Geometry and Joint Systems for Lattice-Based Reconfigurable Space Structures

We describe analytical methods for the design of the discrete elements of ultralight lattice structures. This modular, building block strategy allows for relatively simple element manufacturing, as well as relatively simple robotic assembly of low mass density structures on orbit, with potential for disassembly and reassembly into highly varying and large structures. This method also results in a structure that is easily navigable by relatively small mobile robots. The geometry of the cell can allow for high packing efficiency to minimize wasted payload volume while maximizing structural performance and constructability. We describe the effect of geometry choices on the final system mechanical properties, manufacturability of the components, and automated robotic constructability of a final system. Geometry choices considered include building block complexity, symmetry of the unit cell, and effects of vertex, edge, and face connectivity of the unit cell. Mechanical properties considered include strength scaling, modulus scaling, and structural performance of the joint, including proof load, shear load, mass, and loading area; as well as validation and verification opportunities. Manufacturability metrics include cost and time, manufacturing method (COTS versus custom), and tolerances required. Automated constructability metrics include local effects of loads imparted to the structure by the robot and assembly complexity, encompassing the ability of the robot to clamp and number of placement motions needed for assembly

Novel styryl-indoles as small molecule inhibitors of 25-hydroxyvitamin D-24-hydroxylase (CYP24A1): Synthesis and biological evaluation

The synthesis of a series of imidazole styrylindoles and sulfonyl styrylindoles derivatives is described. Evaluation of binding affinity and inhibitory activity against CYP24A1 identified the imidazole styrylindoles as potent inhibitors with activity greater or comparable with the standard ketoconazole. Flexible alignment and docking studies of the inhibitors in the CYP24A1 enzyme active site confirmed that complete occupation of the vitamin D access tunnel is essential to inhibitory activity, allowing exposure to multiple hydrophobic binding interactions and optimal conformation for the interaction of the imidazole nitrogen lone pair and the active site haem

Small-molecule inhibitors of 25-hydroxyvitamin D-24-hydroxylase (CYP24A1): synthesis and biological evaluation

The synthesis of imidazole styrylbenzamide, tert-butyl styrylimidazole, and tert-butyl styrylsulfonate derivatives is described. Evaluation of binding affinity and inhibitory activity against CYP24A1 identified the imidazole styrylbenzamides as potent inhibitors of CYP24A1, having selectivity with respect to CYP27B1 comparable with or greater than that of the standard ketoconazole. Further evaluation of the 3,5-dimethoxy and 3,4,5-trimethoxy derivatives in chronic lymphocytic leukemia cells revealed that co-treatment of 1α,25-dihydroxyvitamin D3 plus inhibitor coordinately upregulated GADD45α and CDKN1A. Docking experiments on the inhibitors in the CYP24A1 enzyme active site suggest the compounds reach the active site through the vitamin D access tunnel and are exposed to multiple hydrophobic residues. The imidazole styrylbenzamides are optimally positioned to allow interaction of the imidazole with the heme, and, in the case of the methoxy derivatives, a hydrogen bond between the 3-methoxy group and Gln82 stabilizes the molecule in a favorable active conformation

Fentanyl exposure among patients seeking opioid treatment

Aim: Overdoses attributed to the potent opioid agonist fentanyl have substantially increased in recent years. Despite these serious public health consequences, many opioid treatment providers do not currently include a fentanyl assay in their urine toxicology testing. As a result, extent of fentanyl exposure and related risks among individuals with opioid use disorder often remains unknown. We examined the prevalence of fentanyl exposure among patients seeking or enrolled in opioid agonist treatment. Methods: Six hundred urine specimens were collected from adults entering (n = 100) or enrolled in (n = 500) opioid agonist treatment and analyzed using the clinic's standard opioid panel, supplemented with a 100 ng/ml fentanyl assay. Results: Of the 100 specimens collected from patients at treatment intake, 19 (19%) tested positive for fentanyl. Importantly, 17 (90%) of those fentanyl-positive specimens were also positive for heroin. Of the 500 collected from patients in treatment, 17 (3%) of specimens tested positive for fentanyl. Of those, 11 (92%) were also positive for heroin. Conclusion: These data illustrate a concerning degree of fentanyl exposure among patients seeking treatment and suggest that much of this exposure may have stemmed from fentanyl-containing heroin. Given the unprecedented recent surges in fentanyl-related overdoses, efforts to identify fentanyl exposure are critical. In particular, the point of treatment entry permits a rare systematic opportunity for medical and clinical staff to address fentanyl use and risks with incoming patients

Novel styryl-indoles as small molecule inhibitors of 25-hydroxyvitamin D-24-hydroxylase (CYP24A1): Synthesis and biological evaluation

The synthesis of a series of imidazole styrylindoles and sulfonyl styrylindoles derivatives is described. Evaluation of binding affinity and inhibitory activity against CYP24A1 identified the imidazole styrylindoles as potent inhibitors with activity greater or comparable with the standard ketoconazole. Flexible alignment and docking studies of the inhibitors in the CYP24A1 enzyme active site confirmed that complete occupation of the vitamin D access tunnel is essential to inhibitory activity, allowing exposure to multiple hydrophobic binding interactions and optimal conformation for the interaction of the imidazole nitrogen lone pair and the active site haem