113 research outputs found
Properties of Modified Tryptophans in a Membrane- Spanning Channel
An emerging concept in biology assigns the amino acid tryptophan specific roles at the membrane/water interface that help to determine the conformation and biological function of membrane-spanning proteins. Previous studies involving the antibiotic model system gramicidin A (gA) have illustrated the importance of the indole ring of tryptophan (Trp) in anchoring proteins to a bilayer membrane and promoting ionic currents. To further investigate these phenomena, derivatives of Trp that have lost hydrogen-bonding ability (1-methyl-Trp ), have an altered dipole moment (7-aza-Trp), or both (1-methyl-7-azaTrp) were chosen for incorporation into gA. Gramicidin analogues that incorporate these modified Trps were then analyzed by single channel experiments. In addition, methods were developed for the selective exchange of indole hydrogen with deuterium (a heavy isotope of hydrogen, 2 H) using a Raney nickel catalyst. The 2 H labels enable determinations of the orientation of each Trp indole ring with respect to the membrane surface using solid-state deuterium NMR spectroscopy. The last method 1 pursued involves the application of ab initio molecular modeling programs to calculate the side-chain dipole moments of Trp, 1-methyl-Trp, 7-aza-Trp, and 7-aza-1-methyl-Trp. Therefore, this project combines both experimental and theoretical aspects of scientific research. Results from the single-channel experiments of [7-azaTrp 1 and [7-aza-1-methyl-Trp 1 gA analogues indicate that there is a positive correlation between channel conductance and the magnitude of the side chain dipole moments. A new methodology involving a Raney nickel catalyst was also successfully developed that allows for -75% of7-aza-Trp \u27s sixth hydrogen to exchange with deuterium. In addition to these experimental results, the ab initio program PQS was used to generate theoretical predictions of Trp side chain dipoles that were comparable to experimentally determine dipoles, and that allowed for the calculation of 1- methyl-Trp\u27s side chain dipole. Beyond the immediate results, the more general implication of this project is the fundamental knowledge gained concerning the interactions of Trp with other amino acids, water, and lipids. These studies will contribute to a better understanding of folded proteins- especially those that span biological membranes
Cyclin D1 Restrains Oncogene-Induced Autophagy by Regulating the AMPK-LKB1 Signaling Axis.
Autophagy activated after DNA damage or other stresses mitigates cellular damage by removing damaged proteins, lipids, and organelles. Activation of the master metabolic kinase AMPK enhances autophagy. Here we report that cyclin D1 restrains autophagy by modulating the activation of AMPK. In cell models of human breast cancer or in a cyclin D1-deficient model, we observed a cyclin D1-mediated reduction in AMPK activation. Mechanistic investigations showed that cyclin D1 inhibited mitochondrial function, promoted glycolysis, and reduced activation of AMPK (pT172), possibly through a mechanism that involves cyclin D1-Cdk4/Cdk6 phosphorylation of LKB1. Our findings suggest how AMPK activation by cyclin D1 may couple cell proliferation to energy homeostasis
The Simons Observatory microwave SQUID multiplexing detector module design
Advances in cosmic microwave background (CMB) science depend on increasing
the number of sensitive detectors observing the sky. New instruments deploy
large arrays of superconducting transition-edge sensor (TES) bolometers tiled
densely into ever larger focal planes. High multiplexing factors reduce the
thermal loading on the cryogenic receivers and simplify their design. We
present the design of focal-plane modules with an order of magnitude higher
multiplexing factor than has previously been achieved with TES bolometers. We
focus on the novel cold readout component, which employs microwave SQUID
multiplexing (mux). Simons Observatory will use 49 modules containing
60,000 bolometers to make exquisitely sensitive measurements of the CMB. We
validate the focal-plane module design, presenting measurements of the readout
component with and without a prototype detector array of 1728
polarization-sensitive bolometers coupled to feedhorns. The readout component
achieves a yield and a 910 multiplexing factor. The median white noise
of each readout channel is 65 . This impacts the
projected SO mapping speed by , which is less than is assumed in the
sensitivity projections. The results validate the full functionality of the
module. We discuss the measured performance in the context of SO science
requirements, which are exceeded.Comment: Accepted to The Astrophysical Journa
The Simons Observatory Large Aperture Telescope Receiver
The Simons Observatory (SO) Large Aperture Telescope Receiver (LATR) will be
coupled to the Large Aperture Telescope located at an elevation of 5,200 m on
Cerro Toco in Chile. The resulting instrument will produce arcminute-resolution
millimeter-wave maps of half the sky with unprecedented precision. The LATR is
the largest cryogenic millimeter-wave camera built to date with a diameter of
2.4 m and a length of 2.6 m. It cools 1200 kg of material to 4 K and 200 kg to
100 mk, the operating temperature of the bolometric detectors with bands
centered around 27, 39, 93, 145, 225, and 280 GHz. Ultimately, the LATR will
accommodate 13 40 cm diameter optics tubes, each with three detector wafers and
a total of 62,000 detectors. The LATR design must simultaneously maintain the
optical alignment of the system, control stray light, provide cryogenic
isolation, limit thermal gradients, and minimize the time to cool the system
from room temperature to 100 mK. The interplay between these competing factors
poses unique challenges. We discuss the trade studies involved with the design,
the final optimization, the construction, and ultimate performance of the
system
The receptor binding domain of the viral spike protein is an immunodominant and highly specific target of antibodies in SARS-CoV-2 patients
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that first emerged in late 2019 is responsible for a pandemic of severe respiratory illness. People infected with this highly contagious virus can present with clinically inapparent, mild, or severe disease. Currently, the virus infection in individuals and at the population level is being monitored by PCR testing of symptomatic patients for the presence of viral RNA. There is an urgent need for SARS-CoV-2 serologic tests to identify all infected individuals, irrespective of clinical symptoms, to conduct surveillance and implement strategies to contain spread. As the receptor binding domain (RBD) of the spike protein is poorly conserved between SARS-CoVs and other pathogenic human coronaviruses, the RBD represents a promising antigen for detecting CoV-specific antibodies in people. Here we use a large panel of human sera (63 SARS-CoV-2 patients and 71 control subjects) and hyperimmune sera from animals exposed to zoonotic CoVs to evaluate RBD's performance as an antigen for reliable detection of SARS-CoV-2-specific antibodies. By day 9 after the onset of symptoms, the recombinant SARS-CoV-2 RBD antigen was highly sensitive (98%) and specific (100%) for antibodies induced by SARS-CoVs. We observed a strong correlation between levels of RBD binding antibodies and SARS-CoV-2 neutralizing antibodies in patients. Our results, which reveal the early kinetics of SARS-CoV-2 antibody responses, support using the RBD antigen in serological diagnostic assays and RBD-specific antibody levels as a correlate of SARS-CoV-2 neutralizing antibodies in people
The Atacama Cosmology Telescope: A Measurement of the DR6 CMB Lensing Power Spectrum and its Implications for Structure Growth
We present new measurements of cosmic microwave background (CMB) lensing over
sq. deg. of the sky. These lensing measurements are derived from the
Atacama Cosmology Telescope (ACT) Data Release 6 (DR6) CMB dataset, which
consists of five seasons of ACT CMB temperature and polarization observations.
We determine the amplitude of the CMB lensing power spectrum at
precision ( significance) using a novel pipeline that minimizes
sensitivity to foregrounds and to noise properties. To ensure our results are
robust, we analyze an extensive set of null tests, consistency tests, and
systematic error estimates and employ a blinded analysis framework. The
baseline spectrum is well fit by a lensing amplitude of
relative to the Planck 2018 CMB power spectra
best-fit CDM model and relative to
the best-fit model. From our lensing power
spectrum measurement, we derive constraints on the parameter combination
of
from ACT DR6 CMB lensing alone and
when combining ACT DR6 and Planck NPIPE
CMB lensing power spectra. These results are in excellent agreement with
CDM model constraints from Planck or
CMB power spectrum measurements. Our lensing measurements from redshifts
-- are thus fully consistent with CDM structure growth
predictions based on CMB anisotropies probing primarily . We find no
evidence for a suppression of the amplitude of cosmic structure at low
redshiftsComment: 45+21 pages, 50 figures. Prepared for submission to ApJ. Also see
companion papers Madhavacheril et al and MacCrann et a
The Atacama Cosmology Telescope: High-resolution component-separated maps across one-third of the sky
Observations of the millimeter sky contain valuable information on a number
of signals, including the blackbody cosmic microwave background (CMB), Galactic
emissions, and the Compton- distortion due to the thermal Sunyaev-Zel'dovich
(tSZ) effect. Extracting new insight into cosmological and astrophysical
questions often requires combining multi-wavelength observations to spectrally
isolate one component. In this work, we present a new arcminute-resolution
Compton- map, which traces out the line-of-sight-integrated electron
pressure, as well as maps of the CMB in intensity and E-mode polarization,
across a third of the sky (around 13,000 sq.~deg.). We produce these through a
joint analysis of data from the Atacama Cosmology Telescope (ACT) Data Release
4 and 6 at frequencies of roughly 93, 148, and 225 GHz, together with data from
the \textit{Planck} satellite at frequencies between 30 GHz and 545 GHz. We
present detailed verification of an internal linear combination pipeline
implemented in a needlet frame that allows us to efficiently suppress Galactic
contamination and account for spatial variations in the ACT instrument noise.
These maps provide a significant advance, in noise levels and resolution, over
the existing \textit{Planck} component-separated maps and will enable a host of
science goals including studies of cluster and galaxy astrophysics, inferences
of the cosmic velocity field, primordial non-Gaussianity searches, and
gravitational lensing reconstruction of the CMB.Comment: The Compton-y map and associated products will be made publicly
available upon publication of the paper. The CMB T and E mode maps will be
made available when the DR6 maps are made publi
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