Iridium-catalysed synthesis of C, N, N -cyclic azomethine imines enables entry to unexplored nitrogen-rich 3D chemical space

Three-dimensional nitrogen-rich bridged ring systems are of great interest in drug discovery owing to their distinctive physicochemical and structural properties. However, synthetic approaches towards N–N-bond-containing bridged heterocycles are often inefficient and require tedious synthetic strategies. Here we delineate an iridium-catalysed reductive approach to such architectures from C, N, N-cyclic hydrazide substrates using IrCl(CO)[P(OPh)3]2 and 1,1,3,3-tetramethyldisiloxane (TMDS), which provided efficient access to the unstabilized and highly reactive C, N, N-cyclic azomethine imine dipoles. These species were stable and isolable in their dimeric form, but, upon dissociation in solution, reacted with a broad range of dipolarophiles in [3 + 2] cycloaddition reactions with high yields and good diastereoselectivities, enabling the direct synthesis of nitrogen-rich sp3-hybridized pyrazoline polycyclic ring systems. Density functional theory calculations were performed to elucidate the origin of the diastereoselectivity of the cycloaddition reaction, and principal moment of inertia (PMI) analysis was conducted to enable visualization of the topological information of the dipolar cycloadducts

The design and characterization of a 300 channel, optimized full-band millimeter filterbank for science with SuperSpec

SuperSpec is an integrated, on-chip spectrometer for millimeter and sub-millimeter astronomy. We report the approach, design optimization, and partial characterization of a 300 channel filterbank covering the 185 to 315 GHz frequency band that targets a resolving power R ~ 310, and fits on a 3.5×5.5 cm chip. SuperSpec uses a lens and broadband antenna to couple radiation into a niobium microstrip that feeds a bank of niobium microstrip half-wave resonators for frequency selectivity. Each half-wave resonator is coupled to the inductor of a titanium nitride lumped-element kinetic inductance detector (LEKID) that detects the incident radiation. The device was designed for use in a demonstration instrument at the Large Millimeter Telescope (LMT)

Full-Array Noise Performance of Deployment-Grade SuperSpec mm-Wave On-Chip Spectrometers

SuperSpec is an on-chip filter bank spectrometer designed for wideband moderate-resolution spectroscopy at millimeter wavelengths, employing TiN kinetic inductance detectors. SuperSpec technology will enable large-format spectroscopic integral field units suitable for high-redshift line intensity mapping and multi-object spectrographs. In previous results, we have demonstrated noise performance in individual detectors suitable for photon noise-limited ground-based observations at excellent mm-wave sites. In these proceedings, we present the noise performance of a full R∼275 spectrometer measured using deployment-ready RF hardware and software. We report typical noise equivalent powers through the full device of ∼3×10⁻¹⁶ W Hz^(−1/2) at expected sky loadings, which are photon noise dominated. Based on these results, we plan to deploy a six-spectrometer demonstration instrument to the Large Millimeter Telescope in early 2020

SuperSpec: development towards a full-scale filter bank

SuperSpec is a new spectrometer-on-a-chip technology for submm/mm-wave spectroscopy. SuperSpec stands out from other direct-detection submm spectrometer technologies in that the detectors are coupled to a series of resonant filters along a single microwave feedline instead of using dispersive optics. SuperSpec makes use of kinetic inductance detectors (KIDs) to detect radiation in this filter bank. The small profile of this design makes SuperSpec a natural choice to produce a multi-object spectrometer for tomographic mapping or galaxy redshift surveys. We have recently fabricated a device that is a 50 channel subset of a full 280 channel filter bank, which would cover the 190 - 310 GHz range at R = 275. Analysis of the data from this device informs us of the potential design modifications to enable a high-yield background-limited SuperSpec spectrometer. The results indicate that this subset filter bank can scale up to a full filter bank with only a few collisions in readout space and less than 20% variation in responsivity for the detectors. Additionally, the characterization of this and other prototype devices suggests that the noise performance is limited by generation-recombination noise. Finally, we find that the detectors are sufficiently sensitive for ground-based spectroscopy at R = 100, appropriate for tomographic mapping experiments. Further modifications are required to reach the background limit for R = 400, ideal for spectroscopy of individual galaxies

Integrated Approach Reveals Role of Mitochondrial Germ-Line Mutation F18L in Respiratory Chain, Oxidative Alterations, Drug Sensitivity, and Patient Prognosis in Glioblastoma

Glioblastoma is the most common and malignant primary brain tumour in adults, with a dismal prognosis. This is partly due to considerable inter- and intra-tumour heterogeneity. Changes in the cellular energy-producing mitochondrial respiratory chain complex (MRC) activities are a hallmark of glioblastoma relative to the normal brain, and associate with differential survival outcomes. Targeting MRC complexes with drugs can also facilitate anti-glioblastoma activity. Whether mutations in the mitochondrial DNA (mtDNA) that encode several components of the MRC contribute to these phenomena remains underexplored. We identified a germ-line mtDNA mutation (m. 14798T > C), enriched in glioblastoma relative to healthy controls, that causes an amino acid substitution F18L within the core mtDNA-encoded cytochrome b subunit of MRC complex III. F18L is predicted to alter corresponding complex III activity, and sensitivity to complex III-targeting drugs. This could in turn alter reactive oxygen species (ROS) production, cell behaviour and, consequently, patient outcomes. Here we show that, despite a heterogeneous mitochondrial background in adult glioblastoma patient biopsy-derived cell cultures, the F18L substitution associates with alterations in individual MRC complex activities, in particular a 75% increase in MRC complex II_III activity, and a 34% reduction in CoQ10, the natural substrate for MRC complex III, levels. Downstream characterisation of an F18L-carrier revealed an 87% increase in intra-cellular ROS, an altered cellular distribution of mitochondrial-specific ROS, and a 64% increased sensitivity to clomipramine, a repurposed MRC complex III-targeting drug. In patients, F18L-carriers that received the current standard of care treatment had a poorer prognosis than non-carriers (373 days vs. 415 days, respectively). Single germ-line mitochondrial mutations could predispose individuals to differential prognoses, and sensitivity to mitochondrial targeted drugs. Thus, F18L, which is present in blood could serve as a useful non-invasive biomarker for the stratification of patients into prognostically relevant groups, one of which requires a lower dose of clomipramine to achieve clinical effect, thus minimising side-effects