The specificity of intermodular recognition in a prototypical nonribosomal peptide synthetase depends on an adaptor domain

In the quest for new bioactive substances, nonribosomal peptide synthetases (NRPS) provide biodiversity by synthesizing nonproteinaceous peptides with high cellular activity. NRPS machinery consists of multiple modules, each catalyzing a unique series of chemical reactions. Incomplete understanding of the biophysical principles orchestrating these reaction arrays limits the exploitation of NRPSs in synthetic biology. Here, we use nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry to solve the conundrum of how intermodular recognition is coupled with loaded carrier protein specificity in the tomaymycin NRPS. We discover an adaptor domain that directly recruits the loaded carrier protein from the initiation module to the elongation module and reveal its mechanism of action. The adaptor domain of the type found here has specificity rules that could potentially be exploited in the design of engineered NRPS machinery.</p

Discovery of a Bright Field Methane (T-type) Brown Dwarf by 2MASS

We report the discovery of a bright (J = 13.83$\pm$0.03) methane brown dwarf, or T dwarf, by the Two Micron All Sky Survey. This object, 2MASSI J0559191-140448, is the first brown dwarf identified by the newly commissioned CorMASS instrument mounted on the Palomar 60-inch Telescope. Near-infrared spectra from 0.9 - 2.35 \micron show characteristic CH$_4$ bands at 1.1, 1.3, 1.6, and 2.2 \micron, which are significantly shallower than those seen in other T dwarfs discovered to date. Coupled with the detection of an FeH band at 0.9896 \micron and two sets of K I doublets at J-band, we propose that 2MASS J0559-14 is a warm T dwarf, close to the transition between L and T spectral classes. The brightness of this object makes it a good candidate for detailed investigation over a broad wavelength regime and at higher resolution.Comment: 21 pages, 3 figures, 2 tables, accepted to AJ for publication August 200

Primary Meningeal Rhabdomyosarcoma

Primary meningeal rhabdomyosarcoma is a rare primary brain malignancy, with scant case reports. While most reports of primary intracranial rhabdomyosarcoma occur in pediatric patients, a handful of cases in adult patients have been reported in the medical literature. We report the case of a 44-year-old male who developed primary meningeal rhabdomyosarcoma. After developing episodes of right lower extremity weakness, word finding difficulty, and headaches, a brain magnetic resonance imaging (MRI) demonstrated a vertex lesion with radiographic appearance of a meningeal-derived tumor. Subtotal surgical resection was performed due to sagittal sinus invasion and initial pathology was interpreted as an anaplastic meningioma. Re-review of pathology demonstrated rhabdomyosarcoma negative for alveolar translocation t(2;13). Staging studies revealed no evidence of disseminated disease. He was treated with stereotactic radiotherapy with concurrent temozolamide to be followed by vincristine, actinomycin-D, and cyclophosphamide (VAC) systemic therapy

A Sample of Very Young Field L Dwarfs and Implications for the Brown Dwarf "Lithium Test" at Early Ages

Using a large sample of optical spectra of late-type dwarfs, we identify a subset of late-M through L field dwarfs that, because of the presence of low-gravity features in their spectra, are believed to be unusually young. From a combined sample of 303 field L dwarfs, we find observationally that 7.6+/-1.6% are younger than 100 Myr. This percentage is in agreement with theoretical predictions once observing biases are taken into account. We find that these young L dwarfs tend to fall in the southern hemisphere (Dec < 0 deg) and may be previously unrecognized, low-mass members of nearby, young associations like Tucana-Horologium, TW Hydrae, beta Pictoris, and AB Doradus. We use a homogeneously observed sample of roughly one hundred and fifty 6300-10000 Angstrom spectra of L and T dwarfs taken with the Low-Resolution Imaging Spectrometer at the W. M. Keck Observatory to examine the strength of the 6708-A Li I line as a function of spectral type and further corroborate the trends noted by Kirkpatrick et al. (2000). We use our low-gravity spectra to investigate the strength of the Li I line as a function of age. The data weakly suggest that for early- to mid-L dwarfs the line strength reaches a maximum for a few 100 Myr, whereas for much older (few Gyr) and much younger (<100 Myr) L dwarfs the line is weaker or undetectable. We show that a weakening of lithium at lower gravities is predicted by model atmosphere calculations, an effect partially corroborated by existing observational data. Larger samples containing L dwarfs of well determined ages are needed to further test this empirically. If verified, this result would reinforce the caveat first cited in Kirkpatrick et al. (2006) that the lithium test should be used with caution when attempting to confirm the substellar nature of the youngest brown dwarfs.Comment: 73 pages with 22 figures; to appear in ApJ (Dec 20, 2008, v689n2 issue

Impact of collimator leaf width and treatment technique on stereotactic radiosurgery and radiotherapy plans for intra- and extracranial lesions

<p>Abstract</p> <p>Background</p> <p>This study evaluated the dosimetric impact of various treatment techniques as well as collimator leaf width (2.5 vs 5 mm) for three groups of tumors – spine tumors, brain tumors abutting the brainstem, and liver tumors. These lesions often present challenges in maximizing dose to target volumes without exceeding critical organ tolerance. Specifically, this study evaluated the dosimetric benefits of various techniques and collimator leaf sizes as a function of lesion size and shape.</p> <p>Methods</p> <p>Fifteen cases (5 for each site) were studied retrospectively. All lesions either abutted or were an integral part of critical structures (brainstem, liver or spinal cord). For brain and liver lesions, treatment plans using a 3D-conformal static technique (3D), dynamic conformal arcs (DARC) or intensity modulation (IMRT) were designed with a conventional linear accelerator with standard 5 mm leaf width multi-leaf collimator, and a linear accelerator dedicated for radiosurgery and hypofractionated therapy with a 2.5 mm leaf width collimator. For the concave spine lesions, intensity modulation was required to provide adequate conformality; hence, only IMRT plans were evaluated using either the standard or small leaf-width collimators.</p> <p>A total of 70 treatment plans were generated and each plan was individually optimized according to the technique employed. The Generalized Estimating Equation (GEE) was used to separate the impact of treatment technique from the MLC system on plan outcome, and t-tests were performed to evaluate statistical differences in target coverage and organ sparing between plans.</p> <p>Results</p> <p>The lesions ranged in size from 2.6 to 12.5 cc, 17.5 to 153 cc, and 20.9 to 87.7 cc for the brain, liver, and spine groups, respectively. As a group, brain lesions were smaller than spine and liver lesions. While brain and liver lesions were primarily ellipsoidal, spine lesions were more complex in shape, as they were all concave. Therefore, the brain and the liver groups were compared for volume effect, and the liver and spine groups were compared for shape. For the brain and liver groups, both the radiosurgery MLC and the IMRT technique contributed to the dose sparing of organs-at-risk(OARs), as dose in the high-dose regions of these OARs was reduced up to 15%, compared to the non-IMRT techniques employing a 5 mm leaf-width collimator. Also, the dose reduction contributed by the fine leaf-width MLC decreased, as dose savings at all levels diminished from 4 – 11% for the brain group to 1 – 5% for the liver group, as the target structures decreased in volume. The fine leaf-width collimator significantly improved spinal cord sparing, with dose reductions of 14 – 19% in high to middle dose regions, compared to the 5 mm leaf width collimator.</p> <p>Conclusion</p> <p>The fine leaf-width MLC in combination with the IMRT technique can yield dosimetric benefits in radiosurgery and hypofractionated radiotherapy. Treatment of small lesions in cases involving complex target/OAR geometry will especially benefit from use of a fine leaf-width MLC and the use of IMRT.</p

Probing the dynamic stalk region of the ribosome using solution NMR

Abstract: We describe an NMR approach based on the measurement of residual dipolar couplings (RDCs) to probe the structural and motional properties of the dynamic regions of the ribosome. Alignment of intact 70S ribosomes in filamentous bacteriophage enabled measurement of RDCs in the mobile C-terminal domain (CTD) of the stalk protein bL12. A structural refinement of this domain using the observed RDCs did not show large changes relative to the isolated protein in the absence of the ribosome, and we also found that alignment of the CTD was almost independent of the presence of the core ribosome particle, indicating that the inter-domain linker has significant flexibility. The nature of this linker was subsequently probed in more detail using a paramagnetic alignment strategy, which revealed partial propagation of alignment between neighbouring domains, providing direct experimental validation of a structural ensemble previously derived from SAXS and NMR relaxation measurements. Our results demonstrate the prospect of better characterising dynamical and functional regions of more challenging macromolecular machines and systems, for example ribosome–nascent chain complexes

Keck Spectra of Pleiades Brown Dwarf Candidates and a Precise Determination of the Lithium Depletion Edge in the Pleiades

We have obtained intermediate resolution spectra of eleven candidate brown dwarf members of the Pleiades open cluster using the Keck II telescope and LRIS spectrograph. Our primary goal was to determine the location of the "lithium depletion edge" in the Pleiades and hence to derive a precise age for the cluster. All but one of our 11 program objects have radial velocities appropriate for Pleiades members, have moderately strong H alpha emission, and have spectral types M6 to M8.5, as expected for their (R-I) colors. We have constructed a color-magnitude diagram for the faint end of the Pleiades main sequence, including only stars for which high S/N spectra in the region of the lithium 6708 Angstrom absorption line have been obtained. These data allow us to accurately determine the Pleiades single-star lithium depletion edge at I(c0) = 17.80, R-I(c0) = 2.20, spectral type = M6.5. By reference to theoretical evolutionary models, this converts fairly directly into an age for the Pleiades of 125 Myr. This is significantly older than the age that is normally quoted, but does agree with some other recent estimates.Comment: 12 pages, including 3 Figures. Accepted by ApJ Letter