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Now more than ever, the pulsed power field is driven by size, weight, and volume constraints. In both the military and commercial arenas, there is an overwhelming need to provide more and more capability in ever smaller and lighter packages. The need for higher energy density, power density, reliability, and efficiency is driving progress in the field. This paper provides a review of the state of the art in various types of pulsed power components such as solid-state switches, capacitors, and power sources. In some cases, familiar components such as switch tubes are being replaced with whole new classes of devices. Batteries are being replaced by hydrocarbon or hydrogen-fueled mechanical systems that alter our paradigm for prime power sources. Trends over the past few years and future possibilities for ultracompact systems are discussed, including advanced techniques for heat removal and energy recovery. Finally, a few practical examples of ultracompact systems are given, emphasizing peak power and peak power density. [ABSTRACT FROM AUTHOR]

The article presents abstracts of papers on art presented at the SECAC art history session which include the religious art of Van Gogh, the reverse, sources and meaning of the Great Seal of the U.S., and the depiction of Black Africans in Hohenstaufen iconography.

The article presents information on the diagnosis of eruptive xanthoma in a 33-year-old man. Physical examination showed yellowish papules over the elbows, buttocks, knees, flank and palmar creases. The association of eruptive xanthoma with hypertriglyceridemia and chylomicronemia is discussed. Diagnosis may include measuring fasting blood glucose and lipid levels, whereas, treatment involves dietary restrictions and medications to control the hyperlipidemia.

Graphical abstract Highlights • A chemical-genetic strategy to enable cell-specific metabolic labeling of RNA. • Two small molecule-enzyme pairs that enable cell-specific RNA labeling. • Cell-specific labeling can be imaged with orthogonal "click" chemistry pairs. Abstract RNA molecules can perform a myriad of functions, from the regulation of gene expression to providing the genetic blueprint for protein synthesis. Characterizing RNA expression dynamics, in a cell-specific manner, still remains a great challenge in biology. Herein we present a new set of protected alkynyl nucleosides for cell-specific metabolic labeling of RNA. We anticipate these analogs will find wide spread utility toward the goal of understanding RNA expression in complex cellular and tissue environments, even within living animals. [ABSTRACT FROM AUTHOR]

Purpose: The treatment of complex neurological diseases often requires the administration of large therapeutic drugs, such as antisense oligonucleotide (ASO), by lumbar puncture into the intrathecal space in order to bypass the blood-brain barrier. Despite the growing number of ASOs in clinical development, there are still uncertainties regarding their dosing, primarily around their distribution and kinetics in the brain following intrathecal injection. The challenge of taking measurements within the delicate structures of the central nervous system (CNS) necessitates the use of non-invasive nuclear imaging, such as positron emission tomography (PET). Herein, an emergent strategy known as "pretargeted imaging" is applied to image the distribution of an ASO in the brain by developing a novel PET tracer, [18F]F-537-Tz. This tracer is able to undergo an in vivo "click" reaction, covalently binding to a trans-cyclooctene conjugated ASO.Procedures: A novel small molecule tracer for pretargeted PET imaging of ASOs in the CNS is developed and tested in a series of in vitro and in vivo experiments, including biodistribution in rats and non-human primates.Results: In vitro data and extensive in vivo rat data demonstrated delivery of the tracer to the CNS, and its successful ligation to its ASO target in the brain. In an NHP study, the slow tracer kinetics did not allow for specific binding to be determined by PET.Conclusion: A CNS-penetrant radioligand for pretargeted imaging was successfully demonstrated in a proof-of-concept study in rats, laying the groundwork for further optimization. [ABSTRACT FROM AUTHOR]

The article examines federal and state efforts to combat health care fraud by the U.S. Department of Justice (DOJ) and the Department of Health and Human Services (DHS). Topics discussed include statues to address Medicare and Medicaid fraud, types of health care fraud, including those regulating false claims, false statements, and mail and wire fraud and federal and state government agencies' enforcement efforts to investigate and prosecute health care fraud.

An abstract of the article "The Development of the American Skyscraper as Revealed in the Pages of Architectural Record, 1890-1941," by Michael Fazio is presented.

Introduction: Knee osteoarthritis (KOA) is a primary source of long-term disability and decreased quality of life (QoL) in service members (SM) with lower limb loss (LL); however, it remains difficult to preemptively identify and mitigate the progression of KOA and KOA-related symptoms. The objective of this study was to explore a comprehensive cross-sectional evaluation, at the baseline of a prospective study, for characterizing KOA in SM with traumatic LL., Materials and Methods: Thirty-eight male SM with traumatic unilateral LL (23 transtibial and 15 transfemoral), 9.5 ± 5.9 years post-injury, were cross-sectionally evaluated at initial enrollment into a prospective, longitudinal study utilizing a comprehensive evaluation to characterize knee joint health, functionality, and QoL in SM with LL. Presences of medial, lateral, and/or patellofemoral articular degeneration within the contralateral knee were identified via magnetic resonance imaging(for medically eligible SM; Kellgren-Lawrence Grade [n = 32]; and Outerbridge classification [OC; n = 22]). Tri-planar trunk and pelvic motions, knee kinetics, along with temporospatial parameters, were quantified via full-body gait evaluation and inverse dynamics. Concentrations of 26 protein biomarkers of osteochondral tissue degradation and inflammatory activity were identified via serum immunoassays. Physical function, knee symptoms, and QoL were collected via several patient reported outcome measures., Results: KOA was identified in 12 of 32 (37.5%; KL ≥ 1) SM with LL; however, 16 of 22 SM presented with patellofemoral degeneration (72.7%; OC ≥ 1). Service members with versus without KOA had a 26% reduction in the narrowest medial tibiofemoral joint space. Biomechanically, SM with versus without KOA walked with a 24% wider stride width and with a negative correlation between peak knee adduction moments and minimal medial tibiofemoral joint space. Physiologically, SM with versus without KOA exhibited elevated concentrations of pro-inflammatory biomarker interleukin-7 (+180%), collagen breakdown markers collagen II cleavage (+44%), and lower concentrations of hyaluronic acid (-73%) and bone resorption biomarker N-telopeptide of Type 1 Collagen (-49%). Lastly, there was a negative correlation between patient-reported contralateral knee pain severity and patient-reported functionality and QoL., Conclusions: While 37.5% of SM with LL had KOA at the tibiofemoral joint (KL ≥ 1), 72.7% of SM had the presence of patellofemoral degeneration (OC ≥ 1). These findings demonstrate that the patellofemoral joint may be more susceptible to degeneration than the medial tibiofemoral compartment following traumatic LL., (Published by Oxford University Press on behalf of the Association of Military Surgeons of the United States 2022. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Motivated by the complex and multifactorial etiologies of osteoarthritis, here we use a comprehensive approach evaluating knee joint health after unilateral lower limb loss. Thirty-eight male Service members with traumatic, unilateral lower limb loss (mean age = 38 yr) participated in a prospective, two-year longitudinal study comprehensively evaluating contralateral knee joint health (i.e., clinical imaging, gait biomechanics, physiological biomarkers, and patient-reported outcomes); seventeen subsequently returned for a two-year follow-up visit. For this subset with baseline and follow-up data, outcomes were compared between timepoints, and associations evaluated between values at baseline with two-year changes in tri-compartmental joint space. Upon follow-up, knee joint health worsened, particularly among seven Service members who presented at baseline with no joint degeneration (KL = 0) but returned with evidence of degeneration (KL ≥ 1). Joint space narrowing was associated with greater patellar tilt (r[12] = 0.71, p = 0.01), external knee adduction moment (r[13] = 0.64, p = 0.02), knee adduction moment impulse (r[13] = 0.61, p = 0.03), and CTX-1 concentration (r[11] = 0.83, p = 0.001), as well as lesser KOOS Sport and VR-36 General Health (r[16] = - 0.69, p = 0.01 and r[16] = - 0.69, p = 0.01, respectively). This longitudinal, multi-disciplinary investigation highlights the importance of a comprehensive approach to evaluate the fast-progressing onset of knee osteoarthritis, particularly among relatively young Service members with lower limb loss., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

The PS modification enhances the nuclease stability and protein binding properties of gapmer antisense oligonucleotides (ASOs) and is one of very few modifications that support RNaseH1 activity. We evaluated the effect of introducing stereorandom and chiral mesyl-phosphoramidate (MsPA) linkages in the DNA gap and flanks of gapmer PS ASOs and characterized the effect of these linkages on RNA-binding, nuclease stability, protein binding, pro-inflammatory profile, antisense activity and toxicity in cells and in mice. We show that all PS linkages in a gapmer ASO can be replaced with MsPA without compromising chemical stability and RNA binding affinity but these designs reduced activity. However, replacing up to 5 PS in the gap with MsPA was well tolerated and replacing specific PS linkages at appropriate locations was able to greatly reduce both immune stimulation and cytotoxicity. The improved nuclease stability of MsPA over PS translated to significant improvement in the duration of ASO action in mice which was comparable to that of enhanced stabilized siRNA designs. Our work highlights the combination of PS and MsPA linkages as a next generation chemical platform for identifying ASO drugs with improved potency and therapeutic index, reduced pro-inflammatory effects and extended duration of effect., (© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Neuroblastoma (NB) is the most common extracranial solid tumor in children. The outcomes for aggressive forms of NB remain poor. The aim of this study was to develop a new molecular-targeted therapy for NB using an antisense oligonucleotide (ASO) and superparamagnetic iron oxide (SPIO) nanoparticles (NPs), as a delivery vehicle, targeting the transcription regulator MAX dimerization protein 3 (MXD3). We previously discovered that MXD3 was highly expressed in high-risk NB, acting as an anti-apoptotic factor; therefore, it can be a good therapeutic target. In this study, we developed two ASO-NP complexes using electrostatic conjugation to polyethylenimine-coated SPIO NPs and chemical conjugation to amphiphilic polymers on amine-functionalized SPIO NPs. Both ASO-NP complexes demonstrated MXD3 knockdown, which resulted in apoptosis in NB cells. ASO chemically-conjugated NP complexes have the potential to be used in the clinic as they showed great efficacy with minimum NP-associated cytotoxicity., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The cellular RNA pool in animals arises from two separate genomes stored in the nucleus and multiple mitochondria. Chemical methods to track nascent RNA synthesis are unable to distinguish between these two with stringency. Herein, we report that spatially restricting bioorthogonal nucleoside biosynthesis enables, for the first time, selective metabolic labeling of the RNA transcribed in the mitochondria. We envision that this approach could open the door for heretofore-impossible analyses of mitochondrial RNA. Beyond our results revealed herein, our approach provides a roadmap for researchers to begin to design strategies to examine biomolecules within subcellular compartments.

Purification of cell type-specific RNAs remains a significant challenge. One solution involves biosynthetic tagging of target RNAs. RNA tagging via incorporation of 4-thiouracil (TU) in cells expressing transgenic uracil phosphoribosyltransferase (UPRT), a method known as TU-tagging, has been used in multiple systems but can have limited specificity due to endogenous pathways of TU incorporation. Here, we describe an alternative method that requires the activity of two enzymes: cytosine deaminase (CD) and UPRT. We found that the sequential activity of these enzymes converts 5-ethynylcytosine (EC) to 5-ethynyluridine monophosphate that is subsequently incorporated into nascent RNAs. The ethynyl group allows efficient detection and purification of tagged RNAs. We show that 'EC-tagging' occurs in tissue culture cells and Drosophila engineered to express CD and UPRT. Additional control can be achieved through a split-CD approach in which functional CD is reconstituted from independently expressed fragments. We demonstrate the sensitivity and specificity of EC-tagging by obtaining cell type-specific gene expression data from intact Drosophila larvae, including transcriptome measurements from a small population of central brain neurons. EC-tagging provides several advantages over existing techniques and should be broadly useful for investigating the role of differential RNA expression in cell identity, physiology and pathology., (© The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Real-time tracking of RNA expression can provide insight into the mechanisms used to generate cellular diversity, as well as help determine the underlying causes of disease. Here we present the exploration of azide-modified nucleoside analogues and their ability to be metabolically incorporated into cellular RNA. We report robust incorporation of adenosine analogues bearing azide handles at both the 2'- and N6-positions; 5-methylazidouridine was not incorporated into cellular RNA. We further demonstrate selectivity of our adenosine analogues for transcription and polyadenylation. We predict that azidonucleosides will find widespread utility in examining RNA functions inside living cells, as well as in more complex systems such as tissues and living animals., (© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Traumatic brain injury (TBI) generates regional alterations in cerebral metabolism, leading to the potential evolution of persistent metabolic dysfunction. In the case of penetrating, firearm-related TBI, the pathophysiological mechanisms underlying these acute-phase metabolic derangements are not entirely understood-hindering the potential effectiveness of therapeutic intervention. The use of cerebral microdialysis to monitor biochemical alterations that occur, post-TBI, provides critical insight into the events that perpetuate neurological deterioration., Methods: Cerebral microdialysis was used to monitor alterations in the brain tissue chemistry of a 22-year-old female patient who sustained a penetrating gunshot wound to the head. Extracellular glucose, lactate, pyruvate, and lactate pyruvate ratio (LPR) were monitored over the course of the first-week post-injury., Results: Analysis of the microdialysate revealed sustained elevations in LPR with peaks in excess of those seen in patients who have sustained permanent ischemic injury. This interval of persistently elevated LPR was followed by a spontaneous reduction of values, to levels below the defined threshold for metabolic crisis, over a period of several days., Conclusions: Microdialysis studies may significantly improve the understanding of the metabolic alterations that occur in patients who sustain a variety of forms of neurotrauma. Ultimately, monitoring these variations in brain tissue chemistry will improve the insight into the neuropathological mechanisms underlying penetrating traumatic brain injury, and enhance the therapeutic approach of these patients.

The synthesis of a porphyrin-fullerene dyad with "parachute" topology is reported. To determine whether the dyad is "flexing" at room temperature, low-temperature NMR experiments were used. Computational modeling has shown the low-energy conformation of the dyad to be nonsymmetric. Although, (1)H NMR spectroscopy at room temperature is consistent with a molecule with C(2v) symmetry, the spectrum changes on lowering the temperature consistent with "windshield wiper"-like motion, in which the porphyrin moiety rotates from one side of the C(60) sphere to the other. Nanosecond and picosecond fluorescence lifetime experiments show two components contribute to the fluorescence decay, also consistent with the presence of more than one conformer.