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Capsaicin (trans-8-methyl-N-vanillyl-6-noneamide) is a hydrophobic, lipophilic vanilloid phytochemical abundantly found in chili peppers and pepper extracts. Several convergent studies show that capsaicin displays robust cancer activity, suppressing the growth, angiogenesis and metastasis of several human cancers. Despite its potent cancer-suppressing activity, the clinical applications of capsaicin as a viable anti-cancer drug have remained problematic due to its poor bioavailability and aqueous solubility properties. In addition, the administration of capsaicin is associated with adverse side effects like gastrointestinal cramps, stomach pain, nausea and diarrhea and vomiting. All these hurdles may be circumvented by encapsulation of capsaicin in sustained release drug delivery systems. Most of the capsaicin-based the sustained release drugs have been tested for their pain-relieving activity. Only a few of these formulations have been investigated as anti-cancer agents. The present review describes the physicochemical properties, bioavailability, and anti-cancer activity of capsaicin-sustained release agents. The asset of such continuous release capsaicin formulations is that they display better solubility, stability, bioavailability, and growth-suppressive activity than the free drug. The encapsulation of capsaicin in sustained release carriers minimizes the adverse side effects of capsaicin. In summary, these capsaicin-based sustained release drug delivery systems have the potential to function as novel chemotherapies, unique diagnostic imaging probes and innovative chemosensitization agents in human cancers.

USNO Bright Star Catalog (UBSC) is a new astrometric catalog of 1423 brightest stars covering the entire sky, which is published online. It is nearly complete to $V=3$ mag except for three stellar systems. A combined astrometric solution of the Hipparcos Intermediate Astrometry Data and two dedicated ground-based campaigns in 2013 -- 2020 is the basis for this catalog. The astrometric parameters for each star include position coordinates, parallax, proper motion components, and their covariances on the Hipparcos mean epoch 1991.25. 64 percent of the catalog are flagged as known or suspected double or binary stars. UBSC lists 68 stars missing in Gaia EDR3 and another 114 stars without Gaia parallaxes or proper motions. The formal precision achieved for proper motions is comparable to that of Gaia., Accepted for publication in AJ. Astrometric catalog of 1423 bright stars will be published online

Capsaicin displays robust growth-inhibitory activity in multiple human cancers. However, the feasibility of capsaicin as a clinically relevant anticancer drug is hampered by its adverse side effects. This concern has led to extensive research focused on the isolation and synthesis of second-generation nonpungent capsaicin analogues with potent antineoplastic activity. A major class of nonpungent capsaicin-like compounds belongs to the N-acyl-vanillylamide (N-AVAM) derivatives of capsaicin (hereafter referred as N-AVAM capsaicin analogues). This perspective discusses the isolation of N-AVAM capsaicin analogues from natural sources as well as their synthesis by chemical and enzymatic methods. The perspective describes the pharmacokinetic properties and anticancer activity of N-AVAM capsaicin analogues. The signaling pathways underlying the growth-inhibitory effects of N-AVAM capsaicin analogues have also been highlighted. It is hoped that the insights obtained in this perspective will facilitate the synthesis of a second generation of N-AVAM capsaicin analogues with improved stability and growth-suppressive activity in human cancer.

Background: Survival outcomes are poor for patients with metastatic urothelial carcinoma who receive standard, first-line, platinum-based chemotherapy. We assessed the overall survival of patients who received durvalumab (a PD-L1 inhibitor), with or without tremelimumab (a CTLA-4 inhibitor), as a first-line treatment for metastatic urothelial carcinoma. Methods: DANUBE is an open-label, randomised, controlled, phase 3 trial in patients with untreated, unresectable, locally advanced or metastatic urothelial carcinoma, conducted at 224 academic research centres, hospitals, and oncology clinics in 23 countries. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0 or 1. We randomly assigned patients (1:1:1) to receive durvalumab monotherapy (1500 mg) administered intravenously every 4 weeks; durvalumab (1500 mg) plus tremelimumab (75 mg) administered intravenously every 4 weeks for up to four doses, followed by durvalumab maintenance (1500 mg) every 4 weeks; or standard-of-care chemotherapy (gemcitabine plus cisplatin or gemcitabine plus carboplatin, depending on cisplatin eligibility) administered intravenously for up to six cycles. Randomisation was done through an interactive voice–web response system, with stratification by cisplatin eligibility, PD-L1 status, and presence or absence of liver metastases, lung metastases, or both. The coprimary endpoints were overall survival compared between the durvalumab monotherapy versus chemotherapy groups in the population of patients with high PD-L1 expression (the high PD-L1 population) and between the durvalumab plus tremelimumab versus chemotherapy groups in the intention-to-treat population (all randomly assigned patients). The study has completed enrolment and the final analysis of overall survival is reported. The trial is registered with ClinicalTrials.gov, NCT02516241, and the EU Clinical Trials Register, EudraCT number 2015-001633-24. Findings: Between Nov 24, 2015, and March 21, 2017, we randomly assigned 1032 patients to receive durvalumab (n=346), durvalumab plus tremelimumab (n=342), or chemotherapy (n=344). At data cutoff (Jan 27, 2020), median follow-up for survival was 41·2 months (IQR 37·9–43·2) for all patients. In the high PD-L1 population, median overall survival was 14·4 months (95% CI 10·4–17·3) in the durvalumab monotherapy group (n=209) versus 12·1 months (10·4–15·0) in the chemotherapy group (n=207; hazard ratio 0·89, 95% CI 0·71–1·11; p=0·30). In the intention-to-treat population, median overall survival was 15·1 months (13·1–18·0) in the durvalumab plus tremelimumab group versus 12·1 months (10·9–14·0) in the chemotherapy group (0·85, 95% CI 0·72–1·02; p=0·075). In the safety population, grade 3 or 4 treatment-related adverse events occurred in 47 (14%) of 345 patients in the durvalumab group, 93 (27%) of 340 patients in the durvalumab plus tremelimumab group, and in 188 (60%) of 313 patients in the chemotherapy group. The most common grade 3 or 4 treatment-related adverse event was increased lipase in the durvalumab group (seven [2%] of 345 patients) and in the durvalumab plus tremelimumab group (16 [5%] of 340 patients), and neutropenia in the chemotherapy group (66 [21%] of 313 patients). Serious treatment-related adverse events occurred in 30 (9%) of 345 patients in the durvalumab group, 78 (23%) of 340 patients in the durvalumab plus tremelimumab group, and 50 (16%) of 313 patients in the chemotherapy group. Deaths due to study drug toxicity were reported in two (1%) patients in the durvalumab group (acute hepatic failure and hepatitis), two (1%) patients in the durvalumab plus tremelimumab group (septic shock and pneumonitis), and one (

In recent decades, outbreaks of fall cankerworm (Alsophila pometaria, Lepidoptera: Geometridae) have increased in urban and suburban areas of the mid-Atlantic and southeastern U.S.A., including in Richmond, Virginia, as well as in Charlotte, North Carolina. Managers in these regions commonly monitor fall cankerworm population trends using sticky band traps and use established thresholds relating the number of individuals captured to defoliation as a decision-making tool. For this pest, defoliation thresholds were established based on large forest tracts, although these may yield inaccurate predictions in urban and suburban landscapes. Analyses of defoliation and fall cankerworm sticky band traps in Fairfax County, Virginia, U.S.A., indicate that trees with >200 female moths have >50% probability of being defoliated at moderate or greater intensity. This threshold is much larger than the threshold of 45 females previously established for large forest tracts, and a statistical model based on this established threshold proved an extremely poor fit to the data. In addition, we found little spatial correlation in fall cankerworm abundance among trap locations, in contrast to an established rule of thumb proposing that one trap per 40 ha can estimate fall cankerworm abundance for areas over 400 ha. These findings highlight the importance of the ecological context in which management recommendations are made.

We describe the 44 systems discovered to be within 10 parsecs of the Sun by the RECONS team, primarily via the long-term astrometry program at CTIO that began in 1999. The systems --- including 41 with red dwarf primaries, 2 white dwarfs, and 1 brown dwarf --- have been found to have trigonometric parallaxes greater than 100 milliarcseconds (mas), with errors of 0.4--2.4 mas in all but one case. We provide updated astrometric, photometric (VRIJHK magnitudes), spectral type, and multiplicity information here. Among these are 14 systems that are new entries to the 10 parsec sample based on parallaxes measured at the CTIO/SMARTS 0.9m telescope. These are the first parallaxes for nine systems, while the remaining five systems had previously measured parallaxes with errors greater than 10 mas or values placing them beyond 10 parsecs. We also present parallaxes from URAT for seven of these systems, providing additional evidence that they are closer than 10 parsecs. In addition, we provide new data for 22 systems that were previously known to lie within 10 parsecs and 9 systems reported to be closer than that horizon but for which new parallaxes place them further away. In total, we provide data for 75 systems, for which 71 have new or updated parallaxes here. The 44 systems added by RECONS comprise one of every seven systems known within 10 parsecs. We illustrate the evolution of the 10 parsec sample from the 191 systems known when the final Yale Parallax Catalog (YPC) was published in 1995 to the 316 systems known today. Even so close to the Sun, additional discoveries of red and brown dwarfs (and perhaps even white dwarfs) are likely, both as primaries and secondaries, although we estimate that at least 90% of the stellar systems closer than 10 parsecs have now been identified., submitted to AJ, 44 pages, 6 Figures, 4 Tables

We present 1103 trigonometric parallaxes and proper motions from the United States Naval Observatory (USNO) Robotic Astrometric Telescope (URAT) observations taken at the Naval Observatory Flagstaff Station (NOFS) over a 3 year period from April 2012 to June 2015 covering the entire sky north of about minus 10 deg declination. We selected 2 samples previously suspected nearby stars from known photometric distances and stars showing a large, significant parallax signature in URAT epoch data without any prior selection criteria. All systems presented in this paper have an observed parallax greater than equal to 40 mas with no previous published trigonometric parallax. The formal errors on these weighted parallax solutions are mostly between 4 and 10 mas. This sample gives a significant (order 50%) increase to the number of known systems having a trigonometric parallax to be within 25 pc of the Sun (without applying Lutz Kelker bias corrections). A few of these are found to be within 10 pc. Many of these new nearby stars display a total proper motion of less than 200 mas per year. URAT parallax results have been verified against Hipparcos and Yale data for stars in common. The publication of all significant parallax observations from URAT data is in preparation for CDS., Comment: 47 pages includes: 4 tables,18 figures, Accepted for publication in The Astronomical Journal

We present trigonometric parallaxes of 64 stellar systems with proper motions between 0\farcs5 yr$^{-1}$ and 1\farcs0 yr$^{-1}$ from the ongoing RECONS (Research Consortium On Nearby Stars) parallax program at CTIO (the Cerro Tololo Interamerican Observatory). All of the systems are south of DEC $= +30$, and 58 had no previous trigonometric parallaxes. In addition to parallaxes for the systems, we present proper motions, Johnson-Kron-Cousins $VRI$ photometry, variability measurements, and spectral types. Nine of the systems are multiple; we present results for their components, three of which are new astrometric detections. Of the 64 systems, 56 are within 25 parsecs of the Sun and 52 of those are in the southern hemisphere, comprising 5.7\% of the total number of known southern 25 parsec systems.

This paper presents 442 new proper motion stellar systems in the southern sky between declinations –90° and –47° with 040 yr–1 > μ ≥ 018 yr–1. These systems constitute a 25.3% increase in new systems for the same region of the sky covered by previous SuperCOSMOS RECONS (SCR) searches that used Schmidt plates as the primary source of discovery. Among the new systems are 25 multiples, plus an additional 7 new common proper motion (CPM) companions to previously known primaries. All stars have been discovered using the third U.S. Naval Observatory (USNO) CCD Astrograph Catalog (UCAC3). A comparison of the UCAC3 proper motions to those from the Hipparcos, Tycho-2, Southern Proper Motion (SPM4), and SuperCOSMOS efforts is presented and shows that UCAC3 provides similar values and precision to the first three surveys. The comparison between UCAC3 and SuperCOSMOS indicates that proper motions in R.A. are systematically shifted in the SuperCOSMOS data but are consistent in decl. data, while overall showing a significantly higher scatter. Distance estimates are derived for stars having SuperCOSMOS Sky Survey BJ , R 59F , and I IVN plate magnitudes and Two-Micron All Sky Survey infrared photometry. We find 15 systems estimated to be within 25 pc, including UPM 1710-5300 our closest new discovery estimated at 13.5 pc. Such new discoveries suggest that more nearby stars are yet to be found in these slower proper motion regimes, indicating that more work is needed to develop a complete map of the solar neighborhood.

The Brorfelde Schmidt CCD Catalog (BSCC) contains about 13.7 million stars, north of +49 deg Declination with precise positions and V, R photometry. The catalog has been constructed from the reductions of 18,667 CCD frames observed with the Brorfelde Schmidt Telescope between 2000 and 2007. The Tycho-2 catalog was used for astrometric and photometric reference stars. Errors of individual positions are about 20 to 200 mas for stars in the R = 10 to 18 mag range. External comparisons with 2MASS and SDSS reveal possible small systematic errors in the BSCC of up to about 30 mas. The catalog is supplemented with J, H, and K_s magnitudes from the 2MASS catalog. The catalog data file (about 550 MB ASCII, compressed) will be made available at the Strasbourg Data Center (CDS).

The third US Naval Observatory (USNO) CCD Astrograph Catalog, UCAC3 was released at the IAU General Assembly on 2009 August 10. It is the first all-sky release in this series and contains just over 100 million objects, about 95 million of them with proper motions, covering about R = 8 to 16 magnitudes. Current epoch positions are obtained from the observations with the 20 cm aperture USNO Astrograph's "red lens", equipped with a 4k by 4k CCD. Proper motions are derived by combining these observations with over 140 ground- and space-based catalogs, including Hipparcos/Tycho and the AC2000.2, as well as unpublished measures of over 5000 plates from other astrographs. For most of the faint stars in the Southern Hemisphere the Yale/San Juan first epoch plates from the SPM program (YSJ1) form the basis for proper motions. These data are supplemented by all-sky Schmidt plate survey astrometry and photometry obtained from the SuperCOSMOS project, as well as 2MASS near-IR photometry. Major differences of UCAC3 data as compared to UCAC2 include a completely new raw data reduction with improved control over systematic errors in positions, significantly improved photometry, slightly deeper limiting magnitude, coverage of the north pole region, greater completeness by inclusion of double stars and weak detections. This of course leads to a catalog which is not as "clean" as UCAC2 and problem areas are outlined for the user in this paper. The positional accuracy of stars in UCAC3 is about 15 to 100 mas per coordinate, depending on magnitude, while the errors in proper motions range from 1 to 10 mas/yr depending on magnitude and observing history, with a significant improvement over UCAC2 achieved due to the re-reduced SPM data and inclusion of more astrograph plate data unavailable at the time of UCAC2., accepted by AJ, 24 pages, 34 figures, 3 tables

We report 1606 new proper motion systems in the southern sky (declinations -90 degrees to -47 degrees with 0.40 arcsec yr^-1 > mu >= 0.18 yr^-1. This effort is a continuation of the SuperCOSMOS-RECONS (SCR) proper motion search to lower proper motions than reported in Papers VIII, X, XII, and XV in this series. Distance estimates are presented for the new systems, assuming that all stars are on the main sequence. We find that 31 systems are within 25 pc, including two systems -- SCR 0838-5855 and SCR 1826-6542 -- we anticipate to be within 10 pc. These new discoveries constitute a more than ten-fold increase in new systems found in the same region of sky searched for systems with mu >= 0.40 arcsec yr^-1, suggesting a happy hunting ground for new nearby slower proper motion systems in the region just north (declinations -47 degrees to 0 degrees, much of which has not been rigorously searched during previous efforts.

Proper motions are computed and collected in a catalog using the Hipparcos positions (epoch 1991.25) and URAT1 positions (epoch 2012.3 to 2014.6). The goal is to obtain a significant improvement on the proper motion accuracy of single stars in the northern hemisphere, and to identify new astrometric binaries perturbed by orbital motion. For binaries and multiple systems, the longer baseline of Tycho2 (~ 100 yr) makes it more reliable despite its larger formal uncertainties. The resulting proper motions obtained for 67,340 stars have a consequent gain in accuracy by a factor of ~ 3 compared to Hipparcos. Comparison between UrHip and Hipparcos shows that they are reasonably close, but also reveals stars with large discrepant proper motions, a fraction of which are potential binary candidates., 11 pages, 5 figures, accepted for publication in AJ

The polypeptide growth factor, hepatocyte growth factor/scatter factor (HGF/SF), shares the multidomain structure and proteolytic mechanism of activation of plasminogen and other complex serine proteinases. HGF/SF, however, has no enzymatic activity. Instead, it controls the growth, morphogenesis, or migration of epithelial, endothelial, and muscle progenitor cells through the receptor tyrosine kinase MET. Using small-angle x-ray scattering and cryo-electron microscopy, we show that conversion of pro(single-chain)HGF/SF into the active two-chain form is associated with a major structural transition from a compact, closed conformation to an elongated, open one. We also report the structure of a complex between two-chain HGF/SF and the MET ectodomain (MET928) with 1:1 stoichiometry in which the N-terminal and first kringle domain of HGF/SF contact the face of the seven-blade β-propeller domain of MET harboring the loops connecting the β-strands b–c and d–a, whereas the C-terminal serine proteinase homology domain binds the opposite “b” face. Finally, we describe a complex with 2:2 stoichiometry between two-chain HGF/SF and a truncated form of the MET ectodomain (MET567), which is assembled around the dimerization interface seen in the crystal structure of the NK1 fragment of HGF/SF and displays the features of a functional, signaling unit. The study shows how the proteolytic mechanism of activation of the complex proteinases has been adapted to cell signaling in vertebrate organisms, offers a description of monomeric and dimeric ligand-receptor complexes, and provides a foundation to the structural basis of HGF/SF-MET signaling.

We report the discovery of 152 new high proper motion systems (mu >= 0.4"/yr) in the southern sky (Declination = -47 degrees to 00 degrees) brighter than UKST plate R_{59F} =16.5 via our SuperCOSMOS-RECONS (SCR) search. This paper complements Paper XII in The Solar Neighborhood series, which covered the region from Declination = -90 degrees to -47 degrees and discussed all 147 new systems from the southernmost phase of the search. Among the total of 299 systems from both papers, there are 148 (71 in Paper XII, 77 in this paper) new systems moving faster than 0.5"/yr that are additions to the classic ``LHS'' (Luyten Half Second) sample. These constitute an 8% increase in the sample of all stellar systems with mu >= 0.5"/yr in the southern sky. As in Paper XII, distance estimates are provided for the systems reported here based upon a combination of photographic plate magnitudes and 2MASS photometry, assuming all stars are on the main sequence. Two SCR systems from the portion of the sky included in this paper are anticipated to be within 10 pc, and an additional 23 are within 25 pc. In total, the results presented in Paper XII and here for this SCR sweep of the entire southern sky include five new systems within 10 pc and 38 more between 10 and 25 pc. The largest number of nearby systems have been found in the slowest proper motion bin, 0.6"/yr > mu >= 0.4"/yr, indicating that there may be a large population of low proper motion systems very near the Sun.

Fear of Falling (FoF) is the most commonly reported fear among older adults (up to 50%) and can result in the avoidance of physical and social activities, potentially leading to loss of confidence, social isolation, increasing dependency, depression and decreased quality of life. To develop a psychological intervention to address FoF, we investigated how older people make sense of and accommodate fear of falling in their everyday lives.

Aaron Klug's group was one of the first to use a combination of X-ray diffraction and electron microscopy to study the structures of macromolecules. He helped to provide the intellectual framework for understanding the self-assembly of regular viruses and developed methods for analyzing their three-dimensional structures from electron microscope images, as well as the structures of helical polymers. He and his coworkers established the basic features of chromatin organization, including the structure of the repeating units (nucleosomes) and how they are stacked together. He studied a variety of molecules that interact with DNA or RNA, including disks of tobacco mosaic virus protein, a tRNA and a ribozyme, and also discovered the zinc-finger motif in nucleic acid-binding proteins. Thus, he has played a major part in developing the ideas and techniques that established structural molecular biology as an exciting new science during the second half of the twentieth century.∗∗This article is part of the Pioneers series in Trends in Cell Biology. Pioneers articles feature researchers, experiments and concepts that forged the way to modern cell biology.

Each sensory organ of the Drosophila peripheral nervous system is derived from a single sensory organ precursor cell (SOP). These originate in territories defined by expression of the proneural genes of the Achaete-Scute complex (AS-C). Formation of ectopic sensilla outside these regions is prevented by transcriptional repression of proneural genes. We demonstrate that the BTB/POZ-domain transcriptional repressor Tramtrack (Ttk) co-operates in this repression. Ttk is expressed ubiquitously, except in proneural clusters and SOPs. Ttk over-expression represses proneural genes and sensilla formation. Loss of Ttk enhances bristle-promoting mutants. Using neural repression as an assay, we dissected functional domains of Ttk, confirming the importance of the bric-à-brac-tramtrack-broad complex (BTB) motif. We show that the Ttk BTB domain is a protein-protein interaction motif mediating tetramer formation.

A study of papers on amyloid fibers suggested to us that cylindrical β-sheets are the only structures consistent with some of the x-ray and electron microscope data. We then found that our own 7-year-old and hitherto enigmatic x-ray diagram of poly- l -glutamine fits a cylindrical sheet of 31 Å diameter made of β-strands with 20 residues per helical turn. Successive turns are linked by hydrogen bonds between both the main chain and side chain amides, and side chains point alternately into and out of the cylinder. Fibers of the exon-1 peptide of huntingtin and of the glutamine- and asparagine-rich region of the yeast prion Sup35 give the same underlying x-ray diagrams, which show that they have the same structure. Electron micrographs show that the 100-Å-thick fibers of the Sup35 peptide are ropes made of three protofibrils a little over 30 Å thick. They have a measured mass of 1,450 Da/Å, compared with 1,426 Da/Å for a calculated mass of three protofibrils each with 20 residues per helical turn wound around each other with a helical pitch of 510 Å. Published x-ray diagrams and electron micrographs show that fibers of synuclein, the protein that forms the aggregates of Parkinson disease, consist of single cylindrical β-sheets. Fibers of Alzheimer Aβ fragments and variants are probably made of either two or three concentric cylindrical β-sheets. Our structure of poly- l -glutamine fibers may explain why, in all but one of the neurodegenerative diseases resulting from extension of glutamine repeats, disease occurs when the number of repeats exceeds 37–40. A single helical turn with 20 residues would be unstable, because there is nothing to hold it in place, but two turns with 40 residues are stabilized by the hydrogen bonds between their amides and can act as nuclei for further helical growth. The Aβ peptide of Alzheimer's disease contains 42 residues, the best number for nucleating further growth. All these structures are very stable; the best hope for therapies lies in preventing their growth.

When insulin solutions are subjected to acid, heat and agitation, the normal pattern of insulin assembly (dimers-->tetramers-->hexamers) is disrupted; the molecule undergoes conformational changes allowing it to follow an alternative aggregation pathway (via a monomeric species) leading to the formation of insoluble amyloid fibres. To investigate the effect of acid pH on the conformation and aggregation state of the protein, the crystal structure of human insulin at pH 2.1 has been determined to 1.6 A resolution. The structure reveals that the native fold is maintained at low pH, and that the molecule is still capable of forming dimers similar to those found in hexameric insulin structures at higher pH. Sulphate ions are incorporated into the molecule and the crystal lattice where they neutralise positive charges on the protein, stabilising its structure and facilitating crystallisation. The sulphate interactions are associated with local deformations in the protein, which may indicate that the structure is more plastic at low pH. Transmission electron microscopy analysis of insulin fibres reveals that the appearance of the fibres is greatly influenced by the type of acid employed. Sulphuric acid produces distinctive highly bunched, truncated fibres, suggesting that the sulphate ions have a sophisticated role to play in fibre formation, rather as they do in the crystal structure. Analytical ultracentrifugation studies show that in the absence of heating, insulin is predominantly dimeric in mineral acids, whereas in acetic acid the equilibrium is shifted towards the monomer. Hence, the effect of acid on the aggregation state of insulin is also complex. These results suggest that acid conditions increase the susceptibility of the molecule to conformational change and dissociation, and enhance the rate of fibrillation by providing a charged environment in which the attractive forces between the protein molecules is increased.

As a step toward completing and characterizing the census of the solar neighborhood, we present astrometric, photometric, and spectroscopic observations of 32 systems observed with the Cerro Tololo Inter-American Observatory 0.9 m and 1.5 m telescopes. Astrometry from the 0.9 m indicates that among the 17 systems that had no previous published trigonometric parallaxes, 14 are within 25 pc. In the full sample, nine systems have proper motions larger than 0.”5 yr^(−1), including 2MASS J02511490-0352459, which exceeds 2.”0 yr^(−1). VRI photometry from the 0.9 m and optical spectra from the 1.5 m indicate that the targets have V = 11–22 mag and spectral types M3.0V–L3.0V. For 2MASS J23062928-0502285 (TRAPPIST-1), we present updated astrometry and photometric variability based on over 12 years of observations. Of the nine binaries in the sample, two promise mass determinations in the next decade: LHS 6167AB, an M4.5V system for which we present an accurate parallax placing the binary at 9.7 pc, and 2MASS J23515048-2537367AB, an M8.5V system at 21.1 pc for which we present the first evidence of an unseen, low-mass companion. Most importantly, Na I and K I gravity indicators, Hα measurements, long-term photometric variability, locations on the H-R diagram, and kinematic assessments indicate that as many as 13 of the systems are young, including candidate members of young moving groups, with ages less than ~120 Myr.

New astrometric reductions of the US Naval Observatory CCD Astrograph Catalog (UCAC) all-sky observations were performed from first principles using the TGAS stars in the 8 to 11 magnitude range as reference star catalog. Significant improvements in the astrometric solutions were obtained and the UCAC5 catalog of mean positions at a mean epoch near 2001 was generated. By combining UCAC5 with Gaia DR1 data new proper motions on the Gaia coordinate system for over 107 million stars were obtained with typical accuracies of 1 to 2 mas/yr (R = 11 to 15 mag), and about 5 mas/yr at 16th mag. Proper motions of most TGAS stars are improved over their Gaia data and the precision level of TGAS proper motions is extended to many millions more, fainter stars. External comparisons were made using stellar cluster fields and extragalactic sources. The TGAS data allow us to derive the limiting precision of the UCAC x,y data, which is significantly better than 1/100 pixel., Comment: 15 pages, 15 figures, 3 tables, accepted by AJ

22q11.2 deletion syndrome is the most common microdeletion syndrome. Wilms tumor is one of the most common solid tumors in childhood yet 22q11.2 deletion and Wilms tumor only once have been reported in the same patient. Here we describe a young patient with subtle clinical findings suggestive of 22q11.2 at the time of diagnosis who subsequently developed Wilms tumor. We assert the importance of a low threshold for screening for 22q11.2 deletion and the associated phenotypes and maintaining vigilance in screening for common primary malignancies in patients with known 22q11.2 deletion.

We present trigonometric, photometric, and photographic distances to 1748 southern ($\delta \leq$0$^\circ$) M dwarf systems with $\mu \ge$ 0\farcs18 yr$^{-1}$, of which 1404 are believed to lie within 25 parsecs of the Sun. The stars have 6.67 $\leq$ $V_J$ $\leq$ 21.38 and 3.50 $\leq$ ($V_J-K_s$) $\leq$ 9.27, covering the entire M dwarf spectral sequence from M0.0V through M9.5V. This sample therefore provides a comprehensive snapshot of our current knowledge of the southern sky for the nearest M dwarfs that dominate the stellar population of the Galaxy. Roughly one-third of the 1748 systems, each of which has an M dwarf primary, have published high quality parallaxes, including 179 from the RECONS astrometry program. For the remaining systems, we offer photometric distance estimates that have well-calibrated errors. The bulk of these ($\sim$700) are based on new $V_JR_{KC}I_{KC}$ photometry acquired at the CTIO/SMARTS 0.9m telescope, while the remaining 500 primaries have photographic plate distance estimates calculated using SuperCOSMOS $B_JR_{59F}I_{IVN}$ photometry. Confirmed and candidate subdwarfs in the sample have been identified, and a census of companions is included., Comment: accepted by The Astronomical Journal on 25 July, 2014; 75 pages of tables, 11 figures

We use data from the U.S. Naval Observatory fourth CCD Astrograph Catalog (UCAC4) in combination with photometry from the AAVSO Photometric All-Sky Survey (APASS) and Two Micron All-Sky Survey (2MASS) to identify stars within 25 pc of the Sun. A sample of nearby stars with accurate trigonometric parallaxes from the Research Consortium On Nearby Stars (RECONS) is used to generate a set of 16 new photometric color-$M_{K{_s}}$ relations that provide distance estimates with uncertainties of 15\%. This work expands the available suites of well-calibrated photometric distance relations that can be used to identify nearby stellar systems. The distance relations are used with quality cuts to extract an initial sample of stars from the UCAC4 estimated to be within 25 pc. Color, proper motion and existing literature sources are then used to obtain a clean sample of red dwarfs, while limiting the amount of contamination from background giants, resulting in a sample of 1761 candidate nearby stars within 25 pc. Of these, 339 are new discoveries with no previously known published parallax or distance estimate, primarily with proper motions less than 0.2 arcsec/year. Five stars are estimated to be within 10 pc, with the nearest, TYC 3980 1081 1 with V$=$ 10.50, estimated to be at 5.93 pc. That several hundred new stars have been revealed so close to the Sun illustrates once again that there is considerable work yet to be done to map the solar neighborhood, and that additional nearby stars are likely still to be discovered., Comment: 22 pages, 8 figures, 6 tables, accepted to Astronomical Journal August 12, 2014

This chapter investigates measures of journal performance and ranking. It begins by exploring the principal conventional sources of citation data, Web of Science and Scopus, and compares these with alternatives such as Google Scholar. Critical variables in citation analyses include coverage by discipline and different article types, such as review articles compared to articles documenting new research. The chapter concludes with an exploration of alternative metrics.

The type 1 human immunodeficiency virus (HIV-1) contains a conical capsid comprising approximately 1,500 CA protein subunits, which organizes the viral RNA genome for uncoating and replication in a new host cell. In vitro, CA spontaneously assembles into helical tubes and cones that resemble authentic viral capsids. Here we describe electron cryo-microscopy and image reconstructions of CA tubes from six different helical families. In spite of their polymorphism, all tubes are composed of hexameric rings of CA arranged with approximate local p6 lattice symmetry. Crystal structures of the two CA domains were 'docked' into the reconstructed density, which showed that the amino-terminal domains form the hexameric rings and the carboxy-terminal dimerization domains connect each ring to six neighbours. We propose a molecular model for the HIV-1 capsid that follows the principles of a fullerene cone, in which the body of the cone is composed of curved hexagonal arrays of CA rings and the ends are closed by inclusion of 12 pentagonal 'defects'.

Previous epidemiological studies with humans and laboratory studies with chickens and rats linked trichloroethylene (TCE) exposure to cardiac defects. Although the cardiac defects in humans and laboratory animals produced by TCE are diverse, a majority of them involves valvular and septal structures. Progenitors of the valves and septa are formed by an epithelial-mesenchymal cell transformation of endothelial cells in the atrioventricular (AV) canal and outflow tract areas of the heart. Based on these studies, we hypothesized that TCE might cause cardiac valve and septa defects by specifically perturbing epithelial-mesenchymal cell transformation. We tested this hypothesis using an in vitro chick-AV canal culture model. This study shows that TCE affected several elements of epithelial-mesenchymal cell transformation. In particular, TCE blocked the endothelial cell-cell separation process that is associated with endothelial activation. Moreover, TCE inhibited mesenchymal cell formation throughout the concentration range tested (50-250 ppm). In contrast, TCE had no effect on the cell migration rate of the fully formed mesenchymal cells. Finally, the expression of 3 proteins (selected as molecular markers of epithelial-mesenchymal cell transformation) was analyzed in untreated and TCE-treated cultures. TCE inhibited the expression of the transcription factor Mox-1 and extracellular matrix (ECM) protein fibrillin 2. In contrast, TCE had no effect on the expression of alpha-smooth muscle actin. These data suggest that TCE may cause cardiac valvular and septal malformations by inhibiting endothelial separation and early events of mesenchymal cell formation in the heart.

Importin-α is a cytosolic receptor that recognizes classical Nuclear Localization Signals (NLSs) and mediates import into the nucleus. We have used a number of methods to investigate the aggregation state of Xenopus importin-α both as a recombinant, purified protein and in cytosolic extracts. We have found that recombinant importin-α aggregates at a protein concentration similar to that estimated to be present in the Xenopus cytoplasm, and that the importin-α aggregation is relieved by NLS peptide binding, with the importin-α then binding the NLS as a monomer. We have also found that in HeLa cytosolic extracts, importin-α is present in an aggregated form. Similarly to the purified importin-α aggregation, NLS peptides relieve the aggregation of importin-α in the cytosol. These observations indicate that aggregation of importin-α in the cytosol may be an intrinsic property of the import receptor and may be functionally related to NLS binding. Our results suggest a novel mechanism for NLS recognition, whereby NLSs mediate disassembly of importin-α aggregates in the cytosol.

LP 876-10 is a nearby active M4 dwarf in Aquarius at a distance of 7.6 pc. The star is a new addition to the 10-pc census, with a parallax measured via the Research Consortium on Nearby Stars (RECONS) astrometric survey on the Small & Moderate Aperture Research Telescope System's (SMARTS) 0.9-m telescope. We demonstrate that the astrometry, radial velocity, and photometric data for LP 876-10 are consistent with the star being a third, bound, stellar component to the Fomalhaut multiple system, despite the star lying nearly 6 degrees away from Fomalhaut A in the sky. The 3D separation of LP 876-10 from Fomalhaut is only 0.77+-0.01 pc, and 0.987+-0.006 pc from TW PsA (Fomalhaut B), well within the estimated tidal radius of the Fomalhaut system (1.9 pc). LP 876-10 shares the motion of Fomalhaut within ~1 km/s, and we estimate an interloper probability of ~10^{-5}. Neither our echelle spectroscopy nor astrometry are able to confirm the close companion to LP 876-10 reported in the Washington Double Star Catalog (WSI 138). We argue that the Castor Moving Group to which the Fomalhaut system purportedly belongs, is likely to be a dynamical stream, and hence membership to the group does not provide useful age constraints for group members. LP 876-10 (Fomalhaut C) has now risen from obscurity to become a rare example of a field M dwarf with well-constrained age (440+-40 Myr) and metallicity. Besides harboring a debris disk system and candidate planet, Fomalhaut now has two of the widest known stellar companions., 43 pages, 5 figures, AJ, in press, emulateapj version can be downloaded at: http://www.pas.rochester.edu/~emamajek/fomc/index.html

The results of 2408 intensified CCD observations of double stars, made with the 26 inch refractor of the U.S. Naval Observatory, are presented. Each observation of a system represents a combination of over 2000 short-exposure images. These observations are averaged into 1602 mean relative positions and range in separation from 194 to 10741, with a median separation of 1196. This is the twenty-first in this series of papers and covers the period from 2015 January 13 through 2015 December 19. Significant instrumentation changes are reported in this paper.

The Z (Glu342-->Lys) and Siiyama (Ser53-->Phe) deficiency variants of alpha 1-antitrypsin result in the retention of protein in the endoplasmic reticulum of the hepatocyte by loop-sheet polymerization in which the reactive center loop of one molecule is inserted into a beta-pleated sheet of a second. We show here that antitrypsin Mmalton (Phe52-deleted), which is associated with the same liver inclusions, is also retained at an endoglycosidase H-sensitive stage of processing in the Xenopus oocyte and spontaneously forms polymers in vivo. These polymers, obtained from the plasma of an Mmalton/QO (null) bolton heterozygote, were much shorter than other antitrypsin polymers and contained a reactive center loop-cleaved species. Monomeric mutant antitrypsin was also isolated from the plasma. The monomeric component had a normal unfolding transition on transverse urea gradient gel electrophoresis and formed polymers in vitro more readily than M, but less readily than Z, antitrypsin. The A beta-sheet accommodated a reactive center loop peptide much less readily than Z antitrypsin, which in turn was less receptive than native M antitrypsin. The nonreceptive conformation of the A sheet in antitrypsin Mmalton had little effect on kinetic parameters, the formation of SDS-stable complexes, the S to R transition, and the formation of the latent conformation. Comparison of the results with similar findings of short chain polymers associated with the antithrombin variant Rouen VI (Bruce, D., Perry, D., Borg, J.-Y., Carrell, R. W., and Wardell, M. R. (1994) J. Clin. Invest. 94, 2265-2274) suggests that polymerization is more complicated than the mechanism proposed earlier. The Z, Siiyama, and Mmalton mutations favor a conformational change in the antitrypsin molecule to an intermediate between the native and latent forms. This would involve a partial overinsertion of the reactive loop into the A sheet with displacement of strand 1C and consequent loop-C sheet polymerization.

To elicit women's personal understanding of future cardiovascular risk, following a pregnancy complicated by preeclampsia, and to identify the postnatal needs of these women.Semi-structured interviews with 12 women with a recent history of preeclampsia who had attended a postnatal follow-up clinic.The interviews were held at a median of 47 weeks postpartum (range 24-62 weeks). Family history of cardiovascular disease was associated with a greater awareness of future cardiovascular risk. Women without traditional risk factors found it hard to envisage themselves as being at risk and may not see the relevance of such information. It may take several months after delivery for a woman to be able to fully consider her own health as well as the baby's; a reminder of risk and health information is needed.Although receptive to follow-up, the situational factors of being a new mother need to be taken into account to engage successfully with this patient group. Further research is needed to help clarify the extent to which a history of preeclampsia is an independent factor for future cardiovascular disease to provide a solid foundation for effective risk communication.

THE Cys2-His2 zinc-finger is the most widely occurring DNA-binding motif1–3. The first structure of a zinc-finger/DNA complex revealed a fairly simple mechanism for DNA recognition4 suggesting that the zinc-finger might represent a candidate template for designing proteins to recognize DNA5. Residues at three key positions in an α-helical 'reading head' play a dominant role in base-recognition and have been targets for mutagenesis experiments aimed at deriving a recognition code6–8. Here we report the structure of a two zinc-finger DNA-binding domain from the protein Tramtrack complexed with DNA. The amino-terminal zinc-finger and its interaction with DNA illustrate several novel features. These include the use of a serine residue, which is semi-conserved and located outside the three key positions, to make a base contact. Its role in base-recognition correlates with a large, local, protein-induced deformation of the DNA helix at a flexible A-T-A sequence and may give insight into previous mutagenesis experiments9,10. It is apparent from this structure that zinc-finger/ DNA recognition is more complex than was originally perceived.

Background: The steroid/nuclear hormone receptors are a large family of conserved ligand-activated transcription factors that regulate gene expression through binding to response elements upstream of their target genes. Most members of this family bind to DNA as homodimers or heterodimers and recognize the sequence, spacing and orientation of the two half-sites of their response elements. The recognition and discrimination of the sequence and arrangements of these half-sites are mediated primarily by a highly conserved DNA-binding domain. Results: Here we describe the DNA-binding properties of the isolated DNA-binding domain of the oestrogen receptor, the ERDBD, and its refined NMR structure. This domain is monomeric in solution, but two molecules bind cooperatively to specific DNA sequences; this cooperativity determines the arrangement of half-sites that is recognized by the ERDBD. The 10 carboxy-terminal residues and a region of 15 residues within the domain are disordered in the solution structure, yet are important for DNA binding. Conclusion: The cooperative nature of ERDBD binding to DNA is important. The previously-determined X-ray structure of the ERDBD dimer bound to DNA shows that the 15 internal residues disordered in solution make contact both with DNA and with the corresponding region of the other monomer. These results suggest that these residues become ordered during the process of binding to DNA, forming the dimer interface and thus contributing to the cooperative interaction between monomers.

Monoclonal antibodies against the 110-kD component of the yeast spindle pole body (SPB) were used to clone the corresponding gene SPC110. SPC110 is identical to NUF1 (Mirzayan, C., C. S. Copeland, and M. Synder. 1992. J. Cell Biol. 116:1319-1332). SPC110/NUF1 has an MluI cell cycle box consensus sequence in its putative promoter region, and we found that the transcript was cell cycle regulated in a similar way to other MluI-regulated transcripts. Spc110p/Nuflp has a long central region with a predicted coiled-coil structure. We expressed this region in Escherichia coli and showed by rotary shadowing that rods of the predicted length were present. The 110-kD component is localized in the SPB to the gap between the central plaque and the sealed ends of the nuclear microtubules near the inner plaque (Rout, M., and J. V. Kilmartin. 1990. J. Cell Biol. 111:1913-1927). We found that rodlike structures bridge this gap. When truncations of SPC110 with deletions in the coiled-coil region of the protein replaced the wild-type gene, the gap between the central plaque and the ends of the microtubules decreased in proportion to the size of the deletion. This suggests that Spc110p connects these two parts of the SPB together and that the coiled-coil domain acts as a spacer element.

Presented here are the details of the astrometric reductions from the x,y data to mean Right Ascension (RA), Declination (Dec) coordinates of the third U.S. Naval Observatory (USNO) CCD Astrograph Catalog (UCAC3). For these new reductions we used over 216,000 CCD exposures. The Two-Micron All-Sky Survey (2MASS) data are extensively used to probe for coordinate and coma-like systematic errors in UCAC data mainly caused by the poor charge transfer efficiency (CTE) of the 4K CCD. Errors up to about 200 mas have been corrected using complex look-up tables handling multiple dependencies derived from the residuals. Similarly, field distortions and sub-pixel phase errors have also been evaluated using the residuals with respect to 2MASS. The overall magnitude equation is derived from UCAC calibration field observations alone, independent of external catalogs. Systematic errors of positions at UCAC observing epoch as presented in UCAC3 are better corrected than in the previous catalogs for most stars. The Tycho-2 catalog is used to obtain final positions on the International Celestial Reference Frame (ICRF). Residuals of the Tycho-2 reference stars show a small magnitude equation (depending on declination zone) that might be inherent in the Tycho-2 catalog., 14 pages, 9 figures, accepted on 01/21/2010 for publication in the Astronomical Journal

We describe here the purification and partial characterization of a 200 kDa keratan sulphate proteoglycan found in the pericellular matrix of human embryonal carcinoma cells. Previously we have shown that this molecule is recognized by a monoclonal antibody (GCTM-2). The antigen was isolated using ion-exchange chromatography and gel filtration, purification being monitored by e.l.i.s.a. using GCTM-2. Metabolic labelling of GCT 27 C-4 embryonal carcinoma cells with sodium [35S]sulphate resulted in the incorporation of [35S]sulphate into the purified molecule. Throughout the purification procedure, the peaks of 35S radioactivity were coincident with the peaks of immunoreactivity, and this label was released both by digestion with keratanase and chondroitinase, confirming the proteoglycan nature of the antigen. The intact molecule ran as a single broad band of 200 kDa, which has been identified by silver staining and immunoblotting following gel electrophoresis. Amino acid analysis of the purified antigen indicated a high content of serine, glycine and aspartic acid/asparagine residues. Visualization by rotary-shadowing electron microscopy suggests that the purified material forms large aggregates, even under denaturing conditions. Deglycosylation of this preparation with trifluoromethanesulphonic acid yielded a major band of 55 kDa and a minor band of 48 kDa. The biochemical nature of the molecule described here, along with tissue distribution studies using GCTM-2, indicates that the antigen is not related to previously described keratan sulphate proteoglycans.

We have employed the rapid-freeze technique to prepare specimens for electron microscopy of a coat protein solution of tobacco mosaic virus at equilibrium at pH 7·0 and 6·8, ionic strength 0·1 m and 20 °C. The former are the conditions for the most rapid assembly of the virus from its isolated protein and RNA. At both pH values, the equilibrium mixture contains approximately 80% of a “20 S” aggregate and 20% of a “4 S” aggregate (the so-called A-protein). The specimens were prepared either totally unstained or positively stained with methyl mercury nitrate, which binds to an amino acid residue (Cys27) internally located within the subunit, which we show not to affect the virus assembly. The images in the electron microscope are compatible only with the major structure for the “20 S” aggregate at pH 7·0 containing two rings of subunits and these aggregates display the same binding contacts as those seen between the aggregate that forms the asymmetric unit in the crystal, which has been shown by X-ray crystallography to be a disk containing two rings, each of 17 subunits, oriented in the same direction. In contrast, the images from specimens prepared at pH 6·8 show the major structure to be a proto-helix at this slightly lower pH, demonstrating that the technique of cryo-electron microscopy is capable of distinguishing between these aggregates of tobacco mosaic virus coat protein. The main structure in solution at pH 7·0 must therefore be very similar to that in the crystal, although slight differences could occur and there are probably other, minor, components in a mixture of species sedimenting around 20 S under these conditions. The equilibrium between aggregates is extremely sensitive to conditions, with a drop of 0.2 pH unit tipping the disk to proto-helix ratio from approximately 10:1 at pH 7·0 to 1:10 at pH 6·8. This direct determination of the structure of the “20 S” aggregate in solution, under conditions for virus assembly, contradicts some recent speculation that it must be helical, and establishes that, at pH 7·0, it is in fact predominantly a two-layer disk as it had been modelled before.

In view of the likely role of H1-H1 interactions in the stabilization of chromatin higher order structure, we have asked whether interactions can occur between the globular domains of the histone molecules. We have studied the properties of the isolated globular domains of H1 and the variant H5 (GH1 and GH5) and we have shown (by sedimentation analysis, electron microscopy, chemical cross-linking and nucleoprotein gel electrophoresis) that although GH1 shows no, and GH5 little if any, tendency to self-associate in dilute solution, they bind highly cooperatively to DNA. The resulting complexes appear to contain essentially continuous arrays of globular domains bridging 'tramlines' of DNA, similar to those formed with intact H1, presumably reflecting the ability of the globular domain to bind more than one DNA segment, as it is likely to do in the nucleosome. Additional (thicker) complexes are also formed with GH5, probably resulting from association of the primary complexes, possibly with binding of additional GH5. The highly cooperative nature of the binding, in close apposition, of GH1 and GH5 to DNA is fully compatible with the involvement of interactions between the globular domains of H1 and its variants in chromatin folding.

The human immunodeficiency virus type 1 rev protein binds with high affinity (Kd less than 1-3 nM) to a purine-rich "bubble" containing bulged GG and GUA residues on either side of a double-helical RNA stem-loop located toward the 5' end of rev-response element RNA. High-affinity rev binding is maintained when the bubble is placed in heterologous stem-loop structures, but rev binding is reduced when either the bulged residues or flanking base pairs in the stem are altered. Rev binding to the purine-rich bubble nucleates assembly of long filamentous ribonucleoprotein structures containing polymers of rev bound to flanking RNA sequences. It is proposed that rev regulates human immunodeficiency virus RNA expression by selectively packaging viral transcripts carrying the rev-response element sequence into rod-like nucleoprotein complexes that block splicing of the packaged mRNAs.