3DLigandSite: predicting ligand-binding sites using similar structures

3DLigandSite is a web server for the prediction of ligand-binding sites. It is based upon successful manual methods used in the eighth round of the Critical Assessment of techniques for protein Structure Prediction (CASP8). 3DLigandSite utilizes protein-structure prediction to provide structural models for proteins that have not been solved. Ligands bound to structures similar to the query are superimposed onto the model and used to predict the binding site. In benchmarking against the CASP8 targets 3DLigandSite obtains a Matthew’s correlation co-efficient (MCC) of 0.64, and coverage and accuracy of 71 and 60%, respectively, similar results to our manual performance in CASP8. In further benchmarking using a large set of protein structures, 3DLigandSite obtains an MCC of 0.68. The web server enables users to submit either a query sequence or structure. Predictions are visually displayed via an interactive Jmol applet. 3DLigandSite is available for use at http://www.sbg.bio.ic.ac.uk/3dligandsite

Structural Brain Correlates of Childhood Inhibited Temperament: An ENIGMA-Anxiety Mega-analysis

Temperament involves stable behavioral and emotional tendencies that differ between individuals, which can be first observed in infancy or early childhood and relate to behavior in many contexts and over many years.1 One of the most rigorously characterized temperament classifications relates to the tendency of individuals to avoid the unfamiliar and to withdraw from unfamiliar people, objects, and unexpected events. This temperament is referred to as behavioral inhibition or inhibited temperament (IT).2 IT is a moderately heritable trait1 that can be measured in multiple species.3 In humans, levels of IT can be quantified from the first year of life through direct behavioral observations or reports by caregivers or teachers. Similar approaches as well as self-report questionnaires on current and/or retrospective levels of IT1 can be used later in life

Assessing bidirectional relations between infant temperamental negative affect, maternal anxiety and infant affect-biased attention across the first 24-months of life

Developmental theories suggest affect-biased attention, preferential attention to emotionally salient stimuli, emerges during infancy through coordinating individual differences. Here we examined bidirectional relations between infant affect-biased attention, temperamental negative affect, and maternal anxiety symptoms using a Random Intercepts Cross-Lagged Panel Model (RI-CLPM). Infant-mother pairs from Central Pennsylvania and Northern New Jersey (N = 342; 52% White; 50% reported as assigned female at birth) participated when infants were 4, 8, 12, 18 and 24 months of age. Infants completed the overlap task while eye-tracking data were collected. Mothers reported their infant’s negative affect and their own anxiety symptoms. In an RI-CLPM, after accounting for between-person variance (random intercepts representing the latent average of a construct), it is possible to assess within-person variance (individual deviations from the latent average of a construct). Positive relations represent stability in constructs (smaller within-person deviations). Negative relations represent fluctuation in constructs (larger within-person deviations). At the between-person level (random intercepts), mothers with greater anxiety symptoms had infants with greater affect-biased attention. However, at the within-person level (deviations), greater fluctuation in maternal anxiety symptoms at 12- and 18-months prospectively related to greater stability in attention to angry facial configurations. Additionally, greater fluctuation in maternal anxiety symptoms at 18-months prospectively related to greater stability in attention to happy facial configurations. Finally, greater fluctuation in maternal anxiety symptoms at 4- and 12-months prospectively related to greater stability in infant negative affect. These results suggest that environmental uncertainty, linked to fluctuating maternal anxiety, may shape early socioemotional development

Design and On-Orbit Operation of the Adiabatic Demagnetization Refrigerator on the Hitomi Soft X-Ray Spectrometer Instrument

The Soft X-ray Spectrometer instrument on the Astro-H observatory contains a 6x6 array of x-ray microcalorimeters that is cooled to 50 mK by an adiabatic demagnetization refrigerator (ADR). The ADR consists of three stages in order to provide stable detector cooling using either a 1.2 K superfluid helium bath or a 4.5 K Joule-Thomson (JT) cryocooler as its heat sink. When liquid helium is present, two of the ADR's stages are used to single-shot cool the detectors while rejecting heat to the helium. After the helium is depleted, all three stages are used to continuously cool the helium tank (to about 1.5 K) and single-shot cool the detectors (to 50 mK), using the JT cryocooler as its heat sink. The Astro-H observatory, renamed Hitomi after its successful launch in February 2016, carried approximately 36 liters of helium into orbit. On day 5, the helium had cooled sufficiently (<1.4 K) to allow operation of the ADR. This paper describes the design, operation and on-orbit performance of the ADR, and the use of the ADR's heat rejection as a tool for mass gauging the helium tank

Improving the Alignment Quality of Consistency Based Aligners with an Evaluation Function Using Synonymous Protein Words

Most sequence alignment tools can successfully align protein sequences with higher levels of sequence identity. The accuracy of corresponding structure alignment, however, decreases rapidly when considering distantly related sequences (<20% identity). In this range of identity, alignments optimized so as to maximize sequence similarity are often inaccurate from a structural point of view. Over the last two decades, most multiple protein aligners have been optimized for their capacity to reproduce structure-based alignments while using sequence information. Methods currently available differ essentially in the similarity measurement between aligned residues using substitution matrices, Fourier transform, sophisticated profile-profile functions, or consistency-based approaches, more recently

Mice have a transcribed L-threonine aldolase/GLY1 gene, but the human GLY1 gene is a non-processed pseudogene

BACKGROUND: There are three pathways of L-threonine catabolism. The enzyme L-threonine aldolase (TA) has been shown to catalyse the conversion of L-threonine to yield glycine and acetaldehyde in bacteria, fungi and plants. Low levels of TA enzymatic activity have been found in vertebrates. It has been suggested that any detectable activity is due to serine hydroxymethyltransferase and that mammals lack a genuine threonine aldolase. RESULTS: The 7-exon murine L-threonine aldolase gene (GLY1) is located on chromosome 11, spanning 5.6 kb. The cDNA encodes a 400-residue protein. The protein has 81% similarity with the bacterium Thermotoga maritima TA. Almost all known functional residues are conserved between the two proteins including Lys242 that forms a Schiff-base with the cofactor, pyridoxal-5'-phosphate. The human TA gene is located at 17q25. It contains two single nucleotide deletions, in exons 4 and 7, which cause frame-shifts and a premature in-frame stop codon towards the carboxy-terminal. Expression of human TA mRNA was undetectable by RT-PCR. In mice, TA mRNA was found at low levels in a range of adult tissues, being highest in prostate, heart and liver. In contrast, serine/threonine dehydratase, another enzyme that catabolises L-threonine, is expressed very highly only in the liver. Serine dehydratase-like 1, also was most abundant in the liver. In whole mouse embryos TA mRNA expression was low prior to E-15 increasing more than four-fold by E-17. CONCLUSION: Mice, the western-clawed frog and the zebrafish have transcribed threonine aldolase/GLY1 genes, but the human homolog is a non-transcribed pseudogene. Serine dehydratase-like 1 is a putative L-threonine catabolising enzyme

The gene structure and expression of human ABHD1: overlapping polyadenylation signal sequence with Sec12

BACKGROUND: Overlapping sense/antisense genes orientated in a tail-to-tail manner, often involving only the 3'UTRs, form the majority of gene pairs in mammalian genomes and can lead to the formation of double-stranded RNA that triggers the destruction of homologous mRNAs. Overlapping polyadenylation signal sequences have not been described previously. RESULTS: An instance of gene overlap has been found involving a shared single functional polyadenylation site. The genes involved are the human alpha/beta hydrolase domain containing gene 1 (ABHD1) and Sec12 genes. The nine exon human ABHD1 gene is located on chromosome 2p23.3 and encodes a 405-residue protein containing a catalytic triad analogous to that present in serine proteases. The Sec12 protein promotes efficient guanine nucleotide exchange on the Sar1 GTPase in the ER. Their sequences overlap for 42 bp in the 3'UTR in an antisense manner. Analysis by 3' RACE identified a single functional polyadenylation site, ATTAAA, within the 3'UTR of ABHD1 and a single polyadenylation signal, AATAAA, within the 3'UTR of Sec12. These polyadenylation signals overlap, sharing three bp. They are also conserved in mouse and rat. ABHD1 was expressed in all tissues and cells examined, but levels of ABHD1 varied greatly, being high in skeletal muscle and testis and low in spleen and fibroblasts. CONCLUSIONS: Mammalian ABHD1 and Sec12 genes contain a conserved 42 bp overlap in their 3'UTR, and share a conserved TTTATTAAA/TTTAATAAA sequence that serves as a polyadenylation signal for both genes. No inverse correlation between the respective levels of ABHD1 and Sec12 RNA was found to indicate that any RNA interference occurred

Suzaku Observations of the Local and Distant Hot ISM

Suzaku observed the molecular cloud MBM12 and a blank field less than 3 degrees away to separate the local and distant components of the diffuse soft X-ray background. Towards MBM12, a local (D< 275 pc) O VII emission line was clearly detected with an intensity of 3.5 ph cm^{-2} s^{-1} sr^{-1}$ (or line units, LU), and the O VIII flux was <0.34 LU. The origin of this O VII emission could be hot gas in the Local Hot Bubble (LHB), charge exchange between oxygen ions in the solar wind (SWCX) and geocoronal or interplanetary material, or a combination of the two. If entirely from the LHB, the implied temperature and emission measure would predict 1/4 keV emission in excess of observations. There is no evidence in the X-ray light curve or solar wind data for a significant contribution from geocoronal SWCX. In any case, the observed O VII flux represents an upper limit to both the LHB emission and interplanetary SWCX in this direction. The off-cloud observation was performed immediately following the on-cloud. The net off-cloud O VII and O VIII intensities were (respectively) 2.34\pm0.33 and 0.77\pm0.16 LU, after subtracting the on-cloud foreground emission. Assuming the LHB and SWCX components did not change, these increases can be attributed to more distant Galactic disk, halo, or extragalactic emission. If the distant O VII and O VIII emission is from a thermal plasma in collisional equilibrium beyond the Galactic disk, a temperature of (2.1\pm0.1)\times10^6 K with an emission measure of (4\pm0.6)\times10^-3} cm^{-6}pc is inferred.Comment: 10 pages, 8 figures, accepted by PAS

Structural and biochemical characterization of the exopolysaccharide deacetylase Agd3 required for Aspergillus fumigatus biofilm formation

The exopolysaccharide galactosaminogalactan (GAG) is an important virulence factor of the fungal pathogen Aspergillus fumigatus. Deletion of a gene encoding a putative deacetylase, Agd3, leads to defects in GAG deacetylation, biofilm formation, and virulence. Here, we show that Agd3 deacetylates GAG in a metal-dependent manner, and is the founding member of carbohydrate esterase family CE18. The active site is formed by four catalytic motifs that are essential for activity. The structure of Agd3 includes an elongated substrate-binding cleft formed by a carbohydrate binding module (CBM) that is the founding member of CBM family 87. Agd3 homologues are encoded in previously unidentified putative bacterial exopolysaccharide biosynthetic operons and in other fungal genomes. The exopolysaccharide galactosaminogalactan (GAG) is an important virulence factor of the fungal pathogen Aspergillus fumigatus. Here, the authors study an A. fumigatus enzyme that deacetylates GAG in a metal-dependent manner and constitutes a founding member of a new carbohydrate esterase family.Bio-organic Synthesi