Small molecule conjugates with dimetal species for protein inhibition

Methods for targeting a protein by providing an inhibitor covalently linked to a rhodium(II) complex, introducing the inhibitor to the target protein and allowing the inhibitor and protein to interact. The rhodium(II) complex covalently linked to the inhibitor binds the target protein both inorganically and organically and forms stabilizing secondary contacts between the rhodium(II) complex and the protein

Cysteine Modifiers Suggest an Allosteric Inhibitory Site on the CAL PDZ Domain

Protein–protein interactions have become attractive targets for both experimental and therapeutic interventions. The PSD-95/Dlg1/ZO-1 (PDZ) domain is found in a large family of eukaryotic scaffold proteins that plays important roles in intracellular trafficking and localization of many target proteins. Here, we seek inhibitors of the PDZ protein that facilitates post-endocytic degradation of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR): the CFTR-associated ligand (CAL). We develop and validate biochemical screens and identify methyl-3,4-dephostatin (MD) and its analog ethyl-3,4-dephostatin (ED) as CAL PDZ inhibitors. Depending on conditions, MD can bind either covalently or non-covalently. Crystallographic and NMR data confirm that MD attacks a pocket at a site distinct from the canonical peptide-binding groove, and suggests an allosteric connection between target residue Cys319 and the conserved Leu291 in the GLGI motif. MD and ED thus appear to represent the first examples of small-molecule allosteric regulation of PDZ:peptide affinity. Their mechanism of action may exploit the known conformational plasticity of the PDZ domains and suggests that allosteric modulation may represent a strategy for targeting of this family of protein–protein binding modules

A Study of the Diverse T Dwarf Population Revealed by WISE

We report the discovery of 87 new T dwarfs uncovered with the Wide-field Infrared Survey Explorer (WISE) and three brown dwarfs with extremely red near-infrared colors that exhibit characteristics of both L and T dwarfs. Two of the new T dwarfs are likely binaries with L7+/-1 primaries and mid-type T secondaries. In addition, our follow-up program has confirmed 10 previously identified T dwarfs and four photometrically-selected L and T dwarf candidates in the literature. This sample, along with the previous WISE discoveries, triples the number of known brown dwarfs with spectral types later than T5. Using the WISE All-Sky Source Catalog we present updated color-color and color-type diagrams for all the WISE-discovered T and Y dwarfs. Near-infrared spectra of the new discoveries are presented, along with spectral classifications. To accommodate later T dwarfs we have modified the integrated flux method of determining spectral indices to instead use the median flux. Furthermore, a newly defined J-narrow index differentiates the early-type Y dwarfs from late-type T dwarfs based on the J-band continuum slope. The K/J indices for this expanded sample show that 32% of late-type T dwarfs have suppressed K-band flux and are blue relative to the spectral standards, while only 11% are redder than the standards. Comparison of the Y/J and K/J index to models suggests diverse atmospheric conditions and supports the possible re-emergence of clouds after the L/T transition. We also discuss peculiar brown dwarfs and candidates that were found not to be substellar, including two Young Stellar Objects and two Active Galactic Nuclei. The coolest WISE-discovered brown dwarfs are the closest of their type and will remain the only sample of their kind for many years to come.Comment: Accepted to ApJS on 15 January 2013; 99 pages in preprint format, 30 figures, 12 table

Y Dwarf Trigonometric Parallaxes from the Spitzer Space Telescope

Y dwarfs provide a unique opportunity to study free-floating objects with masses <30 M_(Jup) and atmospheric temperatures approaching those of known Jupiter-like exoplanets. Obtaining distances to these objects is an essential step toward characterizing their absolute physical properties. Using Spitzer's Infrared Array Camera (IRAC) [4.5] images taken over baselines of ~2–7 years, we measure astrometric distances for 22 late-T and early Y dwarfs, including updated parallaxes for 18 objects and new parallax measurements for 4 objects. These parallaxes will make it possible to explore the physical parameter space occupied by the coldest brown dwarfs. We also present the discovery of six new late-T dwarfs, updated spectra of two T dwarfs, and the reclassification of a new Y dwarf, WISE J033605.04−014351.0, based on Keck/NIRSPEC J-band spectroscopy. Assuming that effective temperatures are inversely proportional to absolute magnitude, we examine trends in the evolution of the spectral energy distributions of brown dwarfs with decreasing effective temperature. Surprisingly, the Y dwarf class encompasses a large range in absolute magnitude in the near- to mid-infrared photometric bandpasses, demonstrating a larger range of effective temperatures than previously assumed. This sample will be ideal for obtaining mid-infrared spectra with the James Webb Space Telescope because their known distances will make it easier to measure absolute physical properties

The Science Case for an Extended Spitzer Mission

Although the final observations of the Spitzer Warm Mission are currently scheduled for March 2019, it can continue operations through the end of the decade with no loss of photometric precision. As we will show, there is a strong science case for extending the current Warm Mission to December 2020. Spitzer has already made major impacts in the fields of exoplanets (including microlensing events), characterizing near Earth objects, enhancing our knowledge of nearby stars and brown dwarfs, understanding the properties and structure of our Milky Way galaxy, and deep wide-field extragalactic surveys to study galaxy birth and evolution. By extending Spitzer through 2020, it can continue to make ground-breaking discoveries in those fields, and provide crucial support to the NASA flagship missions JWST and WFIRST, as well as the upcoming TESS mission, and it will complement ground-based observations by LSST and the new large telescopes of the next decade. This scientific program addresses NASA's Science Mission Directive's objectives in astrophysics, which include discovering how the universe works, exploring how it began and evolved, and searching for life on planets around other stars.Comment: 75 pages. See page 3 for Table of Contents and page 4 for Executive Summar

Dust Devil Tracks

Dust devils that leave dark- or light-toned tracks are common on Mars and they can also be found on the Earth’s surface. Dust devil tracks (hereinafter DDTs) are ephemeral surface features with mostly sub-annual lifetimes. Regarding their size, DDT widths can range between ∼1 m and ∼1 km, depending on the diameter of dust devil that created the track, and DDT lengths range from a few tens of meters to several kilometers, limited by the duration and horizontal ground speed of dust devils. DDTs can be classified into three main types based on their morphology and albedo in contrast to their surroundings; all are found on both planets: (a) dark continuous DDTs, (b) dark cycloidal DDTs, and (c) bright DDTs. Dark continuous DDTs are the most common type on Mars. They are characterized by their relatively homogenous and continuous low albedo surface tracks. Based on terrestrial and martian in situ studies, these DDTs most likely form when surficial dust layers are removed to expose larger-grained substrate material (coarse sands of ≥500 μm in diameter). The exposure of larger-grained materials changes the photometric properties of the surface; hence leading to lower albedo tracks because grain size is photometrically inversely proportional to the surface reflectance. However, although not observed so far, compositional differences (i.e., color differences) might also lead to albedo contrasts when dust is removed to expose substrate materials with mineralogical differences. For dark continuous DDTs, albedo drop measurements are around 2.5 % in the wavelength range of 550–850 nm on Mars and around 0.5 % in the wavelength range from 300–1100 nm on Earth. The removal of an equivalent layer thickness around 1 μm is sufficient for the formation of visible dark continuous DDTs on Mars and Earth. The next type of DDTs, dark cycloidal DDTs, are characterized by their low albedo pattern of overlapping scallops. Terrestrial in situ studies imply that they are formed when sand-sized material that is eroded from the outer vortex area of a dust devil is redeposited in annular patterns in the central vortex region. This type of DDT can also be found in on Mars in orbital image data, and although in situ studies are lacking, terrestrial analog studies, laboratory work, and numerical modeling suggest they have the same formation mechanism as those on Earth. Finally, bright DDTs are characterized by their continuous track pattern and high albedo compared to their undisturbed surroundings. They are found on both planets, but to date they have only been analyzed in situ on Earth. Here, the destruction of aggregates of dust, silt and sand by dust devils leads to smooth surfaces in contrast to the undisturbed rough surfaces surrounding the track. The resulting change in photometric properties occurs because the smoother surfaces have a higher reflectance compared to the surrounding rough surface, leading to bright DDTs. On Mars, the destruction of surficial dust-aggregates may also lead to bright DDTs. However, higher reflective surfaces may be produced by other formation mechanisms, such as dust compaction by passing dust devils, as this may also cause changes in photometric properties. On Mars, DDTs in general are found at all elevations and on a global scale, except on the permanent polar caps. DDT maximum areal densities occur during spring and summer in both hemispheres produced by an increase in dust devil activity caused by maximum insolation. Regionally, dust devil densities vary spatially likely controlled by changes in dust cover thicknesses and substrate materials. This variability makes it difficult to infer dust devil activity from DDT frequencies. Furthermore, only a fraction of dust devils leave tracks. However, DDTs can be used as proxies for dust devil lifetimes and wind directions and speeds, and they can also be used to predict lander or rover solar panel clearing events. Overall, the high DDT frequency in many areas on Mars leads to drastic albedo changes that affect large-scale weather patterns

Preliminary Trigonometric Parallaxes of 184 Late-T and Y Dwarfs and an Analysis of the Field Substellar Mass Function into the "Planetary" Mass Regime

We present preliminary trigonometric parallaxes of 184 late-T and Y dwarfs using observations from Spitzer (143), USNO (18), NTT (14), and UKIRT (9). To complete the 20-pc census of $\ge$T6 dwarfs, we combine these measurements with previously published trigonometric parallaxes for an additional 44 objects and spectrophotometric distance estimates for another 7. For these 235 objects, we estimate temperatures, sift into five 150K-wide $T_{\rm eff}$ bins covering the range 300-1050K, determine the completeness limit for each, and compute space densities. To anchor the high-mass end of the brown dwarf mass spectrum, we compile a list of early- to mid-L dwarfs within 20 pc. We run simulations using various functional forms of the mass function passed through two different sets of evolutionary code to compute predicted distributions in $T_{\rm eff}$. The best fit of these predictions to our L, T, and Y observations is a simple power-law model with $\alpha \approx 0.6$ (where $dN/dM \propto M^{-\alpha}$), meaning that the slope of the field substellar mass function is in rough agreement with that found for brown dwarfs in nearby star forming regions and young clusters. Furthermore, we find that published versions of the log-normal form do not predict the steady rise seen in the space densities from 1050K to 350K. We also find that the low-mass cutoff to formation, if one exists, is lower than $\sim$5 $M_{Jup}$, which corroborates findings in young, nearby moving groups and implies that extremely low-mass objects have been forming over the lifetime of the Milky Way.Comment: 86 pages with 19 figures. Accepted for publication in The Astrophysical Journal Supplement Series on 2018 Dec 0

Computational Design of a PDZ Domain Peptide Inhibitor that Rescues CFTR Activity

The cystic fibrosis transmembrane conductance regulator (CFTR) is an epithelial chloride channel mutated in patients with cystic fibrosis (CF). The most prevalent CFTR mutation, ΔF508, blocks folding in the endoplasmic reticulum. Recent work has shown that some ΔF508-CFTR channel activity can be recovered by pharmaceutical modulators (“potentiators” and “correctors”), but ΔF508-CFTR can still be rapidly degraded via a lysosomal pathway involving the CFTR-associated ligand (CAL), which binds CFTR via a PDZ interaction domain. We present a study that goes from theory, to new structure-based computational design algorithms, to computational predictions, to biochemical testing and ultimately to epithelial-cell validation of novel, effective CAL PDZ inhibitors (called “stabilizers”) that rescue ΔF508-CFTR activity. To design the “stabilizers”, we extended our structural ensemble-based computational protein redesign algorithm to encompass protein-protein and protein-peptide interactions. The computational predictions achieved high accuracy: all of the top-predicted peptide inhibitors bound well to CAL. Furthermore, when compared to state-of-the-art CAL inhibitors, our design methodology achieved higher affinity and increased binding efficiency. The designed inhibitor with the highest affinity for CAL (kCAL01) binds six-fold more tightly than the previous best hexamer (iCAL35), and 170-fold more tightly than the CFTR C-terminus. We show that kCAL01 has physiological activity and can rescue chloride efflux in CF patient-derived airway epithelial cells. Since stabilizers address a different cellular CF defect from potentiators and correctors, our inhibitors provide an additional therapeutic pathway that can be used in conjunction with current methods

Y Dwarf Trigonometric Parallaxes from the Spitzer Space Telescope

Y dwarfs provide a unique opportunity to study free-floating objects with masses <30 M_(Jup) and atmospheric temperatures approaching those of known Jupiter-like exoplanets. Obtaining distances to these objects is an essential step toward characterizing their absolute physical properties. Using Spitzer's Infrared Array Camera (IRAC) [4.5] images taken over baselines of ~2–7 years, we measure astrometric distances for 22 late-T and early Y dwarfs, including updated parallaxes for 18 objects and new parallax measurements for 4 objects. These parallaxes will make it possible to explore the physical parameter space occupied by the coldest brown dwarfs. We also present the discovery of six new late-T dwarfs, updated spectra of two T dwarfs, and the reclassification of a new Y dwarf, WISE J033605.04−014351.0, based on Keck/NIRSPEC J-band spectroscopy. Assuming that effective temperatures are inversely proportional to absolute magnitude, we examine trends in the evolution of the spectral energy distributions of brown dwarfs with decreasing effective temperature. Surprisingly, the Y dwarf class encompasses a large range in absolute magnitude in the near- to mid-infrared photometric bandpasses, demonstrating a larger range of effective temperatures than previously assumed. This sample will be ideal for obtaining mid-infrared spectra with the James Webb Space Telescope because their known distances will make it easier to measure absolute physical properties