Electrostatic extraction of cold molecules from a cryogenic reservoir

We present a method which delivers a continuous, high-density beam of slow and internally cold polar molecules. In our source, warm molecules are first cooled by collisions with a cryogenic helium buffer gas. Cold molecules are then extracted by means of an electrostatic quadrupole guide. For ND$_3$ the source produces fluxes up to $(7 \pm ^{7}_{4}) \times 10^{10}$ molecules/s with peak densities up to $(1.0 \pm ^{1.0}_{0.6}) \times 10^9$ molecules/cm$^3$. For H$_2$CO the population of rovibrational states is monitored by depletion spectroscopy, resulting in single-state populations up to $(82 \pm 10)$.Comment: 4 pages, 4 figures, changes to the text, updated figures and reference

Complex Numbers, Quantum Mechanics and the Beginning of Time

A basic problem in quantizing a field in curved space is the decomposition of the classical modes in positive and negative frequency. The decomposition is equivalent to a choice of a complex structure in the space of classical solutions. In our construction the real tunneling geometries provide the link between the this complex structure and analytic properties of the classical solutions in a Riemannian section of space. This is related to the Osterwalder- Schrader approach to Euclidean field theory.Comment: 27 pages LATEX, UCSBTH-93-0

Development of a backward-mode photoacoustic microscope using a Fabry-Perot sensor

Optical-resolution photoacoustic microscopy (PAM) has been shown to enable the acquisition of high resolution (μm) functional and anatomical images. For backward-mode operation, conventional piezoelectric ultrasound transducers need to be placed far away from the signal source due to their opacity and size. This can result in reduced acoustic sensitivity. Planar Fabry-Perot polymer film interferometer (FPI) sensors have the potential to overcome this limitation since they are transparent to the excitation wavelength, can be placed immediately adjacent to the signal source for high acoustic sensitivity, and offer a broadband frequency response (0 –50 MHz). In this study, we present a high frame rate, backward-mode OR-PAM system based on a planar FPI ultrasound sensor. A ns-pulsed laser provides excitation pulses (<200 nJ, maximum pulse repetition frequency = 200 kHz, 532 nm) to generate photoacoustic waves that are detected using a planar FPI sensor interrogated at 765-781 nm. For backwardmode operation and highest acoustic sensitivity, the excitation and interrogation beams are coaxially aligned and rasterscanned. The optical transfer function of the sensor, the spatial resolution and the detection sensitivity were determined to characterise the set-up. Images of a leaf phantom and first in vivo images of zebrafish larvae were acquired. This approach will enable fast 3D OR-PAM with high resolution and high sensitivity for functional and molecular imaging applications. FPI-based ultrasound detection also has the potential to enable dual-mode optical- and acousticresolution PAM and the integration of photoacoustic imaging with purely optical modalities such as multi-photon microscopy

Testing Quantile Forecast Optimality

Quantile forecasts made across multiple horizons have become an important output of many financial institutions, central banks and international organizations. This article proposes misspecification tests for such quantile forecasts that assess optimality over a set of multiple forecast horizons and/or quantiles. The tests build on multiple Mincer-Zarnowitz quantile regressions cast in a moment equality framework. Our main test is for the null hypothesis of autocalibration, a concept which assesses optimality with respect to the information contained in the forecasts themselves. We provide an extension that allows to test for optimality with respect to larger information sets and a multivariate extension. Importantly, our tests do not just inform about general violations of optimality, but may also provide useful insights into specific forms of sub-optimality. A simulation study investigates the finite sample performance of our tests, and two empirical applications to financial returns and U.S. macroeconomic series illustrate that our tests can yield interesting insights into quantile forecast sub-optimality and its causes

Rational design of a (S)-selective-transaminase for asymmetric synthesis of (1S)-1-(1,1′-biphenyl-2-yl)ethanamine

Amine transaminases offer an environmentally sustainable synthesis route for the production of pure chiral amines. However, their catalytic efficiency toward bulky ketone substrates is greatly limited by steric hindrance and therefore presents a great challenge for industrial synthetic applications. We hereby report an example of rational transaminase enzyme design to help alleviate these challenges. Starting from the Vibrio fluvialis amine transaminase that has no detectable catalytic activity toward the bulky aromatic ketone 2-acetylbiphenyl, we employed a rational design strategy combining in silico and in vitro studies to engineer the transaminase enzyme with a minimal number of mutations, achieving an high catalytic activity and high enantioselectivity. We found that, by introducing two mutations W57G/R415A, detectable enzyme activity was achieved. The rationally designed variant, W57F/R88H/V153S/K163F/I259M/R415A/V422A, showed an improvement in reaction rate by more than 1716-fold toward the bulky ketone under study, producing the corresponding enantiomeric pure (S)-amine (enantiomeric excess (ee) value of &gt;99%)

Thalamic stimulation for tremor. Subtle changes in episodic memory are related to stimulation per se and not to a microthalamotomy effect

The aim of this study was to investigate the impact of unilateral deep brain stimulation (DBS) of the ventrointermediate (Vim) thalamic nucleus on neuropsychological functioning comparing stimulation-on with stimulation-off conditions. Nine patients [five patients with Parkinson's Disease (PD), two patients with essential tremor (ET) and 2 patients with multiple sclerosis (MS)] underwent comprehensive neuropsychological testing for cognitive functions, including general mental impairment, aphasia, agnosia, executive and constructional abilities, learning, memory, cognitive processing speed and attention as well as depression. The neuropsychological assessments were performed at least 6 months postoperatively (mean 9 months). Testing in the stimulation-on and stimulation-off condition was obtained within a period of 3 to 4 weeks. Unilateral DBS resulted in improvement of tremor in all patients. There were no significant differences between the stimulation-on and the stimulation-off condition with the exception of a decrement of word-recall in the short delay free-recall subtest of the Rey Auditory-Verbal Learning Test (RAVLT). Subgroup analysis indicated that the impairment in word-recall was related to left-sided thalamic stimulation. Our study confirms that chronic unilateral DBS is a safe method with regard to cognitive function. The subtle changes in episodic memory are related to stimulation per se and not to a microthalamotomy effect

Development and application of novel engineered transaminase panels assisted by in- silico rational design for the production of chiral amines

There is a high demand for the synthesis of chiral amines as building blocks for a large number of industrially valuable compounds. Transaminases (TAm) offer an enzymatic route for the synthesis of chiral amines that avoids complex chemical synthesis [1]. However, their catalytic efficiency towards bulky ketone substrates is greatly limited by steric hinderance [2]. This poster highlights a rational design strategy of combining in silico and in vitro methods to engineer the transaminase enzyme with a minimal number of mutations, achieving high catalytic activity and high enantioselectivity. The wildtype TAm showed no detectable activity towards the ketone 2-acetylbiphenyl but upon introduction of two mutations detectable enzyme activity was observed. The reaction rate was improved a further 1716-fold with the rationally designed variant, that contained a further 5 mutations, producing the corresponding enantiomeric pure (S)-amine (enantiomeric excess (ee) value of \u3e99%)[3]. In addition, screening of in silico designed (R)-TAm mutant panels in resolution mode offered an attractive and efficient route for the preparation of problematic (S)-amines. A mutant was identified from the panels that gave complete resolution of the racemic amine (high substrate loading) to leave the desired enantiomer at a low enzyme loading fit for process development towards an economically viable scale up process. [1] R. C. Simon, et al, ACS Catal. 2014, 4(1) [2] F. Steffen-Munsberg, et al, ChemCatChem 2013, 5, (1) [3]D.F.A.R.Dourado et al, ACS Catal. 2016, 6 (11

Chemoenzymatic Probes for Detecting and Imaging Fucose-α(1-2)-galactose Glycan Biomarkers

The disaccharide motif fucose-α(1-2)-galactose (Fucα(1-2)Gal) is involved in many important physiological processes, such as learning and memory, inflammation, asthma, and tumorigenesis. However, the size and structural complexity of Fucα(1-2)Gal-containing glycans have posed a significant challenge to their detection. We report a new chemoenzymatic strategy for the rapid, sensitive detection of Fucα(1-2)Gal glycans. We demonstrate that the approach is highly selective for the Fucα(1-2)Gal motif, detects a variety of complex glycans and glycoproteins, and can be used to profile the relative abundance of the motif on live cells, discriminating malignant from normal cells. This approach represents a new potential strategy for biomarker detection and expands the technologies available for understanding the roles of this important class of carbohydrates in physiology and disease