in vitro and in vivo.ConclusionsAdoptive immunotherapy using ex vivo expanded CD38KO/CD16KI NK cells has the potential to boost the clinical efficacy of DARA. By incorporating complementary genetic engineering strategies into a CD38 KO manufacturing platform, we generated NK cells with substantially augmented CD38-directed antitumor activity, establishing a strong rationale for exploring this immunotherapy strategy in the clinic.

Myelin regeneration (remyelination) in the CNS depends on the recruitment, proliferation and differentiation of oligodendrocyte precursor cells (OPCs) at demyelinated lesions. However, despite the presence of OPCs, very few oligodendrocytes and myelin are regenerated in chronic multiple sclerosis (MS) lesions for reasons that remain poorly understood. Here, using a spontaneous remyelination model in mice, we found that retinaldehyde dehydrogenase 2 (Raldh2), a rate-limiting enzyme for retinoic acid (RA) synthesis, is upregulated in OPCs and in a subpopulation of microglia/macrophages during remyelination. Tamoxifen induced deletion of Raldh2 globally, or conditionally in OPCs, resulted in significantly fewer proliferating OPCs in lesions, leading to decreased oligodendrocyte numbers and myelin density. Moreover, induced deletion of Raldh2 globally also resulted in increased microglia/macrophage density in lesions. Further, exogenous RA delivery into lesions significantly increased oligodendrocyte lineage cells, while also decreasing proinflammatory microglia/macrophages, with no significant effect on anti-inflammatory microglia/macrophages. Postmortem MS brain sections revealed Raldh2 was absent in the majority of OPCs in chronic inactive lesions compared to the other lesion types. These results suggest that Raldh2 upregulation in lesions is critical for OPC proliferation during remyelination, and reveal that the failure to regenerate sufficient oligodendrocytes and myelin in chronic MS lesions may arise from impaired OPC expansion due to the failure to intrinsically synthesize RA.

Traumatic brain injury (TBI) in children can cause persisting cognitive and behavioral dysfunction, and inevitably raises concerns about lost potential in these injured youth. Lateral fluid percussion injury (FPI) in weanling rats pathologically affects hippocampal N-methyl-d-aspartate receptor (NMDAR)- and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated glutamatergic neurotransmission subacutely within the first post-injury week. FPI to weanling rats has also been shown to impair enriched-environment (EE) induced enhancement of Morris water maze (MWM) learning and memory in adulthood. Recently, improved outcomes can be achieved using agents that enhance NMDAR function. We hypothesized that administering D-cycloserine (DCS), an NMDAR co-agonist, every 12 h (i.p.) would restore subacute glutamatergic neurotransmission and reinstate experience-dependent plasticity. Postnatal day 19 (P19) rats received either a sham or FPI. On post-injury day (PID) 1–3, animals were randomized to saline (Sal) or DCS. Firstly, immunoblotting of hippocampal NMDAR and AMPAR proteins were measured on PID4. Second, PID4 novel object recognition, an NMDAR- and hippocampal- mediated working memory task, was assessed. Third, P19 rats were placed in an EE (17 days), and MWM performance was measured, starting on PID30. On PID4, DCS restored reduced NR2A and increased GluR2 by 54%, and also restored diminished recognition memory in FPI pups. EE significantly improved MWM performance in shams, regardless of treatment. In contrast, FPI-EE-Sal animals only performed to the level of standard housed animals, whereas FPI-EE-DCS animals were comparable with sham-EE counterparts. This study shows that NMDAR agonist use during reduced glutamatergic transmission after developmental TBI can reinstate early molecular and behavioral responses that subsequently manifest in experience-dependent plasticity and rescued potential.