Modeling and interpretation of single-cell proteogenomic data

Biological functions stem from coordinated interactions among proteins, nucleic acids and small molecules. Mass spectrometry technologies for reliable, high throughput single-cell proteomics will add a new modality to genomics and enable data-driven modeling of the molecular mechanisms coordinating proteins and nucleic acids at single-cell resolution. This promising potential requires estimating the reliability of measurements and computational analysis so that models can distinguish biological regulation from technical artifacts. We discuss approaches for developing both abstract and mechanistic models that aim to biologically interpret the measured differences across modalities. Mechanistic models of direct molecular interactions will provide generalizable and predictive representations of biological systems

SAMBA: Superconducting antenna-coupled, multi-frequency, bolometric array

We present a design for a multipixel, multiband (100 GHz, 200 GHz and 400 GHz) submillimeter instrument: SAMBA (Superconducting Antenna-coupled, Multi-frequency, Bolometric Array). SAMBA uses slot antenna coupled bolometers and microstrip filters. The concept allows for a much more compact, multiband imager compared to a comparable feedhorn-coupled bolometric system. SAMBA incorporates an array of slot antennas, superconducting transmission lines, a wide band multiplexer and superconducting transition edge bolometers. The transition-edge film measures the millimeter-wave power deposited in the resistor that terminates the transmission line

Integrated Focal Plane Arrays for Millimeter-wave Astronomy

We are developing focal plane arrays of bolometric detectors for sub-millimeter and millimeter-wave astrophysics. We propose a flexible array architecture using arrays of slot antennae coupled via low-loss superconducting Nb transmission line to microstrip filters and antenna-coupled bolometers. By combining imaging and filtering functions with transmission line, we are able to realize unique structures such as a multi-band polarimeter and a planar, dispersive spectrometer. Micro-strip bolometers have significantly smaller active volume than standard detectors with extended absorbers, and can realize higher sensitivity and speed of response. The integrated array has natural immunity to stray radiation or spectral leaks, and minimizes the suspended mass operating at 0.1 - 0.3 K. We also discuss future space-borne spectroscopy and polarimetry applications

Targeting matriptase in breast cancer abrogates tumour progression via impairment of stromal-epithelial growth factor signalling.

Matriptase is an epithelia-specific membrane-anchored serine protease that has received considerable attention in recent years because of its consistent dysregulation in human epithelial tumours, including breast cancer. Mice with reduced levels of matriptase display a significant delay in oncogene-induced mammary tumour formation and blunted tumour growth. The abated tumour growth is associated with a decrease in cancer cell proliferation. Here we demonstrate by genetic deletion and silencing that the proliferation impairment in matriptase-deficient breast cancer cells is caused by their inability to initiate activation of the c-Met signalling pathway in response to fibroblast-secreted pro-HGF. Similarly, inhibition of matriptase catalytic activity using a selective small-molecule inhibitor abrogates the activation of c-Met, Gab1 and AKT, in response to pro-HGF, which functionally leads to attenuated proliferation in breast carcinoma cells. We conclude that matriptase is critically involved in breast cancer progression and represents a potential therapeutic target in breast cancer

Titanium Nitride Films for Ultrasensitive Microresonator Detectors

Titanium nitride (TiNx) films are ideal for use in superconducting microresonator detectors because: a) the critical temperature varies with composition (0 < Tc < 5 K); b) the normal-state resistivity is large, \rho_n ~ 100 $\mu$Ohm cm, facilitating efficient photon absorption and providing a large kinetic inductance and detector responsivity; and c) TiN films are very hard and mechanically robust. Resonators using reactively sputtered TiN films show remarkably low loss (Q_i > 10^7) and have noise properties similar to resonators made using other materials, while the quasiparticle lifetimes are reasonably long, 10-200 $\mu$s. TiN microresonators should therefore reach sensitivities well below 10^-19 WHz^(-1/2).Comment: to be published in AP

Design of broadband filters and antennas for SAMBA

We present a design for multipixel, multiband submillimeter instrument: SAMBA (Superconducting Antenna-coupled, Multi-frequency, Bolometric Array). SAMBA uses antenna coupled bolometers and microstrip filters. The concept allows for a much more compact, multiband imager compared to a comparable feedhorn-coupled bolometric system. SAMBA incorporates an array of slot antennas, superconducting transmission lines, a wide band multiplexer and superconducting transition edge bolometers. The transition-edge film measures the millimeter-wave power deposited in the resistor that terminates the transmission line

Proteomic analyses of native brain KV4.2 channel complexes

Somatodendritic A-type (I(A)) voltage-gated K(+) (K(V)) channels are key regulators of neuronal excitability, functioning to control action potential waveforms, repetitive firing and the responses to synaptic inputs. Rapidly activating and inactivating somatodendritic I(A) channels are encoded by K(V)4 α subunits and accumulating evidence suggests that these channels function as components of macromolecular protein complexes. Mass spectrometry (MS)-based proteomic approaches were developed and exploited here to identify potential components and regulators of native brain K(V)4.2-encoded I(A) channel complexes. Using anti-K(V)4.2 specific antibodies, K(V)4.2 channel complexes were immunoprecipitated from adult wild type mouse brain. Parallel control experiments were performed on brain samples isolated from (K(V)4.2(−/−)) mice harboring a targeted disruption of the KCND2 (K(V)4.2) locus. Three proteomic strategies were employed: an in-gel approach, coupled to one-dimensional liquid chromatography-tandem MS (1D-LC-MS/MS), and two in-solution approaches, followed by 1D-or 2D-LC-MS/MS. The targeted in-gel 1D-LC-MS/MS analyses demonstrated the presence of the K(V)4 α subunits (K(V)4.2, K(V)4.3 and K(V)4.1) and the K(V)4 accessory, KChIP (KChIPI-4) and DPP (DPP6 and 10), proteins in native brain K(V)4.2 channel complexes. The more comprehensive, in-solution approach, coupled to 2D-LC-MS/MS, also called Multidimensional Protein Identification Technology (MudPIT), revealed that additional regulatory proteins, including the K(V) channel accessory subunit K(V)β1, are also components of native brain K(V)4.2 channel complexes. Additional biochemical and functional approaches will be required to elucidate the physiological roles of these newly identified K(V)4 interacting proteins

Silicon nitride micromesh bolometer arrays for SPIRE

We are developing arrays of bolometers based on silicon nitride micromesh absorbers for the Spectral & Photometric Imaging Receiver (SPIRE) on the Far Infra-Red and Submillimeter Space Telescope (FIRST). The bolometers are coupled to a close-packed array of 1 f(lambda) feedhorns which views the primary mirror through a cooled aperture stop. Feedhorn-coupled bolometers minimize the detector area and throughput and have good optical efficiency. A 1 f(lambda) feedhorn array provides, higher mapping speed than a 2 f(lambda) feedhorn array and reduces the number of jitters required to produce a fully sampled map, but at the cost of more detectors. Individual silicon nitride micromesh bolometers are already able to meet the performance requirements of SPIRE. In parallel we are developing transition-edge detectors read out by SQUID current amplifier. The relatively large cooling power available at 300 mK enables the array to be coupled to a cold SQUID multiplexer, creating a monolithic fully multiplexed array and making large format arrays possible for SPIRE