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Patients with axial spondyloarthritis (axSpA) frequently report pain, stiffness, fatigue, and sleep problems, which may lead to impaired physical activity. The majority of reported-on measures evaluating physical activity and sleep disturbance in axSpA are self-reported questionnaires, which can be impacted by patient recall (reporting bias). One objective measure, polysomnography, has been employed to evaluate sleep in patients with axSpA; however, it is an intrusive measure and cannot be used over the long term. More convenient objective measures are therefore needed to allow for the long-term assessment of both sleep and physical activity in patients’ daily lives. Wearable technology that utilizes actigraphy is increasingly being used for the objective measurement of physical activity and sleep in various therapy areas, as it is unintrusive and suitable for continuous tracking to allow longitudinal assessment. Actigraphy characterizes sleep disruption as restless movement while sleeping, which is particularly useful when studying conditions such as axSpA in which chronic pain and discomfort due to stiffness may be evident. Studies have also shown that actigraphy can effectively assess the impact of disease on physical activity. More research is needed to establish the usefulness of objective monitoring of sleep and physical activity specifically in axSpA patients over time. This review summarizes the current perspectives on physical activity and sleep quality in patients with axSpA, and the possible role of actigraphy in the future to more accurately evaluate the impact of treatment interventions on sleep and physical activity in axSpA. Funding: Novartis Pharmaceuticals Corporation. Plain Language Summary: Plain language summary available for this article.

Native highlanders (e.g. Sherpa) demonstrate remarkable hypoxic tolerance, possibly secondary to higher levels of circulating nitric oxide (NO) and increased microcirculatory blood flow. As part of the Xtreme Alps study (a randomised placebo-controlled trial of dietary nitrate supplementation under field conditions of hypobaric hypoxia), we investigated whether dietary supplementation with nitrate could improve NO availability and microvascular blood flow in lowlanders. Plasma measurements of nitrate, nitrite and nitroso species were performed together with measurements of sublingual (sidestream dark-field camera) and forearm blood flow (venous occlusion plethysmography) in 28 healthy adult volunteers resident at 4559 m for 1 week; half receiving a beetroot-based high-nitrate supplement and half receiving an identically-tasting low nitrate ‘placebo’. Dietary supplementation increased plasma nitrate concentrations 4-fold compared to the placebo group, both at sea level (SL; 19.2 vs 76.9 μM) and at day 5 (D5) of high altitude (22.9 vs 84.3 μM, p, Highlights • Xtreme Alps is a randomised controlled field study of dietary nitrate at altitude. • Dietary nitrate significantly increased plasma nitrate, nitrite & nitroso species. • No changes in sublingual blood flow were seen in response to high dietary nitrate. • Dietary nitrate did not alter forearm blood flow under any experimental condition. • Dietary nitrate supplementation did not improve microcirculatory function at 4559 m

Digital technologies such as smartphones are transforming the way scientists conduct biomedical research. Several remotely conducted studies have recruited thousands of participants over a span of a few months allowing researchers to collect real-world data at scale and at a fraction of the cost of traditional research. Unfortunately, remote studies have been hampered by substantial participant attrition, calling into question the representativeness of the collected data including generalizability of outcomes. We report the findings regarding recruitment and retention from eight remote digital health studies conducted between 2014–2019 that provided individual-level study-app usage data from more than 100,000 participants completing nearly 3.5 million remote health evaluations over cumulative participation of 850,000 days. Median participant retention across eight studies varied widely from 2–26 days (median across all studies = 5.5 days). Survival analysis revealed several factors significantly associated with increase in participant retention time, including (i) referral by a clinician to the study (increase of 40 days in median retention time); (ii) compensation for participation (increase of 22 days, 1 study); (iii) having the clinical condition of interest in the study (increase of 7 days compared with controls); and (iv) older age (increase of 4 days). Additionally, four distinct patterns of daily app usage behavior were identified by unsupervised clustering, which were also associated with participant demographics. Most studies were not able to recruit a sample that was representative of the race/ethnicity or geographical diversity of the US. Together these findings can help inform recruitment and retention strategies to enable equitable participation of populations in future digital health research.

Despite the risks associated with hypnotics and their recent increased use in Saudi Arabia, there are no specific national guidelines for using these medicines to treat insomnia nor are there any data on how these medicines are currently prescribed. There is the potential, however, that some physicians might be adhering to the United States guidelines. The current audit study was aimed to assess the current practice in treating insomnia with hypnotics in Saudi Arabia, and to evaluate its agreement with the US guidelines. The audit was conducted using data collected between April 2012 and March 2017 at King Fahad Central Hospital (KFCH, Jazan), of patients who were either prescribed benzodiazepines (BZDs) or Z-drugs or diagnosed with insomnia. The audit criteria followed two US guidelines for the management of insomnia in adults. Data included documented diagnosis, use of CBT-I (Cognitive Behavioral Therapy for Insomnia), use of BZDs and Z-drugs including treatment regimen, and whether physicians prescribed anti-histamines for insomnia. The data were analyzed using STATA 14 after transcription to a MS XL file. Of the 504 records reviewed, 379 patients (75%) were prescribed BZDs or Z-drugs, only 182 (48%) of them had clearly documented indications for their use. Three hundred and seven patients (60%) were diagnosed with insomnia, none of them received CBT-I as initial treatment. No patients on long-term use of hypnotics were reviewed by their physicians after they began using the medication. More than 43% of patients were prescribed anti-histamines for insomnia. No records met all (or even six) of the seven criteria. KFCH physicians do not follow US guidelines. Therefore, the Ministry of Health (MOH) should improve its administrative systems including documentation, and instead of using international guidelines that are seldom followed, physicians should be trained in prescribing hypnotics and national guidelines need to be developed.

The perovskite material (La0.4Pr0.6)0.67Ca0.33MnO3 (LPCMO) has complex electronic and magnetic behavior based on phase competition between ferromagnetic metallic (FMM) and insulating phases with similar free energies. Experimental evidence has indicated that in-plane stress anisotropy influences these phases and can affect electronic and magnetic properties. Here we investigate the roles that both stress and shape anisotropies may play in controlling the coercive field of the material. LPCMO thin films of various thicknesses (20, 25, and 30 nm) were deposited on (110) NdGaO3 (NGO) substrates using pulsed laser deposition and the coercive fields were measured. Photolithography was then used to fabricate microstructured arrays of LPCMO on the NGO substrates for each of the films. The coercive fields of these arrays of LPCMO were compared to the behavior of the corresponding unpatterned LPCMO thin films across a range of temperatures. Microstructure arrays for the thicker (25 and 30 nm) films showed a substantial increase in the coercive field after forming the arrays, whereas a thinner film (20 nm) showed almost no change in the coercive field. Stress anisotropy continues to play a dominant role in the behavior of LPCMO thin films and dimensionality of the magnetic domains also influences the results. The films show 2D behavior when film thickness approaches the size of the critical radius for single-to-multidomain transitions. Making thicker films allows for 3D behavior and a role for shape anisotropy to influence the coercive fields.

Background Healthcare professionals are involved in an array of patient and medicine related stewardship activities, for which an understanding and engagement with antimicrobial stewardship (AMS) is important. Undergraduate education provides an ideal opportunity to prepare healthcare professionals for these roles and activities. Aim To provide United Kingdom national consensus on a common set of antimicrobial stewardship competencies appropriate for undergraduate healthcare professional education. Methods A modified Delphi approach comprising two on-line surveys delivered to a United Kingdom national panel of twenty-one individuals reflecting expertise in prescribing and medicines management with regards to the education and practice of nurses and midwives, pharmacists, physiotherapists and podiatrists; and antimicrobial prescribing and stewardship. Data collection took place between October and December 2017. Findings A total of 21 participants agreed to become members of the expert panel, of whom 19 (90%) completed round 1 questionnaire, and 17 (89%) completed round 2. Panelists reached a consensus, with consistent high levels of agreement reached, on 6 overarching competency statements (sub divided into 6 domains), and 55 individual descriptors essential for antimicrobial stewardship by healthcare professionals. Conclusion Given the consistently high levels of agreement reached on competency statements and their associated descriptors, this competency framework should be used to direct education for undergraduate healthcare professionals, and those working in new clinical roles to support healthcare delivery where an understanding of, and engagement with, AMS is important. Although the competencies target basic education, they can also be used for continuing education.

Recent studies reveal that airway epithelial cells are critical pulmonary circadian pacemaker cells, mediating rhythmic inflammatory responses. Using mouse models, we now identify the rhythmic circadian repressor REV-ERBα as essential to the mechanism coupling the pulmonary clock to innate immunity, involving both myeloid and bronchial epithelial cells in temporal gating and determining amplitude of response to inhaled endotoxin. Dual mutation of REV-ERBα and its paralog REV-ERBβ in bronchial epithelia further augmented inflammatory responses and chemokine activation, but also initiated a basal inflammatory state, revealing a critical homeostatic role for REV-ERB proteins in the suppression of the endogenous proinflammatory mechanism in unchallenged cells. However, REV-ERBα plays the dominant role, as deletion of REV-ERBβ alone had no impact on inflammatory responses. In turn, inflammatory challenges cause striking changes in stability and degradation of REV-ERBα protein, driven by SUMOylation and ubiquitination. We developed a novel selective oxazole-based inverse agonist of REV-ERB, which protects REV-ERBα protein from degradation, and used this to reveal how proinflammatory cytokines trigger rapid degradation of REV-ERBα in the elaboration of an inflammatory response. Thus, dynamic changes in stability of REV-ERBα protein couple the core clock to innate immunity.

A homoglyph (name spoofing) attack is a common technique used by adversaries to obfuscate file and domain names. This technique creates process or domain names that are visually similar to legitimate and recognized names. For instance, an attacker may create malware with the name svch0st.exe so that in a visual inspection of running processes or a directory listing, the process or file name might be mistaken as the Windows system process svchost.exe. There has been limited published research on detecting homoglyph attacks. Current approaches rely on string comparison algorithms (such as Levenshtein distance) that result in computationally heavy solutions with a high number of false positives. In addition, there is a deficiency in the number of publicly available datasets for reproducible research, with most datasets focused on phishing attacks, in which homoglyphs are not always used. This paper presents a fundamentally different solution to this problem using a Siamese convolutional neural network (CNN). Rather than leveraging similarity based on character swaps and deletions, this technique uses a learned metric on strings rendered as images: a CNN learns features that are optimized to detect visual similarity of the rendered strings. The trained model is used to convert thousands of potentially targeted process or domain names to feature vectors. These feature vectors are indexed using randomized KD-Trees to make similarity searches extremely fast with minimal computational processing. This technique shows a considerable 13% to 45% improvement over baseline techniques in terms of area under the receiver operating characteristic curve (ROC AUC). In addition, we provide both code and data to further future research.

Endoplasmic reticulum (ER) stress causes neuronal dysfunction followed by cell death and is recognized as a feature of many neurodegenerative diseases. Using a phenotypic screen, we recently identified benzodiazepinone derivatives that reduce ER stress-mediated apoptosis in a rat neuronal progenitor cell line (CSM14.1). Herein we describe how structure-activity relationship (SAR) studies around these screening hits led to compounds that display robust cytoprotective activity against thapsigargin-induced ER stress in SH-SY5Y and H4 human neuronal cell lines. We demonstrate that the most potent of these derivatives, compound 4hh, inhibits the activation of p38 MAP kinase (p38) and c-Jun N-terminal kinase (JNK), protein kinases that are downstream signal effectors of the unfolded protein response (UPR). Compound 4hh specifically protects against thapsigargin-induced cell death and displays no protection against other insults known to induce cellular stress or activate p38. However, compound 4hh provides moderate inhibition of p38 activity stimulated by compounds that disrupt calcium homeostasis. Our data indicate that probe compound 4hh is a valuable small molecule tool that can be used to investigate the effects of ER stress on human neurons. This approach may provide the basis for the future development of therapeutics for the treatment of neurodegenerative diseases.

Background Classic teaching suggests that diminished availability of oxygen leads to increased tissue oxygen extraction yet evidence to support this notion in the context of hypoxaemia, as opposed to anaemia or cardiac failure, is limited. Methods At 75 m above sea level, and after 7–8 days of acclimatization to 4559 m, systemic oxygen extraction [C(a−v)O2] was calculated in five participants at rest and at peak exercise. Absolute [C(a−v)O2] was calculated by subtracting central venous oxygen content (CcvO2) from arterial oxygen content ( C a O 2 ) in blood sampled from central venous and peripheral arterial catheters, respectively. Oxygen uptake ( V ˙ O 2 ) was determined from expired gas analysis during exercise. Results Ascent to altitude resulted in significant hypoxaemia; median (range) S p O 2 87.1 (82.5–90.7)% and P a O 2 6.6 (5.7–6.8) kPa. While absolute C(a−v)O2 was reduced at maximum exercise at 4559 m [83.9 (67.5–120.9) ml litre−1 vs 99.6 (88.0–151.3) ml litre−1 at 75 m, P=0.043], there was no change in oxygen extraction ratio (OER) [C(a−v)O2/CaO2] between the two altitudes [0.52 (0.48–0.71) at 4559 m and 0.53 (0.49–0.73) at 75 m, P=0.500]. Comparison of C(a−v)O2 at peak V ˙ O 2 at 4559 m and the equivalent V ˙ O 2 at sea level for each participant also revealed no significant difference [83.9 (67.5–120.9) ml litre1 vs 81.2 (73.0–120.7) ml litre−1, respectively, P=0.225]. Conclusion In acclimatized individuals at 4559 m, there was a decline in maximum absolute C(a−v)O2 during exercise but no alteration in OER calculated using central venous oxygen measurements. This suggests that oxygen extraction may have become limited after exposure to 7–8 days of hypoxaemia.

The AWAKE-HF study evaluated the effect of sacubitril/valsartan (S/V) versus enalapril on sleep using actigraphy and a home sleep study in patients (pts) with heart failure with reduced ejection fraction (HFrEF). Pts 18 to 80 years of age with New York Heart Association (NYHA) class II/III HFrEF

The AWAKE-HF trial evaluated the effect of sacubitril/valsartan (S/V) vs enalapril on daytime activity and sleep in patients with heart failure with reduced ejection fraction (HFrEF), using actigraphy. After a 2-week baseline period and 36-hour washout, individuals 18 to 80 years of age with New

The accumulation of unfolded proteins in the endoplasmic reticulum (ER) is caused by many disease-relevant conditions, inducing conserved signaling events collectively known as the unfolded protein response. When ER stress is excessive or prolonged, cell death (usually occurring by apoptosis) is triggered. We undertook a chemical biology approach for investigating mechanisms of ER stress-induced cell death. Using a cell-based high throughput screening assay to identify compounds that rescued a neuronal cell line from thapsigargin-induced cell death, we identified benzodiazepinones that selectively inhibit cell death caused by inducers of ER stress (thapsigargin and tunicamycin) but not by inducers of extrinsic (tumor necrosis factor) or intrinsic (mitochondrial) cell death pathways. The compounds displayed activity in several cell lines and primary cultured neurons. Mechanism of action studies revealed that these compounds inhibit ER stress-induced activation of p38 MAPK and kinases responsible for c-Jun phosphorylation. Active benzodiazepinones suppressed cell death at the level of apoptotic signal kinase-1 (ASK1) within the IRE1 pathway but without directly inhibiting the kinase activity of ASK1 or >400 other kinases tested. Rather, active compounds enhanced phosphorylation of serine 967 of ASK1, promoting ASK1 binding to 14-3-3, an event associated with suppression of ASK1 function. Reducing ASK1 protein expression using small interfering RNA also protected cells from ER stress-induced apoptosis, confirming the importance of this protein kinase. Taken together, these findings demonstrate an essential role for ASK1 in cell death induced by ER stress. The compounds identified may prove useful for revealing endogenous mechanisms that regulate inhibitory phosphorylation of ASK1.

Only two silyldichloramines, (C6H5)3SiNCl2 and (CH3)3SiNCl2, have been reported in the literature. The synthesis of the former was successfully repeated, and its structure was established by single-crystal X-ray diffraction and vibrational spectroscopy. Attempts to prepare (CH3)3SiNCl2 were unsuccessful; however, a new trialkylsilyldichloramine, t-BuMe2Si-NCl2, was prepared and characterized by Raman and multinuclear NMR spectroscopy. The reaction of t-BuMe2SiNCl2 with (CH3)4NF in CHF3 solution at -78 degrees C, followed by removal of all volatile products at -30 degrees C, produced the expected t-BuMe2SiF byproduct and a white solid consisting of NCl3 absorbed on Me4NCl. The NCl3 could be reversibly desorbed from the substrate and was identified as a neat liquid at room temperature by Raman spectroscopy. The observed final reaction products are consistent with the formation of an unstable N(CH3)4+NCl2- intermediate which decomposes to N(CH3)4+Cl- and NCl molecules which can dimerize to N2Cl2. Theoretical calculations confirm that NCl2- can readily lose Cl- and that N2Cl2 also possesses a low barrier toward loss of N2 to give chlorine atoms and, thus, can account for the formation of NCl3.

[reaction: see text] Tributyltin hydride mediated addition of 3-iodosalicylaldehyde to benzene in the presence of catalytic benzeneselenol affords (1,4-cyclohexadien-3-yl)salicylaldehyde. Homologation of the aldehyde group is followed by cycloetherification with dimethyl dioxirane to give a 4,6-disubstituted tetrahydrodibenzofuran. Adjustment of oxidation states and introduction of a second chain by Wittig olefination affords the beta-sheet initiator, ethyl 4-(2-tert-butoxycarbonylaminoethyl)-6-dibenzofuranpropanoate.

REV-ERBα has emerged as an important target for regulation of circadian rhythm and its associated physiology. Herein, we report on the optimization of a series of REV-ERBα agonists based on GSK4112 (1) for potency, selectivity, and bioavailability. (1) Potent REV-ERBα agonists 4, 10, 16, and 23 are detailed for their ability to suppress BMAL and IL-6 expression from human cells while also demonstrating excellent selectivity over LXRα. Amine 4 demonstrated in vivo bioavailability after either iv or oral dosing.

Measurements of neutrino interaction cross-sections are important for the study of neutrino oscillations. For the T2K experiment, which has a near detector with a primarily carbon target and a far detector with an oxygen target, the cross-section difference is important for correctly comparing the neutrino fluxes at the two detectors. This dissertation presents a first measurement of the ratio between oxygen and carbon of the muon neutrino charge-current inclusive cross-section using the T2K near detector, ND280. The design and construction methods of the water target system in the ND280 Fine-Grained Detector (FGD) will be discussed, as will a new algorithm for reconstructing particle tracks contained within the FGD. The data analysis leading to the cross-section ratio measurement will be described. It is based on a statistical subtraction method which extracts the contribution of the FGD water mass to the total interaction rate for the FGD with water targets. We find an oxygen/carbon ratio of 1.129 ± 0.114 (stat) ± 0.044 (syst) from the ND280 data, a 1.39σ difference from the Monte Carlo prediction of 0.954 ± 0.029.

Flight capability for micro air vehicles is rapidly maturing throughout the aviation community; however, mission capability has not yet matured at the same pace. Maintaining trim during a descent or in the presence of crosswinds remains challenging for fixed-wing aircraft but yet is routinely performed by birds. This paper presents an overview of designs that incorporate morphing to enhance their flight characteristics. In particular, a series of joints and structures is adopted from seagulls to alter either the dihedral or sweep of the wings and thus alter the flight characteristics. The resulting vehicles are able to trim with significantly increased angles of attack and sideslip compared to traditional fixed-wing vehicles.

Morphing vehicles have inherently time-varying dynamics due to the alteration of their configurations; consequently, the numerous techniques for analysis and control of timeinvariant systems are inappropriate. A control scheme is introduced that directly considers a concept of time-varying pole to command morphing. The resulting trajectory minimizing tracking error for either a state response or a pole response.

The flight dynamics of morphing aircraft must be analyzed to ensure shapechanging trajectories have the desired characteristics. The tools for describing flight dynamics of fixed-geometry aircraft are not valid for time-varying systems such as morphing aircraft. This paper introduces a method to relate the flight dynamics of morphing aircraft by interpreting a time-varying eigenvector in terms of flight modes. The time-varying eigenvector is actually defined through a decomposition of the state-transition matrix and thus describes an entire response through a morphing trajectory. A variable-sweep aircraft is analyzed to demonstrate the information that is obtained through this method and how the flight dynamics are altered by the time-varying morphing. I. Introduction Morphing provides an ability to alter the shape of an aircraft and thus the flight characteristics. Such morphing is particularly attractive for unpiloted air vehicles due to the relative flexibility in their wings. Also, biologically-inspired concepts for morphing are abundant. The flight dynamics of morphing aircraft have received somewhat less attention than the flight performance. In a sense, studies into flight performance consider the characteristics of steadystate morphing whereas studies into flight dynamics consider the characteristics of time-varying morphing. These flight dynamics are critical to understanding the relative coupling between states when maneuvering. The role of eigenvalues and eigenvectors in describing the flight dynamics is well understood for linear time-invariant aircraft. These parameters are directly computed from the state matrix and directly relate properties of the response. Essentially, every real-valued eigenvalue and associated eigenvector describes a divergence or convergence while every complex-conjugate pair of eigenvalues and associated eigenvectors describe an oscillatory mode. This relationship of the flight dynamics with the eigenvalues and eigenvectors results from the exponential solution that is known for the linear time-invariant dynamics. A notion of eigenvalues and eigenvectors is also defined for linear time-varying systems; however, they actually are computed by decomposing the state-transition matrix rather than the state matrix. This requirement notes that the linear time-varying dynamics do not have a closed-form solution so any decomposition of the response must retain the temporal information within the

In this paper, we investigate the dynamics of a rapidly morphing, variable wing sweep micro air vehicle. The time scales over which the morphing occurs are of the same order as those of the flight dynamics of the MAV. We investigate the time-varying poles and zeros of this MAV for different morphing trajectories. There are several existing notions of timevarying poles and zeros of a linear time-varying system, each with its relative advantages and disadvantages. We explore the use of two of these notions in the study of the timevarying dynamics of the MAV in both the longitudinal as well as the lateral-directional axes.

The intramolecular radical aromatic substitution of heteroaryl sulfones by tethered aryl radicals has been investigated as a source of alkyl radicals. The 1-(2-iodobenzyl)benzimidazole-2-sulfonyl system was found to be the most effective, while a tetrazole-based system did not undergo the desired radical aromatic substitution at all. Application of the benzimidazole-based system to the generation of alkyl radical and their subsequent use in radical cyclizations was demonstrated.

[53317-08-1] C11H19B (MW 162.07) InChI = 1S/C11H19B/c1-2-9-12-10-5-3-6-11(12)8-4-7-10/h2,10-11H,1,3-9H2/t10-,11- InChIKey = VWDZBSSQLJNTMJ-XYPYZODXSA-N (allylating reagent for aldehydes, ketones, acid chlorides, amides, and acid anhydrides;2 reagent for diastereo- and enantioselective allylation of aldimines;6, 8 diastereoselective allylation of acetals9) Alternate Name: allyl-9-BBN. Physical Data: bp 41.5–42 °C/0.05 mmHg. Solubility: sol most organic solvents. Preparative Methods: prepared from Allyl Bromide and B-methoxy-9-BBN according to a literature procedure.1 Crotyl-9-BBN and 2-methallyl-9-BBN are similarly prepared from the corresponding allylic bromides. Handling, Storage, and Precautions: the neat liquid is highly flammable and must be stored in the absence of air and moisture. Allyl-9-BBN may be kept as a CH2Cl2 or THF solution under N2 atmosphere.2 Use in a fume hood.

[865358-58-3] C18H25B (MW 252.20) InChI = 1S/C18H25B/c1-2-14-19-17-12-6-10-16(11-7-13-17)18(19)15-8-4-3-5-9-15/h2-5,8-9,16-18H,1,6-7,10-14H2 InChIKey = MGNDFWIQIFODEO-UHFFFAOYSA-N (asymmetric allylboration of ketones, aldehydes, and ketimines) Alternate Name: B-allyl-10-Ph-9-BBD. Solubility: ether, THF, pentane. Preparative Method: 1 prepared from B-Methoxy-9-BBN, Phenyldiazomethane, and Allylmagnesium Bromide according to the literature procedure. This preparation involves resolution of the enantiomers via a modification of Masamune's protocol,2 which entails the use of enantiopure (1,2)-N -Methylpseudoephedrine. Handling, Storage, and Precautions: the crystalline precursor (eq 1)1 is air stable and can be stored indefinitely at room temperature. Once generated, the title compound must be stored in the absence of air and moisture.

A general method for the synthesis of bis-substituted 1,2,4-oxadiazoles from readily available arylnitriles and activated carbonyls in a single continuous microreactor sequence is described. The synthesis incorporates three sequential microreactors to produce 1,2,4-oxadiazoles in approximately 30 min in quantities (40-80 mg) sufficient for full characterization and rapid library supply.

[27776-21-2] C12H22N6·2HCl (MW 323.33) InChI = 1S/C12H22N6.2ClH/c1-11(2,9-13-5-6-14-9)17-18-12(3,4)10-15-7-8-16-10;;/h5-8H2,1-4H3,(H,13,14)(H,15,16);2*1H InChIKey = LBSPZZSGTIBOFG-UHFFFAOYSA-N Alternate Names: 1H-imidazole, 2,2′-[azobis(1-methylethylidene)]bis[4,5-dihydro- dihydrochloride (9CI); 2,2′-(azodiisopropylidene)di-2-imidazoline dihydrochloride; 2,2′-azobis(2-imidazolinylpropane) dihydrochloride; 2,2′-azobis[2-(2-imidazolin-2-yl)propane] dihydrochloride; AIBI; AIPH; V44; VA-044; Vazo 044; Vazo 44WSP; Wako VA 044. Physical Data: mp 188–193 °C, half-life in water of 10 h at 44 °C. Solubility: freely soluble in water or methanol (30 g and above/ 100 g solvent); insoluble in toluene or hexanes. Form Supplied in: white-pale yellow crystals or crystalline powder, widely available. Handling, Storage, and Precaution: to prevent decomposition store at less than 30 °C.

A general method for the synthesis of bis-substituted 1,2,4-oxadiazoles from readily available arylnitriles and activated carbonyls in a single continuous microreactor sequence is described. The synthesis incorporates three sequential microreactors to produce 1,2,4-oxadiazoles in approximately 30 min in quantities (40-80 mg) sufficient for full characterization and rapid library supply.

Degenerate radical addition fragmentation and nitroxide fragmentation reactions are applied to the expansion of heterobivalent libraries without contamination from homobivalent species. Deconvolution by means of a fluorous tagging process is described.

The discovery and development of the catalysis of stannane-mediated radical chain reactions by benzeneselenol, generated in situ by reduction of diphenyl diselenide with tributyltin hydride, are described. The catalytic sequence is discussed in terms of polarity reversal catalysis of radical chain reactions, and applications to synthesis are presented. These include the prevention of numerous radical rearrangement reactions, the ability to intervene in certain multistep radical rearrangements, especially aryl and vinyl radical cyclizations, at intermediate stages with advantages to the product profile, and the effective trapping of allyl-, benzyl-, and cyclohexadienyl-type radicals, permitting inter alia the isolation of aryl cyclohexadienes and their application in synthesis.

The benzeneselenol-catalyzed, tributyltin hydride-mediated addition of phenolic iodides to benzene gives the 3-(hydroxyaryl)-1,4-cyclohexadienes, predominantly. Under conditions of controlled osmoylation, these are converted to the racemic 1,2-syn-2,3-anti-3-(hydroxyaryl)-4-cyclohexene-1,2-diols, whereas exhaustive osmoylation gives the 3-(hydroxyaryl)-3,5-dideoxymucoinositols, whose stereochemistry is established by X-ray crystallography.

Morphing, which changes the shape and configuration of an aircraft, is being adopted to expand mission capabilities of aircraft. The introduction of biologically-inspired morphing is particularly attractive in that highly-agile birds present examples of aerodynamically-effective shapes. This paper introduces an aircraft with a multiple-joint design that allows variations in sweep to mimic some shapes observed in birds. These variations are independent on the left and right wings along with on the inboard and outboard sections. The aircraft is designed and analyzed to demonstrate the range of flight dynamics which result from the morphing. In particular, the vehicle is shown to have enhanced turning capabilities and crosswind rejection which are certainly critical metrics for the urban environments in which these aircraft are anticipated to operate.

Myocardial dysfunction is a major consequence of septic shock and contributes to the high mortality of sepsis. We have previously reported that glucan phosphate (GP) significantly increased survival in a murine model of cecal ligation and puncture (CLP)-induced sepsis. In the present study, we examined the effect of GP on cardiac dysfunction in CLP-induced septic mice. GP was administered to ICR/HSD mice 1 h before induction of CLP. Sham surgically operated mice served as control. Cardiac function was significantly decreased 6 h after CLP-induced sepsis compared with sham control. In contrast, GP administration prevented CLP-induced cardiac dysfunction. Macrophage migration inhibitory factor (MIF) has been implicated as a major factor in cardiomyocyte apoptosis and cardiac dysfunction during septic shock. CLP increased myocardial MIF expression by 88.3% ( P < 0.05) and cardiomyocyte apoptosis by 7.8-fold ( P < 0.05) compared with sham control. GP administration, however, prevented CLP-increased MIF expression and decreased cardiomyocyte apoptosis by 51.2% ( P < 0.05) compared with untreated CLP mice. GP also prevented sepsis-caused decreases in phospho-Akt, phospho-GSK-3β, and Bcl-2 levels in the myocardium of septic mice. These data suggest that GP treatment attenuates cardiovascular dysfunction in fulminating sepsis. GP administration also activates the phosphoinositide 3-kinase/Akt pathway, decreases myocardial MIF expression, and reduces cardiomyocyte apoptosis.