Photochemical Strategies Enable the Synthesis of Tunable Azetidine-Based Energetic Materials.

Despite their favorable properties, azetidines are often overlooked as lead compounds across multiple industries. This is often attributed to the challenging synthesis of densely functionalized azetidines in an efficient manner. In this work, we report the scalable synthesis and characterization of seven azetidines with varying regio- and stereochemistry and their application as novel azetidine-based energetic materials, enabled by the visible-light-mediated aza Paternò-Büchi reaction. The performance and stark differences in the physical properties of these new compounds make them excellent potential candidates as novel solid melt-castable explosive materials, as well as potential liquid propellant plasticizers. This work highlights the scalability and utility of the visible-light aza Paternò-Büchi reaction and demonstrates the impact of stereochemical considerations on the physical properties of azetidine-based energetics. Considering the versatility and efficiency of the presented synthetic strategies, we expect that this work will guide the development of new azetidine-based materials in the energetics space as well as other industries.

Oxidative damage to epigenetically methylated sites affects DNA stability, dynamics and enzymatic demethylation.

DNA damage can affect various regulatory elements of the genome, with the consequences for DNA structure, dynamics, and interaction with proteins remaining largely unexplored. We used solution NMR spectroscopy, restrained and free molecular dynamics to obtain the structures and investigate dominant motions for a set of DNA duplexes containing CpG sites permuted with combinations of 5-methylcytosine (mC), the primary epigenetic base, and 8-oxoguanine (oxoG), an abundant DNA lesion. Guanine oxidation significantly changed the motion in both hemimethylated and fully methylated DNA, increased base pair breathing, induced BI→BII transition in the backbone 3' to the oxoG and reduced the variability of shift and tilt helical parameters. UV melting experiments corroborated the NMR and molecular dynamics results, showing significant destabilization of all methylated contexts by oxoG. Notably, some dynamic and thermodynamic effects were not additive in the fully methylated oxidized CpG, indicating that the introduced modifications interact with each other. Finally, we show that the presence of oxoG biases the recognition of methylated CpG dinucleotides by ROS1, a plant enzyme involved in epigenetic DNA demethylation, in favor of the oxidized DNA strand. Thus, the conformational and dynamic effects of spurious DNA oxidation in the regulatory CpG dinucleotide can have far-reaching biological consequences.

Impact of Stereo- and Regiochemistry on Energetic Materials.

The synthesis, physical properties, and calculated performances of six stereo- and regioisomeric cyclobutane nitric ester materials are described. While the calculated performances of these isomers, as expected, were similar, their physical properties were found to be extremely different. By alteration of the stereo- and regiochemistry, complete tunability in the form of low- or high-melting solids, stand-alone melt-castable explosives, melt-castable explosive eutectic compounds, and liquid propellant materials was obtained. This demonstrates that theoretical calculations should not be the main factor in driving the design of new materials and that stereo- and regiochemistry matter in the design of compounds of potential relevance to energetic formulators.

Ischemic stroke of the pyramidal decussation causing quadriplegia and anarthria.

A 52-year-old man with a history of hypertension and previously irradiated head and neck cancer presented with quadriplegia and anarthria sparing the face and sensory functions. Brain magnetic resonance imaging (MRI) demonstrated acute infarction of the pyramidal decussation. We describe the clinical and radiological characteristics of infarction at the pyramidal decussation and review the arterial supply to this region in the lower brainstem. Although rare, infarction of the pyramidal decussation should be considered in the differential diagnosis when patients present with atraumatic pure motor quadriplegia.

Synthesis and Characterization of the Potential Energetic Propellant Plasticizer 3-Nitratoethyl-N-nitramino-5-nitratomethyl Isoxazole.

The synthesis of 3-(nitratoethyl-N-nitramino)-5-(nitratomethyl) isoxazole (C6 H7 N5 O9 , 1) is presented, and its energetic properties were ascertained and analyzed for energetic applications potential. 1 was found to be a solid without melting behavior, begins to decompose at 140 °C, and has a thermal onset decomposition temperature of 171.5 °C. 1 was synthesized in 5 steps from glyoxylic acid, and was found to exhibit acceptable sensitivities to impact, friction, and electrostatic discharge. The presence of the nitratoethyl nitramino (NENA) moiety, coupled with the high density (1.71 g cm-3 ) and superior calculated specific impulse (247.6 s) over the commonly employed gun propellant n-butyl NENA (density=1.22 g cm-3 , specific impulse=221 s), makes 1 a potential energetic plasticizer for next generation gun and rocket propellants. In addition, a modified procedure for the synthesis of dibromoformaldoxime (DBFO) was developed to provide this material in respectable yields on one mole scale. The safety considerations of DBFO are also highlighted, in which this compound sublimes, and must be handled with care, as it will cause burns upon contact with the skin.

A Short Review of Nitric Esters and Their Role in Energetic Materials.

A review of energetic materials based on the nitric ester functionality is presented. Examined are materials that are classified as primary explosives, pressable secondary explosives, melt-castable secondary explosives, and rocket- and gun-propellant materials. Disclosed are the molecular structures, physical properties, performances, and sensitivities of the most important legacy nitric esters, as well as the relevant new materials developed within the past several years. Where necessary, discussions of the synthetic protocols to synthesize these materials are also presented.

Synthesis and Characterization of the Potential Melt-Castable Explosive 3-(1,2,4-Oxadiazolyl)-5-Nitratomethyl Isoxazole.

The synthesis of 3-(1,2,4-oxadiazolyl)-5-nitratomethyl isoxazole (C6 H4 N4 O5 ), its physical properties, and its theoretical performances are described. This energetic material was found to have a melting point range of 76.6-79.2 °C, and a thermal onset decomposition temperature of 184.5 °C. These thermal features put this material into the standalone melt-castable explosive class. The material was found to have TNT performance, and was found to be insensitive to impact, friction, and electrostatic discharge, despite having a nitric ester functionality. A critical reaction in making this molecule was the desymmetrization of diaminoglyoxime. The optimization of this transformation is described. Previous reports of this desymmetrization were found to be inaccurate, as the desymmetrization reaction produces a co-crystal of mono- and bi-1,2,4-oxadiazole products.

Precise NMR Method for Titering Organometal Reagents.

The concentration of organometal reagents can be conveniently determined by obtaining the NMR spectra of the neat reagent solution, and, in a second NMR tube, of a neat reference solvent. The PULCON relationship, implemented in all major NMR software, is then used to calculate the concentration of the reagent based on the absolute integrals in the spectra, the known concentration of the reference, and the number of protons under the integrals.

Three-Dimensional Characterization of Trabecular Bone Mineral Density of the Distal Radius Utilizing Quantitative Computed Tomography.

Background: Distal radius (DR) fractures demonstrate patterns of predictable fragments. Bone mineral density (BMD) measurements of these regions of interest (ROIs) may guide more precise treatment. Methods: Computed tomography (CT) scans of the DR of 42 healthy volunteers (23 female) were analyzed using quantitative CT software, measuring BMD within trabecular bone. Seven ROIs were described by alignment with the distal (volar ulnar distal [VUD], dorsal ulnar distal [DUD], volar radial distal [VRD], and dorsal radial distal [DRD]) or proximal (middle ulnar proximal [MUP], middle proximal [MP], and middle radial proximal [MRP]) sigmoid notch. Additional ROIs were the radial styloid (RS) and metadiaphysis (MD). A general estimation equation assessed subject's BMDs with predictive factors of gender, ROI, and age. The interaction between gender, ROI, and age was included in the model to allow for differences in ROI to vary with gender and/or age. Results: Comparing ROIs within the same gender and, separately, within the same age group revealed significantly higher BMD adjacent to the radioulnar and radiocarpal joints. Male and female individuals aged ≥50 years (mean: 172.7 mg/cm3 ± 6.1) had significantly lower BMD than those aged <50 years (mean: 202.7 mg/cm3 ± 5.8) when all ROIs were considered. Males had higher mean BMD at each ROI compared with females; these differences were significant in 5 of the 9 ROIs: VUD, DUD, DRD, RS, MUP. Conclusions: Trabecular BMD of the DR is highest adjacent to the radioulnar and radiocarpal joints. Female patients and those ≥50 years have lower trabecular BMD.

Bis(Nitroxymethylisoxazolyl) Furoxan: A Promising Standalone Melt-Castable Explosive.

The synthesis and crystal structure of the heterocyclic explosive bis(nitroxymethylisoxazolyl) furoxan, C10 H6 N6 O10 , are described. In addition, we report its physical properties and theoretical performance. This material was found to exhibit standalone melt-castable explosive properties, with a melting point of 89.8 °C and an onset decomposition temperature of 193.8 °C. Bis(nitroxymethylisoxazolyl) furoxan features an insensitive behavior to impact, friction, and electrostatic discharge, with a calculated detonation pressure about 25 % higher than the state-of-the-art melt-castable explosive TNT.

Bis(1,2,4-oxadiazolyl) Furoxan: A Promising Melt-Castable Eutectic Material of Low Sensitivity.

A scalable synthesis of bis(1,2,4-oxadiazoyl) furoxan, C6 H2 N6 O4 , its physical properties, and its theoretical performance values are described. Previous attempts to synthesize this compound required expensive reagents, and/or time-consuming synthesis processes and low overall yields. In addition to disclosing a streamlined synthesis of bis(1,2,4-oxadiazolyl) furoxan, we report its molecular configuration and crystal structure, as well as its correct melting point. Bis(1,2,4-oxadiazolyl) furoxan exhibits a very insensitive behavior to impact, friction, and electrostatic discharge, with a calculated detonation pressure 20 % higher than that of TNT. Given its physical properties and theoretical performance values, this material can be classified as a promising ingredient in the development of melt-castable eutectic technology.

Synthesis of bis-Isoxazole-bis-Methylene Dinitrate: A Potential Nitrate Plasticizer and Melt-Castable Energetic Material.

The efficient and scalable synthesis of 3,3'-bis-isoxazole-5,5'-bis-methylene dinitrate and its energetic properties are described. The material has favorable sensitivity properties; energetic properties point toward its potential as both a melt-castable secondary explosive and as a propellant plasticizer.

The Chlamydomonas reinhardtii BBSome is an IFT cargo required for export of specific signaling proteins from flagella.

In humans, seven evolutionarily conserved genes that cause the cilia-related disorder Bardet-Biedl syndrome (BBS) encode proteins that form a complex termed the BBSome. The function of the BBSome in the cilium is not well understood. We purified a BBSome-like complex from Chlamydomonas reinhardtii flagella and found that it contains at least BBS1, -4, -5, -7, and -8 and undergoes intraflagellar transport (IFT) in association with a subset of IFT particles. C. reinhardtii insertional mutants defective in BBS1, -4, and -7 assemble motile, full-length flagella but lack the ability to phototax. In the bbs4 mutant, the assembly and transport of IFT particles are unaffected, but the flagella abnormally accumulate several signaling proteins that may disrupt phototaxis. We conclude that the BBSome is carried by IFT but is an adapter rather than an integral component of the IFT machinery. C. reinhardtii BBS4 may be required for the export of signaling proteins from the flagellum via IFT.

Using absolute and relative muscle endurance to estimate maximal strength in young athletes.

PURPOSE: The purpose of this study was to evaluate the effectiveness of repetitions to fatigue (RTF) using absolute and relative muscle-endurance performances to estimate 1-repetition-maximum (1-RM) bench-press performance in high school male athletes. METHODS: Members of high school athletic teams (n = 118, age = 16.5 +/- 1.1 y, weight = 82.7 +/- 18.7 kg) were tested for 1-RM bench press and RTF with an absolute load of 61.4 kg and a relative load that produced 7 to 10 RTF (7- to 10-RM). All participants had completed a minimum of 4 wk of resistance training before measurement. RESULTS: All 7- to 10-RM-prediction equations had higher correlations between predicted and actual 1-RM (r > .98) than the 61.4-kg absolute-load equation (r = .95). Despite the high correlations, only 3 of 11 equations produced predicted values that were nonsignificantly different from actual 1-RM. The best 7-to 10-RM equation predicted 65% of the athletes'performances within +/-4.5 kg of their actual 1-RM. The addition of simple anthropometric dimensions did not increase the validity correlations or decrease the prediction errors. CONCLUSION: The 7- to 10-RM method can provide an accurate method of estimating strength levels for adjusting loads in a training program and is more accurate for predicting 1-RM bench press in high school athletes than the 61.4-kg repetition method.

Body habitus does not influence spread of sensory blockade after the intrathecal injection of a hypobaric solution in term parturients.

PURPOSE: To determine if the extent of sensory blockade after the intrathecal injection of hypobaric fentanyl (25 micro g) and bupicavaine (2.5 mg) in the sitting position in term parturients is influenced by body habitus. METHODS: A prospective observational study in 245 term parturients who received intrathecal fentanyl and bupivacaine plus an epidural test dose to initiate labour analgesia at an academic university hospital. The highest sensory blockade to ice and pinprick was determined at 15 and 30 min after the intrathecal injection. Correlations between sensory blockade and parturient height, weight and body mass index (BMI) were determined. RESULTS: There was no association between highest sensory blockade and parturients' height. Increasing weight and BMI were associated with increased cephalad sensory blockade at 15 min, but not at 30 min. The estimated difference in sensory level between women at the extremes of BMI, based on our linear regression model, was less than one dermatome. CONCLUSION: Height did not influence the extent of sensory analgesia after initiation of intrathecal labour analgesia using a hypobaric solution injected with the parturient in the sitting position. Weight and BMI were associated with a non-clinically significant increase in the cephalic spread of analgesia, suggesting that dose adjustments based on body habitus in this population are not necessary.

Application of NMR SHAPES screening to an RNA target.

Several NMR screening techniques have been developed in recent years to aid in the identification of lead drug compounds. These NMR methods have traditionally been used for protein targets, and here we examine their applicability for an RNA target. We used the SHAPES compound library to test three different NMR screening methodologies: the saturation transfer difference (STD), the 2D trNOESY, and the WaterLOGSY experiments. We found that the WaterLOGSY experiment was the most sensitive method for our RNA target, the P4P6 domain of the Tetrahymena thermophila Group I intron. Using the WaterLOGSY experiment, we found that 23 of the 112 SHAPES compounds interact with P4P6. To identify which of these 23 hits bind through nonspecific interactions, we counterscreened with a linear duplex RNA control and identified one of the SHAPES compounds as interacting with P4P6 specifically. We thus demonstrated that the WaterLOGSY experiment in combination with the SHAPES compound library can be used to efficiently find RNA binding lead compounds.

Differentiation prevents assessment of neural stem cell pluripotency after blastocyst injection.

Earlier studies reported that neural stem (NS) cells injected into blastocysts appeared to be pluripotent, differentiating into cells of all three germ layers. In this study, we followed in vitro green fluorescent protein (GFP)-labeled NS and embryonic stem (ES) cells injected into blastocysts. Forty-eight hours after injection, significantly fewer blastocysts contained GFP-NS cells than GFP-ES cells. By 96 hours, very few GFP-NS cells remained in blastocysts compared with ES cells. Moreover, 48 hours after injection, GFP-NS cells in blastocysts extended long cellular processes, ceased expressing the NS cell marker nestin, and instead expressed the astrocytic marker glial fibrillary acidic protein. GFP-ES cells in blastocysts remained morphologically undifferentiated, continuing to express the pluripotent marker stage-specific embryonic antigen-1. Selecting cells from the NS cell population that preferentially formed neurospheres for injection into blastocysts resulted in identical results. Consistent with this in vitro behavior, none of almost 80 mice resulting from NS cell-injected blastocysts replaced into recipient mothers were chimeric. These results strongly support the idea that NS cells cannot participate in chimera formation because of their rapid differentiation into glia-like cells. Thus, these results raise doubts concerning the pluripotency properties of NS cells.